Palladium/N-heterocyclic carbene catalysed regio and diastereoselective reaction of ketones with allyl reagents via inner-sphere mechanism

Abstract

The palladium-catalysed allylic substitution reaction is one of the most important reactions in transition-metal catalysis and has been well-studied in the past decades. Most of the reactions proceed through an outer-sphere mechanism, affording linear products when monosubstituted allyl reagents are used. Here, we report an efficient Palladium-catalysed protocol for reactions of β-substituted ketones with monosubstituted allyl substrates, simply by using N-heterocyclic carbene as ligand, leading to branched products with up to three contiguous stereocentres in a (syn, anti)-mode with excellent regio and diastereoselectivities. The scope of the protocol in organic synthesis has been examined preliminarily. Mechanistic studies by both experiments and density functional theory (DFT) calculations reveal that the reaction proceeds via an inner-sphere mechanism-nucleophilic attack of enolate oxygen on Palladium followed by C-C bond-forming [3,3']-reductive elimination.

Figure 1. Examples of Pd-catalysed allylic alkylation following an inner-sphere mechanism.

(a) Pd-Catalysed intramolecular decarboxylative allylic alkylation. (b) Pd-catalysed allyl–allyl cross-coupling reaction, branched products with two stereocentres were given. (c) Pd-catalysed allylic alkylation with nitrogen as nucleophile affording branched products with two stereocentres. (d) Pd-catalysed allylic alkylation with oxygen as nucleophile affording branched products with three contiguous stereocentres.

Figure 2. Applications of the titled reaction.

(a) Reaction on a gram-scale. (b) Allylation of estrone 3-methyl ether at the C16 position. (c) and (d) Reactions with chirality transfer from optically active substrates without loss of optical activity.

Figure 3. Transformation of reaction products.

(a) Pauson–Khand reaction with 3i. (b) Cyclization reaction of 3l without loss of optical activity.

Figure 4. Stereochemistry of Pd-catalysed reaction of nucleophile with (S)-(Z)-5 via outer- and inner-sphere attack mechanisms.

(R)-(E)-3 and/or (S)-(Z)-3 will be obtained by nucleophile attacks on palladium via an inner-sphere mechanism, whereas (R)-(E)-3 and/or (S)-(Z)-3 will be afforded if the nucleophile attacks on carbon via an outer-sphere mechanism.

Figure 5. Mechanistic investigations.

(a) (R, R)-(E)-3a And (S, S)-(Z)-3a were afforded by the reaction of (S)-(Z)-5 with ketone 1a, indicating that the reaction proceeds via the inner-sphere mechanism. (b) (3R, 4S, 5S)-(E)-3i was the only product in the reaction of (S)-(Z)-5 supports an inner-sphere mechanism. (c) Inversion of the stereocentre at the allyl position of cyclohexene 11 in the reaction confirms also the inner-sphere mechanism.

Figure 6. DFT calculations of the free-energy surface of plausible inner-sphere and outer-sphere pathways of reaction of ketone 1b.

Free energies in solvent ΔG_sol (in kcal mol⁻¹) are computed at ωB97XD/def2-TZVP/SMD//ωB97XD/SDDAll level of theory. (More detailed calculations on E-enolate and η¹-allyl-Pd intermediates can be found in Supplementary Figures 69 and 71). These calculations suggest that the inner-sphere pathway leading to branched product is the most favourable pathway, in agreement with experiment.

Figure 7. DFT calculated two major conformations of TS-inner-branched for reactions of ketone 1b and 1c.

For substrate 1b, the chair transition state leading to anti product is favoured, whereas for substrate 1c, the boat transition state leading to syn product is favoured. Detailed analysis and calculations on possible conformations can be found in Supplementary Figures 70–73. Numbers at the bottom of each structure are relative free energies ΔΔG_sol (in kcal mol⁻¹), computed at ωB97XD/def2-TZVP/SMD//ωB97XD/SDDAll level of theory. In the pictures in the central column, some atoms of the bulky substituents on NHC are omitted for clarity.