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Review
13 (
1
); 721-739
doi:
10.1016/j.arabjc.2017.07.012

2,3-Dichloroquinoxaline as a versatile building block for heteroaromatic nucleophilic substitution: A review of the last decade

, , ,
 Química Biológica e Quimiometria, Instituto de Química, Universidade Federal do Rio Grande do Norte, Natal, RN 59072-970, Brazil

⁎Corresponding author. fgmenezes10@gmail.com (Fabrício G. Menezes)

Received: , Accepted: ,
© The Author(s) 2017
Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

An overview of the last decade on the versatility of 2,3-dichloroquinoxaline (DCQX) as building block for the synthesis of relevant quinoxaline derivatives via nucleophilic aromatic substitution is presented.

Abstract

Nucleophilic aromatic substitution (SNAr) is a class of reaction that has become very important over time. This type of transformation usually proceeds without the use of metal catalysts, making it very important for pharmaceutical and industrial purposes. Nevertheless, in order to obtain the desired substituted product, activated substrates are required to allow SNAr reactions under mild conditions. In this context, quinoxaline derivatives are one class of N-heteroarenes that has attracted great attention from the scientific community because of the large variety of applications for their derivatives in many fields, such as biological and technological areas. There are several reported methods for the synthesis of quinoxaline derivatives. Nonetheless, reactions of 2,3-dichloroquinoxaline (DCQX) with nucleophilic species has become a viable alternative because of the possibility to form new carbon-heteroatom bonds (e.g. C—O, C—N, and C—S) directly at C2 and/or C3 positions of the quinoxaline moiety. This current review brings an overview of the last decade on the remarkable versatility of DCQX as a substrate for SNAr reactions. Herein, we show several examples in which DCQX reacts with N-, O-, S-, P- and C-nucleophiles, including controlled processes for the selective formation of mono- and disubstituted substrates. Almost all polyfunctionalized quinoxalines synthesized using this approach have shown applications in different areas such as in biological and technological fields.

Keywords

2,3-Dichloroquinoxaline
Building block
Heteroaromatic nucelophilic substitution
Organic synthesis
1

1 Introduction

Nucleophilic substitution reactions in the aromatic carbon have been the main subject of several scientific reports for over one century and are of great importance owing to their potential for both academic and industrial synthetic purposes (Blaziak et al., 2016). In order to proceed under mild conditions, nucleophilic aromatic substitution (SNAr) reactions normally require substrates which accommodate the negative charge produced after nucleophilic attack. This requirement is usually fulfilled by using nitrogen-containing heterocycles bearing electron-withdrawing groups (e.g. halogen, cyano, nitro, etc.).

Quinoxalines are notably one of the most important classes of nitrogen-containing heterocyclic compounds in synthetic organic chemistry. This structure is found in numerous biologically relevant molecules. For example, quinoxaline derivatives are found to have antibacterial, antimalarial and anticancer activities, among others (Ajani, 2014; Pereira et al., 2015). On the other hand, quinoxaline derivatives are well known for their luminescent properties (Achelle et al., 2013). Because of their wide areas of application, functionalized quinoxalines are desirable species that can lead to new and/or improved drugs and chemical materials. To this end, there are several reported methods for the synthesis of substituted quinoxaline derivatives. Traditionally, condensing an aromatic o-diamine with α-dialdehydes (or α-diketones) in the presence of a catalyst (usually a Lewis or Bronsted acid) is to date one the most employed methods because it utilizes commercially available reagents and is performed in easy experimental conditions. However, this synthetic route lacks diversity when the target molecule contains a heteroatom such as nitrogen, oxygen or sulfur as the substituent of choice at C2 and/or C3.

To overcome these limitations, the substrate 2,3-dichloroquinoxaline (DCQX) emerges as a versatile building block for the synthesis of a large variety of quinoxaline derivatives since the presence of two chlorine atoms at C2 and C3 makes this substrate a suitable electrophilic partner for SNAr reactions. Furthermore, this reagent is commercially available and easily prepared from low-cost starting materials and simple experimental procedures, having its crystallographic structure determined in 2010 (Galal et al., 2011).

The great relevance of DCQX as a synthetic precursor has been well-reported in a review article by Ammar and colleagues covering the use of this reagent in organic reactions from 1923 to 2006 (Ammar et al., 2009). Nevertheless, to the best of our knowledge there are no review articles showing the outstanding work reported over the last decade using DCQX in organic transformations to allow an extensive elaboration of simple quinoxaline motif and synthesis of several new compounds that were found to have applications in many areas. Therefore, this review aims to fill this gap by discussing the use of DCQX in reactions such as SNAr from 2007 up to the present, and is complementary to existing reviews of this unique and important molecule.

