Introduction

Aryl- and heteroaryl-annulated carbazoles play an essential role in various areas of synthetic and medicinal chemistry that have been comprehensively reviewed [1–3], they are particularly noted for their diverse biological and pharmacological activities [4–13]. They are classified into [a], [b] and [c]-types based on the position at which the aryl ring is fused to the carbazole nucleus (Fig. 1). In the case of heteroaryl derivatives, each positional isomer is further sorted according to the mode of annulation, as exemplified by heteroaryl-[2,3-a] and -[3,2-a]carbazoles.

Fig. 1
figure 1

Classification of aryl- and heteroaryl-annulated carbazoles

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Among these derivatives, a number of biologically active compounds possess a benzo[a]carbazole framework. According to their substituents, these compounds can exhibit antifungal and antitumor activities [11, 14], antiestrogenic properties [15], or kinase inhibitory activities [16]. A series of simple benzo[a]carbazoles, e.g., 1, have been shown agonists of the human thrombopoietin receptor [6]. Other benzo[a]carbazoles, such as 2 and 3, exhibit a pronounced antitumor activity against leukemia, renal tumor, colon cancer, and malignant melanoma tumor cell lines (Fig. 2) [7].

Fig. 2
figure 2

Bioactive compounds with a benzo[a]carbazole core structure

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On the other hand, recently applications of aryl- and heteroaryl-annulated carbazoles have been increasing in the field of organic electronics. In this regard, benzo[a] and indolo[3,2-b]carbazole derivatives have been utilized as molecular platforms for luminescent, host materials and hole-transporting materials in OLEDs (4 in Fig. 3) [17–23]. Furthermore, Indolo-[3,2-b]carbazoles 5 represent high-performance p-channel semiconductors with good environmental stability for organic electronic applications (Fig. 3) [24–26].

Fig. 3
figure 3

Electroactive compounds with an Indolocarbazole core structure

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Also, optical, electrochemical, magnetic, and conductive properties of polyindolocarbazoles and polydiindolocarbazoles with incorporation of indolo[3,2-b]carbazoles into a polymer chain have been investigated [27]. It is clear, aryl- and heteroaryl-annulated carbazoles play a fundamental role in a variety of aspects, but a major interest as electroactive and photoactive materials has been poured into indolo[3,2-b]carbazole frameworks perhaps due to the structural accessibility. Therefore, development of straightforward synthetic methods for other aryl- and heteroaryl-annulated carbazoles like benzo[a]carbazoles surely opens up a further opportunity to utilize benzo[a]carbazoles as material sources. Unsurprisingly, many efforts have been made to develop methodologies, ranging from thermal and photochemical cyclization, palladium-catalyzed cross-coupling reactions, Fischer indolization, Diels–Alder reactions, gold-catalyzed intramolecular cyclization reactions, and irradiation of a benzotriazole derivative, for the synthesis of benzo[a]carbazole derivatives [1, 28–34]. In 1993, Hill et al. reported the synthesis of the benzo[a]carbazole derivatives using a palladium-mediated oxidative cyclization as the key step. In last step, oxidative cyclization of intermediate with palladium(II) acetate provided 5,6-maleimido-11H-benzo[a]carbazole in 14 % yield [35]. A few years later, De Koning and co-workers have described the synthesis of the 11H-benzo-[a]carbazoles from 2-bromoindole-3-carbaldehyde using the base-induced photocyclization of the 2-arylindoles as the key step. A palladium-catalyzed Suzuki cross-coupling of intermediate with the boronic acids afforded the corresponding 2-arylindoles, which were transformed to the 11H-benzo[a]carbazoles via a base-induced photocyclization [36]. In 2009, Jiao et al. demonstrated the first palladium-catalyzed cycloaromatization of 2- and 3-arylindoles with internal alkynes through dual activation of C–H bonds. The reaction outcomes provide a new strategy for constructing aromatic compounds from biaryls and internal alkynes [37]. One year later, Fujii and co-workers have developed a novel gold-catalyzed intramolecular cascade cyclization for the synthesis of aryl- and heteroaryl-annulated[a]carbazoles. The reaction is applicable to various aryl-annulated[a]carbazoles containing an alkyl or aryl substituent [38]. Combined directed ortho and remote metalation-cross-coupling of 3-(diethylcarbamoyl)1-methyl-1H-indol-2-ylboronic acid reported by Victor Snieckus and co-workers is another approach for synthesis of benzo[a]carbazoles and their derivatives [39]. Recently, Zhang and co-workers have synthesized benzo[a]carbazoles and indolo[2,3-a]- carbazoles via photoinduced carbene-mediated C–H insertion reaction. With structurally o-toluidine as the starting material, this synthetic strategy can provide benzo[a]carbazoles and their derivatives in 6 or 7 steps [40]. Despite these numerous studies, most of these procedures have involved several steps, and the overall yields were, in general, not very good. Moreover, the starting materials were often not readily available. The development of a direct, concise, and atom-economical synthetic route to this class of compounds, producing minimum waste/byproduct, would therefore be of considerable interest for drug discovery and material chemistry. In modern organic chemistry, both tandem reactions and C–H functionalization are considered as efficient tools for the synthesis of complex molecules in terms of atom economy. As part of our ongoing research program on the development of efficient methods in organic synthesis and on the preparation of heterocyclic compounds [41–46], to develop a more atom economical and direct synthetic method to benzo[a]carbazoles, we designed a direct palladium-catalyzed route for the synthesis of novel benzo[a]carbazoles through sequential C–C bond formation and C–H bond functionalization in one-pot by using readily available starting materials [47]. We now report full details of our study on the synthesis of benzo[a]carbazoles based on a preliminary communication. The overview of our strategy is summarized in Scheme 1. With the broad diversity of benzo[a]carbazole derivatives obtained under the standard reaction conditions, gave us an opportunity to understand the effect of frameworks and substituents on the optical properties of benzo[a]carbazoles.

