Highly Regioselective Heck Coupling Reactions of Aryl Halides and Dihydropyran in the Presence of an NHC-Pyridine Ligand

Abstract

The Heck coupling reactions of aryl halides and 3,4-dihydro-2H-pyran facilitated the regioselective synthesis of arylated cyclic enol ethers. Good yields were obtained using 5 mol% of an NHC-ligand-Pd-catalyst complex in the presence of K₂CO₃ in DMF at 100 ˚C. The use of this catalytic system broadens the substrate scope and improves the selectivity for this cross-coupling process.

Key words

Heck reaction - N-heterocyclic carbine - pyridine ligand - palladium - cyclic enol ether

References and Notes

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8

When using a combination of Pd(OAc)₂ and 1,10-phenan-throline or 2,9-dimethylphenanthroline, the catalyst and ligand were premixed in DMF at r.t. for 30 min before the addition of substrates.

10

General Procedure for the Synthesis of Palladium(II) Complex 5
To a solution of 4 (0.6 mmol) in anhyd CH₂Cl₂ (20 mL) was added Ag₂O (0.3 mmol), and the reaction mixture was stirred at r.t. for 4 h. The reaction mixture was then gravity filtered and dried under nitrogen to obtain a silver complex as a white solid. The silver complex (0.4 mmol) was then suspended in a solution of MeCN (20 mL) in a foil-covered round-bottom flask. To the reaction mixture was then added Pd(OAc)₂ (0.4 mmol), and the reaction mixture was stirred at r.t. for 24 h. The reaction mixture was then gravity filtered, and the filtrate was concentrated in vacuo to obtain 5 (100 mg, 38% over two steps) as an orange solid. ^¹H NMR (250 MHz, CDCl₃): δ = 8.98-9.02 (m, 1 H), 7.82-7.90 (m, 1 H), 7.59 (d, J = 10.0 Hz, 1 H), 7.49-7.55 (m, 1 H), 7.32-7.45 (m, 4 H), 5.96 (br s, 2 H), 4.06 (s, 3 H), 2.02 (s, 6 H). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 178.1, 153.5, 153.4, 139.8, 134.5, 132.7, 125.0, 124.9, 124.4, 124.1, 110.9, 110.4, 51.40, 33.40, 22.60.

