Development of an O-Vinylation–Ring-Closing Metathesis Strategy to Access 3,3′-3,4-Dihydropyrans

Abstract

Dihydropyrans are common structural motifs that appear in both natural products and pharmaceuticals and are intermediates for the synthesis of tetrahydropyrans. Currently, no reports exist in the literature for the synthesis of 3,3′-differentially disubstituted-3,4-dihydro-2-pyrans. We describe an approach employing abundant esters as starting materials that allows access to these heterocyclic scaffolds through a unique O-vinylation–RCM sequence.

Key words

cyclization - heterocycles - metathesis - ring closure - aldol reaction

• References and Notes

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• 17 Example Experimental Procedure for the Preparation of 9c
  Methyl 2-(Hydroxymethyl)-2-phenylpent-4-enoate (7c) An oven-dried vial equipped with a stir bar was charged with methyl 2-phenylpent-4-enoate (5c, 700 mg, 3.68 mmol) and paraformaldehyde (365 mg, 4.05 mmol). The vial was purged with nitrogen for 15 min, then DMSO (7.36 mL, 0.05 M) was added followed by NaOMe (219 mg, 4.05 mmol) at 25 °C. The reaction was heated to 75 °C for 16 h. The reaction was then poured into HCl solution (1 M, 20 mL), extracted with EtOAc (3 × 15 mL). The combined organic extracts were concentrated under reduced pressure and purified via column chromatography (0–70% EtOAc–heptane) to provide the product (422.4 mg, 52%). The reaction was run a second time and a yield of 61% was obtained. Alternatively, similar yields could be obtained using LiHMDS as a base. An oven-dried round-bottom flask equipped with a stir bar was charged with methyl 2-phenylpent-4-enoate (5c, 700 mg, 3.68 mmol). The flask was purged with nitrogen and to this was added THF (0.5 M, 7.36 mL). The reaction was cooled to –78 °C, and LiHMDS (1 M in THF, 4.05 mmol, 4.05 mL) was added dropwise over 15 min. The reaction was aged for 15 min, then paraformaldehyde was added (365 mg, 4.05 mmol), and the reaction was warmed to 25 °C for 16 h. The reaction mixture was then poured into HCl (1 M, 15 mL), extracted with EtOAc (3 × 15 mL), dried over MgSO₄, and concentrated. The crude material was purified via column chromatography (0–60% EtOAc–heptane) to provide the product as a clear oil (407 mg, 50%). ¹H NMR (400 MHz, CDCl₃): δ = 2.16 (br s, 1 H). 2.91–2.89 (dd, J = 7.2 Hz, 1 Hz, 1 H), 3.75 (s, 3 H) 4.10–4.01 (q, J = 11.4 Hz, 2 H), 5.21–5.10 (m, 2 H), 5.82–5.71 (m, 1 H), 7.40–7.28 (m, 5 H). ¹³C NMR (101 MHz, CDCl₃): δ = 28.47, 52.19, 56.00, 66.37, 118.82, 126.70, 127.37, 128.64, 133.58, 139.64, 175.20. ESI-HRMS: m/z calcd for C₁₃H₁₆O₃ [M + H]: 243.10; found: 243.09. Methyl 2-Phenyl-2-[(vinyloxy)methyl]pent-4-enoate (8c) To a vial equipped with a stir bar was added Pd(TFA)₂ (3.15 mg, 0.00949 mmol, 1 mol%) and 4,7-diphenyl-1,10-phenanthroline (3.15 mg, 1 mol%). Butyl vinyl ether (1 mL) was added, and the reaction mixture was aged 15 min. Methyl 2-(hydroxymethyl)-2-phenylpent-4-enoate (7c, 209 mg, 0.949 mmol) was added in butyl vinyl ether (1.5 mL) followed by Et₃N (13.2 μL, 10 mol%) at 25 °C. The reaction was heated to 75 °C for 48 h and then concentrated under reduced pressure. The crude reaction mixture was purified via MPLC (0–15% EtOAc–heptane) to provide the product (139 mg, 60%) as a clear oil. ¹H NMR (400 MHz, CDCl₃): δ = 2.93–2.92 (d, J = 7.6 Hz, 2 H), 3.69 (s, 3 H), 4.01–4.00 (dd, J = 7.0, 1.8 Hz, 1 H), 4.13–4.11 (d, J = 9.4 Hz, 1 H), 4.26–4.24 (m, 2 H), 5.11–5.06 (m, 2 H), 5.59–5.52 (m, 1 H), 6.47–6.43 (dd, J = 14.4, 6.7 Hz, 1 H), 7.29–7.24 (m, 3 H), 7.36–7.34 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 37.81, 52.24, 54.05, 69.03, 86.64, 119.21, 126.32, 127.29, 128.55, 133.04, 139.55, 151.62, 173.93. ESI-HRMS: m/z calcd for C₁₅H₁₈O₃ [M + Na]: 269.12; found: 269.11. Methyl 3-Phenyl-3,4-dihydro-2H-pyran-3-carboxylate (9c) To a vial equipped with a stir bar was added methyl 2-phenyl-2-[(vinyloxy)methyl]pent-4-enoate (8c, 139 mg, 0.56 mmol) in benzene (8.06 mL, 0.07 M). The reaction mixture was sparged with nitrogen for 15 min at which point Grubbs II catalyst (24 mg, 0.028 mmol) was added. The vial was sealed, and the reaction was heated to 70 °C for 16 h. The reaction mixture was concentrated under reduced pressure and purified via column chromatography (0–50% EtOAc–heptane) to provide the product as a clear oil (88 mg, 71%). ¹H NMR (400 MHz, CDCl₃): δ = 2.66–2.38 (m, 1 H), 2.87–2.81 (m, 1 H), 3.61 (s, 3 H), 4.10–4.08 (d, J = 10.5 Hz, 1 H), 4.55–4.52 (dd, J = 10.7, 2.1 Hz, 1 H), 4.78–4.74 (ddd, J = 6.0, 4.5, 3.1 Hz, 1 H), 6.31–6.29 (dt, J = 6.1, 1.8 Hz, 1 H), 7.29–7.17 (m, 5 H). ¹³C NMR (101 MHz, CDCl₃): δ = 29.37, 46.64, 52.54, 69.82, 99.36, 125.92, 127.61, 128.79, 139.58, 143.75, 173.58. ESI-HRMS: m/z calcd for C₁₃H₁₄O₃ [M + Na]: 241.08; found: 241.08.