Design of catalysts for site-selective and enantioselective functionalization of non-activated primary C-H bonds

Abstract

C-H functionalization represents a promising approach for the synthesis of complex molecules. Instead of relying on modifying the functional groups present in a molecule, the synthetic sequence is achieved by carrying out selective reactions on the C-H bonds, which traditionally would have been considered to be the unreactive components of a molecule. A major challenge is to design catalysts to control both the site- and stereoselectivity of the C-H functionalization. We have been developing dirhodium catalysts with different selectivity profiles in C-H functionalization reactions with donor/acceptor carbenes as reactive intermediates. Here we describe a new dirhodium catalyst capable of the functionalization of non-activated primary C-H bonds with high levels of site selectivity and enantioselectivity.

Figure 1:

Figure 1A: General scheme of the carbene-induced C–H functionalization. Figure 1B: Comparison of prior C–H functionalization studies with the current study. This study describes a catalyst that is capable of selective functionalization of the most accessible primary C–H bond.

Figure 2:

Numerical and graphical representations of the catalysts optimization studies for selective primary C–H functionalization. The green product 2 is the desired product and Rh₂[R-tris(p-^tBuC₆H₄)TPCP]₄ (I) is the optimum catalyst. Abbreviations: r.r., regioisomeric ratio; e.e., enantiomeric excess, n.d., not detected.

Figure 3:

Examples of selective primary C–H functionalization. In some instances regioisomer products are formed: ^a When forming the following compounds, a small amount of a secondary C–H functionalization product was formed at the position marked as blue: 5 (10%), 6 (11%), 16 (6%), 18 (16%) ^b A value of >98:2 r.r. means no other regioisomer was detected in the ¹H NMR spectra of the crude reaction mixtures; ^c C–H functionalization took place at other positions of 3,3-dimethylhexane (12): 13% at the position marked green (1° site), 3% at the position marked blue (2° site); ^d C–H functionalization took place at other positions of ((2,2-diethylpentyl)oxy)trimethylsilane (17): 4% at the position marked green (1° site), 3% at the position marked blue (2° site).

Figure 4:

Catalyst-controlled diastereoselective primary C–H functionalization

Figure 5:

Structural information about the dirhodium catalyst I. a, ONIOM partitioning of the catalyst with the atoms inside the purple rectangle modeled with DFT and the atoms outside modeled with the UFF, along with the relative energies of the C₂ and C₄ conformations (U: up; S: side). b, Top and side views of the C₂ and C₄ conformations. The free energies with solvation correction are given in kcal/mol.

Figure 6.

Optimized transition structures for carbene insertion into the primary C–H bond. The free energies with solvation correction are given in kcal/mol. TS1 involves attack to the Si face of the carbene and is the lowest energy, consistent with the observed asymmetric induction.