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Synlett 2009(2): 302-305  
DOI: 10.1055/s-0028-1087518
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Heterocyclizations via TosMIC-Based Multicomponent Reactions: A New Approach to One-Pot Facile Synthesis of Substituted Quinoxaline Derivatives

Constantinos Neochoritis, Julia Stephanidou-Stephanatou*, Constantinos A. Tsoleridis*
Department of Chemistry, Laboratory of Organic Chemistry, University of Thessaloniki, 54124 Thessaloniki, Macedonia, Greece
Fax: +30(2310)997679; e-Mail: ioulia@chem.auth.gr; e-Mail: tsolerid@chem.auth.gr;

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Publication History

Received 6 August 2008
Publication Date:
15 January 2009 (online)

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Abstract

A novel multicomponent reaction involving o-phenylenediamines, aldehydes and p-toluenesulfonylmethyl isocyanide (TosMIC) in the presence of a base leading to the formation of quinoxalines in very good yields is described.

Key words

multicomponent reactions - TosMIC - quinoxalines

Quinoxalines are widely used as intermediates in medicinal chemistry, [¹] [²] since they exhibit a wide range of biological activities, such as antiviral, antibacterial, anti-inflammatory and kinase inhibitor properties. [³-¹0] The echinomycin [¹¹] and the triostins [¹²] are well-known antibiotic families of quinoxaline derivatives. Furthermore, they have found applications as dyes, [¹³a] efficient electroluminescent materials, [¹³b] organic semiconductors, [¹³c] dehydroannulenes, [¹³d] cavidands [¹³e] and chemically controllable switches. [¹³f] Thus, a number of methods have been developed for the synthesis of substituted quinoxalines involving condensation of 1,2-phenylenediamines with α-diketones, also under microwave irradiation, [¹4] 1,4-addition of 1,2-diamines to diazenylbutenes, [¹5] oxidation trapping of α-hydroxyketones with 1,2-diamines, [¹6] oxidative cyclization of phenacyl bromides [¹7] or vicinal diols with o-phenylenediamines, [¹8] oxidative coupling of epoxides [¹9] or ketones [²0] with 1,2-diamines. Very recently, quinoxalines were also synthesized in 33-55% yield, through a two-step reaction sequence, the first step involving a multicomponent reaction between o-phenylenediamines, aldehydes and isonitriles in hydrochloric methanolic solution, whereas in the second step a DDQ oxidation of the isolated dihydroquinoxalines was involved. [²¹]

Sequential transformations and one-pot multicomponent reactions (MCRs) offer significant advantages over conventional linear step syntheses, by reducing time and saving money, energy and raw material thus resulting in both economic and environmental benefits. [²²] Moreover, multicomponent synthesis has been established as a valuable tool to the pharmaceutical industry for construction of low molecular weight compound libraries through combinatorial strategies and parallel synthesis. [²³] Although p-toluene­sulfonylmethyl isocyanide (TosMIC) is a versatile, widely applicable reagent that constitutes a densely functionalized building block bearing an active methylene group apart from its inherent advantage of possessing also an isonitrile functionality, which can serve as a handle for further manipulation, the possibility of its use in multicomponent reactions has not been greatly appreciated. TosMIC has most commonly been used in heterocyclic ring construction, [²4] in particular, of oxazole and pyrrole moieties, but comparatively rarely in multicomponent reactions. [²5]

Since the reaction between imines and TosMIC in basic media constitutes a trusted method for the synthesis of 1,5-disubstituted imidazoles [²6] and in continuation to our previous work [²7] we speculated that formation of quinoxalines would be possible, through a multicomponent reaction, by using o-phenylenediamines with equimolar amounts of an aldehyde and TosMIC.

Initially, a three-component reaction was performed between o-phenylenediamine, benzaldehyde and TosMIC in the presence of DBU as base, using toluene as solvent at room temperature for eight hours to afford the quinoxaline 3a in 45% yield along with the classical benzaldehyde-TosMIC reaction product, the oxazole 4a in 40% yield. In order to minimize the oxazole formation, the reaction was repeated by heating at 80 ˚C for four hours (Scheme  [¹] ), whereupon the yield of 3a was improved considerably (65%), whereas that of 4a was decreased to 27%. By using a milder base, DABCO instead of DBU, the optimum yield of 3a (91%) was achieved. However, in the presence of other bases, such as Et3N and K2CO3, the three-component reaction did not take place, so in the first case only N-benzyl-2-phenylbenzimidazole was isolated (45% yield), whereas in the second only the oxazole 4a in 74% yield.

Concerning the experimental procedure, a TosMIC-base toluene solution was added to an o-phenylenediamine-benzaldehyde solution, which had already been stirred for five minutes. The reaction also proceeded, but with lower yields, by simultaneously mixing all of the reactants. In contrast, initial stirring of o-phenylenediamine-benzaldehyde for longer periods resulted in substantially lower yields, most probably because of double Schiff base formation. This hypothesis is supported by the fact that quinoxaline 3 was not formed after an initial stirring for two hours.

