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Synlett 2006(9): 1434-1436  
DOI: 10.1055/s-2006-941572
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 3-Aryl-Substituted Tetrahydropyran-4-ones and Tetrahydrothiopyran-4-ones

Anna Rosiaka,b, Jens Christoffers*b
a Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany
b Institut für Reine und Angewandte Chemie, Carl von Ossietzky-Universität Oldenburg, 26111 Oldenburg, Germany
Fax: +49(441)7983873; e-Mail: jens.christoffers@uni-oldenburg.de;
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Publikationsverlauf

Received 20 March 2006
Publikationsdatum:
22. Mai 2006 (online)

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Abstract

A series of tetrahydropyran-4-one and tetrahydrothio­pyran-4-one derivatives with 3-aryl or 3,6-diaryl substituents were prepared by double conjugate addition of water or H2S to divinyl ketones. These starting materials were accessed in two steps by ­conversion of lithiated α-bromostyrene derivatives with acrolein or cinnamaldehyde and subsequent oxidation of the divinylalcohols with MnO2.

Key words

building blocks - conjugate addition - heterocyclic compounds - pyran derivatives - thiopyran derivatives

5

3-(3-Ethoxy-4-methoxyphenyl)tetrahydrothiopyran-4-one ( 2c).
NaHS·9H2O (2.7 g, 13 mmol) was added to a solution of dienone 1c (1.9 g, 8.2 mmol) in 2-methoxyethanol (120 mL). The reaction mixture was stirred at 50 °C for 5 h and then poured onto H2O (80 mL). After extraction with EtOAc (4 × 80 mL) the combined organic layers were washed with H2O (80 mL), dried (MgSO4), and all volatile materials removed in vacuum. Chromatography of the residue on SiO2 (PE-EtOAc, 2:1, R f = 0.31) gave the title compound 9 (1.29 g, 4.84 mmol, 59%) as a colorless solid, mp 103-104 °C. 1H NMR (300 MHz, CDCl3): δ = 1.46 (t, J = 7.0 Hz, 3 H, CH3), 2.76-2.92 (m, 2 H), 2.98-3.17 (m, 3 H), 3.24 (dd, J = 13.6 Hz, J = 10.6 Hz, 1 H), 3.86 (s, 3 H), 3.90 (dd, J = 10.6 Hz, J = 4.8 Hz, 1 H), 4.04-4.13 (m, 2 H), 6.71 (d, J = 1.9 Hz, 1 H, Ar-H), 6.74 (dd, J = 8.2 Hz, J = 2.0 Hz, 1 H, Ar-H), 6.85 (d, J = 8.2 Hz, 1 H, Ar-H) ppm. 13C{1H}-NMR (75 MHz, CDCl3): δ = 14.82 (CH3), 30.75 (CH2), 36.74 (CH2), 44.23 (CH2), 55.93 (OCH3), 58.90 (CH), 64.36 (CH2), 111.47 (CH), 113.30 (CH), 120.55 (CH), 129.86 (C), 148.19 (C), 148.64 (C), 207.69 (C=O) ppm. IR (ATR): 2926 (w), 1703 (vs), 1588 (m), 1514 (s), 1444 (m), 1422 (m), 1344 (m), 1306 (m), 1243 (vs), 1182 (m), 1155 (m), 1137 (s), 1111 (m), 1042 (m), 1019 (s), 980 (m), 857 (w) cm-1. MS (EI, 70 eV): m/z (%) = 266 (53) [M+], 178 (100), 150 (26), 91 (5), 77 (7), 28 (9). Anal. Calcd for C14H18O3S (266.35): C, 63.13; H, 6.81. Found: C, 63.01; H, 6.79.

