Carbolines represent a class of fused tricyclic nitrogen-containing heterocycles characterized by their indole and pyridine moieties, serving as core scaffolds of numerous natural products and drug molecules. These structurally diverse tricycles are systematically classified into α-, β-, γ- and δ- carbolines based on the position of the nitrogen atom in the fused pyridine ring.^[1] As privileged motifs, these heterocyclic architectures are extensively present in biologically active natural products and medicinal compounds.^[2] Carbolines exhibit a wide range of important medicinal activities. For instance, grossularine-1 and grossularine-2, isolated from the tunicate Dendrodoa grossularia, exhibit cytotoxic activity against L1210 leukemia cells.^[3] Mescengricin, the first natural product featuring an α-carboline chromophore, was obtained from Streptomyces griseoflavus as a reddish-brown powder.^[4] Harmine and harmane are tricyclic β-carboline alkaloids originally isolated from seeds of Peganum harmala.^[5] Harmine exhibits diverse pharmacological properties, including antimicrobial,^[6] antitumor,^[7] antiplasmodial^[8] and hallucinogenic^[9] properties. Harmane demonstrates vasorelaxant effects, which may underlie its hypotensive activity.^[10] Additionally, abecarnil, a β-carboline alkaloid, exhibits notable anxiolytic^[11] and anticonvulsant^[12] activities. The structure diversity of carbolines extends further γ- and δ-carboline derivatives, exemplified by ingenine B (a γ-carboline alkaloid)^[13] and cryptolepine (a δ-carboline alkaloid),^[14] both of which display significant bioactivity (Figure 1).

In view of the importance of the carboline scaffolds, especially in medicinal chemistry, the development of green and practical synthetic methodologies for these compounds has become increasingly crucial. Traditional methods such as the Pictet-Spengler reaction,^[15] and the Bischler-Napie- ralski^[16] cyclization are the most widely explored methods for the synthesis of β- and γ-carboline derivatives. Nevertheless, the development of novel synthetic strategies to access structurally diverse carboline derivatives remains in high demand. In recent years, several new protocols have been developed for the synthesis of β- and γ-carboline derivatives by using a variety of starting materials and metal catalysts. Various catalytic systems, including palladium, copper, ruthenium, rhodium and gold catalysts, have been successfully employed in the synthesis of these carboline derivatives.^[17] Notably, Langer and coworkers developed an efficient method involving copper- and palladium-catal- yzed C—N coupling reactions of 2,2'-dibromobiaryl compounds with aromatic amines to synthesize carboline derivatives, which were prepared by regioselective Suzuki reactions of 3,4-dibromopyridine with o-bromophenyl- boronic acid followed by sequential Buchwald-Hartwig amination.^[18] Chowdhury’s group reported a facile method for the divergent synthesis of α-carbolines via palladium- catalyzed [3＋3] annulations of tosyliminoindolines with α,β-unsaturated aldehydes.^[19] Subsequently, Wen and coworkers^[20] developed a series of novel heterocyclic iodoniums, which were employed to construct various complex polycyclic heteroarenes through tandem dual arylations. In 2022, Roesner’s group^[21] reported a synthetic route to α- and β-carbolines from fluoropyridines and 2- haloanilines. In our pursuit of more sustainable chemistry, we have primarily focused on transition metal-free C—N bond construction, particularly through a base-mediated coupling reaction. Herein, we report a base-mediated coupling protocol for the synthesis of carboline derivatives from 2,2'-dihalobiaryl compounds and primary amines. Noteworthy features of our protocol include mild reaction conditions, simple experimental procedures, broad substrate scope and general applicability, enabling the universal synthesis of carboline derivatives, encompassing α-, β-, γ-, and δ-substituted derivatives (Figure 2).

4-(2-Bromophenyl)-3-fluoropyridine is recognized as a versatile building block for the synthesis of various heterocyclic compounds. In this study, we report the reactivity of substituted 4-(2-bromophenyl)-3-fluoropyridine with tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate in the presence of lithium tert-butoxide (t-BuOLi) as a base, leading to the formation of functionalized carboline derivatives. A notable advantage of this reaction is the sequential formation of dual C—N bonds in a one-pot synthesis.

