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Communication

Atom-Economic Synthesis of 4-Pyrones from Diynones and Water

by
Yan-Li Xu
1,†,
Qing-Hu Teng
2,†,
Wei Tong
2,
Heng-Shan Wang
2,
Ying-Ming Pan
2,* and
Xian-Li Ma
1,*
1
College of Pharmacy, Guilin Medical University, Guilin 541004, China
2
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2017, 22(1), 109; https://doi.org/10.3390/molecules22010109
Submission received: 21 December 2016 / Revised: 5 January 2017 / Accepted: 5 January 2017 / Published: 10 January 2017
(This article belongs to the Special Issue Reactions of Hydrocarbons and other C‒H Compounds)
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Versions Notes

Abstract

:
Transition-metal-free synthesis of 4-pyrones via TfOH-promoted nucleophilic addition/cyclization of diynones and water has been developed. This transformation is simple, atom economical and environmentally benign, providing rapid and efficient access to substituted 4-pyrones.

Graphical Abstract

1. Introduction

Water (H2O) is inexpensive, safe, and environmentally friendly [1]. It is the most economic and eco-friendly solvent available in Nature and therefore highly desirable for chemical reactions [2]. Generally, water offers several “green chemistry” benefits as a solvent in organic transformations, including high efficiency, lower cost, ease of process, green and environmental protection [3,4]. Recently, there are many reports of clean transformations in water medium [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19], such as coupling reactions [20,21,22,23,24,25,26,27,28,29,30], cyclizations [31,32,33,34], Michael additions [35,36,37,38,39], and condensations [40,41]. Additionally, H2O also participates in organic reactions as a nucleophile [42,43] to provide various kinds of functional compounds such as imidazo[1,2-a]pyridines [44], amino acid salts [45], α-amino ketones [46], and 1,3-oxazinan-2-ones [47]. Thus, the studies of organic reactions in aqueous solvents or H2O-participating reactions are attractive in synthetic chemistry.
4-Pyrones are heterocycles with multiple biological activities [48,49,50], which are widely found in biologically active natural products and functional chemicals [51,52,53,54,55,56,57,58,59]. Particularly, phenoxans, funicones and rapicones possess potent anti-HIV activity (Figure 1) [60,61,62]. In general, 4-pyrones are prepared via the well-known condensation cyclization reaction of carbonyl compounds with polystep reactions [63,64,65,66,67]. Additionally, a transformation of isoxazoles to substituted pyran-4-ones in the presence of Mo(CO)6 and HCO2H in a two-step procedure was established [68]. Although these reported methods have made significant contributions to the applications of 4-pyrones in pharmacology and food manufacture [69], the development of efficient and practical synthetic methods for 4-pyrones from easily accessible starting materials is still highly desirable. Continuing our interest in the conversion of alkynes to heterocycles [70,71,72,73,74,75,76,77], herein, we would like to describe an efficient, transition-metal-free synthesis of 4-pyrones through TfOH-promoted cyclization of diynones. Water acts as both the substrate and solvent, obviating the need for an organic co-solvent. Overall, the reaction is atom-economical and environmentally benign.

