Benjamin N. Rocke

Rhodium-Catalyzed Directed Halogenation of π-Excessive Heterocycles

Significance: The bromination and iodination of π-excessive heterocycles 1 under directed rhodium(III) catalysis is reported. The reaction provides an orthogonal approach to electrophilic halogenation, overriding the inherent reactivity of the starting materials. Additionally, the method is complementary to directed ortho metalation, which can afford similar products (2 and 3) without the need for a heavy metal catalyst, but under strongly basic conditions (e.g., see: E. G. Doadt, V. Snieckus Tetrahedron Lett. 1985, 26, 1149). Bis-halogenated products 3 were also obtained from compounds 2 in a one-pot process by addition of a second equivalent of the electrophile. The reaction was reported to proceed efficiently under air and without special precautions to exclude moisture. Comment: The scope and functional group tolerance of the reported reaction were demonstrated to be broad, with a range of substituted fiveand six-membered heterocycles being demonstrated. However, the viability of directing groups other than dialkyl amides would have provided welcome generality. Kinetic studies demonstrated a dual role for the rhodium(III) catalyst, whereby it additionally functions to suppress the inherent reactivity of the heterocycle. AgSbF6 was also observed to suppress the innate reactivity, and in its presence, the catalyst loading could be decreased to 0.1%. Additional mechanistic evidence showed that C–H bond activation is turnover limiting but electrophilic aromatic substitution and concerted metalation–deprotonation mechanisms could not be distinguished. A

Asymmetric Organocatalytic Synthesis of Lactams and Lactones

Significance: The reported method for the synthesis of lactams and lactones 4 employs quinineand quinidine-derived catalysts 3 to activate α,βunsaturated acid chlorides 1 toward reaction with bisnucleophiles 2. A variety of heterocycles relevant to medicinal and natural product chemistry were obtained, including 2-pyrrolidinones, 2-piperidinones, enol δ-valerolactones, and 3,4-dihydro-2-pyridinones. The yields are modest to good and enantioselectivity is good to excellent. The method was demonstrated to provide two intermediates for drug synthesis (one on a gram scale). Comment: For success of the reported method, significant tuning of the reaction conditions to the substrate, including the use of excess reactant; the choice of base, catalyst, and temperature; and the use of additives, is required. Catalyst 3b affords products of opposite configuration to those obtained using 3a or 3c; although, in our opinion, the publication relies too heavily on assumptions in drawing this conclusion. In the synthesis of piperidinones, a retro-aza Michael side reaction results in low yields of the desired product. Interestingly, Michael addition, not acylation, appears to be the first mechanistic step, a fact essential to explaining the enantioselectivity. R1 Cl O X CO2R3 R2 X O