A Cascade Suzuki–Miyaura/Diels–Alder Protocol: Exploring the Bifunctional Utility of Vinyl Bpin

Published as part of the Special Section 10th EuCheMS Organic Division Young Investigator Workshop

Abstract

Cascade reactions are an important strategy in reaction ­design, allowing streamlining of chemical synthesis. Here we report a cascade Suzuki–Miyaura/Diels–Alder reaction, employing vinyl Bpin as a bifunctional reagent in two distinct roles: as an organoboron nucleo­phile for cross-coupling and as a Diels–Alder dienophile. Merging these two reactions enables a rapid and operationally simple synthesis of functionalized carbocycles in good yield. The effect of the organoboron subtype on Diels–Alder regioselectivity was investigated and postsynthetic modifications were carried out on a model substrate. The potential for a complementary Heck/Diels–Alder process was also assessed.

Key words

Bpin - cascade - cross-coupling - Diels–Alder - Suzuki–Miyaura

• References and Notes

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• 29 General Experimental Procedure for the Tandem Suzuki–Miyaura/Diels–Alder Reaction Pd(OAc)₂(4 mol%), SPhos (8 mol%), vinyl (pseudo)halide (1 equiv), vinyl Bpin (5–7 equiv), and K₃PO₄(3 equiv) were weighed into an oven-dried microwave vial. The reaction vessel was then capped and purged with N₂ before the addition of 1,4-dioxane (0.125 M) and H₂O (5 equiv). The reaction mixture was heated at 50 °C with stirring. After 1 h the temperature was increased to 150 °C, and the reaction mixture was stirred for 23 h. The reaction mixture was allowed to cool to room temperature, vented, and de-capped. The reaction mixture was diluted with EtOAc (20 mL) and passed through a layer of Celite, eluting with EtOAc. The filtrate was concentrated under reduced pressure. THF (0.25 M) was added to the crude residue, and the solution was cooled to 0 °C before the addition of H₂O₂ (30% w/v, 20 equiv) and 2 M NaOH (4 equiv) sequentially. After 5 min the reaction mixture was allowed to warm to room temperature and was stirred for 1 h. The mixture was quenched with Na₂S₂O₃ at 0 °C until effervescence ceases and diluted with sat. aq. NH₄Cl. The organics were extracted with EtOAc, washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to afford the desired products. Compound 4a Prepared according to General Procedure using 6-methoxy-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate (77.0 mg, 0.25 mmol, 1 equiv), Pd(OAc)₂ (2.2 mg, 0.01 mmol, 4 mol%), SPhos (8.2 mg, 0.02 mmol, 8 mol%), vinyl Bpin (192 mg, 1.25 mmol, 5 equiv), K₃PO₄ (159 mg, 0.75 mmol, 3 equiv), 1,4-dioxane (2 mL, 0.125 M) and H₂O (22.5 μL, 1.25 mmol, 5 equiv), then aqueous H₂O₂ (30% w/v, 500 μL, 5 mmol, 20 equiv), 2 M NaOH (500 μL, 1 mmol, 4 equiv), and THF (1 mL). After the reaction was complete, the reaction mixture was subjected to the purification method outlined in the General Procedure (silica gel, 0–60% EtOAc in PE 40–60°) to afford the desired mixture of products as a yellow oil (41.3 mg, 72%, 3:1 r.r.). The major regioisomer was separated by column chromatography (ca. 95% purity). Data for the Major Regioisomer IR (film): ν_max = 3364 (br), 2914, 2847, 2830, 1605, 1493, 1456, 1279, 1253, 1231, 1034 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.51 (dd, J = 8.8, 6.0 Hz, 1 H), 6.71 (dd, J = 8.8, 2.5 Hz, 1 H), 6.60 (d, J = 2.6 Hz, 1 H), 6.07–6.02 (m, 1 H), 4.04–3.95 (m, 1 H), 3.79 (s, 3 H), 2.95–2.75 (m, 2 H), 2.61–2.54 (m, 1 H), 2.52–2.39 (m, 1 H), 2.23–2.10 (m, 2 H), 2.02–1.94 (m, 1 H), 1.54–1.49 (m, 1 H), 1.46–1.36 (m, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 158.7, 138.0, 135.7, 127.1, 125.1, 115.5, 113.4, 112.9, 67.7, 55.4, 40.7, 36.7, 36.1, 31.2, 30.5. HRMS: m/z calcd for [M + H]⁺ (C₁₅H₁₉O₂): 231.1380; found: 231.1378.