Having established the best protocol for the formation of 3, all subsequent reactions were performed by using DABCO, although in some cases for comparison purposes the reactions were also repeated with DBU, and the results are presented in Table  [¹] (entries 1-8). Analogous results were obtained by using the chloro-substituted diamine (entries 9 and 10), whereas by using the dimethyl-substituted diamine the quinoxaline yields were optimized, when the stronger base DBU was used (entries 11-13). DBU was also the best base, when heterocyclic aldehydes were used (entries 14-18), though the yields were generally lower. Finally, the bulky anthracenealdehyde reacted analogously (entries 19 and 20).

Scheme 1 Reagents and conditions: DBU or DABCO, toluene 80 ˚C, 4 h

Table 1 Quinoxalines 3 Synthesized in this Work
Entry R¹ R² Ar Base Quinoxaline (%) Oxazole (%)
1 H H phenyl DBU 3a (65) 4a (27)
2 H H phenyl DABCO 3a (91) -
3 H H 2-methylphenyl DABCO 3b (89) -
4 H H 2,4-dimethylphenyl DABCO 3c (81) -
5 H H 4-methoxyphenyl DABCO 3d (82) -
6 H H 4-chlorophenyl DBU 3e (63) 4e (30)
7 H H 4-chlorophenyl DABCO 3e (84) -
8 H H 4-nitrophenyl DABCO 3f (80) 4f (10)
9 H Cl phenyl DBU 3g (45)a 4a (56)
10 H Cl phenyl DABCO 3g (79)a 4a (16)
11 Me Me phenyl DBU 3h (86) -
12 Me Me phenyl DABCO 3h (72) 4a (trace)
13 Me Me 2-methylphenyl DBU 3i (85) -
14 H H 2-furyl DBU 3j (46) 4j (40)
15 H H 2-thienyl DBU 3k (47) 4k (40)
16 H H 2-thienyl DABCO 3k (trace) -
17 H H 3-thienyl DBU 3l (49) 4l (40)
18 H H 3-thienyl DABCO 3l (trace) -
19 H H 9-anthryl DBU 3m (52) 4m (42)
20 H H 9-anthryl DABCO 3m (trace) -
a Isolated as a mixture of regioisomers in ca. 1:2 ratio.

From a careful inspection of the results given in Table  [¹] it can be concluded that the outcome of the competitive reactions (quinoxaline versus oxazole formation) depends not only on the substituents of the diamine and the aldehyde, affecting the extent of imine (Shiff base) formation (entries 1 vs. 2, 6 vs. 7 and 11 vs. 12), but also on the strength of the base, which affects the rate and the extent of the TosMIC anion formation, thus reacting more readily with aldehydes carrying electron-withdrawing substituents.

Quinoxaline formation can be rationalized via a plausible mechanism depicted in Scheme  [²] . It is conceivable that the initial step is the formation of the imine 5 followed by formation of the intermediate 6 through a nucleophilic attack of the base-activated TosMIC to the imine polarized double bond. Subsequent ring closure by intramolecular nucleophilic attack of the second NH2 group and loss of the tosyl moiety leads to the tetrahydroquinoxaline intermediate 7, from which by oxidation the more stable quinoxaline derivative 3 can be formed. [²8]

Regarding the structure of compounds 3, although they are known (with exception of 3f, 3i and 3m), perusal in the literature revealed no reported assignment of NMR signals to the corresponding atoms. Therefore, a full assignment of signals to corresponding atoms in the case of compound 3e is described, [²9] based on COSY H-H, XHCORR and COLOC spectral data. In Figure  [¹] the C-H COLOC correlations via ³ J CH are depicted.

Scheme 2 Plausible mechanism for the formation of quinoxalines 3

Figure 1 Diagnostic COLOC correlations between protons and ­carbons via ³ J C-H in compound 3e

The one-step synthesis reported herein offers a very convenient and conceptually new alternative to combinatorial synthesis of 2-arylquinoxalines. In addition, the otherwise difficult-to-access quinoxalines, bearing in the 2-position a heterocyclic ring, are isolated in good yields. To the best of our knowledge this new multicomponent reaction constitutes the first example of an aniline-like amino group functioning as internal nucleophile to intercept the TosMIC moiety interacting with an imine moiety. Moreover, the studied reactions constitute the first example wherein TosMIC reacts in this unique way, contributing only one carbon to the reaction.

In summary, we have described a multicomponent reaction leading to quinoxalines from simple, readily available and easy to handle precursors. This reaction can be extended to heterocyclic 1,2-diamines and N-monoalkylated diamines.

28

Evolution of gas with alkaline pH and characteristic amine odor was detected.

