Molybdenum-Catalyzed Directed Activation of Aryl Chlorides and Fluorides

Abstract

A low-valent molybdenum species generated by the reduction of a molybdenum precursor with phenylmagnesium bromide catalytically cleaves a C–Cl or C–F bond in an aromatic ketone under mild conditions, followed by cyclization to produce a hydroxyphthalan (1,3-dihydro-2-benzofuran-1-ol) derivative.

Key words

molybdenum catalysis - chloroarenes - fluoroarenes - phthalans - benzofuranols - cyclization

Publication History

Received: 08 September 2023

Accepted after revision: 09 October 2023

Accepted Manuscript online:
09 October 2023

Article published online:
06 November 2023

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• 17 Hydroxyphthalans 2a–e; General Procedure MoO₂Cl₂(dtbpy) (4.6 mg, 0.010 mmol, 2 mol%) and the appropriate 2-halobenzophenone 1 (0.50 mmol) were added to a dry Schlenk tube equipped with a Teflon-coated magnetic stirrer bar under a N₂ atmosphere. The reaction vessel was fitted with a rubber septum and charged with THF (0.50 mL) from a syringe. The mixture was stirred until a clear light-pinkish solution formed, then cooled to 0 °C (ice bath). Next, a 0.81 mol/L solution of PhMgBr in THF (0.74 mL, 1.2 equiv) was added dropwise by using a syringe pump (addition rate: 0.5 mL/min) at 0 °C under nitrogen. Upon addition, the color of the reaction mixture turned deep violet. After completion of the addition, the septum was removed, the Schlenk tube was sealed under N₂ with a screw cap, and the mixture was stirred at rt for 16 h. Tridecane, as an internal standard for GC, and THF (~0.5 mL) were added, and the resulting mixture was stirred vigorously for 5 min. The reaction was then quenched by the addition of a sat. aq NH₄Cl (~1 mL) and 30% aq potassium sodium tartrate (~1 mL) with continuous stirring for 5 min. An aliquot was taken directly from the upper organic layer and passed through a plug of Florisil with EtOAc. The resulting solution was analyzed by GC to determine the yield. The aliquot for GC measurement was then returned to the reaction mixture, which was extracted with EtOAc. The combined organic phase was passed through a plug of Florisil, dried (Na₂SO₄), and then concentrated under reduced pressure. The resulting mixture was analyzed by ¹H or ¹⁹F NMR to estimate the yield. The product was finally isolated by column chromatography on neutral alumina. 3-(2-Chlorophenyl)-1,3-diphenyl-1,3-dihydro-2-benzofuran-1-ol (2a) Two batches were prepared in by the general procedure from 1a [213.6 mg, (0.98 mmol) and 211.6 mg (0.97 mmol)]. During workup, the two batches were combined, and the yield (89%) was determined by GC analysis. Purification by column chromatography (neutral alumina; 10% EtOAc–hexane) gave a colorless solid; yield: 323.9 mg (83%, 0.81 mmol). Minor impurities were removed by further purification by GPC (CHCl₃). The diastereoselectivity of the product was 1.1:1. ¹H NMR (500 MHz, CDCl₃): δ = 7.65–7.59 (m, 3 H), 7.55 (dt, J = 7.7, 0.8 Hz, 1 H), 7.53–7.49 (m, 2 H), 7.48–7.27 (m, 27 H), 7.24–7.22 (m, 3 H), 7.15 (td, J = 7.6, 1.3 Hz, 1 H), 3.52 (s, 1 H), 3.07 (s, 1 H). ¹³C{1 H} NMR (126 MHz, CDCl₃): δ = 145.7, 143.8, 143.5, 143.0, 142.85, 142.80, 142.5, 142.3, 142.0, 140.64, 134.9, 133.9, 132.2, 132.1, 129.7, 129.5, 129.4, 129.27, 129.25, 129.0, 128.9, 128.6, 128.5, 128.4, 128.35, 128.31, 127.4, 127.2, 126.6, 126.5, 126.3, 126.08, 126.04, 125.7, 125.0, 124.7, 123.78, 123.66, 108.5, 107.8, 93.90, 92.6. HRMS (APCI⁺): m/z [M – OH]⁺ calcd for C₂₆H₁₈ClO: 381.1041; found: 381.1020.