A concise one-pot synthesis of flavones by cyclisation of o-(alkynon-1-yl)phenols
Khalid Widyan
A *
A
Abstract
A concise one-pot process for producing flavones and 2-alkyl-4H-benzopyran-4-one from a variety of salicylic acylbenzotriazoles is described. The in situ generation of o-(alkynon-1-yl)phenols in the ionic liquid 1-butyl-3-methylimidazoliumtetrafluoroborate ([BMIM][BF4]) is also described in this work. Three rounds of usage of the ionic liquid are possible without a noticeable decrease in efficiency.
Keywords: benzopyranone, flavones, green chemistry, ionic liquid, ionic liquid recycling, N-(o-hydroxyarylacyl)benzotriazoles, o-(alkynon-1-yl)phenols, one-pot synthesis.
Introduction
A major challenge of modern synthetic organic chemistry is the design of efficient chemical reaction sequences that afford molecules containing structural diversity with interesting applications in a minimum total number of synthetic steps. One-pot synthesis has attracted the attention of chemical research and has been developed as a useful synthetic route for the preparation of diverse heterocyclic compounds.1,2
Flavones, which are also known as 2-arylbenzopyrones, are present in a wide range of natural and synthetic products3–5 and have various bioactivities,6,7 including antiviral effects-such as inhibition of HIV-1, hepatitis C virus, influenza, dengue and enteroviruses8–10; antifungal activity demonstrated against Candida spp., Aspergillus spp., Trichophyton and dermatophytes11,12; anticancer potential targeting multiple pathways and kinase inhibition13,14; and antibacterial properties such as membrane disruption, inhibition of biofilm formation, ATP and nucleic acid synthesis suppression.15,16
Flavones are frequently produced using a variety of protocols (Scheme 1): (i) cyclodehydration of 1-(2-hydroxyphenyl)-3-phenyl-1,3-propanediones. However, harsh conditions such as treatment with concentrated acid at high temperatures for a long time are required to promote cyclisation of the diketone,17–23 (ii) oxidative cyclisation of 2-hydroxychalcones. However, the synthetic challenges of chalcone derivatives have constrained their wider application,24–27 (iii) deoxygenation and cyclisation of salicylic acid derivatives or benzaldehyde with aryl acetylene; nevertheless, this strategy frequently depends on the use of expensive transition-metal catalysts28,29 and (iv) carbonylative cyclisation of 2-iodophenol with terminal alkynes. However, this protocol requires carbon monoxide under elevated temperatures and pressures, a costly palladium catalyst and an inert atmosphere.30–33
Survey of literature synthesis of flavones. i, Cyclodehydration of 1-(2-hydroxyphenyl)-1,3-diketones; ii, oxidative cyclisation of 2-hydroxychalcones; iii, deoxygenation/cyclisation of salicylic acid or benzaldehyde with aryl acetylene; iv, carbonylative cyclisation of 2-iodophenol with terminal alkynes.
Alternatively, (v) intramolecular cyclisation of o-(alkynon-1-yl)phenols has gained attention as a practical method for flavone synthesis (Scheme 2). However, this approach requires a multi-step synthesis for achieving starting materials and produces both flavones through 6-endo-digonal cyclisation and aurones through 5-exo-digonal cyclisation with ratios influenced by reagents, substituents and solvents. Although 6-endo-digonal cyclisation is typically preferred,34 5-endo-digonal cyclisation is competitive, especially in protic solvents with basic conditions.35,36
To overcome this restriction, reaction conditions and reagents are modified37 to improve the regioselectivity of 6-endo cyclisation using potassium carbonate,38,39 triflic acid,40 4-(dimethylamino)pyridine,41 Tl(p-OTs)342 or sodium 2-pyridinethiolate.43 Others used the O-protected alkynones, using OTBS-protected alkynones requiring excess secondary amines in methanol under reflux,44 acetate-protected alkynones yield flavones with 2.5 equivalents of potassium methoxide.45
Even though these methods successfully produce flavones, a simpler procedure with fewer steps and using easily accessible starting materials under mild conditions is still needed.
