Regioselective Pd(0)-Catalyzed Hiyama Cross-Coupling Reactions at Dihalo-Substituted Heterocycles

Abstract

The regioselectivity of the Hiyama cross-coupling reaction at various dihalo-substituted heterocycles has been studied. Methyl 2,3-dibromo-5-furancarboxylate and n-octyltrifluorosilane were employed to find optimum reaction conditions [CsF; Pd₂dba₃/P(2-furyl)₃ as catalyst, 80-150 ˚C in toluene or benzene] for the desired transformation. Subsequent experiments with the title compounds and with different primary alkyltrifluorosilanes illustrate the generality of this regiochemical process.

catalysis - cross-coupling - heterocycles - palladium - ­regioselectivity - silane

References and Notes

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Activating reagents were screened in the reaction of substrate 3 with n-octyltrifluorosilane in THF at 100 ˚C, employing Pd₂dba₃/P(2-furyl)₃ as the catalyst. Almost no conversion was achieved with the given activating reagents, while anhydrous CsF delivered a significant conversion after 18 h (26% 4a, 34% 5).

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Typical procedure: A flame-dried Schlenk tube was charged with Pd₂dba₃ (9.2 mg, 0.01 mmol), P(2-furyl)₃ (18.6 mg, 0.08 mmol) and benzene (2 mL) under an atmosphere of argon. The solution was stirred at r.t. for 15 min then n-octyltrifluorosilane (74 µL, 0.40 mmol) and CsF (122 mg, 0.80 mmol, which was stored and weighed in a glove box) were added, followed by dibromofuran 3 (56.8 mg, 0.20 mmol). The tube was closed with a Teflon screw plug, situated behind an explosion shield (CAUTION!), heated to 80 ˚C and stirred for 15 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (5 mL) and H₂O (5 mL). After separation of the layers, the aqueous phase was extracted with EtOAc (3 × 5 mL) and the combined organic layers were dried over Na₂SO₄ and concentrated in vacuo. Purification of the crude product by flash column chromatography (silica gel; pentane-Et₂O, 99:1) yielded compound 4a (45.6 mg, 0.14 mmol, 72%) as a colorless liquid. ^¹H NMR (500 MHz, CDCl₃): δ = 0.88 (t, ^³ J = 7.0 Hz, 3 H), 1.20-1.36 (m, 10 H), 1.68 (quint, ^³ J = 7.5 Hz, 2 H), 2.70 (t, ^³ J = 7.5 Hz, 2 H), 3.88 (s, 3 H), 7.11 (s, 1 H); ^¹³C NMR (90.6 MHz, CDCl₃): δ = 14.1, 22.6, 26.5, 27.5, 29.0, 29.1, 29.1, 31.8, 52.0, 97.9, 121.2, 142.6, 158.3, 158.5; HRMS: m/z calcd for C₁₄H₂₁BrO₃: 316.0674; found: 316.0673.

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