Reactions of DCQX with N-, O-, S-, C- and P-nucleophiles and further synthetic transformations will be presented, including nitrogen of the quinoxaline moiety, which supports the relevance of this emerging building block to organic synthesis. In this review article we have organized the reactions using DCQX in SNAr on the basis of the type of bond being formed.

2

2 Reactions of DCQX with N-nucleophiles

C—N bond formation is one of the most important transformations in organic chemistry. In particular, aromatic amines have found broad application as pharmaceuticals, agrochemicals, polymers and dyes. Over the last decade, the use of DCQX in SNAr with Nitrogen-nucleophiles to yield mono- and/or disubstituted products have been extensively studied (Scheme 1). The reaction of DCQX with ammonia affords 2-amino-3-chloroquinoxaline (1) or 2,3-diaminoquinoxaline (2) depending on experimental conditions. For example, ACQX is obtained from the reaction of DCQX with an ammonia ethanolic solution under microwave radiation (Thompson et al., 2013). On the other hand, DAQX is produced from the reaction of neat ammonia under high pressure, and this disubstituted product is an interesting synthetic intermediate for the synthesis of π-extended compounds such as 3 (Miranda et al., 2008). Reactions of DCQX with amines leading to 2-amino-3-chloro-quinoixaline and 2,3-diaminoquinoxaline derivatives have also been reported. One example of the importance of this transformation is the synthesis of simple quinoxaline 4 from the reaction of DCQX and N-methylpiperazine under mild conditions, which was found to have binding affinity properties to 5-HT3 receptors, and which are directly associated to the central nervous system and some of its physiological functions (Thompson et al., 2013). Synthesis of other 2-(N-alkylamino)-3-chloroquinoxaline derivatives from DCQX and alkylamines has also been described, and the desired mono-substituted found synthetic precursors for the synthesis of N-substituted pyrrolo[2,3-b]quinoxaline derivatives (Keivanloo et al., 2010) and 1,4-disubstituted pyrrolo[1,2-a]quinoxalines (Keivanloo et al., 2016b).

Synthesis of 2-amino-3-chloro- and 2,3-diamino-substituted quinoxalines.
Scheme 1 Synthesis of 2-amino-3-chloro- and 2,3-diamino-substituted quinoxalines.

One of the main goals associated to reactions of DCQX with nucleophiles is the possibility to control single or double substituted products. This unique feature of DCQX is very important in the synthesis of specific targets that can be used in a variety of applications. Compound 5 has been prepared from a sequential reaction of DCQX with n-propylamine and a Co(III)cyclen-amine derivative (Chei et al., 2012), aiming at the synthesis of molecules for peptide cleavage and applications as therapeutic agents against type 2 diabetes, Alzheimer’s and Parkinon’s diseases. More elaborated N-nucleophiles such as 5-amino-1-phenyl-3-methylpyrazole (Ryabukhin et al., 2012) and sulphonylhydrazines (Wu et al., 2012a, 2012b, 2011) can also be utilized in SNAr reactions with DCQX. In particular, products with sulphonylhydrazines were idealized in targeting isoform α of the class I phosphoinositide 3-kinases aiming towards cancer treatment purposes. Recently, Ho and coauthors have explored the controlled nucleophilic substitution in DCQX by amines as part of a screening of a new small molecule analog of the anticancer agent YM155, aiming for antiproliferative activity in malignant cells (Ho et al., 2015). For this proposal, DCQX reacted with 2-methoxyethylamine to afford compound 6 at a good yield, which is then N-acylated and sequentially converted into compound 7 by a second nucleophilic substitution by pyrazin-2-yl-methylamine. In acidic media, this latter compound was converted in the target quinoxalinoimidazolium 8 (Scheme 2) without purification.

Controlled synthesis of diamino-substituted quinoxaline derivatives.
Scheme 2 Controlled synthesis of diamino-substituted quinoxaline derivatives.

Contrary to reactions with aliphatic amines, SNAr of DCQX and anilines are found to proceed slowly or under more energetic conditions. For example, guanylate cyclase inhibitor 9 was obtained from a reaction of DCQX and 4-aminophenol in high temperature and under microwave irradiation (Scheme 3) (Mota et al., 2015). Nonetheless, good yields can be achieved for these reactions by the addition of a Lewis acid such as AlCl3, as demonstrated for the synthesis of compound 10 (Scheme 3) (Prasad et al., 2012). This method was applied in order to obtain 2-(N-arylamino)-3-chloroquinoxalines 11 that are further converted into N-substituted 3-chloro-N-(2-(1-tosyl-1H-benzo[d]-imidazol-2-yl)ethyl)quinoxalin-2-amine, such as compound 12. These target molecules were found to have apoptosis inducing properties in an animal model (zebrafish) (Sunke et al., 2014). Additionally, the relevance of this Al-mediated protocol is well illustrated by Luther et al. in the synthesis of combined indole-quinoxaline derivatives aiming toward potential inhibitors of phosphodiesterase 4 (PDE-4), such as compound 13, which was synthesized after synthetic transformations in quinoxaline derivative 14 (Luther et al., 2019).