N-Acyl benzotriazoles 1 have found a wide range of applications in organic synthesis, such as the preparation of esters, acyl azides and amides, as well as Weinreb amides. Most importantly, N-acylbenzotriazoles derived from salicylic acids are used in synthesis without prior protection of the phenolic hydroxy group.46–50 More recently, we have developed a transition metal-free protocol for the preparation of ynones51 and sequential synthesis of pyrazoles in 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF4]) ionic liquid.52 Attracted by this strategy and continuing our interest in the synthesis of heterocycles using N-acylbenzotriazoles, we extend that mild and practical synthetic approach for obtaining flavones and 2-alkyl-4H-benzopyran-4-one by combining terminal alkynes with N-acylbenzotriazoles generated from salicylic acid derivatives.
Results and discussion
N-(o-Hydroxyaryl acyl)benzotriazoles 1a–e were readily obtained from the reaction of salicylic acid derivatives with 1,1′-sulfinylbis(1H-benzotriazole) [Bt2SO] produced in situ from a benzotriazole/thionyl chloride mixture in overall high yields according to an established procedure.46 Then, as a model reaction, benzotriazol-1-yl-(2-hydroxyphenyl)methanone (1a) was used as the substrate to investigate and optimise the coupling reaction conditions for preparation of 4′-methoxyflavone (2a) in the ionic liquid [BMIM][BF4] (Scheme 3, Table 1).
| Entry | Solvent | ZnCl2 equivalents | Temperature (°C) | Time (h) | Yield (%) | |
|---|---|---|---|---|---|---|
| 1 | [BMIM][BF₄] | None | 80 | 8 | 20 | |
| 2 | [BMIM][BF₄] | 0.05 | 80 | 4 | 60 | |
| 3 | [BMIM][BF₄] | 0.15 | 80 | 4 | 91 | |
| 4 | [BMIM][BF₄] | 0.2 | 80 | 4 | 93 | |
| 5 | CH3CN | 0.2 | 80 | 4 | 30 |
Reaction conditions: 2.0 mmol of 2a, catalytic amounts of ZnCl2. There was 5.0 mL of solvent. The yield was an isolated yield.
Harper et al. extensively studied reactions in ionic liquids and demonstrated that both rate constants and reaction outcomes are influenced by the proportion of ionic liquid used.53–56 Since this parameter was not investigated in the present study, the ionic liquid volume was fixed at 5.0 mL in all experiments, thereby ensuring that the outcomes of the reaction were not affected by the proportion of [BMIM][BF₄].
The reaction progress was followed using thin-layer chromatography, which shows the complete disappearance of 1a. After completion, the reaction mixture was extracted with diethyl ether and concentrated under reduced pressure to afford the desired product, 4′-methoxyflavone (2a).
Formation of 2a goes through formation of the o-(alkynon-1-yl)phenols intermediate 2-[3-(4-methoxyphenyl)propynoyl]phenol (2′a), which could be isolated in high yields using 0.1 equivalents of zinc chloride and heating the reaction mixture at a temperature of 60°C.
The best result was obtained when 1a was coupled with two equivalents of p-methoxyphenyl acetylene in [BMIM][BF4] for 4 h at a reaction temperature of 80°C with 0.15 equivalents of zinc chloride. This produced 2a in an excellent yield of 91% with complete conversion of 1a (Table 1, entry 3). A comparable yield was obtained in the same amount of time by raising the catalyst to 0.2 equivalents (Table 1, entry 4). Nevertheless, a lesser yield of 60% was obtained when 0.05 equivalents of the catalyst were used. A longer reaction time of 8 h was needed to perform the reaction, giving 2a in a low yield of 20%, in the absence of ZnCl2 (entry 1). The results of this optimisation demonstrate that the one-pot transformation proceeds under mild reaction conditions with high selectivity, a short reaction time and no side reactions.
The effect of solvent choice was also examined. When the reaction was carried out in acetonitrile under identical conditions, the desired flavone 2a was obtained only in a low yield of 30% (Table 1, entry 5). This result highlights the enhanced performance of the ionic liquid [BMIM][BF₄], which not only promotes higher yields but also ensures cleaner transformations compared to conventional molecular solvents.
