Elsevier

Tetrahedron

Volume 74, Issue 40, 4 October 2018, Pages 5804-5817
Tetrahedron

Xanthate-mediated intermolecular alkylation of pyrazines

This paper is dedicated with respect and admiration to Professor Léon Ghosez.
https://doi.org/10.1016/j.tet.2018.08.040Get rights and content

Abstract

An expedient approach for the intermolecular C-H functionalization of pyrazines and other heteroarenes by the radical chemistry of xanthates is reported. Incorporation of a multitude of functional alkyl groups onto these heteroarenes proceeds in good yield and good to excellent regioselectivity, leading to highly functionalized heteroaromatics.

Introduction

Pyrazines constitute an important member of the class of diazines due to their wide ranging applications as flavoring agents [1], in material sciences [2], and in medicines. For example, disubstituted 2-sec-butyl-3-methoxypyrazine is present in Cabernet-Sauvignon wine. 2,5-Dimethyl-3-(pentan-3-yl)-pyrazine serves as an ant alarm pheromone. As for drugs, amiloride, a potassium-sparing diuretic, is used in the management of hypertension and congestive heart failure. After more than two decades' efforts, a potent small molecule named SHP099 containing a pyrazine core was finally found as inhibitor of SHP2 phosphatase, a stimulator of cancer growth (Fig. 1) [3].

Conventional methods for the preparation of pyrazines include cyclocondensation [4], modification of pyrazinones [5], transition metal catalyzed cross-coupling with halogenopyrazines [6] and metalation [7]. These pathways, however, suffer from various limitations, such as inaccessible substitution patterns, harsh reaction conditions, prefunctionalized substrates, etc. These disadvantages limit the exploitation of the potential of pyrazines.

Recently, radical chemistry has arisen to prominence due to its high promise in the early- and late-stage C-H functionalization of pharmaceutical leads [8]. This demand from industry has resulted in the revival of Minisci-type reactions as powerful tools for the modification of heteroaromatics. Since the seminal work by Minisci et al., in which the radicals were generated from carboxylic acids by silver-catalyzed oxidative decarboxylation [9] or from alkyl iodides with H2O2 and Fe(II)SO4·7H2O in DMSO [10], the toolkits for the generation of radicals useful in this context have considerably expanded. For example, alkyl radicals generated by decarboxylation can now be accessed via Barton's esters [11], amino acids [12] or from acid chlorides and anhydrides under photoredox conditions [13]. Starting from alkyl halides, alkyl radicals can be produced through palladium catalysis [14] or by photoredox [15]. A multitude of other radical precursors suitable for Minisci reactions have been developed, including: alkanes [16], alkyltrifluoroborates [17], organoboronic acids [18], peracetates [19], aldehydes [20], alcohols [21], sulfonyl halides [22], sulfones [23], sulfinates [24], 1,4-dihydropyridines [25] and olefins [26], among others. The alkyl groups introduced, however, are mostly scarcely functionalized.

For over two decades, the unique degenerate addition-fragmentation of xanthates has evolved into a powerful method in the creation of carbon-carbon bonds [27]. Its adoption in the intermolecular functionalization of heteroaromatics, however, dates back to 1992, when Minisci et al. reported in a sole paper the cyclohexylation of heteroarenes via a Barton-McCombie-type dithiocarbonate [28]. Employment of alternative cleavage of the carbon-sulfur bond in xanthates for the intermolecular C-H alkylation of heteroarenes is more recent [29]. For our part, we have developed for example the trifluoroethylamination [29f] and tert-butylation [29g] of a wide array of electron-rich and electron-poor heteroaromatics, demonstrating also a high tolerance towards polar functional groups. Moreover, methyl and related alkyl groups were incorporated into heteroarenes by the intermolecular addition of carboxylic acid xanthates, followed by spontaneous or thermal-induced decarboxylation [29h]. These methods provide an expedient inexpensive alternative for the functionalization of heteroaromatics.

Herein, we would like to report further progress in the introduction of highly functionalized alkyl groups into pyrazines and other heteroaromatics mediated by xanthates under mild reaction conditions (Scheme 1).

Section snippets

Results and discussion

Our investigation commenced with 2-chloro-6-methylaminopyrazine 1a, which was previously examined in the tert-butylation process [29g]. We were pleased to find that exposure of pyrazine 1a and 2.0 equivalents of mildly nucleophilic phthalimidomethyl xanthate 2 to portionwise addition of stoichiometric dilauroyl peroxide (DLP) in refluxing 1,2-dichloroethane (DCE) afforded readily aminomethylated product 3a in 73% yield, together with 5% of double alkylation product 4a, displaying therefore good

General experimental methods

All reactions were carried out under dry, oxygen free nitrogen. Thin Layer Chromatography (TLC) was performed on alumina plates precoated with silica gel (Merck silica gel, 60 F254), which were visualized by the quenching of UV fluorescence when applicable (max = 254 nm and/or 366 nm) and/or by staining with anisadehyde in acidic ethanol solution and/or KMnO4 in basic water followed by heating. Flash chromatography was carried out on Kieselgel 60 (40–63 μm). Petroleum ether refers to the

Acknowledgements

We thank Ecole Polytechnique for a scholarship to Q. H. and L. Q.. We also thank Mr Vincent Jactel (Ecole Polytechnique) for HRMS measurements.

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