Abstract: The electron transport chain (ETC) in the cell membrane consists of a series of redox complexes that transfer electrons from electron donors to acceptors and couples this electron transfer with the transfer of protons (H+) across a membrane. This process generates proton motive force which is used to produce ATP and a myriad of other functions and is essential for the long-term survival of Mycobacterium tuberculosis (Mtb), the causative organism of tuberculosis (TB), under the hypoxic conditions present within infected granulomas. Menaquinone (MK), an important carrier molecule within the mycobacterial ETC, is synthesized de novo by a cluster of enzymes known as the classic/canonical MK biosynthetic pathway. MenA (1,4-dihydroxy-2-naphthoate prenyltransferase), the antepenultimate enzyme in this pathway, is a verified target for TB therapy. In this study, we explored structure-activity relationships of a previously discovered MenA inhibitor scaffold, seeking to improve potency and drug disposition properties. Focusing our campaign upon three molecular regions, we identified two novel inhibitors with potent activity against MenA and Mtb (IC50 = 13-22 μM, GIC50 = 8-10 μM). These analogs also displayed substantially improved pharmacokinetic parameters and potent synergy with other ETC-targeting agents, achieving nearly complete sterilization of Mtb in combination therapy within two weeks in vivo. These new inhibitors of MK biosynthesis present a promising new strategy to curb the continued spread of TB.
Keywords:
1,4-dihydroxy-2-naphthoate prenyltransferase ; MenA ; MenA inhibitors ; Menaquinone ; Mtb ; Mycobacterium tuberculosis ; Piperidine derivatives ; SAR
* 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.
To a mixture of A-14 (4.0 g, 36.4 mmol) in Acetone (50 mL) with K2CO4 (7.7 g, 56 mmol) was added BnBr (4.75 g, 28 mmol). The reaction was stirred for 2 h at 80° C. Water was added, the mixture was extracted with EtOAc thrice. The combined extracts were washed with H2O, brine and dried over Na2SO4. Concentration and chromatograph on silica gel (5:1 PE/EtOAc) gave 6 g (83percent) of B-14 as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.46-7.23 (m, 5H), 7.16 (t, J=8.4 Hz, 1H), 6.60 (dd. J=8.4, 2.4 Hz, 1H), 6.51 (s, 1H), 6.47 (dd, J=8.4, 2.4 Hz, 1H), 5.04 (s, 2H).
68%
at 5 - 10℃; for 12 - 17 h; Heating / reflux
Preparation 55. 3-Benzyloxy phenol; Benzene-l,3-diol (10.0 grams, 90.9 mmol), dissolved in acetone (50 mL), was cooled to 5-10 0C, and added with anhydrous potassium carbonate (18.8 grams, 136.3 mol) under smooth stirring. Benzyl bromide (10.88 grams, 63.6 mmol) was slowly introduced to the reaction mass at this temperature and cooling bath was removed after ten minutes. The reaction mixture was refiuxed for 12 to 17 hours. After bringing to 20 to 40 °C, the solid potassium carbonate was filtered out. The filtrate was concentrated and poured over ice-water, acidified with 6 N hydrochloric acid and extracted with ethyl acetate (3x25 mL). The combined organic layer was washed with water, dried with anhydrous sodiumsulphate and evaporated to get brown colored gummy mass. The dibenzyloxy bye-product was discarded by column chromatographic purification using 230-400 mesh silica-gel and mixture of ethyl acetate and petroleum ether (10:90) to yield pure a light brown gummy mass title compound. Yield: 13.5 g, 68percent 1H NMR (CDCl3, 200 MHz): δ 7.50-7.30 (m, 5H), 7.12 (t, J = 8.2 Hz, IH), 6.57 (dd, J = 1.8 6.2 Hz, IH), 6.50-6.40 (m, 2H), 5.02 (s, 2H), 4.86 (bs, IH, D2O exchangeable). Mass (CI): m/z 201(M++l). IR (cm"1) (KBr): 3406, 3032, 1595, 1490, 1454.
