Synthesis of Functionalized Pyrazin-2(1 H)-ones via Tele-Nucleophilic Substitution of Hydrogen Involving Grignard Reactants and Electrophiles

Pieter Mampuys; Timofey D Moseev; Mikhail V Varaksin; Johan De Houwer; Christophe M L Vande Velde; Oleg N Chupakhin; Valery N Charushin; Bert U W Maes

doi:10.1021/acs.orglett.9b00681

Synthesis of Functionalized Pyrazin-2(1 H)-ones via Tele-Nucleophilic Substitution of Hydrogen Involving Grignard Reactants and Electrophiles

Org Lett. 2019 Apr 19;21(8):2699-2703. doi: 10.1021/acs.orglett.9b00681. Epub 2019 Apr 9.

Authors

Pieter Mampuys¹, Timofey D Moseev², Mikhail V Varaksin^{2

3}, Johan De Houwer¹, Christophe M L Vande Velde⁴, Oleg N Chupakhin^{2

3}, Valery N Charushin^{2

3}, Bert U W Maes¹

Affiliations

¹ Organic Synthesis, Department of Chemistry , University of Antwerp , Groenenborgerlaan 171 , 2020 Antwerp , Belgium.
² Ural Federal University , Mira St. 19 , 620002 Ekaterinburg , Russia.
³ Institute of Organic Synthesis , S. Kovalevskaya St. 22 , 620990 Ekaterinburg , Russia.
⁴ Faculty of Applied Engineering, Advanced Reactor Technology , University of Antwerp , Groenenborgerlaan 171 , 2020 Antwerp , Belgium.

PMID: 30964690
DOI: 10.1021/acs.orglett.9b00681

Abstract

The reaction of 6-chloro-1-methylpyrazin-2(1 H)-one with Grignard reactants followed by quenching with different electrophiles gave access to a variety of 3,6-difunctionalized 1-methylpyrazin-2(1 H)-ones. This regioselective three-component reaction represents the first example of a tele-nucleophilic substitution of hydrogen (S_N^H) in which the anionic σ^H adduct is quenched by electrophiles (other than a proton) before elimination takes place. Quenching the reaction with iodine (I₂) or bromine (Br₂) provides an alternative reaction pathway, yielding a 3-functionalized 6-chloro-1-methylpyrazin-2(1 H)-one or 5-bromo-6-chloro-1-methylpyrazin-2(1 H)-one, respectively. The halogens present offer opportunities for further selective transformations.

Publication types

Research Support, Non-U.S. Gov't