Palladium-Catalyzed Synthesis of Natural and Unnatural 2-, 5-, and 7-Oxygenated Carbazole Alkaloids from N-Arylcyclohexane Enaminones

A palladium-catalyzed synthesis of the carbazole framework is described, including the preparation of 2-, 5-, and 7-oxygenated natural and unnatural carbazole alkaloids. A series of N-arylcyclohexane enaminones, generated by condensation of cyclohexane-1,3-dione with diverse anilines, were aromatized by a Pd(0)-catalyzed thermal treatment to afford the corresponding diarylamines. The latter were submitted to a Pd(II)-catalyzed cyclization and methylation processes to provide the desired carbazoles, including clausine V. Following an inverse strategy, a new and short total synthesis of glycoborine is also reported.

We recently described a general synthetic approach for the construction of 1-methoxycarbazoles, including the naturally occurring alkaloid glycozolicine, which was accomplished with high overall yields through a three-step reaction sequence [37]. Based on this approach, we describe herein a new synthetic route for the preparation of 2-, 7-, and 2,7-oxygenated carbazoles 1. Starting from cyclohexene-1,3-dione (2) and the respective anilines 3a-e, enaminones 4a-e were prepared (Scheme 1). The latter were converted into diarylamines 5a-e and then cyclized to the desired carbazoles 1, via an efficient Pd-catalyzed aromatization and cyclization sequence of reactions. Scheme 1. Synthetic approach for the preparation of 2-oxygenated tricyclic carbazoles 1.
Although the preparation and purification of diarylamines 6a-b and 6d-e resulted in high yields ( Table 2, entries 3-4 and 6-7), the relative instability of these compounds under the conditions of the following cyclization reaction made it necessary to protect the phenol moiety. In order to achieve this protection and taking into account that there are many naturally occurring methoxy-containing oxygenated carbazoles, we decided to obtain the methylated derivatives 5a-e. For this purpose, we employed a direct sequential procedure for the dehydrogenation and methylation of phenols 6 without purification ( Table 2, entries 3-7). Thus, the series of compounds 5a-e was prepared in high yields (81%-87%). Table 2. Conversion of 3-anilino-2-cyclohexen-1-ones 4a-e into diarylamines 6a-b, 6d-e and 5a-e a .
With the aim of testing the utility of this methodology for the total synthesis of natural 7-oxygenated tricyclic carbazoles, we carried out the conversion of derivative 1h into clauszoline-K (1f) and clauszoline-L (clausine C, 1g). Thus, upon applying the well-known procedure [58,59] for the synthesis of these [32] and other natural carbazoles [44], carbazole 1h was treated with DDQ in a mixture of MeOH/H 2 O/acetone (1:1:1) at room temperature for 45 min to give 1f in 70% yield (Scheme 3). Table 3. Preparation of carbazoles 1d and 1h-k via Pd(II)-catalyzed cyclization of diarylamines 5a-e a .  The latter was oxidized with a mixture of MnO 2 /KCN in MeOH [58] to furnish clauszoline-L (1g) in almost quantitative yield. The spectral data of the products obtained agree with those described for the natural [20,23] and synthetic [58] products.

Total Synthesis of Glycoborine (Glycrophylamine, 9)
Recently, 5-methoxy-3-methylcarbazole (9) was isolated from the roots and branches of Glycosmis macrophylla and named glycrophylamine. This compound showed cytotoxic activity against NC1-H187 cancerigene cells [60]. However, the same carbazole had been isolated from Glycosmis arborea a decade earlier, and named glycoborine. This was the first 5-oxygenated tricyclic natural carbazole ever isolated [61]. Nowadays, three routes of synthesis have been developed for 9 based on Fischer [61], Japp-Klingemann [62], and Cadogan cyclizations [33] as the key step. We herein describe a new total synthesis of 9 starting from the key precursor tetrahydrocarbazole 7a (Scheme 4), which was efficiently prepared from 4a (Scheme 2).
When a mixture of 7a, Pd/C (10%) (5.7% mol) and anhydrous MeOH was heated in a sealed vessel to 270 °C for 48 h, 5-hydroxy-3-methylcarbazole (8) was isolated and then purified in good yield (Scheme 4). Methylation of the latter under the usual reaction conditions provided the desired natural carbazole 9, which was synthesized in four steps with high overall yield (53%). The spectral data of 9 agree with those described for the natural [60,61] and synthetic [33,62] products.
All the structures of intermediates and products described in these synthetic sequences were characterized by 1 H-and 13 C-NMR spectroscopy, with the help of 2D (HMQC and HMBC) experiments and mass spectrometric techniques (MS and HRMS).

General
Melting points (uncorrected) were determined with an Electrothermal capillary melting point apparatus. IR spectra were recorded on a Perkin-Elmer 2000 spectrophotometer. 1 H (300 or 500 MHz) and 13 C-NMR (75 or 125 MHz) spectra were recorded on Varian Mercury-300 or Varian VNMR System instruments, with TMS as internal standard. Mass spectra (MS) and high-resolution mass spectra (HRMS) were obtained, in electron impact (EI) (70 eV) mode, on Thermo-Finnigan Polaris Q and Jeol JSM-GcMateII spectrometers, respectively. Microwave (MW) irradiation was performed on a CEM MW reactor. Analytical thin-layer chromatography was carried out using E. Merck silica gel 60 F 254 coated 0.25 plates, visualized by a long-and short-wavelength UV lamp. Flash column chromatography was performed over Natland International Co. silica gel (230-400 mesh). All air moisture sensitive reactions were carried out under nitrogen using oven-dried glassware. Toluene, MeOH, and MeCN were freshly distilled over sodium and DMF over calcium hydride prior to use. Acetone was dried by distillation after treatment with potassium permanganate. K 2 CO 3 was dried overnight at 200 °C prior to use. All other reagents were used without further purification.

Conclusions
In this work, a short and efficient synthetic route for the construction of 2-, 5-, and 7-oxygenated carbazole alkaloids including natural clausine V (1d) is described. As the key steps, this approach includes a palladium(0)-catalyzed aromatization and a palladium(II)-catalyzed cyclization to provide the 2-and 7-oxygenated tricyclic carbazole framework. In the case of the natural 5-oxygenated carbazole glycoborine (glycrophylamine, 9), the palladium-catalyzed sequence was inverted, with cyclization performed before aromatization. The preparation of natural carbazoles clauszoline-K (1f) and clauszoline-L (1g) was also carried out by transformation of carbazole 1h. This methodology is currently being applied to the synthesis of diverse carbazoles, and the results will be reported in due course.