Reactions of DCQX with aromatic amines.
Scheme 3 Reactions of DCQX with aromatic amines.

Compounds made from reactions of DCQX with N-nucleophiles also possess applications in supramolecular chemistry (Bouanane et al., 2017; Budagumpi et al., 2011; Chen et al., 2008; Sangilipandi et al., 2016; Ullah et al., 2010; Xia et al., 2017; W. Zhu et al., 2014; Y. Zhu et al., 2014). For example, Chen and colleagues reported the anion binding ability of a compound such as 15 with F−, AcO− and H2PO4− in DMSO (Chen et al., 2008). These types of molecules were synthesized from reactions of DCQX and hydrazine via double-chlorine substitution, followed by condensation with structural diverse aldehydes to afford Schiff bases. Structures of the products obtained were determined by X-ray crystallography. In the field of coordination chemistry, several compounds from SNAr of DCQX with N-nucleophiles have been reported. Luminescent Zinc(II) complex 16 was obtained from a reaction with imidazole (W. Zhu et al., 2014). Additionally, silver (I) and nickel (II) bis-imidazolium-quinoxaline hybrid complex were synthesized and well characterized by Xia et al. (2017). Recently, Sangilipandi et al. presented the synthesis of 2-chloro-3-(3-(2-pyridyl)pyrazolyl)quinoxaline ligand and their ruthenium, rhod andium iridium complexes such as 17, which was found to present good antibacterial activity against three different bacteria (Sangilipandi et al., 2016). Cu(II) complex 18 is formed from DCQX and 4-aminobenzoic acid, and were found to be effective in CO2 capture as well as being a catalyst for cyanosilation of aldehydes (Y. Zhu et al., 2014). Bouanane et al. recently reported the synthesis and characterization of a series of pyrazoloquinoxaline ligands from a protocol based on DCQX reactions and appropriate equivalents of hydrazine, followed by cyclization with acetylacetone (Bouanane et al., 2017). Some coordination complexes such as 19 were obtained from these ligands, which was found to be an interesting model for catecholase.

In general, DCQX reactions with aromatic bis-N-nucleophiles might lead to interesting heterocyclic compounds. Reactions of DCQX and o-diamines are usually performed by melting both reagents to provide respective good yields of azapentacenesin (Tverskoy et al., 2011). In fact, heteroacenes has attracted great attention in the field of new electronic devices because of their tunable properties, as well as structural issues related to aromaticity/antiaromaticity (Bunz, 2009; Bunz and Engelhart, 2016; Kaupp and Naimi-jamal, 2002; Lindner et al., 2011; Tverskoy et al., 2011). Mishra et al. reported the synthesis of a series of antifungal agents such as 20 (Mishra et al., 2012), while Ali and Ibrahim reported the synthesis of an antimicrobial agent such as 21 (Ali and Ibrahim, 2010) (Scheme 4). In both cases, the products were obtained in only moderate yields. Another interesting cyclization product from DCQX and N-nucleophiles are those obtained using 2-aminothiazoles and 2-amino-thiadiazoles in ionic liquid (products 22 and 23 respectively) (Prasanna et al., 2012).

Synthesis of fused heterocycles from reactions of DCQX and bis-N-nucleophiles.
Scheme 4 Synthesis of fused heterocycles from reactions of DCQX and bis-N-nucleophiles.

The unexpected formation of benzo[1′,2′]imidazo[4,5-b]quinoxaline (24) and quinoxalino[2,3-d]benzo[b]imidazolium chloride (25) have been reported in good yields from reactions of pyridine with 2-amino-3-chloroquinoxaline (1) and DCQX, respectively (Galal et al., 2011). The reactions were performed under reflux using the pyridine nucleophile as solvent (Scheme 5). Both products had their structures determined by X-ray crystallography.

Reactions of pyridine with 2-amino-3-chloroquinoxaline (A) and DCQX (B).
Scheme 5 Reactions of pyridine with 2-amino-3-chloroquinoxaline (A) and DCQX (B).

3

3 Reactions of DCQX with N-, O- and S-combined nucleophiles

There are fewer examples of alcohols as nucleophilic partners in SNAr reactions with DCQX when compared to amines. One interesting example was reported by Liutkus and colleagues. A series of eight 2-alkoxy-3-chloro- and 2,3-dialkoxyquinoxalines such as compounds 26 and 27 were synthesized and the products evaluated as dual PPAR α/γ agonists for Diabetes type 2 treatment (Liutkus et al., 2008). The protocol was developed using DCQX and propargylic alcohol alkoxides. The desired mono- and disubstituted products were obtained in good yields with great selectivity (Scheme 6). Phenols were also found to act as nucleophiles to replace chlorine in SNAr reactions with DCQX (Mickevičienė et al., 2015). 2-Chloro-3-phenoxyquinoxaline derivatives such as compound 28 (Scheme 6) were formed in good yields and have shown antibacterial and antifungal activities.

