Simple synthesis of 2-alkylidene-and 2-keto-7-triazolylquinoxaline systems from 2-nitrosodiarylamines

A synthesis of triazole-substituted 1-arylquinoxaline derivatives from halogenated 2-nitrosodiarylamines by two routes is presented. Regioselective substitution of fluorine or chlorine in the starting compounds by sodium azide followed by double cyclocondensation of both the azide substituent and the nitrosoamine group leads to functionalized 2-methylenequinoxaline derivatives. The alternative route separates the two cyclocondensation reactions, allowing obtention of triazole-substituted quinoxalin-2-one derivatives by using two different dicarbonyl reagents


Introduction
2][3][4] Nitrogen polycyclic heterocycles possessing triazole ring as a substituent attract continuous attention.Synthesis of triazoles is accomplished most frequently using the azido group as a three-nitrogen atom donor.Thus, heteroaromatic azides become crucial starting materials in the synthesis of such polyheterocyclic systems.In 2007, we discovered the reaction of nitroarenes with aromatic amines in the presence of a strong base leading to 2-nitrosodiarylamines .7,8These compounds turned out to be versatile starting materials for synthesis of a number of two-nitrogen-containing heterocycles such as phenazines, 9,10 benzimidazoles 11 and quinoxalinones. 12On the other hand, when the leaving group was present in the ring containing the nitroso group, the latter acted as a strong electron-withdrawing group activating the leaving group for aromatic nucleophilic substitution.The reaction was found efficient for alkoxy or alkylamine nucleophiles.However, due to high reactivity of the nitroso group towards various nucleophiles as well as its susceptibility to redox processes, the choice of potential nucleophiles has been limited. 13ecently we found that the range of suitable nucleophiles can be extended to azide anions.In this report, we present a simple synthesis of 5-azido-2-nitrosodiarylamines which can be further transformed into 2alkylidenequinoxalines bearing triazole group in position 7, via the cascade reaction with β-dicarbonyl compounds.This method allows for obtaining complex structures starting from simple substrates under mild, heavy-metal-free conditions.Furthermore, a complementary approach which make use of 2nitrosodiarylamines in the synthesis of triazole-substituted quinoxalin-2-one derivatives is presented.

