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Home > Copper-Catalyzed Synthesis of 2-Aminocarbazoles through Cascade C–C and C–N Bond Formation and Aromatization
Copper-Catalyzed Synthesis of 2-Aminocarbazoles through Cascade C–C and C–N Bond Formation and Aromatization
Xinlei Liu,[a] Jiangkun Huang,[a] Huibei Xu,[a] Dandan Zhang,[a] Qiu Sun,*[b] and Ling He
Introduction
Carbazoles as structural motifs have been widely applied in material science such as organic electroluminescent materials,[1] organic photorefractive materials,[2] solar cell materials.[3] In addition, carbazoles derivatives are also unique structural units in pharmaceuticals and natural products showing significant bio- logical activities. For example, staurosporine and its derivatives have a variety of biological activities[4] including antifungal, antihypertensive and antitumor. Moreover, carbazoles were also used in the dye industry and supramolecular recognition. Based on carbazoles broad application and their importance (Scheme 1), it is of great significance to propose efficient meth- ods for the construction of carbazole derivatives with biological activity or specific function.[5]
Over the past decades, some general strategies for the synthesis of carbazoles have been developed.[6] These methods include the formation of C–N/C–C bond and C–H cleavage (Scheme 2a), such as transition-metal-catalyzed intramolecular dehydrogenative cross-coupling, oxidative cyclization of diaryl- amines, transition metal free or rhodium catalyzed intramolec- ular C–H amination of anilides and nitrene insertion of 2-azido-biphenyls, and Pd catalyzed one-pot Suzuki-Cadogan cascade reaction of o-halonitrobenzenes. Although these methods are highly efficient and show good compatibility with functional groups, for the synthesis of multifarious carbazoles derivatives, they require the preparation of complex starting materials, such as amino-, azido-, nitro- and halo-substituted biaryls or indol-3- yl-3-yn-2-ols or N, N-biaryl amines or require expensive rea- gents. Therefore, we have exploited the development of a one- pot C–C/C–N bond formation and dehydrogenative tandem reaction that utilizes easily prepared starting materials with low cost and less toxic reagents. More recently, there are reports on the direct carbon-carbon coupling of indoles with alkenes and alkynes to provide carbazoles (Scheme 2b),[7] such as the syn- thesis of carbazoles via Pd-catalyzed and copper(II)-mediated reactions of indoles with in-situ generated aryl vinyl ketones using saturated ß-chloroalkyl aryl ketones as the olefins source[7f] or the preparation of carbazoles via the Pd-catalyzed dehydrogenative cross-coupling of indoles with in situ gener- ated aryl vinyl ketones by using statured ketones as the olefins source under the presence of ligand PCy3, Ag2CO3, LiOAc, TEMPO, O2.[7g] However, the indole to carbazole transformation through direct cross-coupling using alkylketones are sparse in the literature. Especially, the direct intramolecular C–C coupling of indoles with alkanes has not been reported. Therefore, ongo- ing development of a greener and more concise procedure to acquire substituted carbazoles is still desirable.
To take advantage of easily preparable starting materials with a tolerance of most organic functional groups for the prep- aration of new pharmacologically active compounds, we devel- oped a copper-catalyzed oxidative cyclization based on easily available indole saturated side-chain ketones and inexpensive ammonium carbonate as nitrogen source, providing the novel 2-aminocarbazoles derivatives with moderate yields. This reac- tion completes the homogeneous cleavage of C–H bonds and the formation of C–C and C–N bonds in one pot reaction, by a sequence of free radical initiation, cyclization, Schiff base forma- tion, dehydrogenation, rearrangement and aromatization.
Results and Discussion
To initiate the study, the reaction using 1-(1H-indole-3-yl)- pentan-3-one (1a) as the model substrate and (NH4)2CO3 as nitrogen source was used to optimize the reaction conditions (Table 1). In order to evaluate the catalytic efficiency of various metal complexes including Yb(CF3SO3)3, Pd(OAc)2, Ru3(CO)12, (CpRhCl2)2, [Rh(CH3(CH2)6CO2)2]2, Cu(OAc)2, CuCl2, CuBr2,
Cu(CF3SO3)2, the reaction of 1a with (NH4)2CO3 was studied by using a catalyst with acetonitrile as solvent at 80 °C. The results were shown in Table 1. It was found that only copper salts could be led to the formation of the desired carbazoles(3b) (Table 1, Entries 1- 14). Other metal complexes, such as Pd, Yb, and Rh, displayed poor catalytic activity (Entries 15- 18). At the same time, the catalytic effect of bivalent copper is generally better than that of univalent copper on this reaction. Among the cata- lysts of various copper salts, Cu(CF3SO3)2 was the most effective for the reaction (Table 1, entry 3).