Reactions of DCQX and O-nucleophiles under controlled conditions.
Scheme 6 Reactions of DCQX and O-nucleophiles under controlled conditions.

Recently, Keinvaloo and coauthors reported the synthesis of 2-chloro-3-(prop-2-ynyloxy)quinoxaline (29) and 2,3-bis(prop-2-ynyloxy)quinoxaline (30) from reactions of DCQX with one or two equivalents of prop-2-yn-1-ol, respectively, in basic media (Keivanloo et al., 2016a). These alkynyl-quinoxaline derivatives were found to be an interesting synthetic precursor for the synthesis of a library of 1,2,3-triazole-linked quinoxaline scaffold via copper-catalyzed click reactions with appropriate organic azides, as demonstrated in Scheme 7. The compounds were tested against three different bacterial strains, and compound 31 was found to be more active than tetracycline (standard drug) against Pseudomonas aeruginosa. Further, bis-1,2,3-triazole-quinoxaline derivatives such as 32 were also obtained from this protocol.

Reactions of DCQX with propargyl alcohol under controlled conditions and click chemistry-based further transformations.
Scheme 7 Reactions of DCQX with propargyl alcohol under controlled conditions and click chemistry-based further transformations.

There are several reports of quinoxaline derivatives obtained from SNAr with DCQX by using a combination of nitrogen, oxygen, sulfur and carbon nucleophilic species (Scheme 8). In this context, a series of quinoxaline derivatives were synthesized from DCQX and mixed nucleophiles in searching for a H4 receptor with anti-inflammatory activity (Smits et al., 2008). The protocol was developed following a sequence of substitutions, where the first one utilizes N-alkylpiperazine substrates followed by a second substitution with diverse amines, alcohols, phenols, thiophenols or hydroxide nucleophiles (e.g. compound 33). On a path to obtain inhibitors of aldose reductase for Diabetes treatment, DCQX was effectively hydrolyzed to 3-chloroquinoxalin-2(1H)-one, 34 (Yang et al., 2012). The synthesis of a series of disubstituted quinoxaline such as compound 35 was reported and the products were found to have antipsychotic activity (Sekhar et al., 2013). The methodology was based on the sequential substitutions of both chlorines by methoxide and piperazine, respectively, followed by functionalization of the piperazine moiety with a thiazol derivative unit.

Reactions of DCQX with N- and O-nucleophiles.
Scheme 8 Reactions of DCQX with N- and O-nucleophiles.

Aiming at the synthesis of new anticancer agents, Xia and coauthors reported a series of new quinoxaline derivatives such as peptidomimetic of the antineoplastic quinoxaline XK469 (Xia et al., 2016). The protocol was based on the sequential reactions of DCQX with methyl 4-hydroxybenzoate and appropriated docecylamine to afford compounds 36 and 37, respectively, in moderate yields, followed by additional synthetic transformations (Scheme 9). Quinoxaline peptidomimetic 38 was found as promising candidate for further optimization.

Obtainment of peptidomimetic quinoxaline via combined N- and O-nucleophilic substitution in DCQX.
Scheme 9 Obtainment of peptidomimetic quinoxaline via combined N- and O-nucleophilic substitution in DCQX.

Several works using N- and S-combined nucleophiles such as thiosemicarbazone and its analogs for aromatic substitution with DCQX to produce thiazolo(4,5-b)quinoxaline-2-yl-hydrazone (Scheme 10) have been reported. The synthesized products, including some steroidal derivatives such as compound 39, have been found to show antibacterial activity (Khan, 2008; Khan et al., 2008, 2007). Other elaborated heterocyclic compounds exemplified by structures 40 and 41 have also shown interesting biological applications (Abdel-Gawad et al., 2012; Abdel-Wahab et al., 2011; Budakoti et al., 2008).

Obtainment of thiazolo-quinoxalines from DCQX and thiosemicarbazones.
Scheme 10 Obtainment of thiazolo-quinoxalines from DCQX and thiosemicarbazones.

Other attractive double substitution reactions involving DCQX have been reported (Scheme 11), such as the reaction with 6-aminothioriacyl to afford 42 in a synthetic pathway to obtain antiinflammatory and analgesic substances (Abu-Hashem et al., 2010). The synthesis of thiazoloquinoxalines-based “Y-shape” derivatives with attractive photoluminescent properties, thermal stability and electrochemical reversibility, as exemplified by compound 43, have been reported (Sonawane et al., 2010). The synthetic protocol involved a sequential reaction of DCQX with: sodium hydrogen sulfide, ammonia and acetic anhydride to afford 2-methylthiazolo[4,5-b]quinoxaline (44), which further reacts with 4,4′-(hexylimino)bis-(benzaldehyde) to produce the fluorescent target in good overall yields (Scheme 11). Similar methodology was reported by Deshpande and coauthors for the synthesis and study of photochemical properties of new fluorescent phenothiazine-thiazolo[4,5-b]quinoxaline/benzo[e]indole hybrid derivatives (Deshpande et al., 2017).