Scheme 1
scheme 1

Synthesis of benzo[a]carbazoles: our strategy

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Results and discussion

Synthesis of Benzo[a]carbazoles Derivatives

Our preliminary investigation revealed that the best conditions for the formation of 11-methyl-11H-benzo[a]carbazole-6-carbonitrile 8a involved the use of 1 equiv. (1-methyl-1H-indol-3-yl)acetonitrile 6a and 1.6 equiv. 2-bromobenzaldehyde 7a in the presence of cesium acetate (CsOAc, 3 equiv.), diisopropylamine (HN(i-Pr)2, 1 equiv.) and 10 mol% Pd(OAc)2 in N,N-dimethylacetamide (DMA, 3 mL) at 125 °C for 36 h under an argon atmosphere. This led to the formation of 8a in 89 % yield by a route in which both inter- and intramolecular carbon–carbon bond-forming reactions took place in one step. The structure of 8a was characterized by spectroscopic analysis and the constitution of the product could be unambiguously assigned by X-ray crystal structure analysis (Fig. 4) [48].

Fig. 4
figure 4

Solid-state molecular structure of 8a

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Crystal data, refinement details, and selected bond distances and angles for the title compound 8a are listed in Table 1 and Table S1 (electronic supplementary material), respectively. Compound 8a is crystallized in the P212121 space group of the Orthorhombic system. The connections between the layers in the ab plane are face-to-face π–π type stacking interactions between pyrrole and phenyl, phenyl and phenyl rings of two adjacent molecules of 8a with a centroid–centroid distance of 3.50, 3.66, and 3.70 Å (Fig. 5).