2. Results and Discussion

1,5-Diphenylpenta-1,4-diyn-3-one (1a) was chosen as model substrate to identify the optimal conditions for this reaction (Table 1). Originally, the reaction was carried out in the presence of 1 equiv. TfOH for 24 h to afford the desired product 2a in 70% yield (Table 1, entry 1). When other acid catalysts such as CH3COOH, PTSA, HCl, H3PO4 and PhCOOH were screened, the yield of 2a decreased (Table 1, entries 2–6). Further experiments demonstrated that decreasing the amount of TfOH was detrimental to the yield of 2a (Table 1, entries 7 and 8), and no obvious improvement of yield was noted by using 2 equiv. of TfOH (Table 1, entry 9). Poor yield of 2a was obtained when the reaction was performed at 80 °C, while not much change was noted between 100 °C and 130 °C (Table 1, entries 10 and 11). In addition, an 83% yield was achieved when the reaction time was extended to 36 h (Table 1, entry 12). Thus, the best conditions for this transformation involved 1 equiv. of TfOH in H2O at 100 °C for 36 h.
Under the optimized reaction conditions, the one-pot reaction worked well using all kinds of diynones, as shown in Scheme 1. Firstly, various symmetric diynones were identified as suitable substrates for the reaction and provided the desired products in moderate to good yields (Scheme 1, 2b–2j). Aryl groups with electron-donating groups (EDG) gave satisfactory yields (Scheme 1, 2b–2d and 2f–2h), whereas aryl groups with electron-withdrawing groups (EWG) afforded slightly lower yields (Scheme 1, 2e). Gratifyingly, aliphatic diynones worked smoothly to generate the corresponding cyclization products 2i and 2j in 50% and 57%, respectively (Scheme 1, 2i and 2j). After exploring the reaction substrate scope of symmetric diynones, we next examined asymmetric diynones substrates. To our delight, the corresponding 4-pyrones products were obtained in moderate to good yields under the standard conditions (Scheme 1, 2k–2r). The desired products 2k–2q were obtained in 55%–78% yields when asymmetric diynones substrates 1k–1q (R2 = Ph, R1 = aryl- or alkyl-) were subjected to this reaction. Obviously, aryl groups with electron-donating groups gave higher yields than diynones featuring electron-withdrawing groups on the phenyl ring (Scheme 1, 2l and 2m vs. 2n and 2p). Notably, diynone 1p, which possess an electron-withdrawing group at the ortho-position of the phenyl ring (R1 = 2-Cl-Ph, R2 = Ph) reacted readily to afford 2p in 61% yield (Scheme 1, 2p). Furthermore, diynone 1q, which bear both a EDG-incorporated aryl ring and a EWG-incorporated aryl ring (R1 = 4-OMe-Ph, R2 = 4-F-Ph) also participated well in the reaction and offered 2q in 63% yield (Scheme 1, 2q). Finally, diynone 1r also worked smoothly to give 2r in 50% yield (Scheme 1, 2r).
To better understand the reaction mechanism, we carried out control experiments as outlined in Scheme 2. Deuterium-labeled D2O was used in the reaction with diynone 1a to give the deuterium-labeled product 2a-d in 80% yield, where over 95% of deuterium was incorporated into the cyclization product.
This result demonstrated that H2O was introduced into the 4-pyrones. Moreover, an O18-labeled experiment further showed that H2O reacted with diynones to form 4-pyrones.
On the basis of the above results and existing literature [78], a plausible mechanistic description of the nucleophilic addition and cyclization reaction is shown in Scheme 3. First, the carbonyl of the diynone substrate was activated by TfOH, followed by nucleophilic addition of H2O to the carbon−carbon triple bond of diynone and keto–enol tautomerization [79,80] to form intermediate A. Then intermediate A was converted to B through protonation and C–C bond rotation, which was promoted by elevated temperature. Subsequently, an intramolecular nucleophilic attack of the oxhydryl group to the carbon−carbon triple bond of B lead to a cyclization intermediate C. Finally, deprotonation of C gave the desired 4-pyrone 2.
The treatment of 1,5-diphenylpenta-1,4-diyn-3-one 1a in H2O at 100 °C for 36 h in the presence of TfOH afforded the corresponding cyclization product 2a in 83% yield. The preparation of this compound 2a on gram-scale afforded 53% of the isolated product (Scheme 4).

3. Materials and Methods

3.1. General Information

All manipulations were performed under an air atmosphere unless otherwise stated. Column chromatography was performed on silica gel (300–400 mesh). NMR spectra were obtained using an Avance 500 spectrometer (1H at 500 MHz and 13C at 125 MHz) or an Avance 400 spectrometer (1H at 400 MHz and 13C at 100 MHz) (Bruker Corporation, Karlsruhe, Germany). IR spectra were recorded on a Nicolet ESP 360 FT-IR spectrometer (Nicolet, Madison, WI, USA) and only major peaks are reported in cm−1. High resolution mass spectra (HRMS) were recorded on an Exactive Mass Spectrometer (Thermo Fisher Scientific, Waltham, MA, USA) equipped with ESI or APCI ionization sources. Unless stated otherwise, commercial reagents were used without further purification. All reagents were weighed and handled at room temperature. Compounds 1a–1r were prepared by the reported methods [78,81]. The NMR spectra and HRMS spectra of the products can be found in the Supplementary Materials.