33%
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 3 h;
Preparation Example 18. C-(5-(3-Benzyloxy-phenoxy)-thiophen-2-yl)-methylamine To a solution of resorcinol (10g, 90.8mmol) in N,N-dimethylformamide (100mL) was added potassium carbonate (12.6g, 90.8mmol) and benzyl bromide (10.8mL, 90.8mmol), and the mixture was stirred at 60°C for 2 hours. The reaction mixture was allowed to room temperature, ethyl acetate and water were added for partitioning, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, then, the residue was purified by silica gel column chromatography (hexane : ethyl acetate), and 3-benzyloxy-phenol (6.0g, 33percent) was obtained as a pale brown oil. To a solution of the resulting 3-benzyloxy-phenol (2.6g, 13.0mmol) and a 5-nitrothiophene-2-carbonitrile (2.0g, 13.0mmol) in dimethylsulfoxide (25mL) was added potassium carbonate (1.98g, 14.0mmol), and the solution was stirred at 70°C for 3 hours. The reaction solution was allowed to room temperature, ethyl acetate and water were added for partitioning, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane : ethyl acetate = 10 : 1), and 5-(3-benzyloxy-phenoxy)-thiophene-2-carbonitrile (110mg, 2.8percent) was obtained as a pale brown solid. Next, to a solution of lithium aluminum hydride (27mg,0.716mmol) in tetrahydrofuran (2.0mL) was added a solution of 5-(3-benzyloxy-phenoxy)-thiophene-2-carbonitrile obtained above (110mg, 0.358mmol) in tetrahydrofuran (1mL), and the solution was stirred at room temperature for 3 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain the title compound (80mg, 72percent) as a red solid. This compound was used in the next reaction without purification.
33%
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 2 h;
To a solution of resorcinol (10g, 90.8mmol) in N,N-dimethylformamide (100mL) was added potassium carbonate (12.6g, 90.8mmol) and benzyl bromide (10.8mL, 90.8mmol), and the mixture was stirred at 60°C for 2 hours. The reaction mixture was allowed to room temperature, ethyl acetate and water were added for partitioning, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, then, the residue was purified by silica gel column chromatography (hexane : ethyl acetate), and 3-benzyloxy-phenol (6.0g, 33percent) was obtained as a pale brown oil. To a solution of the resulting 3-benzyloxy-phenol (2.6g, 13.0mmol) and a 5-nitrothiophene-2-carbonitrile (2.0g, 13.0mmol) in dimethylsulfoxide (25mL) was added potassium carbonate (1.98g, 14.0mmol), and the solution was stirred at 70°C for 3 hours. The reaction solution was allowed to room temperature, ethyl acetate and water were added for partitioning, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane : ethyl acetate = 10 : 1), and 5-(3-benzyloxy-phenoxy)-thiophene-2-carbonitrile (110mg, 2.8percent) was obtained as a pale brown solid. Next, to a solution of lithium aluminum hydride (27mg,0.716mmol) in tetrahydrofuran (2.0mL) was added a solution of 5-(3-benzyloxy-phenoxy)-thiophene-2-carbonitrile obtained above (110mg, 0.358mmol) in tetrahydrofuran (1mL), and the solution was stirred at room temperature for 3 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain the title compound (80mg, 72percent) as a red solid. This compound was used in the next reaction without purification.
32%
With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 4 h;
3-Benzyloxy-phenol (JRL01015) To a stirred solution of resorcinol (7.05 g, 63.4 mmol) in DMF (100 mL) at 0° C. under nitrogen was added NaH (60percent, 2.54 g, 63.4 mmol). After stirring for 30 min, benzyl bromide (7.72 mL, 63.4 mmol) was added and the resulting mixture was stirred for 4 h at room temperature. The reaction mixture was diluted with ethyl acetate (300 mL) and the organic layer separated washed with brine (300 mL, 4*100 mL), dried (Na2SO4), filtered and evaporated to give the crude product which was fractionated by flash chromatography (hexane/EtOAc 3:1) to give JRL01015 as a pale yellow solid (4.06 g, 32percent); Rf 0.50 (Hexane/EtOAc 3:1); 1H (400 MHz CDCl3) 4.97 (1H, s OH), 5.01 (2H, s, CH2), 6.42 (1H, dd, J 2.3 and 8.0 Hz), 6.47 (1H, t, J=2.3 Hz), 6.56 (1H, dd, J 2.3 and 8.0 Hz), 7.12 (1H, t, J=8.0 Hz) and 7.28-7.46 (5H, m).