Table 1 Crystal data and refinement details for compound 8a
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Fig. 5
figure 5

The π–π interactions in prepared compound 8a

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To delineate this approach, particularly with regard to construction of a library of compounds, the optimized reaction conditions were applied to the synthesis of various benzo[a]-carbazoles. The results are summarized in Table 2. Besides 7a, 2-bromobenzaldehyde derivatives such as 7b–7d having a methoxy, dioxole or fluor group on the phenyl group underwent the palladium-catalyzed cyclization with (1-methyl-1H-indol-3-yl)acetonitrile (6a) to give the corresponding benzo[a]-carbazole (8b–8d) in good to excellent yields (Table 2, entries 1–4). N-Alkylindoles 6b–6d bearing an ethyl, propyl or butyl group on the nitrogen atom also reacted with 7a–7c to afford desired 8 (Table 2, entries 5–13). We also investigated the reaction of 2-(1H-indol-3-yl)acetonitrile 6e containing free NH group (Table 2, entry 14). In this case, a comparable clean reaction was observed and 11H-benzo[a]carbazole-6-carbonitrile 8n was synthesized in one-pot by a domino reaction in good yield. Remarkably, the palladium-catalyzed annulation provides 8n in only one step from commercially available 6e and 7a, in contrast to the multi-step synthetic route reported earlier [8]. Synthetically, it is very useful that free NH indole does not change the reaction pathway, and satisfactory yields of 8 were obtained using these free NH indoles (Table 2, 8n–8q).

Table 2 Synthesis of benzo[a]carbazoles by palladium-catalyzed reactions
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To further explore the potential of this methodology for the synthesis of benzo[a]carbazole derivatives, we investigated the reaction with another indole backbone. We found that the benzo[a]carbazole synthesis protocol is also compatible with ethyl(1-alkyl-1H-indol-3-yl)acetate 9, being transformed into corresponding benzo[a]carbazole derivatives 10 (Table 3).

Table 3 Synthesis of benzo[a]carbazole derivatives
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Ethyl 2-(1-methyl-1H-indol-3-yl)acetate 9a thus reacted with 2-bromobenzaldehyde 7a to give ethyl 11-methyl-11H-benzo[a]carbazole-6-carboxylate 10a as the sole product. Besides 7a, 2-bromo-5-fluorobenzaldehyde 7d having a fluor group on the phenyl group underwent the palladium-catalyzed cyclization with ethyl 2-(1-methyl-1H-indol-3-yl)acetate 9a to give the corresponding benzo[a]-carbazole 10b in good yield (Table 3, entries 2). Ethyl 11H-benzo[a]carbazole-6-carboxylate 10c was produced in 61 % yield by the cyclization reaction between ethyl 2-(1H-indol-3-yl)acetate 9b and 2-bromobenzaldehyde 7a. The reaction of ethyl 2-(1H-indol-3-yl)acetate 9b with 2-bromo-5-fluorobenzaldehyde 7d also proceeded to give the corresponding benzo[a]-carbazole 10d in moderate yield (Table 3, entriy 4). Remarkably, our procedure can be applied for the synthesis of a variety of benzocarbazoles with different functional groups by using other indole backbones or different halobenzaldehydes in only one step from commercially available starting materials [49], in contrast to the multi-step procedures reported in literature. It should be noted that this reaction is also applicable with free NH indoles than most of previously reported procedure [1, 8].

Reaction Mechanism

The mechanism of the reaction has not been established experimentally; however, on the basis of previous chemistry [50–52], a plausible mechanism for the synthesis of the benzo[a]carbazole ring system via Knoevenagel condensation followed by intramolecular ortho-arylation is described in Scheme 2. According to the proposed mechanism, intermediate 11 is formed by the Base-induced Knoevenagel condensation reaction between 6 (or 9) and 7. The first step of the catalytic cycle involves formation of aryl–palladium(II) intermediate 12 by the oxidative addition of C–Br bond to the Pd0 species. Then, intramolecular ortho-arylation to the adjacent aryl C–H bond gives the seven-membered palladacycle intermediate 13, which reductively eliminates to the desired product with the regenerating the Pd(0) catalyst. To confirm the proposed mechanism, we studied the mechanistic pathway of the reaction. The reaction of 6a with 7a was investigated in the absence of Pd(OAc)2, where we isolated the Knoevenagel condensation intermediate after eight hours (Scheme 3). There are two possible products for the Knoevenagel condensation intermediate, (Z)-3-(2-bromophenyl)-2-(1-methyl-1H-indol-3-yl)acrylonitrile 14 and (E)-3-(2-bromophenyl)-2-(1-methyl-1H-indol-3-yl)acrylonitrile 11.