3.2. General Procedure for the Synthesis of Compound 2

The reaction mixture of 1 (0.5 mmol), TfOH (1 equiv.) and H2O (1 mL) in a 15 mL test tube was stirred at 100 °C for 36 h, and monitored periodically by TLC. Upon completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with water and brine, dried over MgSO4 and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography (petroleum ether and ethyl acetate, v/v = 5:1 to 2:1) to afford 4-pyrones 2 (Scheme 5).
2,6-Diphenyl-4H-pyran-4-one (2a) [82]. The general procedure was used with 1,5-diphenylpenta-1,4-diyn-3-one (115.04 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product as a yellow solid (102.90 mg, 83%); m.p. 135.3–136.2 °C (lit: 139–140 °C); 1H-NMR (500 MHz, CDCl3) δ 7.89–7.82 (m, 4H), 7.55–7.50 (m, 6H), 6.81 (s, 2H) ppm; 13C-NMR (125 MHz, CDCl3) δ 180.2, 163.3, 131.4, 131.4, 129.1, 125.9, 111.4 ppm; IR (KBr): 3060, 2925, 1647, 1614, 1604, 1493, 1450, 1392, 943, 770, 683 cm−1; HRMS (m/z) (APCI): calcd. for C17H13O2 249.0917 [M + H+]; found 249.0906.
2,6-Di-p-tolyl-4H-pyran-4-one (2b) [78]. The general procedure was used with 1,5-di-p-tolylpenta-1,4-diyn-3-one (129.05 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product as a yellow solid (117.35 mg, 85%); m.p. 180.5–183.1 °C (lit: 178 °C); 1H-NMR (500 MHz, CDCl3) δ 7.74 (d, J = 8.2 Hz, 42H), 7.32 (d, J = 8.0 Hz, 4H), 6.76 (s, 2H), 2.43 (s, 6H) ppm; 13C-NMR (125 MHz, CDCl3) δ 180.4, 163.4, 141.9, 129.8, 128.7, 125.8, 110.7, 21.5 ppm; IR (KBr): 3066, 1646, 1605, 1507, 1413, 1383, 942, 819, 478 cm−1; HRMS (m/z) (APCI): calcd. for C19H17O2 277.1230 [M + H+]; found 277.1219.
2,6-Bis(4-methoxyphenyl)-4H-pyran-4-one (2c) [82]. The general procedure was used with 1,5-bis(4-methoxyphenyl)penta-1,4-diyn-3-one (145.05 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product as a yellow solid (124.78 mg, 81%); m.p. 190–193.8 °C (lit: 189–191 °C); 1H-NMR (500 MHz, CDCl3) δ 7.79 (d, J = 8.9 Hz, 4H), 7.02 (d, J = 8.9 Hz, 4H), 6.70 (s, 2H), 3.88 (s, 6H) ppm; 13C-NMR (125 MHz, CDCl3) δ 163.2, 162.1, 134.4, 127.5, 123.9, 114.5, 109.7, 55.5 ppm; IR (KBr): 2983, 2875, 2765, 1651, 1607, 1507, 1387, 1262, 1226, 1177, 1020, 829 cm−1; HRMS (m/z) (APCI): calcd. for C19H17O4 309.1129 [M + H+]; found 309.1115.
2,6-Bis(4-(tert-butyl)phenyl)-4H-pyran-4-one (2d) [82]. The general procedure was used with 1,5-bis(4-(tert-butyl)phenyl)penta-1,4-diyn-3-one (171.10 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product as a yellow solid (154.89 mg, 86%); m.p. 192.5–193.1 °C (lit: 192–194 °C); 1H-NMR (500 MHz, CDCl3) δ 7.79 (d, J = 7.2 Hz, 4H), 7.54 (d, J = 7.4 Hz, 4H), 6.81 (s, 2H), 1.36 (s, 18H) ppm; 13C-NMR (125 MHz, CDCl3) δ 180.5, 163.5, 155.0, 128.6, 126.0, 125.7, 34.9, 31.0 ppm; IR (KBr): 3064, 3003, 2998, 2970, 2868, 1715, 1667, 1650, 1450, 1340, 1250, 910 cm−1; HRMS (m/z) (APCI): calcd. for C25H29O2 361.2169 [M + H+]; found 361.2153.