Reference：
[1] Patent: US2014/256657, 2014, A1, . Location in patent: Paragraph 0399
[2] Tetrahedron, 2007, vol. 63, # 43, p. 10698 - 10708
[3] Journal of Organic Chemistry, 1997, vol. 62, # 10, p. 3062 - 3075
[4] Journal of Medicinal Chemistry, 2004, vol. 47, # 17, p. 4155 - 4158
[5] Chemical Communications, 2018, vol. 54, # 39, p. 4935 - 4938
[6] Patent: WO2006/29075, 2006, A2, . Location in patent: Page/Page column 44-45
[7] Chemistry - An Asian Journal, 2016, vol. 11, # 5, p. 757 - 765
[8] Chemical Communications, 2015, vol. 51, # 32, p. 7012 - 7014
[9] Patent: EP1782811, 2007, A1, . Location in patent: Page/Page column 71
[10] Patent: EP1669348, 2006, A1, . Location in patent: Page/Page column 81
[11] Patent: US2004/19016, 2004, A1, . Location in patent: Page/Page column 64
[12] Journal of Organic Chemistry, 2013, vol. 78, # 16, p. 7859 - 7884
[13] Patent: US2006/58361, 2006, A1, . Location in patent: Page/Page column 36
[14] Patent: WO2013/177668, 2013, A1, . Location in patent: Page/Page column 25-26
[15] Patent: US2015/191473, 2015, A1, . Location in patent: Paragraph 0089-0090
[16] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 13, p. 3322 - 3336
[17] RSC Advances, 2016, vol. 6, # 38, p. 32319 - 32327
[18] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 13, p. 3026 - 3029
[19] Patent: WO2009/146112, 2009, A1, . Location in patent: Page/Page column 47-48
4
[ 81499-29-8 ]
[ 3769-41-3 ]
Yield
Reaction Conditions
Operation in experiment
96%
With sodium hydroxide In tetrahydrofuran
b 3-Benzyloxyphenol 3-Benzyloxyphenyl acetate (4.84 g, 20 mmol), as prepared in the preceding step, in tetrahydrofuran (50 mL) was treated with 1N NaOH (30 mL) at room temperature for 3 h. The mixture was acidified with 1N HCl and extracted with ethyl acetate (3*100 mL). The organic phase was washed with brine (2*50 mL) and dried over Na2 SO4. The solvent was removed in vacuo and the residue purified by flash column chromatography (methylene chloride) to give the title compound as a colorless liquid (3.80 g, 96percent). 1 H-NMR (300 MHz, CDCl3) δ 5.01 (s, 2H), 5.09 (s, 1H), 6.47 (t, 2H, J=2.2 Hz), 6.56 (dd, 1H, J=4.1 Hz), 7.11 (t, 1H), and 7.39 (m, 5H).
96%
With sodium hydroxide In tetrahydrofuran
b 3-Benzyloxyphenol 3-Benzyloxyphenyl acetate (4.84 g, 20 mmol), as prepared in the preceding step, in tetrahydrofuran (50 mL) was treated with 1N NaOH (30 mL) for 3 h at room temperature. The mixture was acidified with 1N HCl and extracted into ethyl acetate (3*100 ML). The organic phase was washed with brine (2*50 mL), dried over Na2 SO4, and concentrated in vacuo. The residue was then purified by flash column chromatography (methylene chloride) to give the title compound as a colorless liquid (3.80 g, 96percent). 1 H-NMR (300 MHz, CDCl3) δ 5.01 (s, 2H), 5.09 (s, 1fH), 6.47 (m, 2H), 6.56 (dd, 1H), 7.11 (t, 1H), 7.39 (m, 5H).
