Copper–phenanthroline catalysts for regioselective synthesis of pyrrolo[3′,4′:3,4]pyrrolo[1,2-a]furoquinolines/phenanthrolines and of pyrrolo[1,2-a]phenanthrolines under mild conditions

Summary A new series of pyrrolo[3′,4′:3,4]pyrrolo[1,2-a]furoquinolines/phenanthrolines and pyrrolo[1,2-a]phenanthrolines were efficiently built up from an 8-hydroxyquinoline derivative or phenanthroline via 1,3-dipolar cycloaddition reaction involving non-stabilized azomethine ylides, generated in situ from the parent furo[3,2-h]quinoliniums/phenanthroliums, in presence of a copper(II) chloride–phenanthroline catalytic system. The methodology combines general applicability with high yields.

for several years and established some synthetic routes towards indolizines, pyrrolo [1,2-a]quinolines/isoquinolines, oxazadicyclopenta[a,h]naphthalenes etc., some of which have been evaluated as potential antibacterial and antifungal agents [16][17][18][19]. In order to explore the possibility of using structurally more complex dipoles and dipolarophiles to construct more interesting structural networks, we replaced simple alkenes/ alkynes with maleimide derivatives. Our preference for this dienophile was dictated by a recent patent on the lifespan altering properties of cycloadducts involving maleimide dienophiles [20]. Moreover, very recently we have characterized some furo [3,2-h]quinoliniums as potent non-detergent spermicides [19], which encouraged us for further modification and derivatization of furoquinoline analogues in search for more potent agents. We initially employed the protocols from our recently developed green methodologies [21][22][23][24][25], which however failed to give any promising outcome and forced us to explore new catalytic systems. While searching for this goal, we were attracted by the possible application of copper-catalysis, which has always been an effective tool especially with Diels-Alder reactions [26,27]. Thus, we studied the effect of a number of catalytic systems and after an extensive screening, we found copper(II) chloride-phenanthroline as the best catalytic pair for this purpose. Herein we wish to present the results of our recent synthetic efforts to synthesize a series of unique pentacyclic pyrrolo[3′,4′:3,4]pyrrolo[1,2-a]furoquinolines/phenanthrolines using the above catalytic system. To the best of our knowledge, this is the first report of the application of this catalyst for the regioselective 1,3-dipolar cycloaddition reaction, involving azomethine ylides derived from structurally complex quinolinebased N-heterocycles.
We then studied the feasibility of a metal-catalyzed 1,3-dipolar cycloaddition strategy. A thorough screening of different catalysts, as summarized in Table 1, revealed the supremacy of copper catalysts in this particular reaction over the others; CuCl 2 appeared to be the catalyst of choice (Table 1, entries 8-32). In order to explore the effect of ligands, a number of phosphines, bis-oxazocines, pyrazolyl-pyrimidines and phenanthroline analogues were employed ( Figure 1). As represented in Table 1, the monodentate ligands are in general less effective (55-58% yield; Table 1, entries 21-25) than bi-/tridentate ligands (65-94% yield; Table 1, entries 26-32), and phosphines in general proved less effective in terms of product yield ( Table 1, entries 21-28). Bis-oxazocines and pyrazolyl-pyrimidines on the other hand showed some promising results ( Table 1, entries 29 and 30). However, both in terms of yield and cleaner reaction profile, 1,10-phenanthrolines (L 1 , L 2 ) were identified as the best partners for CuCl 2 ( Table 1, entries 31 and 32). Thus, the 1,3-dipolar cycloaddition reaction between 9a (1 equiv) and 4a (1.1 equiv) yielded 94% of 10a within 3 h, when 5 mol % CuCl 2 and 5 mol % of either L 1 or L 2 were employed with DBU as the base in acetonitrile solvent at 65 °C. This was taken as the best conditions to perform the reaction.
The structure of 10a was deduced from the appearance of a new doublet of doublets at δ 5.50 and δ 6.20. Another doublet at δ 3.90 and a new multiplet at δ 3.50 also indicated the success of the reaction, as these signals could be attributed to the new pyrrolidine core. Besides, the cluster in the aromatic region (δ 6.60-8.50) indicated the presence of 19 aromatic protons in the cycloadduct 10a. This interpretation was also well supported by the 13 Figure 2. No other diastereomer could be detected. In order to establish the general applicability of this protocol, we reacted different furo[3,2-h]quinoliniums 9a-d and maleimide dipolarophiles 4a-c under the standardized reaction conditions. As obvious from the results summarized in Scheme 4, all the reactions proceeded smoothly to give cycloadducts with excellent yields, which were fully characterized by mass and NMR analysis.
In order to test its general applicability further, we replaced furo[3,2-h]quinoliniums with phenanthroliniums 12a,b. These phenanthroliniums were synthesized (Scheme 5) from phenanthroline (11) and 2′-bromoacetophenones 8a and 8d, under basic alumina/microwave (180 W) conditions. These were then subjected to the optimized [3 + 2] cycloaddition protocol with different N-phenylmaleimide dipolarophiles 4a-c, which eventually produced similar cycloadducts 14a-c in high yield. It is interesting to note that every reaction proceeded only up to the cycloaddition stage, without any aromatization of the final cycloadduct. However, a similar reaction of phenanthroliniums 12a,b with alkyne dipolarophiles like acetylenedicarboxylates or monocarboxylates 13a-d proceeded with aromatization of the putative dihydroaromatic intermediates to produce the final cycloaddition products 14d-g.
Characterization of the products was done via mass and NMR spectral studies. Furthermore, the single-crystal X-ray study of cycloadduct 14e undoubtedly confirmed the structure of these cycloadducts, as obvious from the ORTEP diagram presented in Figure 3.

Conclusion
In conclusion, a simple CuCl 2 -phenanthroline catalyzed methodology has been developed to synthesize a series of unique heteroaromatic polycycles 10a-h, 14a-g by a 1,3dipolar cycloaddition reaction, using furo [3,2-     the compounds were performed on a Bruker KAPPA APEXII CCD diffractometer at 296 (2)