Nitrogen-to-functionalized carbon atom transmutation of pyridine

Abstract

The targeted and selective replacement of a single atom in an aromatic system represents a powerful strategy for the rapid interconversion of molecular scaffolds. Herein, we report a pyridine-to-benzene transformation via nitrogen-to-carbon skeletal editing. This approach proceeds via a sequence of pyridine ring-opening, imine hydrolysis, olefination, electrocyclization, and aromatization to achieve the desired transmutation. The most notable features of this transformation are the ability to directly install a wide variety of versatile functional groups in the benzene scaffolding, including ester, ketone, amide, nitrile, and phosphate ester fragments, as well as the inclusion of meta-substituted pyridines which have thus far been elusive for related strategies.

Fig. 1. (A) Effect of nitrogen-to-carbon substitution in drug molecules. (B) Skeletal editing via single-atom (N/C) transmutation. (C) Previous work on pyridine to benzene skeletal editing. (D) This work: nitrogen-to-functionalized carbon atom transmutation of pyridine.

Scheme 1. Optimization of olefination and ring closure.

Fig. 2. Scope of the pyridines. Standard conditions: (i) pyridine (0.2 mmol), Tf₂O (0.24 mmol), Bn₂NH (0.24 mmol), KO^tBu (0.24 mmol), and EtOAc (3 mL) at −78 °C to room temperature for 1.5 h. (ii) NaO^tBu (0.22 mmol), H₂O (0.22 mmol), heated to 120 °C for 15 min, then P2 (0.4 mmol), HCl (0.72 mmol, 4 M in dioxane) and THF (3 mL), heated to 120 °C for 4 h. Isolated yields given. ^aYield determined by ¹H NMR.

Fig. 3. Scope of the olefination partners. Standard conditions: (i) 3-phenyl pyridine (0.2 mmol), Tf₂O (0.24 mmol), Bn₂NH (0.24 mmol), KO^tBu (0.24 mmol), and EtOAc (3 mL) at −78 °C to room temperature for 1.5 h. (ii) NaO^tBu (0.22 mmol), H₂O (0.22 mmol), heated to 120 °C for 15 min, then phosphine reagent (0.4 mmol), HCl (0.72 mmol, 4 M in dioxane) and THF (3 mL), heated to 120 °C for 4 h. Isolated yields given. ^aYield determined by ¹H NMR.

Fig. 4. Computational studies on the impact of (a) acid additive on the barrier for isomerization-electrocyclization and (b) para- vs. meta substituents on the barriers for isomerization. All structures were calculated at the UB3LYP-D3/aug-CC-PVTZ-CPCM(THF)//UB3LYP-d3/def2-svp-CPCM(THF) level of theory. Relative (ΔG_rel) energies are in kcal mol⁻¹.