Reference：
[1] Patent: US6034127, 2000, A,
[2] Patent: US5792769, 1998, A,
With potassium carbonate; potassium iodide In acetone for 48.5 h; Reflux
Resorcinol (11 g, 100 mmol) was dissolved in acetone (100 mL). To this solution, powdered potassium carbonate (13.8 g, 300 mmol) and potassium iodide (pinch) were added slowly. The mixture was refluxed and benzyl chloride (11.6 mL, 100 mmol) added drop wise to the refluxing mixture over a period of 30 min. The reaction was carried at for 48 h and cooled the reaction to room temperature and potassium carbonate was filtered and washed with acetone, the collected filtrates concentrated by vacuum distillation. Product thus obtained was purified by column chromatography using chloroform and hexane (3:7) mixture as eluent to yield pale brown color solid (12 g; 72percent).
Reference：
[1] Journal of Molecular Structure, 2011, vol. 1001, # 1-3, p. 118 - 124
[2] Tetrahedron Letters, 2002, vol. 43, # 39, p. 6893 - 6895
[3] Journal of the Chemical Society, Chemical Communications, 1987, # 14, p. 1058 - 1061
[4] Journal of the American Chemical Society, 1931, vol. 53, p. 3397,3405
[5] Patent: US1888827, 1931, ,
[6] Journal of the American Chemical Society, 1931, vol. 53, p. 3397,3405
[7] Journal of Medicinal Chemistry, 1987, vol. 30, # 1, p. 136 - 142
[8] Pharmazie, 2001, vol. 56, # 7, p. 517 - 522
[9] Synthesis, 2009, # 24, p. 4190 - 4202
[10] Journal of Polymer Science, Part A: Polymer Chemistry, 2013, vol. 51, # 4, p. 936 - 946
[11] Organic Process Research and Development, 2008, vol. 12, # 4, p. 755 - 764
7
[ 185613-44-9 ]
[ 3769-41-3 ]
Reference：
[1] Journal of Organic Chemistry, 1997, vol. 62, # 1, p. 2 - 3
With nitric acid In water; acetic acid at 20℃; for 4h;
To a stirred solution of JRL01015 (4.0 g, 20.0 mmol) in AcOH (40 mL) at 5-10° C. was added HNO3 (69%, 2.74 g, 30.0 mmol) in AcOH (1.80 g, 30.0 mmol). After stirring for 4 h at room temperature, the reaction mixture was diluted EtOAc (150 mL) and the organic layer separated washed with brine (200 mL, 4×100 mL), dried (Na2SO4), filtered and evaporated to give the crude product which was fractionated by a flash chromatography (hexane/EtOAc 3:1) to give JRL01017 as a yellow solid (1.88 g, 38.5%); Rf 0.65 (hexane/EtOAc 3:1); 1H (400 MHz, CDCl3) 5.13 (2H, s, CH2), 6.59 (1H, dd, J 2.4 and 9.0 Hz), 6.62 (1H, d, J=2.4 Hz), 7.34-7.45 (5H, m), 8.04 (1H, d, J=9.0 Hz) and 11.00 (1H, s, OH).
With nitric acid; acetic acid for 3h; Ambient temperature;
With potassium carbonate; In dimethyl sulfoxide; at 70℃; for 3h;
Preparation Example 18. C-(5-(3-Benzyloxy-phenoxy)-thiophen-2-yl)-methylamine To a solution of resorcinol (10g, 90.8mmol) in N,N-dimethylformamide (100mL) was added potassium carbonate (12.6g, 90.8mmol) and benzyl bromide (10.8mL, 90.8mmol), and the mixture was stirred at 60C for 2 hours. The reaction mixture was allowed to room temperature, ethyl acetate and water were added for partitioning, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, then, the residue was purified by silica gel column chromatography (hexane : ethyl acetate), and 3-benzyloxy-phenol (6.0g, 33%) was obtained as a pale brown oil. To a solution of the resulting 3-benzyloxy-phenol (2.6g, 13.0mmol) and a <strong>[16689-02-4]5-nitrothiophene-2-carbonitrile</strong> (2.0g, 13.0mmol) in dimethylsulfoxide (25mL) was added potassium carbonate (1.98g, 14.0mmol), and the solution was stirred at 70C for 3 hours. The reaction solution was allowed to room temperature, ethyl acetate and water were added for partitioning, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane : ethyl acetate = 10 : 1), and 5-(3-benzyloxy-phenoxy)-thiophene-2-carbonitrile (110mg, 2.8%) was obtained as a pale brown solid. Next, to a solution of lithium aluminum hydride (27mg,0.716mmol) in tetrahydrofuran (2.0mL) was added a solution of 5-(3-benzyloxy-phenoxy)-thiophene-2-carbonitrile obtained above (110mg, 0.358mmol) in tetrahydrofuran (1mL), and the solution was stirred at room temperature for 3 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain the title compound (80mg, 72%) as a red solid. This compound was used in the next reaction without purification.