Since this reaction involves aromatization, so we also studied the effects of temperature, oxidants and solvents on the reac- tion yields, and the results are listed in Table 1. Temperature also affected the reaction. At room temperature, the formation of carbazole was not observed. A further increase of tempera- ture (80–120 °C) led to the increase of reaction yields (Table 1, entries 3, 11, 13, 14). Meanwhile, the microwave irradiation has advantages of short reaction time over the traditional heating mode. But the yield was not obviously improved. Subsequently, we screened a series of oxidants to promote the aromatization via dehydrogenation process, such as PhI(OAc)2, I2, O2, NaIO4, Mn(OAc)3·2H2O, DDQ, etc, and it was found that these oxidants resulted in the formation of traces of carbazole products. How- ever, (E) 1- (1H-indol-3-yl) pent-1-en-3-one was obtained. And then the resulting trans-1- (1H-indol-3-yl) pent-1-en-3-one could not continue to cyclize and to form carbazoles under the same conditions. In addition, we investigated the solvent effect on the reaction. 1-(1H-indole-3-yl) pentan-3-one(1a) as model was heated in different solvents. Acetonitrile and methanol were the most effective for the reaction, but the reaction hardly proceeded in xylene and decalin. The reaction carried out in DMF and dimethylsulfoxide resulting in the formation of traces of carbazole under the same condition.
Furthermore, the influence of the nitrogen source on the yield was studied, when other nitrogen sources such as (NH4)2C2O4, NH4Ac, etc. took the place of ammonium carb- onate, no carbazole products were obtained. Other alkyl pri- mary amine and aromatic primary amine were tried as well, but the carbazole products were still not obtained. On the basis of these results, we used the optimum condition in a molar ratio of 1a/ammonium carbonate/catalyst = 1.0:20:0.2 in acetonitrile at 80 °C for subsequent study.
After determining the optimum reaction conditions, in order to investigate the universality of the reaction, we investigated the substrate scope; the results are outlined in Scheme 3. A series of 1-(1H-indole-3-yl)pentan-3-ones(R1 = H, R3 = Me, R4 = H, Me, Ph) can successfully provide the corresponding carbazole products in moderate yields (the structure of 3e was confirmed by X-ray crystal structure CCDC 1589600) under identical condi- tions. Unfortunately, when a carbon chain was extended at the end of the indole side chain, the activity for the reactions was reduced under strictly identical conditions, such as 3i, 3j, 3k, 3l, 3m(R3=Et). Meanwhile, we notice the substrate with the electron-donating substituent on the indole nitrogen (R1=Me) results in moderate yield, however, the substrate with the elec- tron-withdrawing groups on the indole nitrogen gave only trace amount of corresponding products, such as R1=Ph, Bn, Ts, Boc, Ac. The results showed that the reaction rate of indole changed with the presence of the protective groups on the nitrogen atom of indole.
CCDC 1589600 (for 3e) contains the supplementary crystallo- graphic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre.
To understand the observed reactivity, we investigated the reaction mechanism with deuterium-labeling experiments (Scheme 4). No significant kinetic isotope effect (KIE) was ob- served when the rate constants of the reaction of 1 and 1-D2 were measured, thus suggesting that C–H activation might not be involved in the rate-determining step (reaction 1, 2). In order to obtain more information about the reaction process, the rad- ical scavenger 2,2,6,6-tetra-methylpiperidino-oxy(TEMPO) was added to the original reaction system, the products could not be monitored completely under the same reaction conditions.
However, the peak of reactive intermediates could easily be de- tected from the reaction 3 (Scheme 4) by liquid chromatogra- phy-mass spectrometry, such as the peaks of m/z = 357.2, 355.2, 352.2. The reactive intermediates were captured by radical scav- engers, which suggests that the formation reaction of amino- carbazoles might go through a radical process. At the same time, potassium carbonate, cesium carbonate, sodium tert-but- anol and DBU were employed as a reaction promoter. However, these bases have no obvious effect on the yield of the reaction. Thus, combined with our experimental results and the litera- tures,[8] we propose a possible reaction pathway for the forma- tion of 2-amonocarbazoles, as shown in Scheme 5.
The 1-(1H-indol-3-yl)pentan-3-one was oxidized to give radi- cal intermediates by Cu(II), which recombined with side chain to cyclize. Then the cyclic ketones were condensed with ammo- nia to give Schiff base. Finally, the double bonds occurred rear- rangement leading to aromatization and the formation of the 2-aminocarbazoles.
Conclusions
In summary, we report a simple and effective route to synthe- size 2-aminocarbazole derivatives by transition metal catalyzed conversion of indole side-chain ketones in a one-pot reaction with moderate yields. It uses easily made starting materials and many functional groups are tolerated. The indoles to carbazoles conversion protocol involves a cascade reaction with free radi- cal initiation, cyclization, condensation, dehydrogenation, rear- rangement and aromatization. Further studies of the scope, lim- itations and applications of this process are currently underway in our laboratory.
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