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CC BY-ND-NC 4.0 · Synlett 2019; 30(04): 454-458
DOI: 10.1055/s-0037-1611664
DOI: 10.1055/s-0037-1611664
letter
Palladium(II)-Catalyzed C(sp3)–H Activation of N,O-Ketals towards a Method for the β-Functionalization of Ketones
We acknowledge the EPRSC (EP/I00548X/1 & EP/N031792/1) for funding to (D.K.H.H., J.C. and M.J.G.) for funding.Further Information
Publication History
Received: 23 November 2018
Accepted after revision: 07 January 2019
Publication Date:
05 February 2019 (online)
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.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0037-1611664.
- Supporting Information
- CIF File
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References and Notes
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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%). Rf (ethyl acetate in petroleum ether, 25%): 0.23. IR (film): νmax = 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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See also:
For β-functionalization of ketones, see:
For representative examples, see:
For an example of sp3 C–H functionalization at the β-position of an oxime-masked ketone, see:
For a seminal example of a palladium-catalysed β-carbonylation of amides, see:
For examples of C(sp3)–H carbonylation of alklyamine derivatives, see:
We recently reported a distinct pathway for C–H carbonylation, which proceeds via a different mechanism to that operating here, see:
For representative examples, see: