Construction of highly functionalized carbazoles via condensation of an enolate to a nitro group

A transition-metal-free unique tandem annulation reaction has been developed for the synthesis of various functionalized 3-hydroxycarbazoles.


Introduction
The carbazole framework is found in a wide range of bioactive natural products and pharmaceuticals (Fig. 1). 1,2 These carbazole-containing molecules show antiviral, 3 antimalarial, 4 and antitumor activity. 5 Some of them are currently being used as lead compounds for drug development. 6 Carbazoles are also used as building blocks for the synthesis of functional materials, such as organic light-emitting diodes (OLED), because of their wide band gap, high luminescence efficiency, and allowing exible modication of the parent skeleton. 7,8 Owing to the importance and usefulness of these carbazolebased compounds, various approaches for their construction have been developed. The general and representative strategies can be classied into two main types depending on how the carbazole ring is constructed. The rst strategy relies on the formation of a C-C or a C-N bond to construct the middle pyrrole ring starting from arene building blocks (methods A and B, Fig. 2). 9-16 Also, the reaction of arynes with nitrosoarene and the nitrogenation of biphenyl halides have been reported. 17 The second strategy involves the installation of a new aromatic ring onto functionalized indole derivatives via benzannulation (methods C and D, Fig. 2). [18][19][20][21][22][23] Despite their own merits, most, if not all, of these methods suffer from certain drawbacks, including low tolerance of functionality, limited substrate scope, not-easily accessible starting materials, the necessity of complex and expensive transition-metal catalysts, and harsh reaction conditions. In particular, many existing methods require either highly elaborated biaryls or biarylamines to construct the central pyrrole  moiety or pre-functionalized indole derivatives for benzannulation. Therefore, more environmentally benign and modular multi-bond forming approaches accommodating structurally simple building blocks as the feedstock are highly sought-aer to improve on these shortcomings. In relation to the synthesis of 3-hydroxy carbazoles, iron-mediated reactions have also been reported. 24 A recently-reported rhodium-catalyzed tandem annulation uses a new approach, where the [5 + 1] cycloaddition of 3-hydroxy-1,4-enynes with CO generates three bonds and two rings. 25 Yet, even for this transformation, various 3-hydroxy-1,4enyne reagents must be prepared by a multi-step route.
In this regard, the new approach, depicted in E, accommodating a novel double annulation through the consecutive construction of a pyrrole and a benzene moiety reects further innovation (Fig. 2). A unique feature of the current reaction compared with all other reported pyrrole formations or benzannulations is the formation of the carbazole nitrogen atom by electrophilic attack on a nitro group rather than the use of an amine nucleophile. Herein, we describe a unique tandem annulation followed by N-O bond cleavage without any external reductant for the synthesis of various functionalized 3-hydroxycarbazoles from readily available 2-nitrocinnamaldehyde or 2nitrochalcone and b-ketoesters or 1,3-diaryl-2-propanone.