Next, the method’s generality and scope were investigated. At a reaction mixture temperature of 80°C, various N-acyl benzotriazoles 1a–e with electron-donating and electron-withdrawing groups were converted into their respective flavones 2a–f and benzopyran-4-one 2g–k using various alkynes bearing alkyl and aryl groups in 4 h, with good to high yields of 80–92% (Scheme 4, Table 2). Alkynes with a bulky naphthyl group afforded benzopyran-4-one in slightly lower yields 2g,h presumably due to steric factors.
| 2 | X | Y | –R | Yield (%) | |
|---|---|---|---|---|---|
| a | H | H |  | 91 | |
| b | H | H |  | 91 | |
| c | H | H |  | 88 | |
| d | H | Br |  | 91 | |
| e | Cl | H |  | 88 | |
| f | CH3O | H |  | 90 | |
| g | Cl | H |  | 82 | |
| h | CH3O | H |  | 80 | |
| i | H | H |  | 92 | |
| j | H | H | –CH2CH2CH2CH3 | 91 | |
| k | H | H | –C(CH3)3 | 85 |
Reaction conditions: [BMIM][BF4] (5.0 mL), 0.15 equivalents of ZnCl2, 80°C, 4 h. The yield was an isolated yield.
The ionic liquid [BMIM][BF₄] was quantitatively recovered and reused for two consecutive cycles without a significant loss in yield (Table 3). A 2–3% variation in isolated yield falls within typical experimental variability and does not suggest any adverse effect from recycling. The recovery process was simple and efficient: after extracting the flavone with diethyl ether, the ionic liquid was dissolved in acetonitrile, filtered to remove impurities and vacuum dried following solvent evaporation. It was then reused without further purification.
Conclusion
In conclusion, the use of the ionic liquid [BMIM][BF₄] provided an effective reaction medium that enhanced selectivity and yielded a variety of flavones and benzopyran-4-one in good to high isolated yields. The protocol benefits from mild reaction conditions, such as low temperature and short reaction times, which minimise side reactions and improve overall efficiency. Additionally, the reduced formation of by-products simplified purification, while the optimised conditions ensured improved reproducibility across multiple runs. Notably, the process is a one-pot sequential reaction that eliminates the need to isolate the in situ generated o-(alkynon-1-yl)phenols.
Experimental
Melting points were determined and are uncorrected on a Reichert hot-stage microscope. NMR spectra were recorded for 1H at 300 MHz and 13C at 75 MHz on a Varian 300-MHz instrument. Spectra were obtained for the solution in CDCl3. Silica gel 200–245 mesh was used to perform column chromatography. N-Acylbenzotriazoles 1a–e were prepared according to previously published procedures.46
Typical procedure for preparation of 2-[3-(4-methoxyphenyl)propynoyl]phenol (2′a)
p-Methoxyphenyl acetylene (2.2 mmol) was added to a solution of 2.0 mmol of benzotriazol-1-yl-(2-hydroxyphenyl)methanone and zinc chloride (27.2 mg, 0.2 mmol) in 5.0 mL of [BMIM][BF4]. The mixture was stirred while keeping the temperature at 60°C for 2 h. The reaction mixture was extracted with diethyl ether (3 × 5 mL). The combined organic layer was then washed with diluted aqueous sodium hydrogen carbonate and water, then dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under a vacuum, and the residue was purified by flash column chromatography using hexane-ethyl acetate (1:2) to give the pure 2′a. Yellow solid, mp 80–81°C (lit. 79–80°C).40 IR (KBr) 3580, 2865, 2160, 1630, 1263 cm−1. 1H NMR (CDCl3): δ (ppm): 11.1 (s, 1H), 7.89–8.09 (m, 1H), 7.48–7.60 (m, 3H), 6.88–7.10 (m, 4H), 3.82 (s, 3H); 13C NMR (CDCl3): δ (ppm): 182.0, 162.4, 161.7, 136.6, 135.1, 132.5, 120.4, 118.9, 118.1, 114.3, 111.2, 97.6, 86.1, 55.4. Analytically calculated for C16H12O3: C 76.18, H 4.79; found: C 76.29, H 4.89.
Typical procedure for preparation of flavones (2a–k)
Terminal alkyne (4.1 mmol) was added to a solution of the appropriate N-acylbenzotriazole (2.0 mmol) and zinc chloride (40.8 mg, 0.3 mmol) in [BMIM][BF4] (5.0 mL). The mixture was stirred, keeping the temperature at 80°C for 4 h. The reaction mixture was extracted with diethyl ether (3 × 5 mL). The combined ether layer was then washed with dilute aqueous sodium hydrogen carbonate and water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under a vacuum, and the residue was purified by flash column chromatography using hexane-ethyl acetate (1:2) to give the pure flavone.