6

3-(3-Ethoxy-4-methoxyphenyl)tetrahydropyran-4-one ( 3b). KOH (4.34 g, 77.5 mmol) was added to a solution of 1c (4.50 g, 19.4 mmol) in CH2Cl2-H2O (1:1, 200 mL). The reaction mixture was vigorously stirred at 40 °C for 3 d and then poured into a mixture of H2O (100 mL) and aq solution of citric acid (c = 20%, 25 mL). The resulting mixture was extracted with CH2Cl2 (2 × 80 mL). The combined organic layers were washed with H2O (30 mL) and dried (MgSO4). After removal of all volatile materials in vacuum, the residue was chromatographed on SiO2 (PE-EtOAc, 2:1, R f = 0.23) to give title compound 3b (1.21 g, 4.83 mmol, 25%) as a light-yellow oil, which solidified after one day, mp 65-67 °C. 1H NMR (250 MHz, CDCl3): δ = 1.45 (t, J = 7.0 Hz, 3 H, CH3), 2.59-2.65 (m, 2 H, CH2), 3.71 (dd, J = 8.2 Hz, J = 5.9 Hz, 1 H, CH), 3.85 (s, 3 H, OCH3), 3.93-4.13 (m, 4 H, 2 CH2), 4.16-4.25 (m, 2 H, CH2), 6.76-6.87 (m, 3 H, Ar-H) ppm. 13C{1H}-NMR (62 MHz, CDCl3): δ = 14.81 (CH3), 41.84 (CH2), 55.94 (OCH3), 57.48 (CH), 64.39 (CH2), 68.52 (CH2), 73.20 (CH2), 111.62 (CH), 113.57 (CH), 120.99 (CH), 127.39 (C), 148.29 (C), 148.77 (C), 206.11 (C=O) ppm. IR (ATR): 2973 (m), 2934 (w), 1715 (vs), 1589 (m), 1517 (vs), 1474 (w), 1433 (m), 1424 (w), 1389 (m), 1339 (w), 1309 (w), 1251 (vs), 1167 (m), 1094 (m), 1045 (m), 1020 (s), 969 (m), 924 (m), 887 (m), 851 (m), 822 (m), 693 (s) cm-1. MS (EI, 70 eV): m/z (%) = 250 (100) [M+], 222 (4), 178 (72), 150 (34), 107(6), 91 (5), 77 (7), 28 (12). Anal. Calcd for C14H18O4 (250.29): C, 67.18; H, 7.25. Found: C, 67.09; H, 7.29.

7

2-(3-Ethoxy-4-methoxyphenyl)-1,4-pentadien-3-ol ( 6c).
Under an inert atmosphere (N2) n-BuLi (154 mmol, 77.0 mL of a 2 M solution in pentane) was added dropwise at -78 °C to a solution of bromoolefin 4c (18.0 g, 70.0 mmol) in abs. THF (250 mL) over a period of 30 min. The reaction mixture was further stirred at -78 °C for 1.5 h. Then freshly distilled acrolein (5a, 10.5 g, 187 mmol) was dropwise added over a period of 10 min. After being stirred for a further 1.5 h at -78 °C, the reaction mixture was allowed to warm up to r.t. and washed with sat. aq NH4Cl (300 mL) and with H2O (100 mL). The layers were separated, and the combined aqueous layers were extracted with CH2Cl2 (2 × 100 mL). The combined organic layers were dried over MgSO4. After filtration and removal of solvent, the residue was chromatographed on SiO2 [PE-EtOAc, 5:1, R f (PE-EtOAc, 2:1) = 0.31] to give 6c (10.5 g, 44.8 mmol, 64%) as a colorless solid, mp 30-32 °C. 1H NMR (300 MHz, CDCl3): δ = 1.45 (t, J = 7.0 Hz, 3 H, CH3), 2.18 (br d, J = 3.5 Hz, 1 H, OH), 3.87 (s, 3 H, OCH3), 4.06-4.15 (m, 2 H, OCH2), 5.08 (br s, 1 H, 3-H), 5.17 (dt, J = 10.3 Hz, J = 1.4 Hz, 1 H, E-5-H), 5.32 (br t, J = 1.0 Hz, 1 H, 1-H), 5.33 (br s, 1 H, 1-H), 5.34 (dt, J = 17.2 Hz, J = 1.4 Hz, 1 H, Z-5-H), 5.96 (ddd, J = 17.2 Hz, J = 10.4 Hz, J = 5.6 Hz, 1 H, 4-H), 6.81-6.84 (m, 1 H, Ar-H), 6.98-7.01 (m, 2 H, Ar-H) ppm. 13C{1H}-NMR (125 MHz, CDCl3): δ = 14.83 (CH3), 55.94 (OCH3), 64.35 (OCH2), 74.75 (CH), 111.25 (CH), 112.01 (CH), 112.51 (CH2), 115.73 (CH2), 119.38 (CH), 132.03 (C), 139.19 (CH), 148.02 (C), 149.22 (C), 149.55 (C) ppm. IR (ATR): = 3435 (br m), 2934 (w), 1579 (w), 1511 (s), 1441 (w), 1249 (s), 1211 (m), 1178 (w), 1137 (m), 1025 (s), 921 (w), 810 (w), 775 (w) cm-1. MS (EI, 70 eV): m/z (%) = 234 (48) [M+], 177 (100), 149 (14), 117 (7), 77 (6). Anal. Calcd for C14H18O3 (234.29): C, 71.77; H, 7.74. Found: C, 71.44; H, 8.09.

