Cu(i)-catalyzed cross-coupling of primary amines with 2,2′-dibromo-1,1′-biphenyl for the synthesis of polysubstituted carbazole

A Cu(i)-catalyzed cross-coupling of primary amines with 2,2′-dibromo-1,1′-biphenyl for the synthesis of polysubstituted carbazole has been achieved. This protocol provides an efficient strategy for the synthesis of carbazole using cheap copper catalysts with diamine ligand, and it provides convenient access to a series of carbazole derivatives in moderate yields.


Introduction
Carbazole is an important organic nitrogen-containing heterocyclic skeleton, which is extensively applied as a building block in natural products, 1 dyes 2 and pharmaceuticals. 3 As shown in Fig. 1, some representative bioactive molecules possessing carbazole moieties are listed. For example, murrayafoline A has strong antifungal and antitumor properties. 4 Celiptium, as a potent DNA intercalator and topoisomerase II inhibitor, has been used as a medicine for the treatment of breast cancer. 5 Clausenaquinone A showed an effective inhibitory activity on platelet aggregation as well as cytotoxicity in RPMI-7951, HCT-8 and TE671 tumor cells. 6 Calothrixin A and calothrixin B, carbazole quinone alkaloids, are novel DNA topoisomerase inhibitors, which have excellent effects on anti-tumor cells. 7 Curaxin 137 (CBLC137) is an effective inducer of apoptosis. It is toxic for proliferating various tumor cells and pancreatic cancer stem cells. 8 Carbazole and its derivatives are also used in the synthesis of photoelectric functional materials. 9 For these reasons, the synthesis of carbazole using simple substrates and methodologies is still an active research eld. Recently, some novel organic synthesis strategies for the construction of carbazoles have been reported. 10 The traditional approaches for the construction of the carbazole rings were to use the Buchwald-Hartwig C-N crosscoupling reaction. 11 In 2003, the Nozaki group rstly presented the synthesis of carbazole with double N-H arylation of primary amides via the [Pa 2 (dba) 3 ]/ t Bu 3 P/ t BuONa system. 12 Later, Chida et al. revealed the N-arylation protocol via the [Pa 2 (dba) 3 ]/dialkylphosphinobiaryls/ t BuONa system, and further applied it to the synthesis of murrayafoline A. 13 In 2010, Zhou and co-workers developed the [Pa 2 (dba) 3 ]/( t Bu) 2 P]N-P( i BuNCH 2 CH 2 ) 3 N/ t BuONa system for the synthesis of carbazole under mild conditions. 14 However, the need for expensive Pd catalysts and the frequent use of expensive phosphine ligands are the drawbacks of these methods. Recently, copper catalysts have become popular and have been widely used to synthesize carbazole. 15 In 2010, Liao and coworkers developed a convenient Cu-catalyzed double C-N bond-forming reaction using 2,2-diiodobiphenyl and p-methylaniline for the synthesis of carbazole. 15b However, only one example was reported, and the cheaper 2,2-dibromobiphenyl was not used in this reaction. Although Do and coworkers reported dibromide substrates using CuI/proline system for the synthesis of carbazole, 15c the reaction requires higher temperatures and a strong base. Therefore, it is necessary to develop a new system for the synthesis of carbazole to use the cheaper 2,2-dibromobiphenyl as substrates in the copper-catalyzed C-N coupling reaction under mild conditions. Compared to palladium, copper catalyst has the advantages of low price and low toxicity, and it can be suitable for industrial-scale production. The Ullmann-type coupling reaction between aryl halides and nitrogen-based Cite this: RSC Adv., 2022, 12, 24232 nucleophiles has also been used for the synthesis of carbazoles. 16,17 However, these methods usually suffer from several disadvantages, such as the need to use stoichiometric copper catalysts and the high reaction temperatures (normally above 150 C). 17 In order to solve these problems, special ligands need to be designed to promote these coupling reactions. In this scenario, it is highly desirable to develop a simple, efficient and practical approach to the synthesis of carbazole derivatives using cheap Cu catalysts and ligands under mild conditions.
The efficient construction of functional nitrogen-containing heterocycles in a simple way is an important task in synthetic chemistry and some new synthetic strategies have been reported continuously. 18 As a continuation of our long-term interest in the synthesis of heterocyclic compounds, 19 in this study, we present a simple methodology for the synthesis of Narylcarbazoles using substituted 2,2 0 -dihalobiphenyl and aromatic primary amine via the copper-catalyzed cross-coupling reaction.

