Catalytic activation of carbon-carbon bonds in cyclopentanones

Abstract

In the chemical industry, molecules of interest are based primarily on carbon skeletons. When synthesizing such molecules, the activation of carbon-carbon single bonds (C-C bonds) in simple substrates is strategically important: it offers a way of disconnecting such inert bonds, forming more active linkages (for example, between carbon and a transition metal) and eventually producing more versatile scaffolds. The challenge in achieving such activation is the kinetic inertness of C-C bonds and the relative weakness of newly formed carbon-metal bonds. The most common tactic starts with a three- or four-membered carbon-ring system, in which strain release provides a crucial thermodynamic driving force. However, broadly useful methods that are based on catalytic activation of unstrained C-C bonds have proven elusive, because the cleavage process is much less energetically favourable. Here we report a general approach to the catalytic activation of C-C bonds in simple cyclopentanones and some cyclohexanones. The key to our success is the combination of a rhodium pre-catalyst, an N-heterocyclic carbene ligand and an amino-pyridine co-catalyst. When an aryl group is present in the C3 position of cyclopentanone, the less strained C-C bond can be activated; this is followed by activation of a carbon-hydrogen bond in the aryl group, leading to efficient synthesis of functionalized α-tetralones-a common structural motif and versatile building block in organic synthesis. Furthermore, this method can substantially enhance the efficiency of the enantioselective synthesis of some natural products of terpenoids. Density functional theory calculations reveal a mechanism involving an intriguing rhodium-bridged bicyclic intermediate.

Figure 1. Activation of C–C bonds in ring systems

a, Catalytic C–C activation of strained rings (for example, in cyclopropane or cyclobutanone). The unfavourable energetics of C–C activation can be compensated by the release of strain in the ring. M, transition metal. b, Stoichiometric rhodium-mediated C–C activation of less strained cycloketones. This reaction is less efficient than that shown in a. Ph, phenyl. c, Directed catalytic C–C activation of less strained cycloketimines. The yield is high for large cycloketimines, but low for smaller ones. Bu, butyl; coe, cyclooctene; Me, methyl; PCy₃, tricyclohexylphosphine. d, The challenge in terms of activating the C–C bonds of cyclopentanones is that C–C activation is reversible; the thermodynamic driving forces do not always allow oxidative addition with a transition metal, instead favouring the reverse process (C–C reductive elimination). R, hydrocarbon side chain. e, Our strategy for catalytic C–C activation of cyclopentanones: merging the unfavourable C–C activation with C–H activation, to produce an overall thermodynamically favoured reaction. Specifically, when using a cyclopentanone with an aryl group in the C3 position, the imine intermediate (A; with a pendant directing group, DG) should allow the transient C–C activation intermediate (B) to undergo an intramolecular C–H activation, producing rhodacycle (C). Subsequent reductive elimination will lead to α-tetralone derivatives.

Figure 2. Substrate scope

a, Scope of the cyclopentanones. The shaded box at the top shows the basic reaction: the substrates are 3-arylcyclopentanones (1a–29a); the major products, α-tetralones (1b–29b), come from cleavage of the more hindered C1–C2 bond, while the minor products, α-indanones (1c–29c), are generated through cleavage of the less hindered C1–C5 bond. [Rh(C₂H₄)₂Cl]₂ is the catalyst precursor and 2-aminopyridine (C1) is the co-catalyst; TsOH is toluene sulfonic acid. Ar, aryl group. Below the shaded box are shown the major products and their isolated yields. b, Scope of the cyclohexanones. See Supplementary Information for further experimental details. The regioselective ratios (r.r.) were determined by gas chromatography-mass spectrometry or ¹H nuclear magnetic resonance (NMR) of the crude products. The percentages in parentheses are the total yields or the b.r.s.m. (based on recovered starting material) yields determined by ¹H NMR, using 1,1,2,2-tetrachloroethane (TCE) as the internal standard. d.r., diastereomeric ratio; IMes, 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene; IPr, 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene; MS, molecular sieve.

Figure 3. Gram-scale synthesis and synthetic applications

a, Gram-scale reactions. Compared with the small-scale reaction, using substrate 9a in a gram-scale reaction produced a higher percentage yield; similarly, when using substrate 24a, less catalyst was needed. b, Standard protocols can be used to add several new functional groups to our C–C activation product α-tetralone 9b. Bn, benzyl group. c, Applications in asymmetric total syntheses of terpenoids. It is known that α-tetralone (2b) is an intermediate for accessing erogorgiaene^,, (R)-ar-himachalene and (−)-heliophenanthrone in three to seven steps (shown at the bottom). However, enantioselective preparation of α-tetralones with a C4 stereocentre is non-trivial and generally requires many steps (top left, pale grey). In our technique (top right, dark grey), we synthesized optically enriched 3-arylcyclopentanones in a single step through asymmetric conjugate addition of cyclopentenone and arylboronic acids; then, using our C–C activation approach, we isolated α-tetralone ((R)-2b) in 64% yield over two steps, with 94.5% chirality transfer. e.r., enantiomeric ratio.

Figure 4. DFT-computed pathways for the activation of C–C bonds in cyclopentanones

a, The computed reaction energy profile of the reaction with cyclopentanone 1a. L, ligand; TS, transition state; ΔG_sol, Gibbs free energy with respect to 41b (given in kcal mol⁻¹); ΔH_sol, enthalpy with respect to 41b (given in kcal mol⁻¹). b, Transition states during C–C bond activation. ΔG^‡, Gibbs free energy of activation. c, Transition states during C–H bond cleavage. Energies are computed at the M06/SDD–6-311+G(d,p)/SMD (1,4-dioxane) level of theory, with geometries optimized at the B3LYP/LANL2DZ–6-31G(d) level (see Supplementary Information for more details and references).