8

2-(3-Ethoxy-4-methoxyphenyl)-1,4-pentadien-3-one ( 1c).
MnO2 (25.0 g, 287 mmol) was added portionwise to a solution of 6c (2.00 g, 8.55 mmol) in CH2Cl2 (60 mL) at ambient temperature. The progress of the reaction was monitored by TLC [product 1c: R f (SiO2, PE-EtOAc, 2:1) = 0.45]. After being stirred for 60 min at 23 °C, the reaction mixture was filtered with vacuum through SiO2 to separate MnO2, the residue was washed several times with EtOAc (total ca. 600 mL). The filtrate was concentrated under vacuum to give 1c as a yellow oil (1.47 g, 6.33 mmol, 74%) with 90-95% purity by 1H NMR. The product decomposes under ambient conditions. 1H NMR (300 MHz, CDCl3): δ = 1.46 (t, J = 7.0 Hz, 3 H, CH3), 3.88 (s, 3 H, OCH3), 4.10 (q, J = 7.0 Hz, 2 H, OCH2), 5.87 (dd, J = 10.5 Hz, J = 1.5 Hz, 1 H, E-5-H), 5.87 (s, 1 H, 1-H), 5.89 (s, 1 H, 1-H), 6.34 (dd, J = 17.4 Hz, J = 1.6 Hz, 1 H; Z-5-H), 6.73 (dd, J = 17.3 Hz, J = 10.5 Hz, 1 H, 4-H), 6.84-6.93 (m, 3 H, ArH) ppm. 13C{1H}-NMR (75 MHz, CDCl3): δ = 14.77 (CH3), 55.97 (OCH3), 64.40 (OCH2), 111.25 (CH), 112.44 (CH), 120.50 (CH), 121.93 (CH2), 129.44 (C), 130.35 (CH2), 134.45 (CH), 148.04 (C), 148.30 (C), 149.64 (C), 193.97 (C=O) ppm. IR (ATR): 2932 (br m), 2186 (w), 1671 (m), 1604 (m), 1514 (s), 1398 (w), 1255 (s), 1141 (m), 1028 (m) cm-1. MS (EI, 70 eV): m/z (%) = 232 (100) [M+], 177 (89), 149 (43), 117 (5), 89 (8), 77 (4), 55 (16). HRMS (EI, 70 eV): m/z calcd for C14H16O3: 232.1099; found: 232.1099 [M+].