2.8%
With potassium carbonate; In dimethyl sulfoxide; at 70℃; for 3h;
To a solution of resorcinol (10g, 90.8mmol) in N,N-dimethylformamide (100mL) was added potassium carbonate (12.6g, 90.8mmol) and benzyl bromide (10.8mL, 90.8mmol), and the mixture was stirred at 60C for 2 hours. The reaction mixture was allowed to room temperature, ethyl acetate and water were added for partitioning, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, then, the residue was purified by silica gel column chromatography (hexane : ethyl acetate), and 3-benzyloxy-phenol (6.0g, 33%) was obtained as a pale brown oil. To a solution of the resulting 3-benzyloxy-phenol (2.6g, 13.0mmol) and a <strong>[16689-02-4]5-nitrothiophene-2-carbonitrile</strong> (2.0g, 13.0mmol) in dimethylsulfoxide (25mL) was added potassium carbonate (1.98g, 14.0mmol), and the solution was stirred at 70C for 3 hours. The reaction solution was allowed to room temperature, ethyl acetate and water were added for partitioning, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane : ethyl acetate = 10 : 1), and 5-(3-benzyloxy-phenoxy)-thiophene-2-carbonitrile (110mg, 2.8%) was obtained as a pale brown solid. Next, to a solution of lithium aluminum hydride (27mg,0.716mmol) in tetrahydrofuran (2.0mL) was added a solution of 5-(3-benzyloxy-phenoxy)-thiophene-2-carbonitrile obtained above (110mg, 0.358mmol) in tetrahydrofuran (1mL), and the solution was stirred at room temperature for 3 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain the title compound (80mg, 72%) as a red solid. This compound was used in the next reaction without purification.
With sodium hydride In dimethyl sulfoxide at 20℃; for 2h;
1
[Reference Example 1] O-(3-Benzyloxy)phenyldimethylthiocarbamate (11) A 60% sodium hydride (19.9 g, 498 mmol) was slowly added to a solution of 3-benzyloxyphenol (10) (83.0g, 415 mmol) in dehydrated dimethylsulfoxide (DMSO) (415 mL) while the solution was water-cooled and stirred. The mixture was stirred for 30 min. Subsequently, dimethylthiocarbamoyl chloride (61.5 g, 498 mmol) was slowly added while the mixture was water-cooled and stirred. The mixture was then stirred at room temperature for 1.5 hours. Subsequently, the reaction mixture was slowly poured into ice water (2L) and was extracted with ethyl acetate twice (1.5 L and 500 mL) . The organic layers were combined, washed sequentially with water (2L) and 28% brine (1L) and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was subjected to silica gel column chromatography (silica gel 60, 3 L, hexane: ethyl acetate = 10:1 --> 5:1) to give O-(3-benzyloxy)phenyldimethylthiocarbamate (2) as a pale yellow oil (107 g, 90%). 400 MHz 1H-NMR (CDCl3) 5; 3.32 (3H, s), 3.45 (3H, s), 5.04 (2H, s), 6.68-6.73 (2H, m),6.86-6.89 (1H, m), 7.25-7.44 (6H, m). EI-MS m/z; 287 (M+).
