Pyrrolo quinoxalines, formation

The principle of systematization of data is the same as used in our previous reviews (Kalinin and Mamedov 2010 Mamedov and Kalinin 2010) focusing on pyrrolo[l,2-a]quinoxalines. Formation of the structure of each heterocyclic system is considered without including the benzene ring. The corresponding figures show all possible assembly variants in which quinoxaline or imidazole derivatives act as the initial compounds. 

Scheme 66 Pyrrolo[l,2-a]quinoxaline formation via CuI/L-proline catalyzed coupling of 2-halotrifluoroacetanilides and pyrrole-2-carboxylate esters...

Inspired by the bioorganometallic approach, two series of ferrocenyl pyrrolo[ 1,2-a] quinoxalines were designed and prepared (Fig. 17). The derivatives were tested in vitro against three different strains of P. falciparum F32, FcBl, and PFB [107]. The best results (IC50 between 30 and 70 nM in comparison to CQ IC5o = 225 nM) were observed in the first series with a bis(3-aminopropyl)piperazine as a linker. These compounds were tested for then ability to inhibit p-hematin formation. For all but one case, the derivatives did not interfere with hemozoin formation... 

Nitration of pyrrolo[l,2-a]quinoxaline by adding a mixture of the compound and potassium nitrate to concentrated sulfuric acid yields a mixture of 25% 1-nitro and 48% 3-nitro derivatives. No significant reaction was observed with potassium nitrate in trifluoroacetic acid, or in fuming nitric acid alone or fuming nitric acid and acetic anhydride." The attempts to avoid the use of sulfuric acid were made because of the ease with which the heterocycle undergoes sulfonation. Thus treatment with concentrated sulfuric acid at room temperature readily gave the 3-sulfonic acid. Apparently the electrophile is too large to allow formation of detectable amounts of the isomeric 1-sulfonic acid. The 1-methyl and... 

Catalytic hydrogenation of l-chloropyrrolo[l,2-a]quinoxalines results in removal of the halogen atom. Apparently the dechlorinated products are themselves reducible, and care must be taken in dechlorinations to allow the absorption of only one mole of hydrogen. A recent paper describes reduction of the 4,5 bond in pyrrolo[l,2-a]quinoxalines. 1,5-Dihydro-1-0X0 compounds are resistant to hydrogenation at atmospheric pressure. Reduction of the 1-oxo compound 117 over palladium on charcoal at 2000 psi gave an unidentified tetrahydro derivative. " The dioxo compounds 118 have been reduced with lithium aluminum hydride to give the hexahydro products 119. Heating 4,5-dihydro-4-thioxo derivatives with Raney nickel results in formation of the aromatic, desulfurized compound. Stannous chloride has been used to reduce... 

Recently, copper salts alone have been reported to effect the direct annulation of terminal alkynes by AT-(o-iodophenyl)trifluoroacetamide (Eq. 17) [49] and the analogous formation of pyrrolo[2,3-b]quinoxalines [50] with loss of the trifluoroacetyl group. 

Scheme 2.73 One-pot synthesis of the pyrrolo[l, 2-a]quinoxalines 406 and a plausible mechanism for their formation...

A plausible mechanism of the reaction involves the formation of compound 406 by the nucleophilic substitution by 405 on 2-halonitroarenes 383, 404 or 1,2-dihalobenzenes (see Sect. 2.7.3) and the formation of carboxamide anion 408. Finally, an intramolecular nucleophilic reaction of 408 with the displacement of the leaving group by carboxamide anion would lead to pyrrolo[l,2-a]quinoxaline 406 (Scheme 2.73). 

One of the most widespread and most widely used among methods for the synthesis of pyrrolo[ 1,2-a]quinoxaUnes is the method involving the intramolecular cycliza-tion of derivatives of quinoxaline with substituents at position 2 and containing at least three carbon atoms with reaction centers capable of nucleophilic attack. Quinoxalines 1, containing a ycarbonylalkyl substituent at position 2 (ketones, carboxylic acids, esters) undergo intramolecular cyclization under the influence of acids with the formation of pyrroloquinoxalines 2-4 (Scheme 3.1) (Kumashiro 1961 Taylor and Hand 1962, 1963 Cheeseman and Roy 1969). 

Matoba et al. 1983), which have competing reaction centers capable of undergoing nucleophilic attack, in this reaction leads not to the supposed derivatives of azepino [ 1,2-a]quinoxaline 17 hut to the formation of the pyrrolo[l,2-a]quinoxalines 15j, k (Scheme 3.5). 