11

General Procedure for the Preparation of Substituted Dihydropyrans
An oven-dried resealable Schlenk flask was evacuated and filled with argon, then were added 4-iodoanisole (117 mg, 0.5 mmol), 3,4-dihydro-2H-pyran (0.55 mL, 6 mmol), K₂CO₃ (104 mg, 0.75 mmol), DMF (1 mL), palladium complex 5 (22 mg, 0.05 mmol). The reaction mixture was stirred at 100 ˚C. After 48 h the solution was then allowed to cool to r.t. EtOAc (20 mL) was added to the reaction mixture, and then the reaction mixture was washed with H₂O (3 × 10 mL). The organic layer was dried over Na₂SO₄. After filtration, solvent was evaporated and purified by column chromatography (hexanes-EtOAc, 19:1), to afford 2-(4-methoxy-phenyl)-3,4-dihydro-2H-pyran (76 mg, 80%) as a light orange oil.
Compound 11a: yellow oil (62 mg, 71%). ^¹H NMR (250 MHz, CDCl₃): δ = 7.43 (m, 1 H), 7.17-7.26 (m, 3 H), 6.56 (d, J = 7.5 Hz, 1 H), 5.00 (dd, J = 10.0 Hz, 1 H), 4.80 (m,
1 H), 2.35 (s, 3 H), 2.20-2.32 (m, 2 H), 1.84-2.12 (m, 2 H). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 144.7, 140.0, 134.6, 130.4, 127.5, 126.3, 125.6, 100.6, 74.37, 29.29, 20.93, 18.95. GC-MS: m/z calcd for C₁₂H₁₄O: 174.1; found: 173.9. Anal. Calcd for C₁₂H₁₄O: C, 82.72; H, 8.10. Found: C, 82.56; H, 8.12.
Compound 11b: yellow oil (65 mg, 75%). ^¹H NMR (250 MHz, CDCl₃): δ: = 7.45-7.48 (m, 1 H), 7.38-7.42 (m, 1 H), 7.31-7.35 (m, 1 H), 7.17-7.27 (m, 1 H), 6.61 (d, J = 7.5 Hz, 1 H), 4.87-4.89 (m, 1 H), 4.83-4.87 (m, 1 H), 2.44 (s, 3 H), 2.26-2.36 (m, 2 H), 1.96-2.16 (m, 2 H). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 144.1, 137.9, 128.5, 127.9, 126.5, 124.2, 122.9, 100.5, 77.06, 30.22, 21.35, 20.29. GC-MS m/z calcd for C₁₂H₁₄O: 174.1; found: 174.0. Anal. Calcd for C₁₂H₁₄O: C, 82.72; H, 8.10. Found: C, 82.69; H, 8.11
Compound 11c: yellow oil (54 mg, 62%). ^¹H NMR (250 MHz, CDCl₃): δ = 7.48 (d, J = 10.0 Hz, 2 H), 7.22 (d, J = 10.0 Hz, 2 H), 6.53 (d, J = 7.5 Hz, 1 H), 4.82 (m, 1 H), 4.77 (m, 1 H), 2.35 (s, 3 H), 2.13-2.25 (m, 2 H), 1.90-2.08 (m, 2 H). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 140.1, 137.0, 129.0, 128.9, 126.8, 125.9, 92.47, 77.50, 32.67, 22.49, 21.10. GC-MS: m/z calcd: 174.1; found: 174.0.
Compound 12a: yellow oil (59 mg, 62%). ^¹H NMR (250 MHz, CDCl₃): δ = 7.43 (d, J = 10.0 Hz, 1 H), 7.22-7.35 (m, 1 H), 6.98 (t, J = 7.5 Hz, 1 H), 6.88 (d, J = 7.5 Hz, 1 H), 6.66 (d, J = 7.5 Hz, 1 H), 5.21 (d, J = 7.5 Hz, 1 H), 4.74-4.80 (m, 1 H), 3.84 (s, 3 H), 1.94-2.30 (m, 2 H), 1.72-1.88 (m, 2 H). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 158.1, 144.5, 128.1, 128.0, 126.4, 122.5, 111.0, 100.6, 72.47, 56.26, 29.58, 20.50. GC-MS: m/z calcd for C₁₂H₁₄O₂: 190.1; found: 190.0. Anal. Calcd for C₁₂H₁₄O₂: C, 75.76; H, 7.42. Found: C, 75.71; H, 7.48.
Compound 13: yellow oil (17 mg, 15%). ^¹H NMR (250 MHz, CDCl₃): δ = 7.62 (d, J = 10.0 Hz, 2 H), 7.47 (d, J = 10.0 Hz, 2 H), 6.54 (d, J = 7.5 Hz, 1 H), 4.90 (d, J = 7.5 Hz, 1 H), 4.75-4.84 (m, 1 H), 1.65-2.15 (m, 2 H), 1.55-1.64 (m, 2 H). GC-MS: m/z calcd: 230.1; found: 229.7.
Compound 16: orange oil (52 mg, 55%). ^¹H NMR (250 MHz, CDCl₃): δ = 6.98-7.11 (m, 3 H), 6.51 (d, J = 7.5 Hz, 1 H), 5.20 (d, J = 10.0 Hz, 1 H), 4.76-4.82 (m, 1 H), 2.39 (s, 6 H), 2.02-2.30 (m, 2 H), 1.80-1.94 (m, 2 H). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 143.9, 137.1, 136.0, 129.2, 127.2, 100.2, 75.11, 26.03, 20.80, 20.51. GC-MS: m/z calcd for C₁₃H₁₆O: 188.1; found: 188.0. Anal. Calcd for C₁₃H₁₆O: C, 82.94; H, 8.57. Found: C, 82.89; H, 8.59.
Compound 17: a yellow oil (49 mg, 61%). ^¹H NMR (250 MHz, CDCl₃): δ = 8.61 (s, 1 H), 8.53-8.57 (m, 1 H), 7.67-7.73 (m, 1 H), 7.27-7.33 (m, 1 H), 6.53 (d, J = 7.5 Hz, 1 H), 4.88 (d, J = 10.0 Hz, 1 H), 4.78-4.84 (m, 1 H), 2.18-2.30 (m, 2 H), 1.88-2.14 (m, 2 H). ^¹³C NMR (62.5 MHz, CDCl₃): δ = 149.1, 147.8, 143.9, 133.6, 123.4, 101.0, 74.82, 30.14, 20.02. GC-MS: m/z calcd for C₁₀H₁₁NO: 161.1; found: 161.0. Anal. Calcd for C₁₀H₁₁NO: C, 74.51; H, 6.88; N, 8.69. Found: C, 74.39; H, 6.91; N, 8.61.