2,6-Bis(4-fluorophenyl)-4H-pyran-4-one (2e) [82]. The general procedure was used with 1,5-bis(4-fluorophenyl)penta-1,4-diyn-3-one (133.12 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product as a white solid (85.22 mg, 60%); m.p. 160–161.3 °C (lit: 167–170 °C); 1H-NMR (500 MHz, CDCl3) δ 7.84 (dd, J = 8.5, 5.2 Hz, 4H), 7.22 (t, J = 8.4 Hz, 4H), 6.75 (s, 2H) ppm; 13C-NMR (125 MHz, CDCl3) δ 179.9, 164.6 (d, J = 253.4 Hz), 162.5, 128.1 (d, J = 8.8 Hz), 127.6 (d, J = 3.3 Hz), 116.5(d, J = 22.2 Hz), 111.3 ppm; IR (KBr): 3059, 2924, 1662, 1599, 1504, 1417, 1380, 1241, 1223, 1160, 837 cm−1; HRMS (m/z) (APCI): calcd. for C17H11F2O2 285.0729 [M + H+]; found 285.0716.
2,6-Bis(4-pentylphenyl)-4H-pyran-4-one (2f). The general procedure was used with 1,5-bis(4-pentylphenyl)penta-1,4-diyn-3-one (185.11 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product as a yellow solid (163.06 mg, 84%); m.p. 66.7–67.9 °C; 1H-NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.1 Hz, 4H), 7.32 (d, J = 8.1 Hz, 4H), 6.77 (s, 2H), 2.70–2.66 (m, 4H), 1.69–1.61 (m, 4H), 1.36–1.33 (m, 8H), 0.90 (t, J = 6.9 Hz, 6H) ppm; 13C-NMR (125 MHz, CDCl3) δ 180.5, 163.5, 146.9, 129.2, 128.9, 125.9, 110.7, 35.8, 31.4, 30.8, 22.5, 13.9 ppm; IR (KBr): 3032, 2956, 2929, 2857, 1717, 1649, 1609, 1419, 1380, 1186, 944, 849, 649 cm−1; HRMS (m/z) (APCI): calcd. for C27H33O2 389.2482 [M + H+]; found 389.2466.
2,6-Bis(4-ethylphenyl)-4H-pyran-4-one (2g) [78]. The general procedure was used with 1,5-bis(4-ethylphenyl)penta-1,4-diyn-3-one (143.07 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product as a brown solid (124.70 mg, 82%); m.p. 119.5–121.5 °C; 1H-NMR (500 MHz, CDCl3) δ 7.77 (d, J = 8.1 Hz, 4H), 7.34 (d, J = 8.1 Hz, 4H), 6.77 (s, 2H), 2.72 (q, J = 7.6 Hz, 4H), 1.28 (t, J = 7.6 Hz, 6H) ppm; 13C-NMR (125 MHz, CDCl3) δ 180.4, 163.5, 148.2, 128.9, 128.6, 125.9, 110.6, 28.8, 15.2 ppm; IR (KBr): 3070, 2965, 2875, 1647, 1610, 1510, 1451, 1420, 1383, 1187, 1014, 945, 837, 643 cm−1; HRMS (m/z) (APCI): calcd. for C21H21O2 305.1543 [M + H+]; found 305.1532.
2,6-Di-m-tolyl-4H-pyran-4-one (2h) [78]. The general procedure was used with 1,5-di-m-tolylpenta-1,4-diyn-3-one (129.05 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product as a light yellow solid (100.78 mg, 73%); m.p. 73.5–75.5 °C; 1H-NMR (500 MHz, CDCl3) δ 7.66–7.62 (t, J = 7.6 Hz, 4H), 7.41 (t, J = 7.6 Hz, 2H), 7.34 (d, J = 7.6 Hz, 2H), 6.78 (s, 2H), 2.45 (s, 6H) ppm; 13C-NMR (125 MHz, CDCl3) δ 163.6, 138.9, 132.1, 131.4, 129.0, 126.5, 123.1, 111.3, 21.5 ppm; IR (KBr): 3063, 2923, 1646, 1611, 1485, 1384, 1260, 1075, 929, 784, 694, 435 cm−1; HRMS (m/z) (APCI): calcd. for C19H17O2 277.1230 [M + H+]; found 277.1219.
2,6-Dipropyl-4H-pyran-4-one (2i) [78]. The general procedure was used with undeca-4,7-diyn-6-one (81.05 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product as a brown oil (45.03 mg, 50%); 1H-NMR (500 MHz, CDCl3) δ 6.05 (s, 1H), 2.44 (t, J = 7.5 Hz, 4H), 1.69–1.61 (m, 4H), 0.95 (td, J = 7.4, 1.1 Hz, 6H) ppm; 13C-NMR (125 MHz, CDCl3) δ 180.6, 169.1, 113.0, 35.4, 20.1, 13.3 ppm; IR (KBr): 3437, 2965, 2875, 1663, 1619, 1411, 1398, 1148, 933, 864 cm−1; HRMS (m/z) (APCI): calcd. for C11H14O2 181.1230 [M + H+]; found 181.1221.