Results and Discussion
Substitution of halogens (F, Cl) at the para position to the nitroso group with sodium azide proceeded smoothly with very good to excellent yields at room temperature in the systems: water-alcohol, dipolar aprotic solvents or catalytic two-phase solid-liquid system (PTC).PTC was chosen for a standard procedure (Table 1).The obtained crude products were pure enough for further use, thus, as they are not stable under column chromatographic conditions, they were used without purification.
The reaction was highly regioselective.Azide ions exclusively substituted the para-chloro position in 3,5dichloro-2-nitrosodiarylamine (Table 1, entry 7).This is in accordance with the results of the previously examined reactions of halogenated nitrosodiarylamines with alkyl amines or alcohols. 13The regioselectivity has been attributed to the significant contribution of the quinoid structure in the substrate, which is a result of the conjugation between the nitroso and the ortho-arylamine group .13Table 1.Substitution of halogens in 2-nitrosodiarylamines 1 by azide ions Substitution of ortho-chloride, when it is the only leaving group in the molecule, occurs very slowly and is followed by intramolecular condensation of the azido and nitroso groups resulted in formation of a benzofurazan system 4a (Scheme 2).The ortho azido nitroso compounds 3 were not isolated nor observed, but it seems reasonable to assume them as intermediates leading to 4. Surprisingly, the methoxy group at para position resists of substitution by azide ions in 1i, while it was preferentially substituted with pyrrolidine in 3-chloro-5-methoxy-2-nitrosodiarylamines. 13The substitution of ortho halogens by azide ions forming benzofurazan derivatives was observed and described earlier for a few 2,6-dihalonitrosobenzenes in their reaction with sodium azide in DMSO at elevated temperature. 14,15Since the cyclization seems to be much faster than the substitution, obtaining oazidonitrosoarenes this way was not possible.
Functionalization of 2-nitrosodiarylamines with an azido group opened up a new perspective for building complex heterocyclic systems containing multiple rings.Initially we tried to build a triazole ring by coppercatalyzed cycloaddition 16 of the azido group with propargyl alcohol derivatives but the results were disappointing, probably because of reactivity of the nitroso group under the reaction conditions.Thus, we turned out to the most straightforward and reasonable idea to build two different heterocyclic rings on the two reactive centers, the ortho-nitrosoaniline and the azido functions, in the reaction with the same shared reagent.While double condensation reactions of 2 with benzyl cyanide, cyanoacetic acid esters and malonates were unsuccessful, with 1,3-diketones or β-ketoesters gave positive results.The reaction worked satisfactorily in MeCN with various β-diketones, provided that they possessed at least one terminal methyl group.tert-Butylamine was chosen as a catalyst since it had been found to be the best catalyst for the previously developed reaction of 2-nitrosodiarylamines with β-diketones leading to the condensed pyrazine ring. 17,18ble 2. Double cyclization of 2 with 1,3-dicarbonyl compounds Formation of the triazole ring proceeds most likely via the dipolar cycloaddition of the enolate form of βdicarbonyl compound and aryl azide, [19][20][21] for which detailed mechanistic studies and explanation of the observed regioselectivity have been reported. 19The reactions 2 -> 5 are also regioselective.The expected structure of the regioisomer formed was confirmed for selected triazoles (5a, d and f) by NMR techniques HMBC and NOESY.The latter proved proximity of the triazole methyl group and appropriate protons of the dihydroquinoxaline aromatic ring.
Our efforts to perform consecutively both cyclizations failed, i.e. by using different dicarbonyl reagents with NO and N 3 groups.This was probably because of a multistep character of both cyclizations, and because they take place in distant regions of the starting molecule.Hence, they may occur independently of each other at the same time.Consecutive, controlled formation of both heterocyclic rings, using different dicarbonyl reagents dedicated for particular cyclization, required a different approach.Thus, we tried to introduce the azido function into bicyclic systems obtained by condensation of 2-nitrosodiarylamines with dicarbonyl compounds.This condensation, which has been described previously, 11,12 allows for the formation of quinoxalin-2-one derivatives possessing alkoxycarbonyl substituent at C3. Carbocyclic rings of these compounds seem to be electrophilic enough for the nucleophilic substitution of halogens, placed in the activated positions 5 or 7, with azide ions.Thus, further condensation of the bicyclic azides could be carried out with another carbonyl reagent.As an illustration of this approach, the three-step synthetic sequence starting from representative 2-nitrosodiarylamines was accomplished (Table 3).While fluorine was substituted by sodium azide in quinoxalin-2-ones 6a and 6b efficiently at room temperature, the reaction of chloro derivative 6c required elevated temperature (80 °C) and gave much lower yield of 7c.On the other hand, relatively low yield of the cyclization of 7a is difficult to explain.Nevertheless, the approach can be useful for the synthesis of complex nitrogen heterocyclic compounds of a specific structure.

Conclusions
It was demonstrated that halogenated 2-nitrosodiarylamines can be useful starting materials in the synthesis of triazole-substituted 1-arylquinoxaline systems by two routes.The two-step method benefits from the

Experimental Section
General. 1 H and 13 C NMR spectra were recorded on a Varian-NMR-vnmrs600 and a Varian Mercury 500 instruments at 298 K.Chemical shifts are expressed in ppm referred to TMS ( 1 H NMR) or to the solvent used ( 13 C NMR), with coupling constants in Hertz.Mass spectra were obtained on an AutoSpec Premier (Waters) spectrometer (EI, 70 eV) and an API 365i spectrometer (ESI in MeOH).Silica gel Merck 60 (230-400 mesh) was used for column chromatography.THF was distilled from sodium/benzophenone ketyl prior to use.DMF was dried over CaH 2 , distilled and stored over molecular sieves.Common reagents and materials were purchased from commercial sources and used as received.Preparation and characterization of 2-nitrosodiarylamines 1, except 1a, 1e and 1f, have been described in our previous papers. 8,17,18Quinoxalinones 6a-c were prepared following the procedure published earlier. 12

Figure 1 .
Figure 1.Examples of important structures of polyheterocyclic compounds A 5 and B 6 bearing triazole ring.
bCrude products, pure enough for further transformations.c Isolated and purified by column chromatography. 5 b Isolated yields.