Selectivity, Speciation, and Substrate Control in the Gold-Catalyzed Coupling of Indoles and Alkynes

Abstract

A convenient and mild protocol for the gold-catalyzed intermolecular coupling of substituted indoles with carbonyl-functionalized alkynes to give vinyl indoles is reported. This reaction affords 3-substituted indoles in high yield, and in contrast to the analogous reactions with simple alkynes which give bisindolemethanes, only a single indole is added to the alkyne. The protocol is robust and tolerates substitution at a range of positions of the indole and the use of ester-, amide-, and ketone-substituted alkynes. The use of 3-substituted indoles as substrates results in the introduction of the vinyl substituent at the 2-position of the ring. A combined experimental and computational mechanistic study has revealed that the gold catalyst has a greater affinity to the indole than the alkyne, despite the carbon-carbon bond formation step proceeding through an η²(π)-alkyne complex, which helps to explain the stark differences between the intra- and intermolecular variants of the reaction. This study also demonstrated that the addition of a second indole to the carbonyl-containing vinyl indole products is both kinetically and thermodynamically less favored than in the case of more simple alkynes, providing an explanation for the observed selectivity. Finally, a highly unusual gold-promoted alkyne dimerization reaction to form a substituted gold pyrylium salt has been identified and studied in detail.

Scheme 1. Intra- and Intermolecular Reactions of Indoles with Alkynes Catalyzed by Au(I) and Ag(I)

Scheme 2. Selective Gold-Catalyzed Monovinylation of Indoles with Electron Deficient Alkynes

2 h reaction time. 3 h reaction time. 18 h reaction time. 19 h reaction time. 21 h reaction time at room temperature. 24 h reaction time. 27 h reaction time. 48 h reaction time.

Figure 1

(a) Isodesmic reaction used to compare η¹(O) and η²(π)-bound forms of substituted alkynes. Energies are Gibbs energies at 298.15 K at the D3(BJ)-PBE0/def2-TZVPP//BP86/SV(P) level with COSMO solvation in CH₂Cl₂. (b) ³¹P{¹H} NMR spectra in CD₂Cl₂ solution showing the interaction between [Au(NTf₂)(PPh₃)]₂·Tol and different substrates performed at a 1:2 gold:substrate (c) proposed η¹(O) and η²(π) binding for DMF and PhC₂C₆H₄-4-NMe₂.

Figure 2

Isodesmic reaction used to calculate affinity of alkynes for gold. Energies are Gibbs energies at 298.15 K at the D3(BJ)-PBE0/def2-TZVPP//BP86/SV(P) level with COSMO solvation in CH₂Cl₂ (top). Linear free energy relationship between the calculated change in free energy against Hammett parameter σ_p (bottom). Dashed line shows fit to a least mean squares linear regression (R² = 0.92).

Figure 3

³¹P{¹H} NMR spectra of a mixture of [Au(NTf₂)(PPh₃)]₂·Tol and ynones in a 1:10 gold:substrate ratio in CD₂Cl₂ solution.

Figure 4

³¹P{¹H} NMR spectra of [Au(NTf₂)(PPh₃)]₂·Tol with different ratios of 5 (top) and 31 (bottom) in CD₂Cl₂.

Scheme 3. Relative Changes in Free Energy on Coordination of Indole, 5, Skatole, 31, and 13 to [Au(PPh₃)]⁺

Energies are Gibbs energies at 298.15 K at the D3(BJ)-PBE0/def2-TZVPP//BP86/SV(P) level with COSMO solvation in toluene.

Scheme 4. DFT-Calculated Changes in Energy for Products Arising from C₂- and C₃-Addition to Indole and Skatole

Energies are Gibbs energies at 298.15 K at the D3(BJ)-PBE0/def2-TZVPP//BP86/SV(P) level with COSMO solvation in toluene.

Figure 5

DFT-calculated pathways for the addition of 5 or 31 to gold-coordinated alkyne complex B₁₃. Energies are Gibbs energies in kJ mol^–1 at 298.15 K at the D3(BJ)-PBE0/def2-TZVPP//BP86/SV(P) level with COSMO solvation in toluene.

Scheme 5. DFT-Calculated Pathways for the Acid Catalyst Addition to Vinylindole 14 (a) and the Corresponding Species Derived from Phenylacetylene (b)

Energies are Gibbs energies at 298.15 K (in kJ mol⁻¹ for (c) and (d)) at the D3(BJ)-PBE0/def2-TZVPP//BP86/SV(P) level with COSMO solvation in CH₂Cl₂.

Scheme 6. Formation of Pyrylium Salt 12

Ar = C₆H₄-4-NMe₂.

Figure 6

Expansion of a ¹³C{¹H} NMR spectrum of 12 in CD₂Cl₂ solution. Ar = C₆H₄-4-NMe₂.

Figure 7

DFT-calculated pathways for the gold-mediated dimerization of alkynes. All energies are Gibbs energies at 298.15 K in kJ mol⁻¹ at the D3(BJ)-PBE0/def2-TZVPP//BP86/SV(P) level with COSMO solvation in CH₂Cl₂.