Substituent Effects of 2-Pyridones on Selective O-Arylation with Diaryliodonium Salts: Synthesis of 2-Aryloxypyridines under Transition­-Metal-Free Conditions

Abstract

An efficient transition-metal-free strategy to synthesize 2-aryloxypyridine derivatives has been developed by a selective O-arylation of 2-pyridones with diaryliodonium salts. The reaction was compatible with a series of functional groups for 2-pyridones and diaryliodonium salts such as halides, nitro, cyano, and ester groups. The substituents at the C6-position of 2-pyridones favored O-arylation products because of steric hindrance. The reaction was easily performed on a gram-scale and 6-chloro-2-pyridone was a good precursor to access various unsubstituted 2-aryloxypyridines by dehalogenation. A P2Y1 lead compound analogue could be prepared in good yield over two steps.

Regioselective O-alkylation of 2-pyridones by TfOH-catalyzed carbenoid insertion

“…5 For instance, the ambident nucleophilic nature of 2-pyridone usually gives a mixture of N - and O -alkylated products in the presence of base (Scheme 2B). 6…”

A Mild and Highly Diastereoselective Preparation of N-Alkenyl-2-Pyridones via 2-Halopyridinium Salts and Aldehydes

“…The compound was prepared using the general procedure using 2 equiv of 2t and obtained as a yellow oil (10 mg, 37% yield): chromatography conditions 1:1 EtOAc/Hex; to 3:1 EtOAc/Hex 1 H NMR (400 MHz, CDCl 3 ) δ 7.41 (ddd, J = 9.3, 6.6, 2.1 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.04 (dd, J = 6.8, 2.1 Hz, 1H), 6.63 (d, J = 9.3 Hz, 1H), 6.22 (td, J = 6.1, 1.1 Hz, 1H), 4.27 (q, J = 7.1 Hz, 3H), 2.12 (d, J = 6.2 Hz, 2H), 1. 30 N-Alkenyl-2-pyridone 3v. The compound was prepared using the general procedure starting with 1.5 mmol of 1 and 2 equiv of 2u in 15 mL of toluene and obtained as a yellow oil, (0.141 g, 45% yield): chromatography conditions 1:1 EtOAc/Hex to 3:1 EtOAc/Hex; 1 H NMR (400 MHz, CDCl 3 ) δ 7.43 (m, 1H), 7.24 (q, J = 7.2 Hz, 1H), 7.08 (d, J = 6.7 Hz, 1H), 6.61 (d, J = 9.30 Hz, 1H), 6.26 (t, J = 6.69 Hz, 1H) (4.26 (q, J = 7.1 Hz, 2H), 1.77 (d, J = 7.2, 3H), 1.29 (t, J = 7.1 Hz, 3H); 13 N-Alkenyl-2-pyridone 5a.…”

“…N -Alkyl-2-pyridones are important heterocycles encountered in various active pharmaceutical ingredients, bioactive compounds, and natural products (Figure ). − Accordingly, a diverse set of methods to prepare these valuable compounds is highly desired. ,,− While a straightforward means of obtaining N -alkyl-2-pyridones is through direct N -alkylation of 2-hydroxypyridine (2-pyridone), this method often suffers from competitive O -alkylation. ,− Methods to isomerize 2-alkoxypyridines to N -alkyl-2-pyridones ( O - to N - alkyl migration) using transition metal catalysts or Brønsted/Lewis acid promoters have also been described. ,,− ,− …”

Copper-Catalyzed Chemoselective O-Arylation of Oxindoles: Access to Cyclic Aryl Carboxyimidates

“…Chen and their co-workers also reported iodonium salt-assisted O-arylation of pyridyl amidates with Cu­(OTf) 2 as a catalyst (Scheme b) . In this context, 2-aryloxy pyridine derivatives were also synthesized with iodonium salts, but the substrate selection was limited to C-6 substitution . On the other hand, Onomura and co-workers reported quinoline-mediated efficient construction of 2-pyridyl ether derivatives using symmetrical diaryl iodonium salts and chlorobenzene as solvent (Scheme c) .…”