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

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

References and Notes

• For reviews, see:
• 1a Fukuyama T. Tokuyama H. Aldrichimica Acta  2004,  37:  87 
• 1b Prokopcová H. Kappe CO. Angew. Chem. Int. Ed.  2009,  48:  2276 
• 2 Fukuyama T. Kin S.-C. Li L. J. Am. Chem. Soc.  1990,  112:  7050 
• 3a Tokuyama H. Yokoshima S. Yamashita T. Fukuyama T. Tetrahedron Lett.  1998,  39:  3189 
• 3b Tokuyama H. Yokoshima S. Yamashita T. Lin S.-C. Li L. Fukuyama T. J. Braz. Chem. Soc.  1998,  9:  381 
• 4 Tokuyama H. Miyazaki T. Yokoshima S. Fukuyama T. Synlett  2003,  1512 
• 5a Wittenberg R. Srogl J. Egi M. Liebeskind LS. Org. Lett.  2003,  5:  3033 
• 5b Li H. Yang H. Liebeskind LS. Org. Lett.  2008,  10:  4375 
• 6a Liebeskind LS. Srogl J. J. Am. Chem. Soc.  2000,  122:  11260 
• 6b Savarin C. Srogl J. Liebeskind LS. Org. Lett.  2000,  2:  3229 
• For example, see:
• 7a Danishefsky S. Kerwin JF. Kobayashi S. J. Am. Chem. Soc.  1982,  104:  358 
• 7b Keck GE. Li X.-Y. Krichnamurthy D. J. Org. Chem.  1995,  60:  5998 
• 8a Reiter M. Ropp S. Gouverneur V. Org. Lett.  2004,  6:  91 
• 8b Reiter M. Turner H. Mills-Webb R. Gouverneur V. J. Org. Chem.  2005,  70:  8478 
• For example, see:
• 9a Wang C. Forsyth CJ. Org. Lett.  2006,  8:  2997 
• 9b Nicolaou KC. Frederick MO. Burtoloso ACB. Denton RM. Rivas F. Cole KP. Aversa RJ. Gibe R. Umezawa T. Suzuki T. J. Am. Chem. Soc.  2008,  130:  7466 
• 9c Schuler M. Silva F. Bobbio C. Tessier A. Gouverneur V. Angew. Chem. Int. Ed.  2008,  47:  7927 

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.