2,6-Dicyclopropyl-4H-pyran-4-one (2j) [78]. The general procedure was used with 1,5-dicyclopropylpenta-1,4-diyn-3-one (79.04 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product as a white solid (50.19 mg, 57%); m.p. 146.7–150.7 °C; 1H-NMR (500 MHz, CDCl3) δ 6.04 (s, 2H), 1.72 (tt, J = 8.3, 5.0 Hz, 2H), 1.00–0.95 (m, 4H), 0.92–0.88 (m, 4H) ppm; 13C-NMR (125 MHz, CDCl3) δ 179.5, 168.6, 111.1, 13.7, 7.8 ppm; IR (KBr): 3045, 3010, 2955, 1655, 1602, 1586, 1401, 1095, 1053, 858 cm−1; HRMS (m/z) (APCI): calcd. for C11H13O2 177.0917 [M + H+]; found 177.0908.
2-Phenyl-6-propyl-4H-pyran-4-one (2k) [78]. The general procedure was used with 1-phenylocta-1,4-diyn-3-one (98.04 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product as a brown solid (83.50 mg, 78%); m.p. 49.8–51.5 °C; 1H-NMR (500 MHz, CDCl3) δ 7.75 (dd, J = 7.7, 1.8 Hz, 1H), 7.51–7.46 (m, 1H), 6.72 (s, 1H), 6.19 (s, 1H), 2.60 (t, J = 7.5 Hz, 1H), 1.82–1.73 (m, 1H), 1.03 (t, J = 7.4 Hz, 1H) ppm; 13C-NMR (125 MHz, CDCl3) δ 180.1, 168.8, 163.6, 131.5, 131.3, 129.0, 125.8, 114.0, 111.1, 35.6, 20.3, 13.5 ppm; IR (KBr): 3060, 2926, 1653, 1617, 1493, 1450, 1409, 1061, 937, 866, 772, 691 cm−1; HRMS (m/z) (APCI): calcd. for C14H15O2 215.1074 [M + H+]; found 215.1065.
2-Phenyl-6-(p-tolyl)-4H-pyran-4-one (2l) [83]. The general procedure was used with 1-phenyl-5-(p-tolyl)penta-1,4-diyn-3-one (112.04 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product as a yellow solid (85.18 mg, 65%); m.p. 155.1–156.4 °C (lit: 150 °C); 1H-NMR (500 MHz, CDCl3) δ 7.88–7.83 (m, 2H), 7.75 (d, J = 8.2 Hz, 2H), 7.54–7.51 (m, 3H), 7.32 (d, J = 8.1 Hz, 2H), 6.83–6.78 (m, 2H), 2.44 (s, 3H) ppm; 13C-NMR (125 MHz, CDCl3) δ 180.4, 163.6, 163.3, 142.0, 131.5, 131.4, 129.8, 129.1, 128.6, 125.91, 125.86, 111.3, 110.7, 21.5 ppm; IR (KBr): 3064, 2922, 2854, 1646, 1606, 1448, 1413, 1387, 943, 816 cm−1; HRMS (m/z) (APCI): calcd. for C18H15O2 263.1074 [M + H+]; found 263.1061.
2-(4-Methoxyphenyl)-6-phenyl-4H-pyran-4-one (2m) [78]. The general procedure was used with 1-(4-methoxyphenyl)-5-phenylpenta-1,4-diyn-3-one (130.04 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product as a brown solid (97.33 mg, 70%); m.p. 161.3–162.2 °C (lit: 162 °C); 1H-NMR (500 MHz, CDCl3) δ 7.82 (dd, J = 6.6, 3.0 Hz, 2H), 7.78 (d, J = 8.9 Hz, 2H), 7.50 (dd, J = 5.0, 1.7 Hz, 3H), 7.00 (d, J = 8.9 Hz, 2H), 6.76 (d, J = 1.7 Hz, 1H), 6.70 (d, J = 1.7 Hz, 1H), 3.86 (s, 3H) ppm; 13C-NMR (125 MHz, CDCl3) δ 180.2, 163.3, 163.0, 162.2, 131.5, 131.2, 129.0, 127.5, 125.8, 123.6, 114.5, 111.1, 109.8, 55.4 ppm; IR (KBr): 3443, 3067, 2900, 2843, 1647, 1604, 1509, 1448, 1423, 1383, 1023, 832, 767, 684 cm−1; HRMS (m/z) (APCI): calcd. for C18H15O3 279.1014 [M + H+]; found 279.1013.
2-(4-Fluorophenyl)-6-phenyl-4H-pyran-4-one (2n). The general procedure was used with 1-(4-fluorophenyl)-5-phenylpenta-1,4-diyn-3-one (124.03 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product as a yellow solid (77.16 mg, 58%); m.p. 145.5–150.6 °C; 1H-NMR (500 MHz, CDCl3) δ 7.89–7.82 (m, 4H), 7.56–7.51 (m, 3H), 7.22 (t, J = 8.5 Hz, 2H), 6.82 (d, J = 1.8 Hz, 1H), 6.77 (d, J = 1.8 Hz, 1H) ppm; 13C-NMR (125 MHz, CDCl3) δ 180.1, 165.6, 163.6, 163.4, 162.5, 131.5, 131.3, 129.2, 128.1 (d, J = 8.9 Hz), 127.6, 125.9, 116.4 (d, J = 22.1 Hz), 111.3 (d, J = 24.2 Hz) ppm; IR (KBr): 3061, 2924, 1659, 1505, 1508, 1417, 1449, 1388, 1232, 1162 cm−1; HRMS (m/z) (APCI): calcd. for C17H12FO2 267.0823 [M + H+]; found 267.0813.
