molecules Communication Nucleophilic Substitution on 2-Monosubstituted Quinoxalines Giving 2,3-Disubstituted Quinoxalines: Investigating the Effect of the 2-Substituent Ndumiso Thamsanqa Ndlovu and Winston Nxumalo * Department of Chemistry, Faculty of Science and Agriculture, University of Limpopo, Private Bag X 1106, Sovenga 0727, South Africa; [email protected] * Correspondence: [email protected]; Tel.: +27-015-268-2331 Academic Editor: Philippe Belmont Received: 30 August 2016; Accepted: 23 September 2016; Published: 30 September 2016 Abstract: An investigation on the effect of substituent at the 2-position of mono-substituted quinoxalines in the synthesis of di-substituted quinoxaline derivatives via nucleophilic substitution reactions, is reported. Di-substituted quinoxalines bearing aryl-alky, aryl-aryl, aryl-heteroaryl, aryl-alkynyl, and amino-alkyl substituents were prepared in moderate to good yields. 2-Monosubstituted quinoxalines bearing a phenyl and butyl substituent reacted readily with alkyl-, aryl-, heteroaryl- and alkynyl- nucluephiles, giving di-substituted quinoxalines. 2-Monosubstituted quinoxalines bearing an amine and alkynyl substituent only reacted with alkyl nucleophiles. Oxidative rearomatization to give 2,3-disubstituted quinoxaline products occurred in atmospheric O2. Keywords: 2,3-disubsituted quinoxaline; nucleophilic substitution; oxidative rearomatization 1. Introduction Quinoxaline derivatives possess extensive applications in medicinal chemistry, due to their broad spectrum of biological activity [1,2]. A large number of synthetic quinoxalines have been reported to exhibit anti-tubercular [3], anti-viral [4,5], anti-microbial [6,7], and neuroprotective [8,9] activity. Quinoxaline derivatives have been reported to be prepared, but not limited, by intramolecular cyclisation of N-substituted aromatic ortho-diamines [10], ring transformation of benzofurazans [11], and condensation of benzofuran-1-oxide to form quinoxaline-N-oxides [12]. The most common method for the preparation of quinoxaline derivatives relies on the condensation of an aryl 1,2-diamine with a 1,2-dicarbonyl compound, of which this type of reaction has limitations due to the use of pre-defined starting materials [13–16], which limit the number of substituents that can be added. A more convenient approach for the synthesis of quinoxaline derivatives is the substitution of hydrogen at the 2- or 3-position of quinoxaline by C-nucleophiles. Substitution of hydrogen by C-nucleophiles on electron deficient arenes has been reported extensively [17–19]. The reaction of quinoxaline derivatives with aryl and alkyl nucleophiles has been investigated [20–26]. C-nucleophiles have been shown to add to 6-aminoquinoxaline [9,20] affording alkyl- and aryl-substituted quinoxalines in low to high yields. Although efficient, these reactions require the use of an oxidising agent to afford aromatic substitution products. Azev et al. [21], reported formation of resorcinol derivative, 2-(2,4-dihydroxyphenyl)quinoxaline after reacting quinoxaline and resorcinol in refluxing ethanol (EtOH) in the presence of an acid. The reaction of quinoxaline with this nucleophile continues to oxidative rearomatization of the compound without the need of having an oxidizing agent, but requires the use of concentrated HCl and high temperature. The use of nucleophilic substitution has been extended to other functional groups like aromatic amines and heteroaryls, but examples of quinoxaline derivatives containing these groups are limited. The reaction of 2-chloro-3-methylquinoxaline with Molecules 2016, 21, 1304; doi:10.3390/molecules21101304 www.mdpi.com/journal/molecules Molecules 2016, 21, 1304 2 of 11 MoleculesMolecules 20162016,, 2121,, 13041304 22 ofof 1111 aromatic amines as nucleophilic reagents in the presence of anhydrous potassium carbonate and iodide,potassiumiodide, formingforming iodide, thetheforming correspondingcorresponding the corresponding 2-arylamino-3-methylquinoxalines,2-arylamino-3-methylquinoxalines, 2-arylamino-3-methylquinoxalines, hashas beenbeen describeddescribed has been byby BadrBadr described etet al.al. [22].by[22]. Badr ThisThis etmethodmethod al. [22 onlyonly]. This describesdescribes method 2-arylaminoquinoxali2-arylaminoquinoxali only describes 2-arylaminoquinoxalinenene derivativesderivatives containingcontaining derivatives aa methyl-substituentmethyl-substituent containing atat a themethyl-substituentthe 3-position.3-position. AA moremore at the recentrecent 3-position. strategystrategy A byby more ZhouZhou recent entailsentails strategy directdirectby heteroarylationheteroarylation Zhou entails directofof NN-heteroarenes-heteroarenes heteroarylation byby heteroarylofheteroarylN-heteroarenes GrignardGrignard by reagents.reagents. heteroaryl AlthoughAlthough Grignard thisthis method reagents.method gigivesves Although highhigh yieldsyields this and methodand isis efficient,efficient, gives high itit focusesfocuses yields solelysolely and onison efficient,heterobiarylheterobiaryl it focuses preparationpreparation solely forfor on doubledouble heterobiaryl functionafunctiona preparationlizationlization [23,25,26].