3-Nitro-2(1H)-quinolone derivatives as 2π components in 1,3-dipolar cycloadditions of azomethine ylides: A new synthesis of pyrrolo[3,4-c]quinolines

Abstract The 1,3-dipolar cycloaddition of 3-nitro-2(1H)-quinolones with ester-stabilized azomethine ylides derived from sarcosine ester and various aromatic aldehydes has been investigated. The structure and stereochemistry of cycloadducts were studied in detail by X-ray and NMR spectroscopy methods. GRAPHICAL ABSTRACT


Introduction
The design of simple and efficient chemical reactions for the synthesis of structurally complex, bioactive compounds is one of the major challenges often encountered in modern drug discovery. The traditional approaches involve the use of multistep, linear reaction sequences which are often associated with low overall yields, high cost, as well as tedious isolation and purification of the products. Multicomponent reactions (MCRs) offer a convenient strategy for the rapid and convergent synthesis of complex polyheterocycles in a single reaction, resulting in substantial reduction of labor, time, cost, and associated waste, and as such, they play a vital role in combinatorial and diversity-oriented syntheses.
[1] Among MCRs, the intermolecular (3 þ 2)-cycloaddition of azomethine ylides to olefinic dipolarophiles constitutes a facile approach for the efficient assembly of five-membered heterocyclic rings of biological importance, particularly pyrrolidines and pyrroles due to their frequent occurrence in natural products. [2] Pyrroles combined with quinolines are important structural motifs that can be often observed in bioactive molecules as well as in natural products, such as martinelline alkaloids with a pyrrolo[3,2-c]quinoline core. [3] Our long-standing interest in the chemistry of the pyrrolo-quinoline ring system and our recent involvement in a work project at Servier led us to explore new routes for obtaining 2H-pyrrolo [3,4-c]quinolines.
Pyrrolo [3,4-c]quinoline derivatives display a wide range of important biological activities. For example, compound 1 proved to be an effective 5-HT 3 -antagonist [4] while 2 was identified as a potent aggrecanase inhibitor. [5] Compound 3 showed antibacterial activity against Gram positive and negative bacteria [6] and the compound series 4 was patented based on their serotonergic activity. [7] Compound 5 and its derivatives were found to be caspase inhibitors (Fig. 1). [8] The pyrrolo [3,4-c]quinoline core is also incorporated in several polycyclic marine alkaloids, such as plakinidines A-E or alplakinidine (Fig. 2). [9] Synthetic methods for pyrrolo [3,4-c]quinolines are scarce in the literature: a few examples are described, with little variation in their synthetic strategies. Most of the approaches are based on the cyclization of 4-(2-aminophenyl)-pyrrolidin-3-carboxylates [10] and on the intramolecular rearrangement of various 2-oxindole derivatives. [11] Besides these two strategies, several interesting syntheses were described based on, e.g., the cyclization of azido-diynes catalyzed by copper and gold, [12] iridium catalyzed photocyclization, [13] or the domino reaction of tosylmethyl isocyanides and aminochalcones. [14] We envisaged that this heterocyclic ring system could be synthesized in a single step, involving the reaction of azomethine ylides and an appropriately functionalized quinolone used as a dipolarophile. Despite 3-nitro-2(1H)-quinolones are promising starting materials for the synthesis of functionalized heterocyclic frameworks, to our knowledge, they have never been used as 2p components in cycloaddition reactions with 1,3-dipoles. A single example in the literature describes their reaction with various dienes as a dienophile resulting in the formation of 5(6H)phenanthridones. [15] Results and discussion The 3-nitro-2(1H)-quinolone derivatives (9a-e) were prepared by the modification of the method described by Chen [16] from the corresponding 2-amino-benzaldehydes (6a-e) and ethyl 2-nitroacetate 7 by refluxing in acetic acid, in a single step. The products (9a-e) were isolated by a simple filtration after cooling the reaction mixture and they were used in the next step without any purification (Scheme 1, Table 1).
The condensation of various aldehydes with N-alkyl or N-aryl a-amino esters leads to N-substituted azomethine ylides. [17] These ylides can be trapped smoothly by the added dipolarophiles since there are no other reactive reagents (e.g., base, Lewis acids) in the reaction mixture. The cycloaddition of 9 with the azomethine ylides 12 derived from methyl sarcosinate 10 and benzaldehydes 11 in refluxing toluene under Dean-  Stark conditions resulted in the formation of cycloadducts 13 and/or 14 in moderate yields (Scheme 2, Table 2). In almost all cases, the regio-and stereoselective formation of the expected 14 anti-endo cycloadducts was observed. While in the case when the aromatic aldehyde or the quinolone had an orto-substituents close to the reaction center, it had a direct effect on the stereochemical outcome of the cycloaddition and resulted in the formation of a mixture of cycloadducts: the 14 anti-endo and the corresponding 13 syn-endo isomers were both isolated (endo and exo being referenced to the nitro group on the dipolarophile). The yields and the isomeric ratios are collected in Table 2.
The formation of the different diastereomers was clearly indicated by the changes in the chemical shifts in the corresponding 1 H-and 13 C-NMR spectra of the isolated products; for example, the H-1 and H-9b protons of 13d compared with the analogous antiendo adducts (14d) had a significant upfield shift, while the coupling constants of H-1 and H-9b also changed significantly (Table 3). Interestingly, the chemical shift of the C-3a quaternary carbon also indicated the change in the relative stereochemistry, which was first confirmed by 1 Hf 1 Hg n.O.e and ROESY studies. Finally, these results were validated by single crystal X-ray studies on three selected compounds (14b, 14c, and 13d) which revealed the proposed structures (Figs. 3-5).
In conclusion, we have synthesized a series of novel pyrrolo [3,4-c]quinoline derivatives that carry diverse substitution patterns by choice. This method offers the synthesis of the desired products from readily available and affordable starting materials in a simple, selective, one-pot three-component single-step reaction under mild conditions.