2-Cyclopropyl-6-phenyl-4H-pyran-4-one (2o) [84]. The general procedure was used with 1-cyclopropyl-5-phenylpenta-1,4-diyn-3-one (97.04 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product as a yellow solid (58.33 mg, 55%); m.p. 106.5–107.8 °C (lit: 106 °C); 1H-NMR (500 MHz, CDCl3) δ 7.67 (dd, J = 7.9, 1.7 Hz, 2H), 7.50–7.45 (m, 3H), 6.69 (d, J = 2.1 Hz, 1H), 6.23 (d, J = 2.1 Hz, 1H), 1.90 (tt, J = 7.9, 5.4 Hz, 1H), 1.12 (tt, J = 4.7, 2.5 Hz, 4H) ppm; 13C-NMR (125 MHz, CDCl3) δ 179.8, 169.5, 162.7, 131.3, 131.2, 129.0, 125.6, 111.6, 111.0, 14.1, 8.5 ppm; IR (KBr): 3059, 2927, 1651, 1609, 1544, 1496, 1448, 1394, 1253, 1193, 1087, 931, 878, 766, 685 cm−1; HRMS (m/z) (APCI): calcd. for C14H13O2 213.0917 [M + H+]; found 213.0908.
2-(2-Chlorophenyl)-6-phenyl-4H-pyran-4-one (2p) [85]. The general procedure was used with 1-(2-chlorophenyl)-5-phenylpenta-1,4-diyn-3-one (132.02 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product as a yellow solid (86.03 mg, 61%); m.p. 123.5–124.6 °C (lit: 122–124 °C); 1H-NMR (400 MHz, CDCl3) δ 7.86–7.81 (m, 2H), 7.60 (dd, J = 7.5, 1.8 Hz, 1H), 7.57–7.54 (m, 1H), 7.52–7.48 (m, 2H), 7.48–7.46 (m, 1H), 7.44 (dd, J = 6.6, 1.7 Hz, 1H), 7.41 (dd, J = 7.4, 1.4 Hz, 1H), 6.86 (d, J = 2.2 Hz, 1H), 6.67 (d, J = 2.2 Hz, 1H) ppm; 13C-NMR (100 MHz, CDCl3) δ 178.0, 164.1, 162.6, 132.8, 131.9, 131.5, 131.4, 131.2, 130.9, 130.7, 129.1, 127.2, 126.0, 116.8, 111.2 ppm; IR (KBr): 3059, 2931, 1667, 1650, 1600, 1580, 1403, 1250, 1000, 910, 665 cm−1; HRMS (m/z) (ESI): calcd. for C17H12ClO2 283.0528 [M + H+]; found 283.0513.
2-(4-Fluorophenyl)-6-(4-methoxyphenyl)-4H-pyran-4-one (2q) [85]. The general procedure was used with 1-(4-fluorophenyl)-5-(4-methoxyphenyl)penta-1,4-diyn-3-one (139.04 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product as a yellow solid (93.27 mg, 63%); m.p. 138.7–140.5 °C (lit: 144–148 °C); 1H-NMR (400 MHz, CDCl3) δ 7.86–7.82 (m, 2H), 7.80–7.77 (m, 2H), 7.27–7.18 (m, 2H), 7.05–7.00 (m, 2H), 6.72 (dd, J = 3.7, 1.9 Hz, 2H), 3.89 (s, 3H) ppm; 13C-NMR (100 MHz, CDCl3) δ 180.2, 165.8, 163.4, 163.3, 162.2 (d, J = 8.9 Hz), 128.1 (d, J = 8.8 Hz), 127.8 (d, J = 3.3 Hz), 127.6, 123.6, 116.4 (d, J = 22.1 Hz), 114.6, 111.0, 109.9, 55.5 ppm; IR (KBr): 3673, 3067, 2969, 1657, 1610, 1509, 1422, 1385, 1270, 1227, 1169, 1074, 1021, 841 cm−1; HRMS (m/z) (ESI): calcd. for C18H14FO3 297.0929 [M + H+]; found 297.0913.
2-Phenyl-4H-pyran-4-one (2r) [86]. The general procedure was used with 1-phenylpenta-1,4-diyn-3-one (77.02 mg, 0.5 mmol, 1 equiv.) and water (1 mL). The crude obtained was purified by column chromatography (petroleum ether/ethyl acetate = 5:1 to 2:1) to afford the product as a yellow solid (43.02 mg, 50%); yellow solid; m.p. 102.2–103.5 °C (lit: 100–102 °C); 1H-NMR (400 MHz, CDCl3) δ 7.84 (d, J = 5.8 Hz, 1H), 7.74 (dd, J = 7.9, 1.7 Hz, 2H), 7.51–7.44 (m, 3H), 6.78 (d, J = 2.3 Hz, 1H), 6.38 (dd, J = 5.8, 2.3 Hz, 1H) ppm; 13C-NMR (100 MHz, CDCl3) δ 179.0, 163.9, 154.8, 131.4, 131.0, 129.0, 125.7, 117.0, 112.3 ppm; IR (KBr): 3090, 1675, 1650, 1590, 1549, 1490, 1450, 1402, 1350, 1050, 931, 875, 795, 730, 650 cm−1; HRMS (m/z) (ESI): calcd. for C11H9O2 173.0604 [M + H+]; found 173.0603.