Scheme 2
scheme 2

Proposed mechanism for the formation of the benzo[a]carbazole ring

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Scheme 3
scheme 3

Two possible products in the Knoevenagel condensation reaction

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However, it is anticipated that the both isomers are formed in the Knoevenagel condensation reaction but to our surprise only the E isomer was obtained in 86 % yield under the reaction conditions which was confirmed by NMR analysis of the crude product and X-ray crystallography data (Please see the electronic supplementary material) (Fig. 6) [53].

Fig. 6
figure 6

Solid-state molecular structure of E isomer 11

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Z and E interconversion to the more stable isomer, probably E under conditions reaction, may be facilitated by resonance in the conjugated system (Scheme 4) [54].

Scheme 4
scheme 4

Plausible interconversion of Z and E isomers

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Crystal data, refinement details, and selected bond distances and angles for the title compound 11 are listed in Tables 4 and Tables S2 (electronic supplementary material), respectively. Compound 11 is crystallized in the P21/c space group of the monoclinic system. The connections between the layers in the ab plane are face-to-face C–H-π interaction between C–H of methyl group and phenyl rings of two adjacent molecules of 11 with distance of 2.69 Å (Table 5; Fig. 7).

Table 4 Crystal data and refinement details for compound 11
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Table 5 Significant intermolecular interactions [interatomic distance (Å) and bond angels (°)] for 11
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Fig. 7
figure 7

A perspective view of C–H–π interaction in compound 11

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The proposed mechanism was confirmed by subjecting intermediate 11 to the reaction conditions, which led to the formation of the desired product (Scheme 5). The reaction did not go to completion and we obtained 8a in only 77 % yield.

Scheme 5
scheme 5

Formation of the desired product from intermediate 11

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Photophysical properties of benzo[a]carbazole

With the broad diversity of benzo[a]carbazole derivatives obtained under the standard reaction conditions, we became intensely interested in the potential of the products as electroactive materials and the photophysical properties of the benzo[a]carbazoles was investigated; the results are collected in Table 6. Quantum yields were determined by the comparative method described by Williams et al. [55] and the results were obtained according to Eq. (1):

Table 6 Photophysical properties of benzo[a]carbazoles
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$$\varPhi_{\text{X}} = \varPhi_{\text{ST}} \left( {\frac{{{\text{Grad}}_{\text{X}} }}{{{\text{Grad}}_{\text{ST}} }}} \right)\left( {\frac{{\eta_{\text{X}}^{ 2} }}{{\eta_{\text{ST}}^{ 2} }}} \right)$$
(1)

where the subscripts ST and X denote standard and test respectively, Φ is the Quantum yield, Grad the gradient from the plot of integrated emission intensity vs. absorbance, and η the refractive index of the solvent. Quantum yields were measured with Quinine sulfate (Φ = 0.54 in 0.1 M H2SO4) as the Ref. [56]. First, we focused on evaluating the effect of substituents on benzo[a]carbazole core structure. For example, in the UV–Vis spectrum of 11H-benzo[a]carbazole-6-carbonitrile (8n), the absorption bands ascribed to the π–π* transitions with the relatively large extinction coefficients were detected, ranging from 250 to 371 nm. It was then found that 8n (Φ = 0.199) exhibits purple emission derived from the emission λ max around 388 and 403 nm.

Although the absorption and emission patterns of 8a, 8e, 8h, and 8k containing alkyl group on the nitrogen atom of 8n resemble those of 8n, the introduction of the alkyl group was always accompanied by a red-shift of the emission spectra (8n vs 8a, 8e, 8h, or 8k, Fig. 8). Moreover, quantum yield of these compounds increased with introduction of alkyl group on the nitrogen atom except for butyl group.

