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Synlett 2010(8): 1239-1242  
DOI: 10.1055/s-0029-1219794
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

An Efficient Synthesis of 2,6-Disubstituted 2,3-Dihydro-4H-pyran-4-ones via Sonogashira Coupling of p-Toluenethiol Esters

Haruhiko Fuwa*, Seiji Matsukida, Makoto Sasaki
Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan
Fax: +81(22)7178896; e-Mail: hfuwa@bios.tohoku.ac.jp;
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Publication History

Received 15 February 2010
Publication Date:
23 March 2010 (online)

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Abstract

An efficient strategy for the synthesis of 2,6-disubstituted 2,3-dihydro-4H-pyran-4-ones has been developed, which relied on Sonogashira coupling of alkynes and p-toluenethiol esters and AgOTf-promoted 6-endo-dig cyclization of the derived β-hydroxy ynones.

Key words

palladium - cross-coupling - cyclization - heterocycles - dihydropyrans

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10

Typical Procedure for Sonogashira Coupling of p -Toluenethiol Esters and Terminal Alkynes (Table 2, Entry 1)
To a solution of Pd2(dba)3˙CHCl3 (13.2 mg, 0.0128 mmol), CuI (82.7 mg, 0.434 mmol), and (2-furyl)3P (23.7 mg, 0.102 mmol) in degassed DMF (1.1 mL) was added a solution of 1b (118.7 mg, 0.2555 mmol) in degassed DMF (1.1 mL), 1-hexyne (0.059 mL, 0.51 mmol), and Et3N (0.430 mL). The resultant mixture was stirred at 50 ˚C for 4.4 h. After being cooled to r.t., the reaction mixture was diluted with H2O and extracted with Et2O. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (5-10% EtOAc-hexanes)
gave ynone 10 (86.7 mg, 80%) as a yellow oil.
Spectroscopic Data for Ynone 10 IR (film): 2930, 2210, 1670, 1513, 1455, 1247, 1095, 698 cm-¹. ¹H NMR (500 MHz, CDCl3): δ = 7.32 -7.26 (m, 5 H), 7.21 (d, J = 8.0 Hz, 2 H), 6.83 (d, J = 8.5 Hz, 2 H), 4.47-4.37 (m, 4 H), 4.00 (m, 1 H), 3.77 (s, 3 H), 3.44 (t, J = 5.0 Hz, 2 H), 2.86 (dd, J = 7.5, 7.0 Hz, 1 H), 2.63 (dd, J = 5.0, 4.5 Hz, 1 H), 2.36-2.29 (m, 2 H), 1.74-1.60 (m, 4 H), 1.58-1.50 (m, 2 H), 1.49-1.36 (m, 2 H), 0.89 (t, J = 7.5 Hz, 3 H). ¹³C NMR (125 MHz, CDCl3): δ = 186.1, 159.1, 138.4, 130.4, 129.3 (2 C), 128.3 (2 C), 127.5 (2 C), 127.4, 113.6 (2 C), 94.9, 81.2, 74.7, 72.8, 71.1, 70.1, 55.2, 50.6, 31.0, 29.6, 25.4, 21.9, 18.6, 13.4. ESI-HRMS: m/z calcd for C27H34NaO4 [M + Na]+: 445.2349; found: 445.2365.

11

Typical Procedure for Deprotection and AgOTf-Promoted 6- endo - dig Cyclization of β-Alkoxy Ynone (Table 3, Entry 1) To a solution of ynone 10 (79.4 mg, 0.188 mmol) in CH2Cl2-pH 7 buffer (10:1, v/v, 1.9 mL) cooled to 0 ˚C was added DDQ (48.4 mg, 0.207 mmol), and the resultant mixture was stirred at r.t. for 1 h. The reaction was quenched with sat. aq NaHCO3 solution. The whole mixture was filtered through a pad of Celite, and the filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (10-30% EtOAc-hexanes) gave a β-hydroxy ynone (48.5 mg, 85%) as a yellow oil.
Spectroscopic Data for β-Hydroxy Ynone
IR (film): 3427, 2930, 2862, 2210, 1669, 1455, 1362, 1160, 1097 cm-¹. ¹H NMR (500 MHz, CDCl3): δ = 7.33-7.25 (m, 5 H), 4.49 (s, 2 H), 4.12 (m, 1 H), 3.49 (t, J = 6.5 Hz, 2 H), 3.06 (br, 1 H), 2.69 (d, J = 6.0 Hz, 2 H), 2.35 (t, J = 7.5 Hz, 2 H), 1.79-1.67 (m, 2 H), 1.63-1.49 (m, 4 H), 1.45-1.37 (m, 2 H), 0.90 (t, J = 7.5 Hz, 3 H). ¹³C NMR (125 MHz, CDCl3): δ = 187.5, 138.2, 128.4 ( 2 C), 127.6 (2 C), 127.5, 95.5, 81.0, 72.9, 70.1, 67.3, 52.3, 33.5, 29.6, 25.9, 21.9, 18.6, 13.4. ESI-HRMS: m/z calcd for C19H26NaO3 [M + Na]+: 325.1774; found: 325.1770.
To a solution of the above β-hydroxy ynone (38.0 mg, 0.126 mmol) in CH2Cl2 (12.6 mL) was added AgOTf (35.5 mg, 0.138 mmol), and the resultant mixture was stirred at r.t. for 3.2 h under exclusion of light. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (30% EtOAc-hexanes) gave 2,3-dihydro-4H-pyran-4-one 17 (36.5 mg, 96%) as a yellow oil.
Spectroscopic Data for 2,3-Dihydro-4 H -pyran-4-one 17 IR (film): 2955, 1666, 1604, 1398, 1099, 737 cm-¹. ¹H NMR (500 MHz, CDCl3): δ = 7.35-7.26 (m, 5 H), 5.29 (s, 1 H), 4.49 (s, 2 H), 4.31 (m, 1 H), 3.50 (t, J = 5.0 Hz, 2 H), 2.43-2.30 (m, 2 H), 2.25-2.15 (m, 2 H), 1.89-1.68 (m, 4 H), 1.53-1.46 (m, 2 H), 1.35-1.28 (m, 2 H), 0.89 (t, J = 7.5 Hz, 3 H). ¹³C NMR (125 MHz, CDCl3): δ = 193.4, 177.9, 138.33, 128.4 (2 C), 127.6 (2 C), 104.1, 104.0, 78.9, 73.0, 69.6, 41.0, 34.5, 31.3, 28.4, 25.3, 22.1, 13.7. ESI-HRMS: m/z calcd for C19H27O3 [M + H]+: 303.1955; found: 303.1965.