White solid, mp: 151–153°C (lit. 156°C).23 IR (KBr) 3582, 3425, 2930, 1643, 1608, 1270, 1070 cm−1. 1H NMR (CDCl3): δ (ppm): 8.23 (dd, J = 7.8, 1.6 Hz, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.61–7.72 (m, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.36–7.44 (m, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.75 (s, 1H), 3.87 (s, 3H). 13C NMR (CDCl3) δ (ppm): 178.4, 163.3, 162.5, 156.3, 133.6, 128.1, 125.8, 125.1, 124.3, 124.2, 118.1, 114.3, 106.3, 55.6. Analytically calculated for C16H12O3: C 76.18, H 4.79; found: C 76.38, H 4.61.
White solid, mp 95–96°C (lit. 97°C).23 IR (KBr) 3580, 3390, 1644, 1604, 1250, 1068 cm−1. 1H NMR (CDCl3): δ (ppm): 8.26 (d, J = 8.1 Hz, 1H), 7.90–8.11 (m, 2H), 7.61–7.74 (m, 1H), 7.51–7.59 (m, 4H), 7.45 (t, J = 7.6 Hz, 1H), 6.80 (s, 1H); 13C NMR (CDCl3): δ 178.6, 163.5, 156.4, 133.7, 131.6, 131.7, 129.2, 126.4, 125.6, 125.2, 124.1, 118.2, 107.7. Analytically calculated for C15H10O2: C 81.07, H 4.54; found: C 81.29, H 4.39.
Pale yellow solid, mp: 102–104°C (lit. 101–103°C).29 IR (KBr) 3080, 2962, 1640, 1580, 1440, 1050 cm−1. 1H NMR (CDCl3): δ (ppm): 8.21 (d, J = 7.6, 1H), 7.81 (d, J = 8.1 Hz, 2H), 7.64 (t, J = 8.6 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 8.1 Hz, 2H), 6.76 (s, 1H), 2.41 (s, 3H); 13C NMR (CDCl3): δ (ppm): 178.3, 163.6, 156.2, 142.3, 133.4, 129.8, 128.6, 126.3, 125.1, 123.8, 118.2, 106.6, 21.4; analytically calculated for C16H12O2: C 81.34, H 5.12; found: C 81.49, H 4.98.
White solid, mp: 202–204°C (lit. 201–203°C).43 IR (KBr) 3085, 2950, 1639, 1586, 1290 cm−1. 1H NMR (CDCl3) δ (ppm): 8.34 (d, J = 2.4 Hz, 1H), 7.79 (d, J = 8.1 Hz, 2H), 7.76 (dd, J = 8.7, 2.4 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 7.33 (d, J = 8.1 Hz, 2H), 6.76 (s, 1H), 2.43 (s, 3H); 13C NMR (CDCl3) δ (ppm): 171.1, 163.8, 155.1, 142.7, 136.6, 129.7, 128.6, 128.5, 126.3, 125.3, 120.1, 118.6, 107.1, 21.4. Analytically calculated for C16H11BrO2: C 60.98, H 3.52; found: C 61.23, H 3.31.
White solid; mp: 155–157°C (lit. 156–157°C).19 IR (KBr) 3092, 1644, 1590, 1293 cm−1. 1H NMR (CDCl3): δ (ppm): 8.20 (d, J = 8.4 Hz, 1H), 7.85 (dd, J = 8.1, 2.1 Hz, 2H), 7.50–7.62 (m, 4H), 7.41 (dd, J = 8.4, 2.1 Hz, 1H), 6.78 (s, 1H); 13C NMR (CDCl3): δ (ppm): 177.4, 163.4, 156.4, 139.7, 131.7, 131.2, 129.0, 127.2, 126.4, 126.1, 122.4, 118.3, 107.9. Analytically calculated for C15H9ClO2: C 70.19, H 3.53; found: C 70.41, H 3.41.
White solid. mp: 108–110°C (lit. 111–112°C).19 IR (KBr) 3440, 3060, 1640, 1609, 1238, 1065 cm−1. 1H NMR (CDCl3): δ (ppm): 8.14 (d, J = 8.8 Hz, 1H), 7.86–7.94 (m, 2H), 7.42–7.59 (m, 3H), 6.90–7.02 (m, 2H), 6.73 (s, 1H), 3.91 (s, 3H). 13C NMR (CDCl3): δ (ppm): 177.6, 164.2, 163.1, 158.1, 131.7, 131.3, 129.1, 127.2, 126.3, 117.6, 114.3, 107.2, 100.4, 55.6. Analytically calculated for C16H12O3: C 76.18, H 4.79; found: C 76.37, H 4.61.
