Intermolecular C–H Amination of Complex Molecules: Insights into the Factors Governing the Selectivity

Transition-metal-catalyzed C–H amination via nitrene insertion allows the direct transformation of a C–H into a C–N bond. Given the ubiquity of C–H bonds in organic compounds, such a process raises the problem of regio- and chemoselectivity, a challenging goal even more difficult to tackle as the complexity of the substrate increases. Whereas excellent regiocontrol can be achieved by the use of an appropriate tether securing intramolecular addition of the nitrene, the intermolecular C–H amination remains much less predictable. This study aims at addressing this issue by capitalizing on an efficient stereoselective nitrene transfer involving the combination of a chiral aminating agent <b>1</b> with a chiral rhodium catalyst <b>2</b>. Allylic C–H amination of terpenes and enol ethers occurs with excellent yields as well as with high regio-, chemo-, and diastereoselectivity as a result of the combination of steric and electronic factors. Conjugation of allylic C–H bonds with the π-bond would explain the chemoselectivity observed for cyclic substrates. Alkanes used in stoichiometric amounts are also efficiently functionalized with a net preference for tertiary equatorial C–H bonds. The selectivity, in this case, can be rationalized by steric and hyperconjugative effects. This study, therefore, provides useful information to better predict the site of C–H amination of complex molecules

Catalyst-Controlled Intermolecular Homobenzylic C(sp³)–H Amination for the Synthesis of β‑Arylethylamines

The combination of a tailored sulfamate with a C4-symmetrical rhodium(II) tetracarboxylate allows to uncover a selective intermolecular amination of unactivated homobenzylic C(sp3)–H bonds. The reaction has a broad scope (>30 examples) and proceeds with a high level of regioselectivity with homobenzylic/benzylic ratio of up to 35:1, thereby providing a direct access to β-arylethylamines that are of utmost interest in medicinal chemistry. Computational investigations evidenced a concerted mechanism, involving an asynchronous transition state. Based on a combined activation strain model and energy decomposition analysis, the regioselectivity of the reaction was found to rely mainly on the degree of orbital interaction between the [Rh2]–nitrene and the C–H bond. The latter is facilitated at the homobenzylic position due to the establishment of specific noncovalent interactions within the catalytic pocket

Catalyst-Controlled Intermolecular Homobenzylic C(sp³)–H Amination for the Synthesis of β‑Arylethylamines

The combination of a tailored sulfamate with a C4-symmetrical rhodium(II) tetracarboxylate allows to uncover a selective intermolecular amination of unactivated homobenzylic C(sp3)–H bonds. The reaction has a broad scope (>30 examples) and proceeds with a high level of regioselectivity with homobenzylic/benzylic ratio of up to 35:1, thereby providing a direct access to β-arylethylamines that are of utmost interest in medicinal chemistry. Computational investigations evidenced a concerted mechanism, involving an asynchronous transition state. Based on a combined activation strain model and energy decomposition analysis, the regioselectivity of the reaction was found to rely mainly on the degree of orbital interaction between the [Rh2]–nitrene and the C–H bond. The latter is facilitated at the homobenzylic position due to the establishment of specific noncovalent interactions within the catalytic pocket