As a mle, in these reactions, the quinoxaline derivative directly or indirectly fulfills the function of a 1,3-dipolar compound, and this determines the path to the formation of the final product-pyrrolo[l,2-a]quinoxaline-and its structure almost irrespective of the nature of the 1,3-dipolarophile. During the reaction of 2,3-dimethylquinoxaline monooxide 41 and 2,3-dimethylquinoxaline dioxide 44 with methyl phenylpropargylate 42 in molar ratios of 1 1 and 1 2, respectively, compounds 43 and 45 are formed (Scheme 3.15) (Kaupp et al. 1987). 

However, the reaction of 2,3-dimethylquinoxaline 51a with maleic anhydride 46a under standard conditions (Taylor and Hand 1963) takes place with the formation of a compound with the empirical formula C14H12N2O3, the IR spectrum of which does not contain bands for the stretching vibrations of the anhydride groups but there are bands for the stretching vibrations characteristic of NH, the OH of the carboxyl function, the double bond, and an amide vinylog (Scheme 3.16). The NMR spectra and the chemical properties of the adduct show that pyrrolo[l,2-a]quinoxaline 52a is formed as a result of the reaction, and this can be represented by the Scheme 3.16 (Taylor and Hand 1962, 1963). Accordingly, the condensation of maleic anhydride with 2-methylquinoxaline and 2-methyl-3-phenylquinoxaline gives 2-carboxymethyl- 52b and 2-carboxymethyl-4-phenylpyrrolo[l,2-a] quinoxalin-l(5H)-ones 52c (Taylor and Hand 1963 Taylor and Cheeseman 1964). 

To realize the strategy for the synthesis of pyrrolo[l,2-a]quinoxalines denoted by the symbol QC2 it could be possible to use the 1,3-dipolar cycloaddition of the quinoxalinium A-ylide, produced in situ by the reaction of 1 -phenacylquinoxalium bromide with triethylamine, with various 1,3-dipolarophiles if the formation of the... 

Under these methods of synthesis of pyrrolo[l,2-a]quinoxalines, we include methods based either on condensed derivatives of quinoxaline (a) or on compounds containing neither a pyrrole ring nor a quinoxaline system (b). In method (b), the pyrroloquinoxaline system can be formed with the initial formation of the pyrrole ring (b-7) or the quinoxaline system (b-IT). In this review, we examine only the second version (h-IT). 

The reaction of methyl propargylate (propiolate) with benzylimidazole and its 2-alkyl and aryl derivatives in acetonitrile leads to the formation of the methyl esters of 3-fran -(l-benzimidazolyl)acrylic acid 106a and 107a, b, whereas the reaction with benzimidazole in methanol leads exclusively to the corresponding cis isomer 106b in the absence of the solvent, the treatment of benzimidazole with methyl propiolate gives a mixture of compounds 106a, b, and pyrrolo[l,2-a]ben-zimidazole 108 (Fig. 3.5). At the same time, the 2-isopropyl, 2-phenyl, and 2-benzyl derivatives of benzimidazole in reaction with methyl propiolate without a solvent form the pyrrolo[l,2-a]quinoxalines 114 and 115 (Scheme 3.35) (Acheson and Verlander 1973). 

The formation of the pyrrolo[l,2-a]quinoxaline stmcture in this reaction can be represented in one of two ways (Scheme 3.38) (a) isomerization of the 2-hydroxy-1,5-diketone 118 to the 5-hydroxy-l,4-diketone 121 with the subsequent formation of the o-aminophenylpyrrole 122 and closure of the dihydroquinoxaline structure 123 (b) reaction of the a-hydroxyketone fragment with 1,2-DAB with the formation of the hydroquinoxaline derivative 125 and subsequent closure of the dihydropyrrole ring and isomerization of the 3,3a-dihydropyrrolo[l,2-a]quinoxaline structure 124 to the more stable 4,5-dihydropyrrolo[l,2-a]quinoxaline structure 123. 

The reaction of l-(2-isocyanoaryl)pyrroles with Eschenmoser s salt 147 also goes smoothly with the formation of dimethyl(pyrrolo[l,2-tz]quinoxalin-4-ylmethyl)ammonium iodides 148 (Scheme 3.44), which after treatment with an aqueous solution of NaHCOs readily give quantitative yields of the free bases. In the case of the reactions of l-(2-isocyanophenyl)pyrroles 137a, b with other salts of the iminium type 149 and 151, obtained from secondary amines and aldehydes in the presence of MesSiCl/Nal/EtsN, it was shown that such a synthesis of 4-(l-dialk yl-aminoalkyl)pyrrolo[l,2-ti]quinoxalines 150, 152, and 153 is universal (Kobayashi et al. 2001b). 