Results and discussion
First, the reaction of 2-nitrocinnamaldehyde (1a) and methyl 2oxobutanoate (2a) was examined with several bases and solvents to optimize the reaction conditions (Table 1). The initial attempt with NaOMe (1 equiv.) in reuxing toluene for 12 h did not provide product 3a (Table 1, entry 1), but produced an intractable mixture. With triethylamine (1 equiv.), product 3a was also not formed (Table 1, entry 2), but with DBU (1 equiv.), 3a was produced in 10% yield (Table 1, entry 3). Encouraged by this result, other bases were screened. With K 2 CO 3 (1 equiv.) for 6 h, the yield of 3a increased to 67% (Table 1, entry 4). The highest yield (81%) was achieved with 1.0 equivalent of Cs 2 CO 3 in reuxing toluene for 4 h (Table 1, entry 5). Increasing the amount of Cs 2 CO 3 to 1.5 equivalents (entry 6) or decreasing it to 0.1 equivalent (Table 1, entry 7) lowered the yield of 3a. Based on these results, this transformation was found to be sensitive towards the base strength used. For example, strong bases like NaOMe (1 equiv.) or DBU (1 equiv.) provided very little or no desired product, while weak bases provided better yields. Among the screened bases, Cs 2 CO 3 was superior in terms of both reaction time and yield for this reaction, probably due to its mild and optimum base strength. 26 In two other nonpolar solvents (benzene or dichloroethane), 3a was produced in 35 and 51% yield, respectively, whereas 3a was not obtained in a more polar solvent, such as methanol, DMSO, or water (Table 1, entries 8-12). The structure of 3a was established by spectroscopic analysis. The 1 H NMR of 3a showed a characteristic singlet of the OH group at d 11.12 ppm and another broad singlet for the NH proton at d 8.17 ppm. The 13 C NMR showed the expected characteristic ester carbonyl carbon at d 171.6 ppm and an aromatic carbon containing OH at d 157.7 ppm. The structural conrmation of 3a was further evidenced by X-ray crystallographic analysis of the related compound 7a (see ESI †).
Having conrmed the general applicability of the reaction by using 2-nitrocinnamaldehyde and the 2-nitrochalcones as starting materials, the possibility of using the 2-nitrochalcones bearing a heteroatom was examined, which would lead to the formation of carbazole derivatives with extended structural space. To our delight, the reactions of 8a or 8b with b-ketoesters 2b, 2d, and 2e provided the expected products 9a-9f in the range of 71-75% yield (Table 5).
We propose that the formation of the observed carbazole products may involve a mechanism shown in Scheme 1. In a basic medium, enolate 10 derived from 2a undergoes Michael addition onto 1a to give the new enolate intermediate 11, which subsequently reacts with the nitro group to form the bicyclic intermediate 12. 27 The reorganization of the O-N-OH moiety in Table 3 Formation of carbazoles 5a-5k from various 2-nitrochalcones (4a-4f) and several b-ketoesters (2a-2e and 2i) a a Reactions were performed on a 1.0 mmol scale according to the standard conditions described in Table 1. Table 4 Formation of carbazoles 7a-7g from 1a or the 2-nitrochalcones and 6a or 6b a a Reactions were performed on a 1.0 mmol scale according to the standard conditions described in Table 1. Table 5 Formation of carbazoles 9a-9f from various 2-nitrochalcones (8a and 8b) and b-ketoesters (2b, 2d and 2e) a 12 to N-O-OH would generate 15 via 13 or 14. The base-induced elimination of the hydrogen peroxide from 15 would generate 16, which would then undergo sequential double tautomerization via 17 or 18 to generate the observed product 3a.
To obtain evidence for the formation of H 2 O 2 during the reaction sequence, a control experiment was carried out with added aryl boronic acid (Scheme 2). To our delight, this reaction involving 1a, 2a and 2-naphthyl boronic acid 19 under the standard reaction conditions provided product 3a (61%) together with 2-naphthol 20 in 31% yield. The formation of 2naphthol 20 implies the existence of in situ generated H 2 O 2 in the reaction, although other mechanistic possibilities cannot be excluded. 28 Next, we broaden the carbazole structures to those that do not carry a carboethoxy group at the 4-position (Scheme 3). By carrying out the reaction at a higher temperature (145 C) for a prolonged time using 2 equivalents of Cs 2 CO 3 for decarboethoxylation, carbazoles 21a-21d were obtained in 68-75% yield.
The utility of this new protocol was demonstrated by the conversion of 21b and 21d to biologically active natural products (Scheme 4). Upon treating 21b and 21d with iodomethane in reuxing acetone in the presence of K 2 CO 3 , hyellazole (22) and chlorohyellazole (23) were obtained in 94% and 92% yields, respectively. Our concise synthesis of hyellazole and chlorohyellazole was achieved in two steps from commercially available starting materials in 67% and 63% overall yields, respectively. This protocol has several advantages such as higher yields, lower cost, fewer steps, transition metal-free, and environmentally benignity. 29,30 The identity of these two natural products was conrmed by the comparison of their spectroscopic data with those previously reported. 29,30 Conclusions A highly efficient, transition-metal-free, modular and operationally simple tandem annulation process was developed for the synthesis of diverse carbazole derivatives starting from readily available 2-nitrocinnamaldehydes or 2-nitrochalcones and b-ketoesters or 1,3-diaryl-2-propanones. This synthetic approach for the rapid construction of various functionalized carbazoles involves the intramolecular addition of an enolate to a nitro group and a unique in situ N-O bond cleavage under non-reductive conditions. As an application of this new synthetic methodology, a concise synthesis of naturally occurring bioactive hyellazole and chlorohyellazole has been realized in two steps. Scheme 1 Proposed mechanism for the formation of 3a.
Scheme 2 Control experiment to detect H 2 O 2 in the reaction pathway.