Efficient synthesis of polyfunctionalized carbazoles and pyrrolo[3,4-c]carbazoles via domino Diels–Alder reaction

The p-TsOH-catalyzed Diels–Alder reaction of 3-(indol-3-yl)maleimides with chalcone in toluene at 60 °C afforded two diastereoisomers of tetrahydropyrrolo[3,4-c]carbazoles, which can be dehydrogenated by DDQ oxidation in acetonitrile at room temperature to give the aromatized pyrrolo[3,4-c]carbazoles in high yields. On the other hand, the one-pot reaction of 3-(indol-3-yl)-1,3-diphenylpropan-1-ones with chalcones or benzylideneacetone in acetonitrile in the presence of p-TsOH and DDQ resulted in polyfunctionalized carbazoles in satisfactory yields. The reaction mechanism included the DDQ oxidative dehydrogenation of 3-(indol-3-yl)-1,3-diphenylpropan-1-ones to the corresponding 3-vinylindoles, their acid-catalyzed Diels–Alder reaction and sequential aromatization process.


Results and Discussion
According to our previously established reaction conditions for the preparation of spiro[indoline-3,5'-pyrrolo [3,4-c]carbazoles] [48], an equivalent amount of 3-(indol-3-yl)maleimide with chalcone was stirred in toluene at 60 °C for two hours in the presence of p-toluenesulfonic acid. After workup, two diastereoisomers 3a and 3b of tetrahydropyrrolo [3,4-c]carbazoles were successfully isolated in 18% and 71% yields, respectively (Scheme 1). It should be pointed out that nearly no reaction was detected in the absence of p-toluenesulfonic acid. The structures of both products were fully characterized by various spectroscopy methods and confirmed by determination of their single crystal structures ( Figure 2 and Figure 3).
From Figure 2, it can be seen that the phenyl group and the adjacent p-chlorobenzoyl group are trans-oriented. Additionally, the phenyl group is cis-oriented to the 1-benzylpyrrolidine-2,5-dione ring in compound 3a. On the other hand, for compound 3b (Figure 3), it can be seen that the phenyl group is trans-oriented to both, the p-chlorobenzoyl group and the 1-benzylpyrrolidine-2,5-dione ring in this compound. Thus, the isomers 3a and 3b are diastereoisomers. It is known that the starting chalcones usually have E-configuration. The phenyl group and p-chlorobenzoyl group still exist in the trans-position in both diastereoisomers 3a and 3b as in the starting chalcone. This result clearly showed that this acid-catalyzed cycloaddition reaction proceeded through a concerted Diels-Alder reaction mechanism.
The acid-catalyzed Diels-Alder reaction afforded a mixture of two diastereoisomers, which decreased the synthetic value of the reaction. Thus, after the first step reaction, a DDQ dehydrogenation reaction was carried out in acetonitrile at room temper-  ature. A series of aromatized pyrrolo[3,4-c]carbazoles 4a-l were successfully synthesized by the one-pot two-step reaction and the results are summarized in Table 1. All reactions proceeded smoothly to give the corresponding pyrrolo [3,4c]carbazoles 4a-l in satisfactory yields. Indole itself and N-methylindole could also be successfully employed in the reaction. The N-Me, N-Ph, and N-Bn substitution in the maleimide moiety showed only a marginal effect on the reaction outcome. Various chalcones with electron-donating methyl and methoxy groups and electron-withdrawing m-chloro and p-chloro substituents gave the products in good yields. However, the nitro-substituted chalcone gave the product 4h in a slightly lower yield. The structures of the pyrrolo[3,4c]carbazoles 4a-l were established by various spectroscopy methods. Further, the single crystal structure of compound 4g was determined by X-ray diffraction ( Figure 4). It can be seen that the ring of pyrrolo [3,4-c]carbazole exists in a slightly twisted plane. The dihedral angles of the phenyl and the benzoyl group to the central benzene ring are 72.018° and 88.402°.
To further expand the scope of this domino Diels-Alder reaction, another kind of 3-vinylindoles was employed in the onepot reaction. First, the 3-(indol-3-yl)-1,3-diphenylpropan-1-ones prepared through Friedel-Crafts alkylation of indole with chalcones, were oxidized by DDQ in acetonitrile to generate in situ the expected active diene, indole-substituted chalcones. Then, the p-TsOH-catalyzed Diels-Alder reaction of indole-chalcones with second chalcones and sequential aromatization through DDQ dehydrogenation resulted in the polyfunctionalized carbazoles 6a-l in good yields (Table 2). Additionally, the similar reaction with benzylideneacetone gave the desired carbazoles 6m and 6n albeit in significantly lower yields. Thus, this one-pot domino reaction successfully constructed carbazoles with four substituents on the benzene ring from the corresponding indole derivatives with two molecules of chalcones. It should be pointed out that the Diels-Alder reaction resulted in a complex mixture comprising four diastereoisomers of the tetrahydrocarbazoles, which was very difficult to    separate. After oxidation with DDQ, the aromatized carbazole derivatives 6a-n were easily obtained as single products in good yields. The chemical structures of the carbazoles were fully characterized by 1 H NMR, 13 C NMR, IR, and HRMS spectra.
To explain the formation of the products, a plausible reaction mechanism was proposed in Scheme 2 on the basis of the previously reported reaction [48,53]. Firstly, the DDQ oxidative dehydrogenation of 3-(indol-3-yl)-1,3-diphenylpropan-1-one gave the expected indole-substituted chalcone A, which comprises the desired 3-vinylindole scaffold as the reactive diene. In the meantime, the carbonyl group of the chalcone is protonated to give the activated dienophile in the presence of p-toluenesulfonic acid. Secondly, the Diels-Alder reaction of indolechalcone A with the dienophile results in the tetrahydrocarbazole B having an exocyclic C=C bond. Thirdly, a new tetrahydrocarbazole intermediate C is formed by a 1,3-H shifting process. The resulting tetrahydrocarbazole intermediate (C) might be a mixture of several possible diastereoisomers because it has four substituents on the cyclohexenyl ring. After a further DDQ oxidation, the aromatized carbazole 6 is successfully produced as the final product.

