HETEROCYCLES

Note | Special issue | Vol. 82, No. 1, 2010, pp. 881-886
Received, 7th June, 2010, Accepted, 2nd July, 2010, Published online, 5th July, 2010.
DOI: 10.3987/COM-10-S(E)48

■ Concise and Efficient Synthesis of 4-Hydroxy-2-pyrones from Pentane-2,4-diones

Masahiro Yoshida,* Hironobu Takai, Chika Mitsuhashi, and Kozo Shishido*

Graduate School of Pharmaceutical Sciences, University of Tokushima, Sho-machi, Tokushima 770-8505, Japan

Abstract

A concise method for the synthesis of 4-hydroxy-2-pyrones has been developed. Various 5-substituted 4-hydroxy-2-pyrones were efficiently prepared in two steps from 3-substituted pentane-2,4-diones.

2-Pyrones are an important class of heteroaromatic molecules which are components in a variety of biologically active compounds.1 They are also extensively utilized in organic synthesis as dienes in Diels–Alder reactions2 and as precursors to other carbo- and heterocyclic systems.3 For these reasons, considerable effort has been devoted toward finding an efficient synthesis of substituted 2-pyrones.4 For example, 4-hydroxy-2-pyrones were prepared via the intramolecular cyclization of β,δ-diketo esters under basic conditions.5 Although this method is useful for the synthesis of various 4-hydroxy-2-pyrones, there are problems with the low yields of the products and the lack of reproducibility. We report herein an improved method for the synthesis of 4-hydroxy-2-pyrones, in which various 5-substituted derivatives were efficiently prepared in two steps from 3-substituted pentane-2,4-diones.6

Our procedure for the synthesis of 4-hydroxy-2-pyrones is described in Scheme 1. Thus, methoxycarbonylation of the pentane-2,4-diones 1 in the presence of sodium bis(trimethylsilyl)amide (NaHMDS) gives β,δ-diketo esters 2. Subsequent cyclization of 2 by treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in refluxing benzene produces 4-hydroxy-2-pyrones 3.

The results of the reactions using various pentane-2,4-diones 1a–1i are summarized in Table 1. When 3-methylpentane-2,4-dione (1a) was subjected to the reaction, the 4-hydroxy-5,6-dimethyl-2-pyrone (3a) was obtained in two steps in 68% overall yield (entry 1). The reactions of the 3-ethyl- and 3-heptylpentane-2,4-diones (1b and 1c) uneventfully afforded the corresponding products 3b and 3c in 62% and 89% overall yields, respectively (entries 2 and 3). The allyl- and p-fluorobenzyl-substituted substrates 1d and 1e also reacted to deliver the 4-hydroxy-2-pyrones 3d and 3e in moderate yields, respectively (entries 4 and 5). The pentane-2,4-diones 1f and 1g having a propargylic substituent at the 3-position were successfully transformed to the 4-hydroxy-2-pyrones 3f and 3g, respectively, in good yields (entries 6 and 7). When 3-phenylpentane-2,4-dione (1h) was subjected to the reaction, the phenyl-substituted product (3h) was produced in 43% overall yield (entry 8). The reactions of the parent pentane-2,4-dione (1i) also afforded the corresponding non-substituted product 3i in 62% overall yield (entry 9).
Thus, we have developed a practical methodology for the synthesis of 5-substituted 4-hydroxy-2-pyrones. The reaction afforded a variety of substituted 4-hydroxy-2-pyrones, and the process provided an efficient and convenient protocol for the preparation of these derivatives.7

EXPERIMENTAL
Solvents were dried and distilled according to standard protocols. The phrase ‘residue upon workup’ refers to the residue obtained when the organic layer was separated and dried over anhydrous MgSO4 and the solvent was evaporated under reduced pressure.