Synthesis of relevant N- and S-combined quinxoaline derivatives.
Scheme 11 Synthesis of relevant N- and S-combined quinxoaline derivatives.

In 2013, the interesting synthesis of 1,4-oxathiino[2,3-b]quinoxalines (45) via sequential S- and O—nucleophilic attack on DCQX was reported and the products were obtained in moderate yields (Kobayashi et al., 2013). This one pot methodology is based on three steps: (i) chlorine substitution with sodium sulfide; (ii) S-alkylation with alkyl-arylketones; (iii) nucleophilic substitution with O-nucleophilic attack on an enolate species (Scheme 12).

Synthetic procedure for the synthesis of 1,4-oxathiino[2,3-b]quinoxalines from DCQX.
Scheme 12 Synthetic procedure for the synthesis of 1,4-oxathiino[2,3-b]quinoxalines from DCQX.

Beldi and co-workers published a very interesting synthetic work about the synthesis of mono- and di- S- and N-substituted quinoxaline derivatives (Beldi et al., 2010). The most attractive results were obtained from thioglycoside-based quinoxaline derivatives such as 46 and 47, synthesized by a protocol involving sulfurization of DCQX by a reaction with thiourea, followed by base treatment and further neutralization with aqueous HCl. Later, a reaction of 2,3-dimercaptoquinoxaline (48) with an appropriate aceto-halo sugars in the presence of a base provided the referred products (Scheme 13). Additionally, a reaction of DCQX with morpholine afforded the respective 2-amino-3-chloroquinoxaline (49), which was similarly converted into 3-glycosylsulfanyl-2-morpholinyl-quinoxalines such as 47. One relevant goal of this work was the application of microwave irradiation, which led to a considerable decrease in the reaction and improved yields.

Synthesis of thioglycoside-based quinoxalines via nucleophilic substitution.
Scheme 13 Synthesis of thioglycoside-based quinoxalines via nucleophilic substitution.

Cyclizations involving catechol derivatives and DCQX afford tetracyclic heteroacene substrates in good yields (Scheme 14), as demonstrated by Nafe and co-workers (Nafe et al., 2015) for compound 50, which showed a photoluminescent quantum yield (PLQY) of 65% in the blue region. The method was further extrapolated to reactions with other nucleophilic species, such as 1,2-benzenedithiol (compound 51) (Nafe et al., 2015). Additionally, the synthesis of diazadioxaacenes has also been reported from reactions of DCQX and more elaborated catechol derivatives, as demonstrated by Nafe for the synthesis of compound 52 with PLQY of 65% (Nafe et al., 2015), and Schaffroth et al. through a copper-catalyzed and base promoted modular coupling to afford 53 (Schaffroth et al., 2013). Double nucleophilic substitution in DCQX also effectively proceeds when 2-aminothiophenol is the nucleophilic species of choice, as demonstrated by Podsiadły in the synthesis of 12H-quinoxalino[2,3-b][1,4]benzothiazine, 54, which was proposed to find application as a UV–Vis-based initiator of acrylate polymerization via free radical-based mechanism (Podsiadly, 2009).

Synthesis of π-extended heterocycles from DCQX and catechol derivatives, 1,2-benzenedithiol and 2-aminothiophenol.
Scheme 14 Synthesis of π-extended heterocycles from DCQX and catechol derivatives, 1,2-benzenedithiol and 2-aminothiophenol.

In 1882, Moran and colleagues reported a class of molecular cavitands composed by resorcin[4]arenes bridged with quinoxaline moieties as artificial receptors (Moran et al., 1982). From that time to the present, several works have been published focusing on the structural parameters of these compounds and reporting host-guest applications, including the detection of toxic solvents, biologically relevant compounds and also explosives (Cacciarini et al., 2005; Clément et al., 2015; Fankhauser et al., 2014; Galán et al., 2014; Hu et al., 2013; Roncucci et al., 2006; Vachon et al., 2010). In general, a synthetic approach for forming these molecular cavitands is based on the nucleophilic substitution reactions of resorcin[4]arenes with DCQX in dipolar aprotic solvent, such as DMF or DMSO in the presence of a base, usually carbonate, which may lead to mono- up to tetrasubstituted quinoxaline derivatives, depending on the nature of the phenolic starting material and the experimental conditions. As an example, the synthesis of tetraquinoline-based calix[4]pyrrole-resorcinarene (55) reported by Galán et al. from the reaction of the specific polyphenolic species with an excess of DCQX to afford the referred cavitands in a moderate yield (Scheme 15) (Vachon et al., 2010). In this work, it was verified that the pyrrole-based rigid system induces formation of the kite conformer, allowing the synthesis of stable complexes with pyridine-N-oxide derivatives.