White solid. mp: 217–219°C (lit. 219–220°C).19 IR (KBr) 3090, 2928, 1640, 1530, 1265, 1031 cm−1. 1H NMR (CDCl3): δ (ppm): 8.46 (s, 1H), 8.21 (d, J = 8.6 Hz, 1H), 7.71–7.98 (m, 5H), 7.54–7.65 (m, 2H), 7.39 (dd, J = 8.6, 2.0 Hz, 1H), 6.89 (s, 1H). 13C NMR (CDCl3): δ (ppm): 177.3, 163.4, 156.6, 134.7, 133.1, 129.1, 129.0, 128.6, 128.3, 127.9, 127.3, 127.2, 127.1, 126.2, 122.8, 122.3, 118.1, 108.3. Analytically calculated for C19H11ClO2: C 74.40, H 3.61; found: C 74.59, H 3.48.
White solid; mp: 179–181°C (lit. 181–182°C).19 IR (KBr) 3092, 2935, 1641, 1590, 1483, 1021 cm−1; 1H NMR (CDCl3) δ (ppm): 8.41 (s, 1H), 8.11 (d, J = 8.9 Hz, 1H), 7.81–8.02 (m, 4H), 7.46–7.61 (m, 2H), 6.92–6.99 (m, 2H), 6.81 (s, 1H), 3.87 (s, 3H). 13C NMR (CDCl3): δ (ppm): 177.8, 164.2, 162.8, 158.2, 134.6, 128.8, 128.7, 128.6, 127.7, 127.5, 127.1, 126.8, 126.4, 122.4, 117.9, 114.3, 107.8, 100.3, 55.8. Analytically calculated for C20H14O3: C 79.46, H 4.67; found: C 79.61, H 4.59.
Colorless oil. IR film 3470, 2935, 1635, 1460, 1225, 1082 cm−1. 1H NMR (CDCl3): δ (ppm): 8.20 (dd, J = 8.1, 1.6 Hz, 1H), 7.61 (td, J = 8.8, 1.6 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.36 (td, J = 8.1, 1.2 Hz, 1H), 6.20 (s, 1H), 2.51 (tt, J = 11.4, 3.6 Hz, 1H), 2.03–2.16 (m, 2H), 1.82–1.96 (m, 2H), 1.71–1.80 (m, 1H), 1.20–1.56 (m, 5H). 13C NMR (CDCl3): δ (ppm): 178.8, 173.3, 156.4, 133.2, 125.8, 124.7, 123.6, 117.6, 107.8, 42.6, 30.2, 25.4. Analytically calculated for C15H16O2: C 78.92, H 7.06; found: C 79.13, H 7.19.
Colorless oil. IR film 3580, 1633, 1465, 1221, 1080 cm−1. 1H NMR (CDCl3): δ (ppm): 8.21 (dd, J = 8.1, 1.6 Hz, 1H), 7.62 (td, J = 8.8, 1.6 Hz, 1H), 7.38–7.48 (m, 2H), 6.21 (s, 1H), 2.61 (t, J = 7.6 Hz, 2H), 1.65–1.78 (m, 2H), 1.36–1.49 (m, 2H), 0.98 (t, J = 7.6 Hz, 3H). 13C NMR (CDCl3): δ (ppm): 178.3, 169.7, 156.6, 133.6, 125.5, 124.6, 123.8, 117.6, 109.9, 34.1, 28.6, 22.3, 13.6. Analytically calculated for C13H14O2: C 77.20, H 6.98; found: C 77.41, H 6.83.
Colorless oil. IR film 3382, 1638, 1460, 1335, 1075 cm−1. 1H NMR (CDCl3): δ (ppm): 8.20 (dd, J = 8.1, 1.6 Hz, 1H), 7.48–7.62 (m, 2H), 7.40 (td, J = 8.1, 1.2 Hz, 1H), 6.30 (s, 1H), 1.34 (s, 9H). 13C NMR (CDCl3): δ (ppm): 178.8, 176.1, 156.3, 133.2, 125.6, 124.6, 123.5, 117.6, 106.8, 36.2, 27.3. Analytically calculated for C13H14O2: C 77.20, H 6.98; found: C 77.43, H 7.18.
Dedication
Dedicated to the memory of the late Prof. Alan R. Katritzky for his excellent contributions to benzotriazole chemistry.
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