Palladium(II)-Catalyzed C(sp³)–H Activation of N,O-Ketals towards a Method for the β-Functionalization of Ketones

Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue

Abstract

A method for the formal β-functionalization of aliphatic ketones via a palladium-catalyzed sp³ C–H activation pathway is reported. An N,O-ketal directs an aliphatic C–H carbonylation to form γ-lactams which upon hydrolysis generate γ-keto carboxylic acids. This C–C bond-forming reaction is tolerant of a range of functional groups, enabling the synthesis of a range of synthetically important building blocks. Furthermore, the concepts underlying this transformation have also enabled the development of a related C–H alkenylation process to highly functionalised heterocycles.

Key words

oxazolidine - palladium - carbonylation - lactam - ketone - C–H activation

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• 13 General Experimental Procedure for a Representative C–H Carbonylation to 5l To a flame-dried round-bottom flask, equipped with a stir bar, was charged the oxazolidine (0.20 mmol), palladium(II) acetate (0.02 mmol, 0.1 equiv), silver(I) acetate (0.40 mmol, 2.0 equiv), and toluene (0.05 M). The reaction flask was evacuated and back-filled with carbon monoxide (3 times, balloon). A balloon filled with carbon monoxide was fitted, and then the flask was placed in a pre-heated oil bath at 120 °C and heated at this temperature for 16 h under vigorous stirring. The reaction mixture was then cooled to room temperature and filtered through a small pad of Celite^®. The filtrate was concentrated in vacuo and purified by flash chromatography (eluting with 0–20% ethyl acetate in petroleum ether) provided the desired lactam 5l (54 mg, 79%). R_f (ethyl acetate in petroleum ether, 25%): 0.23. IR (film): ν_max = 2976, 2952, 1773, 1704, 1466, 1396, 1366, 1273, 1124, 1058, 1002, 882, 721, 667 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.85 (dd, J = 5.5, 3.0 Hz, 2 H), 7.73 (dd, J = 5.5, 3.0 Hz, 2 H), 4.00 (d, J = 9.2 Hz, 1 H), 3.94 (d, J = 8.9 Hz, 1 H), 3.81–3.64 (m, 2 H), 2.63 (ddd, J = 17.0, 12.3, 8.0 Hz, 1 H), 2.56–2.40 (m, 1 H), 2.20 (ddd, J = 12.3, 8.0, 0.8 Hz, 1 H), 2.02–1.66 (m, 5 H), 1.55 (s, 3 H), 1.40 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 173.5, 168.3, 134.1, 132.0, 123.3, 102.6, 81.6, 58.1, 37.9, 35.4, 33.0, 32.5, 26.7, 24.5, 23.5. HRMS (ESI): m/z calcd for C₁₉H₂₃N₂O₄: 343.1652; found [M + H]⁺: 343.1656.
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