Tuning Reactivity and Site Selectivity of Simple Arenes in C–H Activation: Ortho-Arylation of Anisoles via Arene–Metal π-Complexation

Current approaches to achieve site selectivity in the C–H activation of arenes involve the use of directing groups or highly electron-poor arenes. In contrast, simple arenes, such as anisole, are characterized by poor reactivity and selectivity. We report that π-complexation to a Cr(CO)3 unit enhances the reactivity of anisoles providing an unprecedented ortho-selective arylation. This mild methodology can be used for the late stage functionalization of bioactive compounds containing the anisole motif, allowing the construction of novel organic scaffolds with few synthetic steps.


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Determination of the KIE.
After removal of the solvents in vacuo, yields were determined by 1 H NMR analysis of the crude mixture using an internal standard (1,3-dinitrobenzene, 0.100 mmol). Two runs were performed.
Integration in the 1 H NMR was performed between protons A (3p-Da) and A' (3aq) and between protons C (3p-Da) and C' (3aq) (see spectrum below).
Recrystallization from cold hexane gave the title product 1f as a yellow solid in 80% yield (1.142 g, 3.99 mmol). 1
Recrystallization from cold hexane gave the title product 1p as a yellow solid in 77% yield (1.148 g, 3.85 mmol). 1
Recrystallization from cold hexane gave the title product 1q as a yellow solid in 80% yield (1.238 g, 3.96 mmol). 1

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An oven-dried microwave 10 mL glass vial was charged with PdCl 2 (PPh 3 ) 2 (3.5 mg, 0.006 mmol, 3 mol %), placed under vacuum and refilled with an Ar balloon. Then THF (1 mL), LiHMDS (1.0 M in THF/ethylbenzene, 0.32 mmol, 1.6 equiv) and finally 4-bromoanisole (60 mg, 0.32 mmol, 1.6 equiv) were added. The resulting mixture was stirred for 10 min and was then transferred by syringe to an oven-dried microwave 10 mL glass vial under Ar, containing complex 6 (mixture of facial diastereoisomers, 104 mg, 0.2 mmol, 1.0 equiv). The orange suspension was stirred for 16 h at 60 o C and then quenched with AcOH (1 mL). MnO 2 (90 mg, 0.6 mmol, 3 equiv) was added in small portions and the black suspension was vigorously stirred for 30 min. The suspension was then loaded on a short silica plug (2 x 4 cm) and eluted with Et 2 O (30 mL) before concentrating in vacuo.
Analysis on the crude 1 H NMR showed the product as a mixture of diastereoisomers 8a: 8b in a 3:1 ratio (42% yield for 8a and 15% yield for 8b). Purification via flash chromatography (gradient hexane/Et 2 O 98:2 to 95:5) afforded a pure sample of the main diastereoisomer 8a in order to assign its absolute configuration. 1 H NMR, 13 C NMR, HSQC and NOESY analysis allowed the tentative assignment of the benzylic configuration for compound 8a as shown below.       3-Methylanisole tricarbonyl chromium (1i).