General procedure for the synthesis of 4-hydroxy-2-pyrones 3
Synthesis of 3c (Table 1, entry 3): To a stirred solution of 1.06 M solution of NaHMDS in THF (14.3 mL, 15.1 mmol) was added dropwise 3-heptylpentane-2,4-dione (1c) (1.00 g, 5.04 mmol) in THF (30 mL) at −78 ºC. Stirring was continued for 2 h at rt, and dimethyl carbonate (0.42 mL, 5.04 mmol) was added dropwise to the reaction mixture at −78 ºC; stirring continued for another 10 h at rt. The reaction mixture was quenched with 10% HCl and extracted with AcOEt. The combined extracts were washed with brine, and the residue upon workup was chromatographed on a small amount of silica gel with hexane-AcOEt (30:70 v/v) as eluent to give the corresponding β,δ-diketo ester as a yellow oil. To a stirred solution of this β,δ-diketo ester in benzene (25 mL) was added DBU (1.51 mL, 10.08 mmol) at rt, and stirring was continued for 2.5 h under refluxing conditions. The reaction mixture was quenched with 10% HCl and extracted with AcOEt. The combined extracts were washed with brine, and the residue upon workup was chromatographed on silica gel with hexane-AcOEt (60:40 v/v) as eluent to give the 4-hydroxy-2-pyrone 3c (1.00 g, 89%, 2 steps) as a colorless solid.

5-Methyl-4-hydroxy-6-methylpyran-2-one (3a)7
Colorless powder; mp 204.5−206.8 °C (recrystallized from MeOH); IR (KBr) 3355, 2938, 1680, 1625 cm−1; 1H-NMR (400 MHz, CDCl3) δ 1.94 (3H, s), 2.26 (3H, s), 5.62 (1H, s); 13C-NMR (100 MHz, DMSO-d6) δ 9.2 (CH3), 17.1 (CH3), 88.3 (CH), 106.4 (Cq), 158.5 (Cq), 163.2 (Cq), 170.2 (Cq); HRMS (ESI) m/z calcd for C7H8O3 [M+Na]+ 163.0371, found 163.0373.

5-Ethyl-4-hydroxy-6-methylpyran-2-one (3b)
Colorless powder; mp 140.0−141.6 °C (recrystallized from MeOH-H2O); IR (KBr) 3370, 2976, 2606, 1683, 1605 cm−1; 1H-NMR (400 MHz, CDCl3) δ 1.09 (3H, t, J = 7.6 Hz), 2.26 (3H, s), 2.41 (2H, q, J = 7.6 Hz), 5.62 (1H, s); 13C-NMR (100 MHz, CDCl3) δ 13.4 (CH3), 17.0 (CH3), 17.7 (CH2), 90.1 (CH), 114.9 (Cq), 159.3 (Cq), 167.5 (Cq), 172.5 (Cq),; HRMS (ESI) m/z calcd for C8H10O3 [M+Na]+ 177.0528, found 177.0532.

5-Heptyl-4-hydroxy-6-methylpyran-2-one (3c)8
Colorless plates; mp 88.8−90.0 °C (recrystallized from MeOH-H2O); IR (KBr) 3394, 2924, 2360, 1732, 1654 cm−1; 1H-NMR (400 MHz, CDCl3) δ 0.88 (3H, t, J = 7.6 Hz), 1.28−1.46 (10H, m), 2.26 (3H, s), 2.36 (2H, t, J = 7.6 Hz), 5.63 (1H, s); 13C-NMR (100 MHz, CDCl3) δ 14.0 (CH3), 17.2 (CH3), 22.6 (CH2), 24.3 (CH2), 29.0 (CH2), 29.1 (CH2), 29.4 (CH2), 31.8 (CH2), 90.0 (CH), 113.7 (Cq), 159.4 (Cq), 167.5 (Cq), 172.6 (Cq); HRMS (ESI) m/z calcd for C13H20O3 [M+Na]+ 247.1310, found 247.1306.

5-Allyl-4-hydroxy-6-methylpyran-2-one (3d)9
Colorless plates; mp 128.0−129.1 °C (recrystallized from MeOH-H2O); IR (KBr) 3446, 2928, 2742, 1714, 1698, 1645, 1620 cm−1; 1H-NMR (400 MHz, CDCl3) δ 2.25 (3H, s), 3.16 (2H, d, J = 6.0 Hz), 5.01−5.07 (2H, m), 5.65(1H, s), 5.79−5.89 (1H, m); 13C-NMR (100 MHz, CDCl3) δ 17.2 (CH3), 28.0 (CH2), 90.0 (CH), 111.0 (Cq), 115.6 (CH2), 134.1 (CH), 160.6 (Cq), 167.3 (Cq), 172.1 (Cq); HRMS (ESI) m/z calcd for C9H10O3 [M+Na]+ 189.0528, found 189.0531.

