Intramolecular cascade annulation triggered by rhodium(III)-catalyzed sequential C(sp2)–H activation and C(sp3)–H amination

A rhodium(III)-catalyzed intramolecular oxidative annulation of O-substituted N-hydroxyacrylamides for the construction of indolizinones via sequential C(sp2)–H activation and C(sp3)–H amination has been developed. This approach shows excellent functional-group tolerance. The synthesized scaffold forms the core of many natural products with pharmacological relevance.


Results and Discussion
We selected N-hydroxyacrylamide 1a as our model substrate under standard conditions. In the presence of [RhCp*Cl 2 ] 2 (5 mol %) and CsOAc (2 equiv) in 1,4-dioxane (0.1 M) at 60 °C under air, the desired product 3a was obtained in 40% yield, together with 2a in 34% yield ( CsOPiv instead of CsOAc, the products 3a and 2a were obtained in 32% and 21% yields, respectively (Table 1, entry 7). Without adding CsOAc, no products were formed (Table 1, entry 8). Also, when the reaction was treated under standard conditions for 0.5 h, the products 3a and 2a were isolated in 14% and 12% yields, respectively (Table 1, entry 9), which suggested that 3a was formed as soon as the reaction was performed.
Next, diverse substrates were explored to evaluate the scope of this approach under the optimal reaction conditions (Scheme 2). α-Methylacrylamide smoothly proceeded to give the corresponding indolizinone 3b in 41% yield. Acrylamide afforded the corresponding indolizinone 3c in 43% yield. Compared to α-substituted acrylamides, β-substituted acrylamides performed the reaction with lower yields under the same conditions (3d-f).
It should be pointed out that α,β-disubstituted acrylamides were also suitable substrates for this transformation, and the corresponding indolizinones 3g-i were obtained in 39-45% yield. Substrates with different substituents on the alkyne, including 4-methylphenyl, 4-chlorophenyl, phenethyl and a TMS group, could deliver the corresponding indolizinones 3j-m in 47-52% yield. Interestingly, 2-ethynylquinoline as substrate worked well, yielding the corresponding indolizinone 3n in 32%, which has the same skeleton as mappicine.
To investigate the mechanism of this method, control experiments were carried out (Scheme 3). When 2a was performed under standard conditions, 3a could be obtained in 5% yield. Increasing the temperature to 80 °C or 100 °C has no dramatic effect on the yield of 3a. Other bases, like NaOAc or KOAc, could not improve the yield of 3a from 2a. On the contrary, 2a did not give 3a in the absence of CsOAc. These results indicate that 3a could be formed through two pathways, and the one from 2a is the minor pathway. The main pathway is directly from 1a.

Conclusion
In summary, we have developed a rhodium(III)-catalyzed sequential C(sp 2 )-H activation and C(sp 3 )-H amination of O-substituted N-hydroxyacrylamides for the synthesis of indolizinones. This method shows excellent functional-group tolerance. The family of indolizinone products represents potential bioactive molecules for further studies.

Supporting Information
Supporting Information File 1 Experimental details and characterization data.