Aromatic nitrogen scanning by ipso-selective nitrene internalization

Abstract

Nitrogen scanning in aryl fragments is a valuable aspect of the drug discovery process, but current strategies require time-intensive, parallel, bottom-up synthesis of each pyridyl isomer because of a lack of direct carbon-to-nitrogen (C-to-N) replacement reactions. We report a site-directable aryl C-to-N replacement reaction allowing unified access to various pyridine isomers through a nitrene-internalization process. In a two-step, one-pot procedure, aryl azides are first photochemically converted to 3H-azepines, which then undergo an oxidatively triggered C2-selective cheletropic carbon extrusion through a spirocyclic azanorcaradiene intermediate to afford the pyridine products. Because the ipso carbon of the aryl nitrene is excised from the molecule, the reaction proceeds regioselectively without perturbation of the remainder of the substrate. Applications are demonstrated in the abbreviated synthesis of a pyridyl derivative of estrone, as well as in a prototypical nitrogen scan.

Fig. 1.. Background and motivation.

(A) General outline of the nitrogen scan strategy. (B) Examples of nitrogen scans examined in the discovery of recently approved pharmaceuticals. (C) Outline of relevant precedent for formal nitrene internalization, emphasizing drawbacks associated with the prior art. EP2, prostaglandin E₂ receptor; RET, rearranged during transfection proto-oncogene; K-Ras G12C, Kirsten rat sarcoma protein with glycine 12 to cysteine mutation; iPr, isopropyl; Me, methyl.

Fig. 2.. Design and mechanism.

(A) Design hypothesis for ipso-carbon deletion of azepines. (B) Precedent in benzenoid systems, demonstrating hybridization effects. (C) Discovery of oxidant-dependent cyclization and thermolytic extrusion of pyridine, with optimized conditions and control experiments lacking a pendant alcohol. (D) Computed mechanism for carbene extrusion from spirocyclic azahexatriene. NBS, N-bromosuccinimide; NBC, N-bromocaprolactam; decomp., decomposition; conv., conversion; DBU, diazabicycloundecene; OTBS, tert-butyldimethylsilyloxy.

Fig. 3.. Scope and selectivity.

(A) Scope of the reaction. Standard conditions: (i) 0.3 mmol aryl azide, 0.3 mmol ethylaminoethanol, 3 ml MeCN, and 427-nm light-emitting diode (LED); (ii) 0.3 mmol DBU, 3 ml dioxane heated to 80°C, and 0.6 mmol N-bromocaprolactam added dropwise at 80°C. Isolated yield of pyridine from aryl azide (black). Proton NMR (¹H-NMR) yield of photolysis (blue) and interpolated yield of pyridine based on azepine yield (purple), shown in parentheses. Asterisk indicates NMR yield. (B) Demonstration that nonsymmetric substrates form only one pyridine isomer.

Fig. 4.. Applications of nitrene internalization.

(A) Synthesis of an azasteroid from estrone and comparison with published route from nortestosterone. (B) Demonstration of a prototypical nitrogen scan leveraging an unselective C–H borylation.