3.3. Control Experiments

3.3.1. Deuterium Labeling Experiments

The reaction mixture of 1 (0.5 mmol), TfOH (1 equiv.), and D2O (1 mL) in a 15 mL test tube was stirred at 100 °C for 36 h, and monitored periodically by TLC. Upon completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with water and brine, dried over MgSO4 and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography (petroleum ether and ethyl acetate, v/v = 5:1 to 2:1) to afford 4-pyrone 2a-d (100.04 mg, 80%) as a yellow solid; m.p. 116.1–119.5 °C; 1H-NMR (500 MHz, CDCl3) δ 7.90–7.83 (m, 4H), 7.55–7.51 (m, 6H), 6.84 (s, 0.12H) (Scheme 6).

3.3.2. O18-Labelling Experiment

The reaction mixture of 1a (0.5 mmol), TfOH (1 equiv.), and H2O18 (1 mL) in a 15 mL test tube was stirred at 100 °C for 36 h, and monitored periodically by TLC. Upon completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with water and brine, dried over MgSO4 and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography (petroleum ether and ethyl acetate, v/v = 5:1 to 2:1) to afford 4-pyrone O18-2a (78%) (Scheme 7).

3.3.3. Gram-Scale Synthesis

The reaction mixture of 1a (5 mmol), TfOH (1 equiv.) and H2O (10 mL) in a 50 mL round-bottom flask was stirred at 100 °C for 36 h, and monitored periodically by TLC. Upon completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with water and brine, dried over MgSO4 and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography (petroleum ether and ethyl acetate, v/v = 5:1 to 2:1) to afford 4-pyrone 2a (53%) (Scheme 8).

4. Conclusions

We have developed a simple and efficient transition-metal-free method for the synthesis of substituted 4-pyrones from diynones and H2O. Water is a cheap, green and readily available staring material, which converted to the desired 4-pyrone products via a nucleophilic addition/cyclization/ dehydrogenation process. The operational simplicity, good yields, and environmentally benign nature of this method make it an attractive route to 4-pyrones. Further studies on the applications of 4-pyrones in drug design are currently ongoing in our laboratory.

Supplementary Materials

Supplementary materials can be accessed at: https://www.mdpi.com/1420-3049/22/1/109/s1: copies of NMR spectra and HRMS spectra of products.

Acknowledgments

We would like to thank the National Natural Science Foundation of China (21362002 and 81260472), Guangxi Natural Science Foundation of China (2014GXNSFDA118007 and 2016GXNSFEA380001), Project of Guangxi Department of Education (KY2014037), State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (CMEMR2014-A02 and CMEMR2012-A20), the Fund of Guangxi Key Laboratory of Functional Phytochemicals Research and Utilization (FPRU2015-2), and Guangxi’s Medicine Talented Persons Small Highland Foundation (1306).

