Mild Regioselective Halogenation of Activated Pyridines with N-Bromosuccinimide

Abstract

Regioselective mono and dihalogenations of amino, hydroxy and methoxy pyridines (2-, 3-, and 4-substituted) as well as 2,6-dimethoxy pyridine with N-bromosuccinimide in different solvents have been studied. Reactivity of the substrates decreases in the order amino>hydroxy>methoxy and regioselectivity depends on the position of the substituent (2-substituted > 3-substituted). In most of the cases we obtained monobrominated derivatives regioselectively and in high yields. Hydroxy and amino pyridines can also be dibrominated in almost quantitative yield with 2 equivalents of NBS.Polyfunctional pyridines are very useful compounds which have found applications as precursors of pharmacological compounds, 1 in the synthesis of liquid crystals 2 and polymers, 3 as well as ligands for different transition metal cations. 4 The wide range of halopyridines, 5,6 which are able to undergo metal-halogen exchange with n-BuLi, nucleophilic substitutions and oxidative additions with Pd(0) allowing the introduction of many functional groups to the pyridine ring, means they are of great interest from a synthetic point of view. Moreover, halopyridines are themselves important final products as herbicides, 7 insecticides 8 and fungicides. 9 As a consequence of these features the regioselective synthesis of halopyridines is a matter of great interest.Data published in the literature up to 1970 showed that bromination of activated pyridines must be carried out with bromine in polar protic solvents, such as water or ethanol. 10 Several years later, it was reported the bromination of aminopyridines and N-oxides 11 with bromine in mixtures of CH 3 CN/CH 2 Cl 2 , while bromination of methoxypyridines 10,12 was carried out in acetic acid. Also tetrabromocyclohexa-2,5-dienone 10 has been used for the bromination of 3-aminopyridine. In most of these papers, the formation of mixtures of monohalo and dihalo derivatives is reported but their relative proportions as well as their 1 H NMR characterisation is omitted. Recently, Br 2 / NaOH has successfully been employed by Schnatterer et al. 13 for the highly regioselective bromination of 3-hydroxypyridine to yield exclusively 2-bromo-3-hydroxypyridine but, to our knowledge, the authors have not extended this study to other pyridine derivatives.N-Halosuccinimides have previously been reported as reagents for the nuclear bromination of 8-quinolinol and its copper (II) chelate 14 but they have scarcely been used on pyridines bearing activating groups. 15 By contrast, radical brominations at lateral chains of alkylpyridines with NBS in the presence of radical initiators have been widely documented. 16 The good results obtained by our group in the regioselective bromination of methoxybenzenes and methoxynaphtalenes, 17 as well as phenols and napthols 18 under very mild conditions with NBS, prompted us to investigate the behaviour of activated pyridines. In this paper we report a systematic study of the bromination with NBS of pyridines bearing OH, NH 2 , and OMe groups at different positions and under ...

Luminescent Excited‐State Intramolecular Proton‐Transfer (ESIPT) Dyes Based on 4‐Alkyne‐Functionalized [2,2′‐Bipyridine]‐3,3′‐diol Dyes

“…Similar bromination reactions were previously performed on 3-hydroxypyridines. [15] A Sonogashira cross-coupling reaction of 2 with trimethylsilylacetylene allowed us to obtain 3 in good yields (Scheme 2) despite the presence of free hydroxy groups. The silyl protective group was readily removed by the action of fluoride salt to give 4.…”

Regioselective synthesis of symmetrical pyridyl selenium compounds by bromine–magnesium exchange of bromopyridines using isopropyl magnesium chloride: X‐ray crystal structure of 2,2′,5,5′‐tetrabromo‐3,3′‐dipyridyldiselenide

“…Bromopyridines were prepared from the corresponding 2-aminopyridines by literature methods. 18,19 General method for the preparation of symmetrical dipyridyl diselenides Bromopyridine (20 mmol) was added dropwise to a vigorously stirred solution of i PrMgCl (20 mmol) in tetrahydrafuran (THF). After 2 h of continuous stirring at room temperature, elemental selenium (20 mmol) was added after cooling in an ice bath.…”

Total Syntheses of the Thiopeptides Amythiamicin C and D

“…[24] We found the bromination with N-bromosuccinimide (NBS) to occur beneficially in acetonitrile relative to tetrachloromethane providing 3-amino-2,6-dibromopyridine in 58 % yield. Subsequent iodo-de-amination turned out to proceed smoothly and delivered pyridine 17 in 71 % yield (41 % overall).…”