With potassium carbonate; N,N-dimethyl-formamide Heating;
57
To stirred mixture of 3-benzyloxyphenol (2.00 g, 10 mmole), potassium carbonate (4.15 g, 30 mmole) and 25 ml DMF was added 4-nitroquinoline-N-oxide (2.09 g, 1 1 mmole). This was stirred and heated to a gentle reflux and kept there overnight. The reaction mixture was cooled to room temperature and quenched into 250 ml water. The solid that formed was collected by filtration, washed with water, and dried to give a beige solid, 2.79 g. A mixture of this N-oxide (250 mg, 0.73 mmole), p-tosyl chloride (167 mg, 0.87 mmole, 1.2 eq) and dichloroethane, 10 ml, was stirred and heated to reflux. This mixture was stirred for 1 hour, cooled, 10% sodium carbonate solution was added and stirred overnight. The reaction mixture was filtered, the solid was washed with water, and dried to give the product, (if no solid is present the mixture is portioned between water and ether, the ether layer was dried over sodium sulfate, filtered, evaporated, and the residue chromatographed on silica gel using a chloroform to 15% methanol in chloroform gradient, fractions containing product are combined, evaporated to give product) 149 mg (60%), mp 262-5 0C; HRMS: calcd for C22H17NO3 + H+, 344.12812; found (ESI-FTMS, [M+H]1+), 344.12832.
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; Cooling with ice;
42
To a solution of 1,4-dioxaspiro[4.5]dec-8-ylmethanol (946 mg), 3-(benzyloxy)phenol (1 g), and triphenylphosphine (1.57 g) in THF (15 mL) was added azodicarboxylate diethyl (944 µL) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction liquid was concentrated under reduced pressure, benzene was added to the residue, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=92/8-85/15) to obtain 8-[3-(benzyloxy)phenoxy]methyl}-1,4-dioxaspiro[4.5]decane (846 mg).
With di-isopropyl azodicarboxylate; triphenylphosphine; In toluene; at 20℃;
To a mixture of 3-benzyloxyphenol (2.96 g), Compound I (2.63 g), triphenylphosphine (3.88 g) and toluene (60 mL) was added diisopropyl azodicarboxylate (3.0 mL), and the mixture was stirred at room temperature overnight. The reaction solution was washed with 1M aqueous sodium hydroxide solution, 1M hydrochloric acid, and brine. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=6/1) to give Compound II (4.2 g).
bis(3-(benzyloxy)phenyl) ethyl phosphate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With sodium hydride; In tetrahydrofuran;Reflux;
To a solution of 3-benzyloxyphenol (8.36 g, 41.8 mmol) in THF (150 mL) was added 95% NaH (1.05 g, 41.8 mmoles). After the reaction was complete, ethyl dichlorophosphate (2.5 mL, 20.9 mmoles, 0.5 eq) was added dropwise. The mixture was refluxed overnight and then cooled to ambient temperature. 100 mL water was then added. The layers were separated and the aqueous layer was extracted with 100 mL ether. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give 10.06 g (98%) of a thick yellow oil.
With potassium carbonate In N,N-dimethyl-formamide at 80 - 150℃; for 27h; Inert atmosphere;
O-Monobenzylresorcinol (220 mg, 1.10 mmol) was added to a solutionof m-fluoronitrobenzene (149 mg, 1.05 mmol) and potassiumcarbonate (173 mg, 1.25 mmol) in DMF (1.5 ml) under an argon atmosphere,and the mixture was stirred at 150 °C for 3 h and at 80 °C for24 h. It was allowed to cool to room temperature, then poured into 1MHCl, and extracted with ethyl acetate. The organic layer was dried oversodium sulfate, and evaporated. The residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate 19:1) to afford 24a(273 mg, 80%).24a: 1H NMR (600 MHz, CDCl3) δ 7.94 (ddd, J=8.4, 2.4, 0.6 Hz,1H), 7.81 (t, J=2.4 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.36 (m, 7H),6.84 (dd, J=8.4, 2.4 Hz, 1H), 6.67 (m, 2H), 5.06 (s, 2H).
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