Author Contributions

Yan-Li Xu and Qing-Hu Teng conceived and designed the experiments. The experimental work was conducted by Qing-Hu Teng under the supervision of Ying-Ming Pan and Xian-Li Ma who are the lead author; Qing-Hu Teng and Wei Tong analyzed the data; Heng-Shan Wang contributed reagents/materials/analysis tools; Yan-Li Xu and Qing-Hu Teng wrote the paper.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

TfOHtrifluoromethanesulfonic acid
PTSA4-methylbenzenesulfonic acid
HClhydrochloric acid
HIVhuman immunodeficiency virus
HOAcacetic acid
Phphenyl
Memethyl
OMemethoxyl
Etethyl
tButertiary butyl
nPrn-propyl
NMRnuclear magnetic resonance
HRMShigh-resolution mass

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  • Sample Availability: Samples of the compounds 2a–2r, 2a-d and 2a-o18 are available from the authors.
Molecules 22 00109 g001 550
Figure 1. 4-Pyrones disclosed as biologically active organic molecules.
Figure 1. 4-Pyrones disclosed as biologically active organic molecules.
Molecules 22 00109 g001
Molecules 22 00109 sch001 550
Scheme 1. Synthesis of 4-pyrone derivatives a,b. a Reaction conditions: 1 (0.5 mmol), TfOH (1 equiv.), H2O (1 mL), at 100 °C, 36 h; b Isolated yields.
Scheme 1. Synthesis of 4-pyrone derivatives a,b. a Reaction conditions: 1 (0.5 mmol), TfOH (1 equiv.), H2O (1 mL), at 100 °C, 36 h; b Isolated yields.
Molecules 22 00109 sch001
Molecules 22 00109 sch002 550
Scheme 2. Control experiments.
Scheme 2. Control experiments.
Molecules 22 00109 sch002
Molecules 22 00109 sch003 550
Scheme 3. Proposed mechanism.
Scheme 3. Proposed mechanism.
Molecules 22 00109 sch003
Molecules 22 00109 sch004 550
Scheme 4. Gram-scale synthesis.
Scheme 4. Gram-scale synthesis.
Molecules 22 00109 sch004
Molecules 22 00109 sch005 550
Scheme 5. Synthesis of Compounds 2.
Scheme 5. Synthesis of Compounds 2.
Molecules 22 00109 sch005
Molecules 22 00109 sch006 550
Scheme 6. Deuterium Labeling Experiments.
Scheme 6. Deuterium Labeling Experiments.
Molecules 22 00109 sch006
Molecules 22 00109 sch007 550
Scheme 7. O18-Labelling Experiment.
Scheme 7. O18-Labelling Experiment.
Molecules 22 00109 sch007
Molecules 22 00109 sch008 550
Scheme 8. Gram-Scale Synthesis.
Scheme 8. Gram-Scale Synthesis.
Molecules 22 00109 sch008
Table
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
Molecules 22 00109 i001
EntryCatalystTime (h)Yield (%) b
1TfOH2470
2CH3COOH240
3PTSA2450
4HCl240
5H3PO4240
6PhCOOH2410
7 cTfOH24 10
8 dTfOH2450
9 eTfOH2480
10 fTfOH2420
11 gTfOH2475
12TfOH3683
a Reaction conditions: 1a (0.5 mmol), catalyst (1 equiv.), H2O (1 mL), at 100 °C; b Isolated yields; c TfOH (0.2 equiv.); d TfOH (0.5 equiv.); e TfOH (2 equiv.); f At 80 °C; g The reaction was carried out in a sealed tube at 130 °C.

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MDPI and ACS Style

Xu, Y.-L.; Teng, Q.-H.; Tong, W.; Wang, H.-S.; Pan, Y.-M.; Ma, X.-L. Atom-Economic Synthesis of 4-Pyrones from Diynones and Water. Molecules 2017, 22, 109. https://doi.org/10.3390/molecules22010109

AMA Style

Xu Y-L, Teng Q-H, Tong W, Wang H-S, Pan Y-M, Ma X-L. Atom-Economic Synthesis of 4-Pyrones from Diynones and Water. Molecules. 2017; 22(1):109. https://doi.org/10.3390/molecules22010109

Chicago/Turabian Style

Xu, Yan-Li, Qing-Hu Teng, Wei Tong, Heng-Shan Wang, Ying-Ming Pan, and Xian-Li Ma. 2017. "Atom-Economic Synthesis of 4-Pyrones from Diynones and Water" Molecules 22, no. 1: 109. https://doi.org/10.3390/molecules22010109

APA Style

Xu, Y.-L., Teng, Q.-H., Tong, W., Wang, H.-S., Pan, Y.-M., & Ma, X.-L. (2017). Atom-Economic Synthesis of 4-Pyrones from Diynones and Water. Molecules, 22(1), 109. https://doi.org/10.3390/molecules22010109

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