Synthesis of a quinoxaline-based molecular cavitands.
Scheme 15 Synthesis of a quinoxaline-based molecular cavitands.

In recent years, several other examples of quinoxaline-based molecular cavitands were synthesized from DCQX, and have been applied for several purposes, including encapsulation of organic molecules in their cavity such as chloroform (Hu et al., 2013), in addition to other organic solvents such as 1,4-dioxane, 1,4-dithiane and 1,4-thioxane (Fankhauser et al., 2014). Benzene when anchored into gold nanoparticles decorated multiwall carbon nanotubes (Clément et al., 2015), as well as for recognition of biologically relevant molecules in solution such as stereoids (Cacciarini et al., 2005), or even identification of enantiomeric pure L-adrenaline (Vachon et al., 2010).

Some interesting reports involving double chlorine substitution by S-nucleophiles through cyclization processes are presented in the recent literature (Scheme 16). A reaction of DCQX with thiourea followed by sequential base/acid treatment leads to 2,3-dithiolquinoxaline (48), which then reacts with its own DCQX to furnish the high conjugated dye [1,4]dithiino[2,3-b:5,6-b′]diquinoxaline (56) in good yield (Podsiadly and Sokolowska, 2012). Berridge et al. (2007) reported the synthesis and electrochemical properties of the dithiinoquinoxalined-based conjugated polymer from monomer 57, which was obtained in good yields from a synthetic protocol based on the reaction of DCQX with 1,3-dithiole-2-one (50) in basic media. Compound 57 had its structure determined by X-ray crystallography.

Reactions of DCQX with bis-S-nucleophiles: synthesis of 6,13-dithia-5,7,12,14-tetraaza-pentacene (A) and 1,3-Di-thiophen-2-yl-2,4,11-trithia-5,10-diaza-cyclopenta[b]anthracene-based conjugated polymer (B).
Scheme 16 Reactions of DCQX with bis-S-nucleophiles: synthesis of 6,13-dithia-5,7,12,14-tetraaza-pentacene (A) and 1,3-Di-thiophen-2-yl-2,4,11-trithia-5,10-diaza-cyclopenta[b]anthracene-based conjugated polymer (B).

Other quinoxaline derivatives obtained from double-chlorine substitution have recently been reported in literature, such as the compounds 59 and 60, which were interesting from the view of coordination chemistry (Hu et al., 2012; Peng et al., 2010).

4

4 Reactions of DCQX with P-nucleophiles

The contribution of phosphorous-based ligands to advances in asymmetric organometallic catalysis is well established (Fernández-Pérez et al., 2011). There are some interesting papers concerning the synthesis of phosphorous-based quinoxaline derivatives from nucleophilic reactions involving DCQX. In this context, Imamoto et al. (2005) reported the first example of P-chiral phosphine ligand (61) in which electron-withdrawing nature of the quinoxaline unit substantially increased the stability of the phosphine moieties to air hydrogenation (Imamoto et al., 2005). The synthetic route started with a two-step procedure for conversion of phosphine-borane (62) into its derivative 63, which is subsequently deprotonated by n-butyllithium. A reaction of an anionic specie with DCQX afforded the chiral P-quinoxaline after treatment with tetramethylethylenediamine. The authors applied this ligand 53 in Rh-catalyzed enantioselective hydrogenation of dehydroamino acid esters and enamines, and Rh- and Pd-catalyzed C—C bond-forming reactions involving asymmetric 1,4-addition of arylboronic acid to enones, as well as an asymmetric ring opening of epoxides (Scheme 17). A high yield and enantioselectivity were found in these reactions.

Synthesis of a quinoxaline-based asymmetric phosphines.
Scheme 17 Synthesis of a quinoxaline-based asymmetric phosphines.

Some other ligands have been sequentially synthesized from reactions of DCQX and P-nucleophiles, such as compounds 64 (Fox et al., 2008) and 65 (Zhang et al., 2012), among others (Fox et al., 2008; Hou et al., 2016; Imamoto et al., 2015, 2012; Zhang et al., 2012), which were also relevant in asymmetric catalytic hydrogenation and hydrocarboxylation of alkynes. On the other hand, some synthesized P-based quinoxaline derivatives presented interesting results in coordination chemistry (Adam et al., 2013; Cain et al., 2011; Hunt et al., 2011), such as compounds 66 and its Palladium complex 67, and its application in a C—N cross-coupling reaction (Adam et al., 2013).