Fig. 8
figure 8

Comparison emission spectrum of N-alkyl derives in CH2Cl2 (c = 1.5 × 10−6 M), excited at 360 nm

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A similar correlation was also observed between the other N-alkylbenzo[a]carbazole compared with NH free benzo[a]carbazole derivative (8q vs. 8d, 8o vs. 8b, 8p vs. 8 g, 10c vs. 10a, 10d vs. 10b, Please see the electronic supplementary material). Moreover, FL efficiency was found to be highly dependent on the methoxy and fluoro groups, for example, the quantum yield is increased from 8n (0.199) to 8q (0.271), and 8o (0.234). Also, in comparison with 8n, the methoxy- and fluoro-containing derivatives,8q and 8o, show red-shift and blue-shift, respectively, in the FL spectra (Fig. 9).

Fig. 9
figure 9

Emission spectrum of 8n, 8q and 8o in CH2Cl2 (c = 1.5 × 10−6 M), excited at 360 nm

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Furthermore, the functional group change from 8n (CN) to 10c (CO2Et) or 8q (CN) to 10d (CO2Et) resulted in a red-shift of the emission spectra and also a decrease in the quantum yield (Fig. 10).

Fig. 10
figure 10

Comparison emission spectrum of 8n with 10c and 8q with 10d in CH2Cl2 (c = 1.5 × 10−6 M), excited at 360 nm

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Next, to gain further insight into the photophysical properties of benzo[a]carbazoles, we investigated their spectral dependence on solvent polarity. When benzo[a]carbazoles were excited at 360 nm in different solvents, such as ethyl acetate (AcOEt), dichloromethane (CH2Cl2), and dimethyl sulfoxide (DMSO), their emission spectra were affected by the solvent polarity. For example, increasing the solvent polarity from EtOAc to DMSO caused a significant positive solvatochromism, with 16 and 14 nm red-shift in the emission spectrums of 8d and 10b, respectively (Figs. 11, 12). These results clearly show the solvatochromic properties of the benzo[a]carbazoles. The considerable red-shift observed in 8d and 10b may be mainly due to the charge transfer character of the emission state leading to the significant change in the dipole moment from the ground state to the excited state in polar solvents [57, 58].

Fig. 11
figure 11

Solvent-dependent emission spectra of 8d (c = 1.5 × 10−6 M in each solvent) excited at 360 nm

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Fig. 12
figure 12

Solvent-dependent emission spectra of 10b (c = 1.5 × 10−6 M in each solvent) excited at 360 nm

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Conclusion

In conclusion, we have demonstrated an efficient and simple method that allows the assembly of two readily accessible building blocks, (1-alkyl-1H-indol-3-yl)acetonitrile and 2-bromobenzaldehydes, into benzo[a]carbazole. The methodology with substrate diversity enables us to synthesize various derivatives of benzo[a]carbazole. The achievement of the short step process is attributed to the successive cross-coupling reaction and subsequent pd-catalyzed cyclization. The reaction can be applied for the synthesis of a variety of benzocarbazoles with different functional groups by using other indole backbones such as ethyl (1- alkyl-1H-indol-3-yl)acetate 9 or different 2-halobenzaldehydes. The reaction is also applicable with free NH indoles. Photophysical properties of different derivatives of benzo[a]carbazole are described. The evaluation of emission spectra of the products showed that almost all the emission bands appear in the visible region (purple to blue) and that quantum yields are highly dependent on the character of the substituents. Some structure–property correlations on benzo[a]carbazoles elucidated in the present study are as follows: (1) Introduction of an alkyl group onto the nitrogen atom enhances quantum yield and causes a red-shift in emission spectra. (2) A butyl group on the nitrogen atom causes decrees in quantum yield values. (3) Change the cyano group to the ester group, shows a large bathochromic shift. (4) The title compounds exhibit positive solvatochromic behavior by increasing the solvent polarity.