5-(4-Fluorobenzyl)-4-hydroxy-6-methylpyran-2-one (3e)
Colorless powder; mp 195.9−197.4 °C (recrystallized from MeOH-H2O); IR (KBr) 3447, 2946, 2577, 2531, 1689, 1643, 1613 cm−1; 1H-NMR (400 MHz, CDCl3) δ 2.29 (3H, s), 3.73 (2H, s), 5.58 (1H, s), 6.98 (2H, d, J = 8.8 Hz), 7.29 (2H, d, J = 8.8 Hz); 13C-NMR (100 MHz, CDCl3) δ 17.2 (CH3), 28.2 (CH2), 88.7 (CH), 110.0 (Cq×2), 115.0 (CH, d, J = 11.5 Hz), 129.5 (CH, d, J = 7.4 Hz), 135.6 (Cq), 160.3 (Cq), 163.0 (Cq), 169.8 (Cq); HRMS (ESI) m/z calcd for C13H11FO3 [M+Na]+ 257.0590, found 257.0588.

5-But-2-ynyl-4-hydroxy-6-methylpyran-2-one (3f)
Colorless needles; mp 196.8−199.1 °C (recrystallized from MeOH-H2O); IR (KBr) 3385, 3107, 2926, 2738, 2672, 2615, 1700, 1652, 1622 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ 1.70 (3H, s), 2.20 (3H, s), 3.16 (2H, s), 3.33 (2H, s), 5.29 (1H, s); 13C-NMR (100 MHz, DMSO-d6) δ 3.0 (CH3), 13.2 (CH2), 17.0 (CH3), 75.4 (Cq), 76.1 (Cq), 88.4 (CH), 107.9 (Cq), 160.1 (Cq), 162.8 (Cq), 169.1 (Cq); HRMS (ESI) m/z calcd for C10H10O3 [M+Na]+ 201.0528, found 201.0527.

5-[3-(tert-Butyldimethylsilanyl)prop-2-ynyl]-4-hydroxy-6-methylpyran-2-one (3g)
Colorless powder; mp 173.0−174.9 °C (recrystallized from MeOH-H2O); IR (KBr) 3393, 2930, 2858, 2177, 1715, 1644 cm−1; 1H-NMR (400 MHz, CDCl3) δ 0.07 (6H, s), 0.94 (9H, s), 2.37 (3H, s), 3.39 (2H, s), 5.70 (1H, s); 13C-NMR (100 MHz, CDCl3) δ −4.6 (CH3), 14.8 (CH2), 16.5 (Cq), 17.7 (CH3), 26.0 (CH3), 83.9 (Cq), 90.2 (CH), 102.5 (Cq), 109.2 (Cq), 161.4 (Cq), 166.9 (Cq), 170.9 (Cq); HRMS (ESI) m/z calcd for C15H22O3Si [M+H]+ 279.1416, found 279.1417.

5-Phenyl-4-hydroxy-6-methylpyran-2-one (3h)10
Colorless powder; mp 189.1–191.4 °C (recrystallized from MeOH-H2O); IR (KBr) 3363, 2927, 2683, 2625, 2595, 1658 cm−1; 1H-NMR (400 MHz, CDCl3) δ 2.13 (3H, s), 5.68 (1H, s), 7.26−7.29 (2H, m), 7.45−7.53 (3H, m); 13C-NMR (100 MHz, CDCl3) δ 18.1 (CH3), 88.4 (CH), 113.8 (Cq), 127.6 (CH), 128.1 (CH), 130.5 (CH), 132.2 (Cq), 160.2 (Cq), 162.8 (Cq), 169.4 (Cq); HRMS (ESI) m/z calcd for C12H10O3 [M+Na]+ 225.0528, found 225.0524.

4-Hydroxy-6-methylpyran-2-one (3i)11
Colorless needles; mp 187.3−188.9 °C (recrystallized from MeOH-H2O); IR (kBr) 3382, 2926, 2735, 2622, 1715, 1660, 1625 cm−1; 1H-NMR (400 MHz, CDCl3) δ 2.25 (3H, s), 5.48 (1H, s), 5.88 (1H, s); 13C-NMR (100 MHz, DMSO-d6) δ 19.4 (CH3), 88.1 (CH), 100.2 (CH), 163.3 (Cq), 163.9 (Cq), 170.5 (Cq); HRMS (ESI) m/z calcd for C6H6O3 [M+H]+ 127.0395, found 127.0395.

ACKNOWLEDGEMENT
This study was supported in part by the Program for the Promotion of Basic and Applied Research for Innovations in the Bio-oriented Industry (BRAIN) and a Grant-in-Aid for the Encouragement of Young Scientists (B) from the Japan Society for the Promotion of Science (JSPS).

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