4.1

4.1 DCQX reactions with C─nucleophiles

The literature presents interesting works involving C—C bond formation from DCQX and/or its direct derivative. Based on the combined substitution in DCQX by C- and N-nucleophiles. Ancizu and colleagues found urea-based quinoxaline derivatives in the search for targets that bind to MT1 and MT2 melatonin receptor, aiming at regulation of insomnia and other sleep disorders (Ancizu et al., 2012). In this work, 3-methoxyquinoxaline-2-carbonitrile (68) was obtained from sequential reactions of DCQX with methoxide and tetraethylammonium cyanide, and further converted in amide and urea derivatives. Another interesting approach for obtaining combined C- and N-functionalized quinoxalines from DCQX reactions with nucleophilic species was presented by Wang and co-workers, synthesizing several quinoxaline derivatives aiming for the therapeutic target of treating autoimmune disease by inhibiting the human IgC; human FcRn protein-protein interaction (Wang et al., 2013). The synthetic methodology was based on the sequential substitution of the chlorine in the halogenated building block by C-attack of cyanoacetamides, followed by a second substitution of chlorine by specific amine, with compound 69 being one of the main active compounds obtained in this work. These two latter examples are illustrated in Scheme 18.

Synthesis of quinoxaline derivatives from DCQX reactions in C-, N- and C-, O-combined nucleophilic substitution.
Scheme 18 Synthesis of quinoxaline derivatives from DCQX reactions in C-, N- and C-, O-combined nucleophilic substitution.

Soliman and Amer reported a very interesting work about the synthesis of biologically active quinoxaline-based heterocycles (Soliman and Amer, 2012). The protocol was based on the initial reaction of DCQX and hydrazine under controlled conditions for obtaining 2-hydrazino-3-chloroquinoxaline (70), followed by sequential reactions with active methylene compounds (Scheme 19). Reactions of 70 with malonitrile, diethyl malonate and cyano-acetic acid ethyl ester affords 3-amino-1,4-dihydropyridazino[3,4-b]quinoxaline-4-carbonitrile (71), 1-(3-chloroquinoxalin-2-yl)-1H-pyrazole-3,5-diol (72) and 5-amino-1-(3-chloroquinoxalin-2-yl)-1,2-dihydro-3H-pyrazol-3-one (73), respectively. Furthermore, a reaction of 70 and potassium thiocyanate led to forming 3-hydrazinoquinoxalin-2-yl thiocyanate, which undergoes a subsequent intramolecular cyclization in refluxing dimethylformamide to generate 1H-[1,3,4]thiadiazino[5,6-b]quinoxalin-3-amine. The compounds synthesized in this work were obtained in moderate to good yields and were found to have relevant antifungal and antibacterial activities.

Synthesis of quinoxaline-based heterocycles from reactions of compound 70 with active methylene compounds.
Scheme 19 Synthesis of quinoxaline-based heterocycles from reactions of compound 70 with active methylene compounds.

One very interesting methodology concerned the SNAr reactions of DCQX and C-nucleophiles was reported by Kumar and coworkers, as summarized in Scheme 20 (Kumar et al., 2012a, 2012b). This method consists in the AlCl3-mediated reactions of DCQX with phenols to afford monosubstituted quinoxaline derivatives such as 74, as well as mono- and disubstituted products from reactions with indoles, exemplified by compound 75 and 76, respectively. Furthermore, controlling the conditions led to the possibility of obtaining double substitution products from both phenol/indole-combined nucleophiles, such as compound 77. Two more interesting goals of these works consist in the possibility of one pot synthesis of the disubstituted products, as well as benzofuran-quinoxaline fused heterocycles from the C- and N- and O-combined nucleophilic substitution, as demonstrated by compound 78, which had its structure determined by X-ray crystallography. The reactions presented in Scheme 20 were performed in relative mild conditions and provided good yields for a representative scope. Moreover, some of the compounds were found to be an inhibitor of phosphodiesterase 4 enzyme (PDE4), which becomes relevant for the development of safer drugs.

AlCl3-based protocol for obtaining mono- and disubstituted quinoxaline derivatives.
Scheme 20 AlCl3-based protocol for obtaining mono- and disubstituted quinoxaline derivatives.

5

5 “Side heterocyclization”

The literature brings some interesting examples related to the synthesis of biologically active imidazo[1,2-a]quinoxalines as presented in Scheme 21. For example, compound 79 (EAPB0203) and its derivatives have emerged as promising agents against the human melanoma cell line A375 (Deleuze-Masquefa et al., 2009; Lafaille et al., 2012; Moarbess et al., 2008). Some derivatives of these imidazole-quinoxalines have been synthesized from reactions of DCQX with aminoalcohols via chlorine substitution via N-nucleophilic attack, followed by a sequential oxidation of the carbinol carbon, condensation similar to imine and Mn-induced aromatization of the dihydro-imidazol ring. Lastly, the target molecules are obtained when an amine replaces the remaining chlorine. This protocol is represented for obtaining compound 79 (Yoo et al., 2014). Two other methodologies for obtaining more elaborated imidazo[1,2-a]quinoxalines were recently published, as exemplified by compound 80 (Marjani et al., 2012) and 81 (Bakherad et al., 2012). For the first, the synthesis was performed in two steps including a DCQX reaction with arylaminoisoxazolone, followed by base-mediated cyclization and descarboxilation. For the second, the synthetic protocol was initiated by the reaction of DCQX with propargylamine followed by a sequential Pd-catalyzed cyclization and base-induced isomerization. Good yields were obtained for both methods.