Conclusion
In summary, we have investigated the domino Diels-Alder reaction of 3-(indol-3-yl)maleimides and in situ-generated indole-chalcones with dienophilic chalcones. This one-pot twostep reaction successfully provided the polyfunctionalized carbazole derivatives in an extremely simple and highly effi-    cient fashion. This protocol has the advantages of using readily available starting reagents, simple manufacture, high efficiency and atomic economy. The unusual feature of this reaction is the normal electron-demand Diels-Alder reaction between elec-tron-deficient dienes such as (3-(indol-3-yl)maleimides and indole-chalcone to electron-deficient dienophilic chalcones. The potential applications of this reaction in organic and medicinal chemistry might be significant. The solution was heated to 60 °C for two hours. After removing the solvent by rotatory evaporation, DDQ (1.2 mmol) and acetonitrile (10.0 mL) were added and the mixture was stirred at room temperature for two hours. After removing the solvent, the residue was subjected to column chromatography with petroleum ether and ethyl acetate 8:1 (v/v) as eluent to give the pure products for analysis. 2. General procedure for the preparation of carbazoles 6a-n: To a round-bottomed flask were added 3-(indol-3-yl)-1,3-diphenylpropan-1-one (0.6 mmol), DDQ (0.72 mmol), and acetonitrile (15.0 mL). The mixture was stirred at room temperature for 30 min. Then, the chalcone (0.5 mmol) and p-toluenesulfonic acid (0.06 mmol) were added and the solution was refluxed for four hours. After cooling to room temperature, DDQ (0.6 mmol) was added and the mixture was stirred at room temperature for one hour. After removing the solvent by rotatory evaporation at reduced pressure, the residue was subjected to column chromatography with a mixture of petroleum ether, ethyl acetate and methylene dichloride 20:1:5 (v/v/v) to give the pure products for analysis.