Results and discussion
In our initial investigation, 2,2 0 -dibromo-1,1 0 -biphenyl 1a and aniline 2a were chosen as the model substrates in the presence of CuI (20 mol%), DMEDA (N,N 0 -dimethylethylenediamines) (20 mol%) and K 2 CO 3 (3 equiv.) at 110 C in 3 mL DMF for 72 h (Table 1, entry 1). To our disappointment, the required product 3a was not obtained. Other solvents such as THF, DMSO and toluene were screened and to our delight, the desired product 3a was obtained, in toluene with small polarity, in 64% yield (Table 1, entries 2-4). Changing base to Cs 2 CO 3 , t BuOK, DABCO, DBU and Et 3 N failed to improve the yield of the product 3a (Table 1, entries 5-9). Other Cu catalysts such as CuCl, CuBr, Cu(OTf) 2 and Cu powder were also investigated for this crosscoupling reaction but no better results were observed (Table  1, entries 10-13). The effects of ligands in the cross-coupling reaction were then evaluated. The results showed that double N-chelated ligands played a signicant role in the formation of carbazole; other ligands such as TMEDA (N,N,N 0 ,N 0 -tetramethylethylenediamine), EDA (ethylenediamines) and 4,4 0dimethyl-2,2 0 -dipyridine only obtained lower yields, and PPh 3 gave no desired product (  1, entry 21). Thus, the optimized reaction conditions chosen for all subsequent coupling reactions are as follows: 0.2 mmol of 2,2 0 -dibromo-1,1 0 -biphenyl, 0.6 mmol aniline, and 0.04 mmol CuI, 0.04 mmol DMEDA and 3 equiv. K 2 CO 3 in 3 mL toluene, stirred at 110 C, under the Ar atmosphere in a sealed tube for 72 h. With the optimized reaction conditions, the scope of this coupling reaction was examined and the results are summarized in Scheme 1. Firstly, a series of functional groups were tolerated in different positions of arylamine in this reaction, such as -CH 3 , -OCH 3 , -Br and -Cl substituents on arylamine. When introducing the electron-donating groups, such as -CH 3 and -OCH 3 on the arylamine, the desired carbazoles were obtained in 50-70% yields (Scheme 1, 3b-3f). When bearing electron-withdrawing groups on arylamine, it slightly hindered the reaction (Scheme 1, 3g-3j). It should be noted that relatively lower yields were observed when ortho-substituted aromatic amines were used, and this might be due to steric hindrance (Scheme 1, 3b, 3e and 3j). Naphthylamine was also compatible with this coupling reaction, and the desired product 3k was obtained in 53% yield (Scheme 1, 3k). We continued to elucidate the scope of this reaction by replacing the hydrogen atom at the R 1 position with -CH 3 and -OCH 3 groups (Scheme 1, 3l-3w). The results showed that strong electron-donating substituents on 2,2 0 -dibromo-1,1 0 -biphenyl gave lower yields (Scheme 1, 3s-3w). To further conrm the applicability of this reaction, a gram-scale reaction of 1a (1.56 g, 5.0 mmol) with 2a (1.40 g, 15 mmol) was carried out under the standard conditions, providing the corresponding product 3a in 54% yield (0.66 g).
To further expand the scope of this reaction, butylamine and benzylamine, which were also compatible with this reaction, were investigated and the corresponding carbazoles were obtained in 63% and 75% yields, respectively. In the presence of oxygen, N-benzylcarbazole reacted with t BuOK in DMSO to quickly remove benzyl groups to obtain carbazole in 90% yield (Scheme 2). This result is consistent with that reported in the literature. 20 The possible mechanism of this copper-catalyzed crosscoupling reaction for the synthesis of carbazole is proposed in Scheme 3. Firstly, DMEDA combined with CuI to form A, which subsequently reacted with 2,2 0 -dibromobiphenyl via oxidative addition to form intermediate B. Then, the aniline, as a nucleophile, attacked B to produce C, in which HBr was also lost in Scheme 1 The scope of the coupling reaction.
Scheme 3 A plausible mechanism for the formation of 3a.
the presence of base. The intermediate D was formed by reductive elimination. Subsequently, a similar oxidative addition occurred to give intermediate E, and then another HBr was lost with base. Finally, the desired product 3a was obtained with another reductive elimination, and Cu catalyst A was regenerated.

Conclusions
In summary, we have developed a one-pot method, via Cucatalyzed coupling of primary amines with 2,2 0 -dibromo-1,1 0biphenyl, for the synthesis of polysubstituted carbazole. This reaction provides a simple and facile route to the straightforward synthesis of polysubstituted carbazole in moderate yields. Further synthetic applications are ongoing in our laboratory.

Author contributions
The design of this protocol was carried out by Y.

Conflicts of interest
There are no conicts to declare.