The key stage in the synthesis of pyrrolo[l,2-a]quinoxalines 183 (Scheme 3.54) by type PA3 (Campiani et al. 1991, 1997) involves intramolecular substitution of a fluorine atom in the aromatic ring by the carboxamide group formed in sim in the l-aryl-2-cyanopyrroles 182 by the action of KOH. The formation of compounds 182 is a multistage process synthesis of the 1-arylpyrroles by the Clauson-Kaas reaction (Clauson-Kaas and Tyle 1952) and introduction of the CN group at position 2 of the pyrrole ring according to the Scheme 3.54. 

The stmcture and the mechanism of formation of the pyrroloquinoxaline 190 in this reaction were partly clarified by realizing closure of the ring in compound 187 in an atmosphere of argon in the absence of carbon monoxide. Moreover, it was shown that heating of compound 187 in an atmosphere of argon in the absence of the palladium catalyst also leads to a small yield of the pyrrolo[l,2-a]quinoxalines. The part played by the catalyst in the closure of the pyrazine ring is not understood. 

An excellent example illustrating the production of pyrroloquinoxalines by the PBl path is the cyclization of l-(2-aminophenyl)pyrroles with formic acid. Thus, boiling of compound 164a in formic acid leads to the formation of unsubstituted pyrrolo [l,2-ti]quinoxaline 138 with a yield of 80 % (Cheeseman and Tuck 1966 Gob and Cheeseman 1986). However, the reaction of the diaminophenylpyrrole 164e under these conditions leads to the formation of 9-formyl-amidopyrroloquinoxaline 191d (Scheme 3.57) (Hou and Balli 1992). 

Thus, a rare one-pot reaction for assembling pyrrolo[l,2-fl]quinoxalines from 1-(2-nitrophenyl)pyrroles and various alcohols. The nitro reduction, alcohol oxidation, heterocycle formation, and heterocycle oxidation were realized in a cascade. A wide range of these fused heterocycles bearing different alkyl and aryl groups in position 4 have been elaborated from suitable substrates thereby 3-nitro-2-pyrrolopyridine was also compatible with this process, giving the corresponding fused tricyclic compounds. 

The reduction with sodium dithionite in aqueous acetic acid gives imidazoquinoxaline 73c in nearly quantitative yield (Lee and Brown 1984). It should be noted that this method is universal for synthesis of derivatives of other heterocyclic systems, in particular, thiazolo[3,4-a]- (Adegoke and Alo 1983), pyrrolo[l, 2-a]- (Silvestri et al. 2000) and indolo[l,2-a]quinoxalines (Basanagoudar et al. 1991). Their formation depends on the type of heterocyclic moiety in compounds 71 (Scheme 4.33). 

Returning to the synthesis of 2,3-few(benzimidazol-2-yl)quinoxalines 100a-g (Scheme 6.41 Table 6.5) it should be noted that in one case, i.e., in the case of the synthesis of 2,3-fcw(benzimidazol-2-yl)-6-nitroquinoxaline lOOe, the less-reactive l,2-diamino-4-nitrobenzene 5h was used as a reagent. In this case a derivative of pyrrolo[l,2-a]quinoxaline containing one benzimidazolone (in position 1) and two benzimidazole (at positions 2 and 3) fragments in the newly formed pyrrole ring from the reaction mixture were isolated in trace amounts as an unexpected product. The formation of compound 159 could be due to the condensation of 3-(benzimidazo-2-yl) quinoxalin-2(lf/)-one 37s with its predecessor-3-(benzimidazol-2-yl)methylene-... 

Scheme 6.68 The formation of l-(benzimidazol-2-on-l-yl)-2,3-(dibenzimidazol-2-yl)pyrrolo-[l,2-a]quinoxalin-4(5W)-one 159...

As can be seen in Scheme 6.69, the formation of compound 159 occurs as a result of a cascade reaction involving (a) the intermolecular ene reaction (Naruse et al. 2005 Hilt and Treutwein 2007 Shen et al. 2009) between the enamine 107 and ketone 37s with the formation of compound A, (b) the intramolecular ene reaction (Oppolzer et al. 1973 Keck and Webb 1979, 1981) with the formation of the spiro-derivative quinoxalinono[2, l]pyrrolo[l,2-a]quinoxaline B, and (c) a new... 

A. Nicolescu, C. Deleanu, E. Georgescu, F. Georgescu, A.M. lurascu, S. Shova, P. FiUp, Unexpected formation of pyrrolo[l,2-fl]quinoxaline derivatives during the multicomponent synthesis of pyrrolo[l,2-a]benzimidazoles. Tetrahedron Lett. 54 (2013) 1486-1488. 

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