Efficient C(sp³)–H Bond Arylation of Tetrahydroisoquinolines with Knochel-Type Arylzinc Reagents under Oxidative Conditions

Abstract

A novel C(sp³)–H bond arylation of tetrahydroisoquinoline (THIQ) derivatives with Knochel-type arylzinc reagents has been developed. In the presence of MgCl₂, arylzinc reagents readily reacted with THIQ derivatives under oxidative conditions, affording a wide range of potentially biologically active compounds in good yields. Moreover, the developed method can tolerate a variety of sensitive functional groups such as an ester group.

Key words

oxidative conditions - arylation - tetrahydroisoquinolines - arylzinc reagents - esters

• References and Notes

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• 15 General Procedure for the Reaction of 1,2,3,4-Tetrahydroisoquinoline Derivatives with Aryl Zinc Reagents A clean Schlenk tube was dried for 5 min at 380 °C (heat gun) under high vacuum (1 mbar). After cooling to r.t., the tube was evacuated and backfilled with nitrogen three times. To the mixture of PIFA (0.5 mmol) and 2-​methyltetrahydrofura​n (2.5 mL) was added the starting material N-substituted 1,2,3,4-tetrahydroisoquinoline (0.5 mmol). The reaction mixture was stirred for 1 h. The corresponding aromatic Zn reagent was added dropwise at r.t. After 12–16 h, water (20 mL) was then added to the reaction mixture. The organic layer was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine and dried over MgSO₄. The solvent was removed by rotary evaporation. Purification by flash column chromatography on silica gel using PE–EtOAc as an eluent gave the expected products. Compound 3a: white solid; yield 78% (112 mg); mp 63.1–65.0 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.25–7.04 (m, 11 H), 6.77 (d, J = 8.1 Hz, 2 H), 6.67 (t, J = 7.3 Hz, 1 H), 5.76 (s, 1 H), 3.65 (ddd, J = 11.2, 5.5, 5.3 Hz, 1 H), 3.43 (ddd, J = 11.2, 8.7, 5.3 Hz, 1 H), 2.93–2.78 (m, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 149.5, 143.1, 137.9, 135.7, 129.1, 128.2, 128.1, 127.8, 127.3, 127.0, 126.8, 126.1, 117.4, 113.8, 62.8, 43.8, 28.0 ppm. IR (diamond-ATR, neat): 3019.4, 2915.6, 1591.9, 1504.0, 1324.5, 745.8. HRMS: m/z calcd [C₂₁H₁₉N + H]: 286.1596; found: 286.1590 [M⁺ + H].