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

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.

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

References and Notes

1 Baliah V. Jeyaraman R. Chandrasekaran L. Chem. Rev.  1983,  83:  379 

2a Clarke PA. Martin WHC. Hargreaves JM. Wilson C. Blake AJ. Chem. Commun.  2005,  1061 

2b Wang J.-K. Zong Y.-X. An H.-G. Xue G.-Q. Wu D.-Q. Wang Y.-S. Tetrahedron Lett.  2005,  46:  3797 

2c Ruijter E. Schültingkemper H. Wessjohann LA. J. Org. Chem.  2005,  70:  2820 

2d Kulesza A. Ebetino FH. Mishra RK. Cross-Doersen D. Mazur AW. Org. Lett.  2003,  5:  1163 

2e Petasis NA. Lu S.-P. Tetrahedron Lett.  1996,  37:  141 

2f Hatam NAR. Whiting DA. J. Chem. Soc. C  1969,  1921 

3a Faulkner S. Whitehead RC. Aarons RJ. Science of Synthesis   Vol. 14:  Thomas EJ. Thieme; Stuttgart: 2003.  p.771-786  

3b Rule NG. Detty MR. Kaeding JE. Sinicropi JA. J. Org. Chem.  1995,  60:  1665 

3c Pantaleo NS. van der Helm D. Ramarajan K. Bailey BR. Berlin KD. J. Org. Chem.  1981,  46:  4199 

3d Ried W. Bopp H. Synthesis  1978,  211 

3e Schönberg A. van Ardenne R. Chem. Ber.  1966,  99:  3316 

4a Grotjahn DB. Hoerter JM. Hubbard JL. J. Am. Chem. Soc.  2004,  126:  8866 

4b Kuroda C. Koshio H. Koito A. Sumiya H. Murase A. Hirono Y. Tetrahedron  2000,  56:  6441 

4c Kopinski RP. Pinhey JT. Aust. J. Chem.  1983,  36:  311 

4d Jones TK. Denmark SE. Helv. Chim. Acta  1983,  66:  2377 

4e Steinfels MA. Krapf HW. Riedl P. Sauer J. Dreiding AS. Helv. Chim. Acta  1972,  55:  1759 

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⁺].