29

All melting points were determined on a Büchi apparatus and are uncorrected. The ¹H NMR and ¹³C NMR spectra were recorded on a Bruker AM 300 spectrometer in CDCl3 with TMS as internal standard. All coupling constants are given in Hz and chemical shifts are given in ppm.
Typical Experimental Procedure for the Preparation of 3e: To a stirred solution of o-phenylenediamine (1a; 1.0 mmol) in toluene (20 mL), 4-chlorobenzaldehyde (1.0 mmol) was added and stirring was continued for 5 min. Then TosMIC (1.0 mmol) and DABCO (1.2 mmol) were added and the reaction mixture was heated to 80 ˚C for 4 h. The resulting solution was initially washed with 5% HCl, then with H2O and dried. The solvent was distilled off under reduced pressure to yield the corresponding crude product mixture, which was purified by silica gel chromatography using petroleum ether-EtOAc (10:1) as eluent, to give quinoxaline 3e in 84% yield; yellow crystals; mp 136-
137 ˚C (ethanol) (lit. [³0] 137 ˚C). ¹H NMR: δ = 7.51 (dd, J = 8.8, 2.1 Hz, 2 H, 3′-H, 5′-H), 7.74 (dd, J = 8.8, 2.1 Hz, 1 H, 7-H), [³¹] 7.77 (dd, J = 8.8, 2.1 Hz, 1 H, 6-H), 8.10 (dd, J = 8.8, 2.1 Hz, 1 H, 5-H), 8.11 (dd, J = 8.8, 2.1 Hz, 1 H, 8-H), 8.12 (dd, J = 8.8, 2.0 Hz, 2 H, 2′-H, 6′-H), 9.27 (s, 1 H, 3-H). ¹³C NMR: δ = 128.7 (C-2′, C-6′), 129.1 (C-5), 129.4 (C-3′, C-5′), 129.5 (C-8), 129.8 (C-7), 130.4 (C-6), 135.1 (C-1′), 136.5 (C-4′), 141.6 (C-4a), 142.1 (C-8a), 150.5 (C-2). Anal. Calcd for C14H9ClN2 (240.69): C, 69.85; H, 3.74; N, 11.64. Found: C, 70.01; H, 3.83; N, 11.68.

31

The multiplicities and chemical shifts of the aromatic protons have been confirmed after simulation with program SpinWorks, version 2.5, available from
ftp://davinci.chem.umanitoba.ca.

28

Evolution of gas with alkaline pH and characteristic amine odor was detected.

29

All melting points were determined on a Büchi apparatus and are uncorrected. The ¹H NMR and ¹³C NMR spectra were recorded on a Bruker AM 300 spectrometer in CDCl3 with TMS as internal standard. All coupling constants are given in Hz and chemical shifts are given in ppm.
Typical Experimental Procedure for the Preparation of 3e: To a stirred solution of o-phenylenediamine (1a; 1.0 mmol) in toluene (20 mL), 4-chlorobenzaldehyde (1.0 mmol) was added and stirring was continued for 5 min. Then TosMIC (1.0 mmol) and DABCO (1.2 mmol) were added and the reaction mixture was heated to 80 ˚C for 4 h. The resulting solution was initially washed with 5% HCl, then with H2O and dried. The solvent was distilled off under reduced pressure to yield the corresponding crude product mixture, which was purified by silica gel chromatography using petroleum ether-EtOAc (10:1) as eluent, to give quinoxaline 3e in 84% yield; yellow crystals; mp 136-
137 ˚C (ethanol) (lit. [³0] 137 ˚C). ¹H NMR: δ = 7.51 (dd, J = 8.8, 2.1 Hz, 2 H, 3′-H, 5′-H), 7.74 (dd, J = 8.8, 2.1 Hz, 1 H, 7-H), [³¹] 7.77 (dd, J = 8.8, 2.1 Hz, 1 H, 6-H), 8.10 (dd, J = 8.8, 2.1 Hz, 1 H, 5-H), 8.11 (dd, J = 8.8, 2.1 Hz, 1 H, 8-H), 8.12 (dd, J = 8.8, 2.0 Hz, 2 H, 2′-H, 6′-H), 9.27 (s, 1 H, 3-H). ¹³C NMR: δ = 128.7 (C-2′, C-6′), 129.1 (C-5), 129.4 (C-3′, C-5′), 129.5 (C-8), 129.8 (C-7), 130.4 (C-6), 135.1 (C-1′), 136.5 (C-4′), 141.6 (C-4a), 142.1 (C-8a), 150.5 (C-2). Anal. Calcd for C14H9ClN2 (240.69): C, 69.85; H, 3.74; N, 11.64. Found: C, 70.01; H, 3.83; N, 11.68.

31

The multiplicities and chemical shifts of the aromatic protons have been confirmed after simulation with program SpinWorks, version 2.5, available from
ftp://davinci.chem.umanitoba.ca.

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Scheme 1 Reagents and conditions: DBU or DABCO, toluene 80 ˚C, 4 h

Scheme 2 Plausible mechanism for the formation of quinoxalines 3

Figure 1 Diagnostic COLOC correlations between protons and ­carbons via ³ J C-H in compound 3e