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. 2015 Oct 1;6(10):5802-5814.
doi: 10.1039/c5sc01885d. Epub 2015 Jun 29.

RhI/RhIII catalyst-controlled divergent aryl/heteroaryl C-H bond functionalization of picolinamides with alkynes

Ángel Manu Martínez  1 , Javier Echavarren  1 , Inés Alonso  1 , Nuria Rodríguez  1 , Ramón Gómez Arrayás  1 , Juan C Carretero  1
Affiliations

RhI/RhIII catalyst-controlled divergent aryl/heteroaryl C-H bond functionalization of picolinamides with alkynes

Ángel Manu Martínez et al. Chem Sci. .

Abstract

The ability to establish switchable site-selectivity through catalyst control in the direct functionalization of molecules that contain distinct C-H bonds remains a demanding challenge that would enable the construction of diverse scaffolds from the same starting materials. Herein we describe the realization of this goal, namely a divergent heteroaryl/aryl C-H functionalization of aromatic picolinamide derivatives, targeting two distinct C-H sites, either at the pyridine ring or at the arene unit, to afford isoquinoline or ortho-olefinated benzylamine (or phenethylamine) derivatives. This complementary reactivity has been achieved on the basis of a RhIII/RhI switch in the catalyst, resulting in different mechanistic outcomes. Notably, a series of experimental and DFT mechanistic studies revealed important insights about the mechanism of the reaction and reasons behind the divergent regiochemical outcome.

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Figures

Fig. 1
Fig. 1. Proposed catalyst-controlled divergent aryl/heteroaryl C–H functionalization.
Scheme 1
Scheme 1. RhIII-catalyzed pyridyl C–H functionalization, leading to the isoquinoline derivatives. Conditions: benzylamine derivative (0.15 mmol), alkyne (0.30 mmol), [RhCp*Cl2]2 (5 mol%), Cu(OAc)2 (2.0 equiv.), dioxane (0.1 M), μW, 120 °C, 1 h. aUnder conventional heating at 120 °C for 24 h.
Scheme 2
Scheme 2. RhI-catalyzed ortho-olefination of benzylamine derivatives. aThe mono-ortho-olefinated product was also isolated in 8% yield. bThe di-olefinated product was also isolated in 6% yield.
Scheme 3
Scheme 3. Rhodium-controlled divergent aryl/heteroaryl C–H functionalization in the reaction of 1 with ethyl pent-2-ynoate.
Scheme 4
Scheme 4. RhI-catalyzed ortho-olefination of 1 with 1,3-enynes.
Scheme 5
Scheme 5. RhI-catalyzed ortho-olefination of 1 with aryl-cyclohexyl-acetylenes. aUsing 5 mol% [Rh(cod)Cl]2 and 10 mol% of AgSbF6.
Scheme 6
Scheme 6. RhI-catalyzed ortho-olefination of phenethylamine derivatives.
Scheme 7
Scheme 7. RhIII-catalyzed pyridyl C–H functionalization leading to a 1,7-naphthyridin-8(7H)-one derivative.
Scheme 8
Scheme 8. Deprotection of the N-benzyl group and removal of the COPy directing group.
Fig. 2
Fig. 2. ORTEP view of RhIII-complex A and RhI-complex B. The hydrogen atoms have been removed for simplicity.
Scheme 9
Scheme 9. Stoichiometric studies with isolated RhIII- and RhI-picolinamide complexes.
Scheme 10
Scheme 10. H/D exchange experiments in the RhIII-promoted C–H functionalization process. aThe H/D exchange was detected using mass spectrometry in this case (the exact deuterium content could not be determined by NMR).
Scheme 11
Scheme 11. H/D exchange experiments in the RhI-promoted C–H functionalization process.
Scheme 12
Scheme 12. Simplified plausible mechanistic pathways.
Fig. 3
Fig. 3. Energy profile for the C–H functionalization pathways of 1 with diphenylacetylene from neutral model RhIII complexes in the gas phase (M06/6-311+G(d,p)(C,H,N,O),SDD (Rh)//6-31G(d)(C,H,N,O), LANL2DZ(Rh). The relative G values are in kcal mol–1 at 298 K).
Fig. 4
Fig. 4. Energy profile for the C–H functionalization pathways of 1 with diphenylacetylene from anionic model RhI complexes in the gas phase (M06/6-311+G(d,p)(C,H,N,O),SDD (Rh)//6-31G(d)(C,H,N,O), LANL2DZ(Rh). The relative G values are in kcal mol–1 at 298 K). For simplicity, the negative charge has been omitted.
Fig. 5
Fig. 5. Energy profile for the C–H activation pathways of picolinamides from anionic model RhI complexes with monocoordinated “cod” or alkyne ligands in the gas phase (M06/6-311+G(d,p)(C,H,N,O),SDD (Rh)//6-31G(d)(C,H,N,O), LANL2DZ(Rh). The relative G values are in kcal mol–1 at 298 K).
Fig. 6
Fig. 6. Molecular structures of the key transition states. The bond lengths are given in Å and the relative free energies with respect to modA and modB are indicated in parentheses (kcal mol–1).
Scheme 13
Scheme 13. Synthesis and activity of RhI-complex M.
Fig. 7
Fig. 7. Kinetic profiles of complexes B and M as catalysts in parallel dialkenylation reactions of 1 with diphenylacetylene.
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