Mechanistic Understanding of the Aryl-Dependent Ring Formations in Rh(III)-Catalyzed C–H Activation/Cycloaddition of Benzamides and Methylenecyclopropanes by DFT Calculations

Abstract

The divergence between Rh(III)-catalyzed C− H activation/cycloaddition of phenyl-and 2-furanyl-containing benzamides with methylenecyclopropanes (MCP) was studied by DFT calculations. Calculations found that the C−H activation via a CMD mechanism is the most difficult step of the reaction involving phenyl. In contrast, the C−H activation of the 2-furanyl-containing substrate is kinetically easier but the formed five-membered rhodacycle is relatively unstable, making the following MCP insertion more difficult. Thus, different KIE data was obtained in experiments. The MCP insertion forms a seven-membered-ring rhodacycle intermediate, from which the chemoselectivity of the whole reaction is determined by the competitive pivalate migration (path I) and β-C elimination (path II). While the β-C elimination is lower in energy when a furanylene is contained in the intermediate, a reversed preference of pivalate migration was predicted for the phenylene counterpart. Structural analysis suggested that the unfavorable β-C elimination in the phenylene case should be attributed to the obviously increased ring strain in the corresponding transition state, instead of the difference in electronic properties between the aryl groups. This accounts for why aryl-dependent chemoselectivity was observed. In addition, the results indicated that for both paths I and II the generation of a Rh(V)−nitrenoid intermediate from pivalate migration is crucial for the final C−N bond formation. This explains why no reaction occurred when the N−OPiv moiety was replaced with an N−OMe group, as no Rh(V) intermediate could be formed in this system.

Theoretical Insights into the Synthesis of 2,3‐Dihydropyridines from Unsaturated Oximes by RhIII‐Catalyzed C–H Activation – A DFT Study

“…The length of the Rh–H 1 (Rh–H 1 = 2.26 Å) bond in TS M2 – 3 indicates that the Rh atom mediates the C–H activation. Similar acetate‐assisted C–H activations through CMD processes have been reported by Xia,[23e], [28b], Fu,[29c] Zhao,[28a] Bi,[24b] You, Macgregor, and Wang et al, and their calculated energy barriers are 8–22 kcal/mol. The large differences in the energy barriers can be ascribed partly to the electron‐deficient CF 3 substituent on the Cp* ligand.…”

“…As shown in Figure a, for M1 ‐CH 3 , ligand‐assisted C–H activation via TS M26 – 27 (Rh–C 1 = 2.20 Å, Rh–H 1 = 2.28 Å, C 1 –H 1 = 1.32 Å, and O 4 –H 1 = 1.32 Å; see Figure ) requires an energy of 14.3 kcal/mol, which is larger than that (4.8 kcal/mol) for M1 ‐CF 3 . The value of 14.3 kcal/mol is in the range reported for similar processes in other Rh III ‐catalyzed reactions , , , . In contrast to the process for M1 ‐CF 3 , which is exergonic by 7.6 kcal/mol, that for M1 ‐CH 3 is endergonic by 3.1 kcal/mol.…”

“…Xia and Bi et al also reported similar intermediates. [24b], Taking into consideration the effect of CF 3 , which is more electron‐deficient, the calculated energy barriers of approximately 20 kcal/mol for the migratory insertion of alkene b 1 are comparable to that (23.6 kcal/mol) for 1,3‐allylic migration and are larger than that (12.2 kcal/mol) for methylenecyclopropane (MCP) insertion. [23e], …”

“…In this reaction, the dihydropyridines were assumed to be synthetic intermediates. In addition, several theoretical studies on Rh‐catalyzed reactions have been performed to elucidate the reaction mechanisms . Recently, Rovis and co‐workers reported the Cp*Rh III ‐catalyzed (Cp* = pentamethylcyclopentadienyl) synthesis of 2,3‐dihydropyridines .…”

Metallkatalysierte Anellierungen durch Aktivierung und Spaltung von C‐H‐Bindungen

“…Aufgrund der Gegenwart des Furanrings scheint eine Cyclopropylcarbinyl‐Butenyl‐Umlagerung gegenüber der alternativen reduktiven Eliminierung bevorzugt, wobei sich ein intermediärer achtgliedriger Metallacyclus bildet. Der abschließende C‐N‐Bindungsbildungsschritt führt bei Spaltung der N‐O‐Bindung zu den Cycloheptanprodukten …”