[23,25,26]. for double PhenylacetylidePhenylacetylide functionalization nucleophilenucleophile [23,25 waswas,26]. alsoPhenylacetylidealso reportedreported toto add nucleophileadd toto quinoxalinequinoxaline was also viavia reported nucleophilicnucleophilic to add substitution,substitution, to quinoxaline affordingaffording via nucleophilic mono-substitutedmono-substituted substitution, andand di-substitutedaffordingdi-substituted mono-substituted quinoxalinequinoxaline [24].[24]. and TheThe di-substituted influenceinfluence ofof substitusubstitu quinoxalineentsents atat the [the24 ]. 2-position2-position The influence onon nucleophilicnucleophilic of substituents substitutionsubstitution at the by2-positionby CC-nucleophiles-nucleophiles on nucleophilic hashas notnot beenbeen substitution fullyfully ininvestigated.vestigated. by C-nucleophiles Herein,Herein, wewe has wishwish not toto been reportreport fully nucleophilicnucleophilic investigated. substitutionsubstitution Herein, reactionswereactions wish to onon report mono-substitutedmono-substituted nucleophilic quinoxalines,quinoxalines, substitution reactions bearinbearingg anan on aryl,aryl, mono-substituted alkyl,alkyl, alkynyl,alkynyl, quinoxalines, andand aminoamino substituentssubstituents bearing an ataryl,at thethe alkyl, 2-position.2-position. alkynyl, and amino substituents at the 2-position. ByBy startingstarting withwith quinoxalinequinoxaline bearingbearing aa benzenesulfonyloxybenzenesulfonyloxy leavingleaving group,group, whichwhich wewe previouslypreviously reportedreported toto to bebe be anan an efficientefficient efficient leavingleaving leaving groupgroup group inin in couplingcoupling coupling ofof ofpteridinespteridines pteridines [27,28],[27,28], [27,28 wewe], weenvisagedenvisaged envisaged thatthat that wewe cancan we preparecanprepare prepare mono-substitutedmono-substituted mono-substituted quinoxalinequinoxaline quinoxaline derivatives,derivatives, derivatives, employingemploying employing thethe NegishiNegishi the Negishi [29],[29], [SonogashiraSonogashira29], Sonogashira [30],[30], and [and30], BuchwaldandBuchwald Buchwald couplingcoupling coupling conditionsconditions conditions [31].[31]. [ 31]. 2.2. ResultsResults Results OurOur investigation investigation beganbegan with with the the prepar preparationpreparationation of of 2-benzensu 2-benzensulfonyloxyquinoxaline2-benzensulfonyloxyquinoxalinelfonyloxyquinoxaline 11 whichwhich was was preparedprepared fromfrom from ourour our previouslypreviously previously reportreport reportededed methodmethod method [27].[27]. [ 2-Phenylquinoxaline272-Phenylquinoxaline]. 2-Phenylquinoxaline 22 waswas preparedprepared2 was prepared viavia NegishiNegishi via couplingNegishicoupling coupling ofof 11 andand of 1.141.141 and MM 1.14 solutionsolution M solution ofof phenyl-ZnCl,phenyl-ZnCl, of phenyl-ZnCl, inin 75%75% in 75% yieldyield yield (Scheme(Scheme (Scheme 1).1).1 ). TreatingTreating Treating 2 withwithwith 0.50.5 equivalents equivalents of of nn-BuLi-BuLi gave 3-butyl-2-phenylquinoxaline 3-butyl-2-phenylquinoxaline 2a2a inin 12% 12% yield. yield. TheThe oxidative oxidative elimination elimination ofof HH 22 occursoccursoccurs inin in atmosphericatmospheric atmospheric oxygen,oxygen, oxygen, toto to exclusivelyexclusively exclusively provprov provideideide thethe aromaticaromatic aromatic product.product. IncreasingIncreasing thethe amountamount nn-BuLi-BuLi to to 1.5 1.5 equivalentsequivalents gave gave 2a2a inin 66%66% yield,yield, whichwhich is is aa significantsignificant significant improvement.improvement. ThisThis method method was was extendedextended toto other; other; aryl-, aryl-, heteroaryl-, heteroaryl-, al alkynyl-,alkynyl-,kynyl-, and and alkyl-nucleophiles alkyl-nucleophiles onon compoundcompound 22,, ofof which which the the compoundscompounds 2a2a––2g2g werewere synthesised synthesised (Table (Table1 1).1).). N SO Ph Ph-ZnClPh-ZnCl N SO22Ph NN Pd(PPhPd(PPh33))22ClCl22 EtEt3NN N 3 N NN 11 THF,THF, RT,RT, 18hrs18hrs 76%76% 22 SchemeScheme 1. 1. NegishiNegishi Coupling.Coupling. TableTable 1. 1. NucleophilicNucleophilic substitution substitution on on 2-phenylquinoxaline. 2-phenylquinoxaline. R Metal NN R Metal NN THF,THF, RT,RT, 1818 hrshrs NN NN RR 22 2a-g2a-g EntryEntry ProductProduct R-MetalR-Metal R R % % YieldYield Entry Product R-Metal R % Yield 11 2a2a n-n-BuLiBuLi -Butyl-Butyl