Synthesis of imidazo[1,2-a]quinoxaline derivatives.
Scheme 21 Synthesis of imidazo[1,2-a]quinoxaline derivatives.

Other interesting heterocycles can be obtained from side cyclization of DCQX, such as [1,2,4]triazolo[4,3-a]quinoxaline and tetrazolo[1,5-a] quinoxalines, represented by compound 82 and 83, respectively, in Scheme 22. While the first is generated from an initial nucleophilic substitution in DCQX by hydrazine followed by the reaction with triethyl orthoformate, the second is directly obtained from the reaction of the referred building block with sodium azide. These abovementioned compounds were further functionalized in attempt to obtain anticonvulsant (Sarges et al., 1990) and dual antibacterial/antifungal agents (Kumar et al., 2011), respectively.

Synthesis of [1,2,4]triazolo[4,3-a]quinoxaline and 1,2,3,5,9b-Pentaaza-cyclopenta[a]naphthalene derivatives.
Scheme 22 Synthesis of [1,2,4]triazolo[4,3-a]quinoxaline and 1,2,3,5,9b-Pentaaza-cyclopenta[a]naphthalene derivatives.

The synthesis of a series of substituted 4-chloro[1,2,4]triazolo[4,3-a]quinoxaline derivatives was reported by Soliman and Amer (Soliman and Amer, 2012). The synthetic protocol involves an initial nucleophilic substitution in DCQX by hydrazine to afford 70, followed by sequential reactions with electrophilic partners: triethyl orthoformate to form 82, carbon disulfide, phenyl isothiocyanate and ethylchloroformate to afford, respectively, 1-thiol-, 1-phenylamino- and 1-hydroxy-derivatives (84–86), and acetic acid to form compound 87 (Scheme 23). Furthermore, the authors also proved that a reaction of 70 with 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-dithione (Lawesson’s reagent) leads to the formation of 4-chloro-1-(4-methoxyphenyl)-1,2-dihydro[1,2,4,3]triazaphospholo-[4,5-a]quinoxaline-1-sulfide (88).

Synthesis substituted 4-chloro[1,2,4]triazolo[4,3-a]quinoxaline from compound 70 and electrophilic partners.
Scheme 23 Synthesis substituted 4-chloro[1,2,4]triazolo[4,3-a]quinoxaline from compound 70 and electrophilic partners.

The method presented in Scheme 23 was also found to be effective for the synthesis of bis[1,2,4]triazolo[4,3-a:3′,4′-c]quinoxaline (89–92) from reactions of compound 93 (originated from double-chlorine substitution in DCQX by hydrazine) and two equivalents of appropriate electrophilic partners under similar conditions (Soliman and Amer, 2012). All relevant heterocyclic compounds reported in this work were found to exhibit relevant antibacterial and antifungal activities.

As a last example, Preβler and colleagues synthesized two bridged bis-benzimidazo[1,2-a:2′,1′-c]quinoxaline (94) from oxidative cyclization of previously prepared N,N'-di-aryl-quinoxaline-2,3-diamine (95) (Scheme 24) (Preβler et al., 2012). Although the yields of these reactions were low, compound 94 (which had is structure determined by X-ray crystallography) was very fluorescent, presenting a quantum yield of 0.96 in dioxane solution.

Oxidative cyclization of N,N′-di-aryl-quinoxaline-2,3-diamine.
Scheme 24 Oxidative cyclization of N,N′-di-aryl-quinoxaline-2,3-diamine.

6

6 Conclusion

The compound 2,3-dichloroquinoxaline (DCQX) has been widely used as a synthetic intermediate in organic and pharmaceutical chemistry, as well as materials science. Although there are reviews documenting the use of this reagent up to 2006, the considerable progress witnessed in the last ten years in developing new methods using this compound are scarce. The current review summarized these findings using DCQX focusing on one main type of reaction: SNAr for the construction of C—N, C—O, C—S, C—P and C—C bonds. Furthermore, other relevant synthetic transformations are presented and many of the products synthesized by the methods compiled in this article are unprecedented and have shown new and improved properties when compared to similar known structural compounds.

Acknowledgements

The authors would like to acknowledge the structural and financial support from CAPES, CNPq and UFRN.

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