Our study began by reacting 1a with 2a in the presence of t-BuOK in dimethyl sulfoxide (DMSO) at 120 ℃ under an argon atmosphere for 12 h (Table 1). From this reaction, a carboline derivative 3aa was obtained in a 30% yield under this condition (Table 1, Entry 1). Encouraged by this preliminary result, we undertook further optimization of the reaction conditions. Various inorganic and orga- nic bases were first evaluated, finding that t-BuOLi pro-vided the best result, increasing the yield of 3aa to 33% (Table 1, Entry 2). Other bases such as Cs₂CO₃, NaOH, NaH and DIPEA were not effective for the reaction (Table 1, Entries 3~8). Next, the effect of other solvents, such as NMP, toluene, acetonitrile and N,N-dimethylformamide (DMF), was explored, which was not beneficial for the current transformation. The results indicated that DMSO was the most effective solvent, yielding a higher amount of 3aa compared to all other tested solvents (Table 1, Entries 9~12). These results demonstrate the critical role of both the base and the solvent in the efficiency of the reaction. Subsequently, increasing the equivalent of base to 6.0 equiv. resulted in a significant enhancement of the yield to 60% (Table 1, Entry 13). Further optimization by extending the reaction time to 24 h and decreasing the temperature to 100 ℃ led to an improved yield of 73% (Table 1, Entries 14~15). Finally, reducing the solvent volume to 0.5 mL afforded an isolated yield of 80% for compound 3aa (Entry 16). Reducing the equivalent of t-BuOLi or lowering the reaction temperature both resulted in dec-reased yields (Entries 17~18). Notably, no reaction occurred in the absence of t-BuOK (Entry 19).

When the optimized reaction conditions were established, the substrate scope of this transformation using different 2,2'-dihalogenated pyridyl biaryls (Table 2). A series of products were successfully synthesized. When substrate 1 contains electron-donating or electron-withdrawing groups, the β-carboline products can be obtained in moderate to good yields (3ba~3ja). The structure of 3ca was configurationally confirmed via single crystal X-ray analysis. Furthermore, an α-carboline derivative was isolated in 83% yield (3ka). However, the yield of the obtained α-car- boline derivatives decreased when the pyridine derivatives contained an electron-withdrawing trifluoromethyl group (3la). Additionally, when a methyl group was present, increasing the temperature to 120 ℃ resulted in a 50% yield of the α-carboline derivative (3ma). Similarly, this method could be employed to obtain γ- and δ-carboline derivatives (3na~3oa). The reaction proceeded smoothly with moderate to high yields when using bipyridine derivatives, regardless of the position of the nitrogen atoms on the bipyridine framework (3pa~3sa). To demonstrate the preparative utility of the strategy, gram-scale reactions were carried out, affording the desired products 3ca and 3ia without a significant decrease in efficiency.

Next, the scope of N-heterocycles was investigated. Pyridine, quinoline and isoquinoline were all found to be viable amine substrates (Table 3). These heteroaryl amines reacted well to obtain 3ab~3ag in 55%~89% yields un-der the standard conditions. Subsequently, the scope of aromatic amines was evaluated. With regard to potentially reactive functional groups, some variety of functionalities, such as methoxy (3ai~3al), N,N-dimethyl (3am), thiomethyl (3an), tert-butyl (3ao), halogens (3aq~3as) and ethyl (3ap) at the para- or meta-positions of the phenyl rings were tolerated to provide 3ah~3as in 40%~78% yields. Notably, the sterically crowded amines, such as 1-naphth- ylamine (3at), benzo[d][1,3] dioxol-5-amine (3au) and quinoline amines (3av, 3aw) were also well tolerated.

Then, the scope of aliphatic amine nucleophiles was evaluated using 4-phenylpyridine N-oxides under basic conditions. The benzylamine, 2-phenylethan-1-amine and 3-phenylpropylamine reacted smoothly with 4a to give the desired products 6ab, 6ac and 6ad in 72%, 83% and 72% yields, respectively. Notably, primary aliphatic amines 5e~5g furnished the corresponding β-carboline products 6ae~6ag in 45%~55% yields. Satisfactorily, the electron-rich 4-phenylpyridine N-oxides substituted at the meta- (4b), and para- (4c) positions of the phenyl ring worked well with 5d to afford the desired products 6bd and 6cd in moderate yields. Importantly, the synthetically valuable cyano functional group remained intact, as evidenced by the formation of product (6dd) (Table 4).

To demonstrate the synthetic utility of the obtained β-carbolines, several synthetic applications were performed (Scheme 1). The Suzuki-Miyaura cross-coupling of 3ia with phenylboronic acid produced 4-phenyl-β-car- bolines 3ia-1 in high yield. The alkyne functionality was introduced by the Sonogashira reaction under palladium- catalyzed condition giving the desired alkynes 3ia-2 in acceptable yield. N-Phenyl-6-amino-β-carboline 3ia-3 was obtained in moderate yield through Buchwald-Hartwig cross-coupling of 3ia with aniline. Meanwhile, this strate- gy can also be applied to the synthesis of material molecules. 2,6-CbPy, an organic optoelectronic material with strong electron transport capability and excellent hole transport properties, was synthesized from 3-(2-bromo-phenyl)-2-fluoropyridine and 2,6-diamino pyridine under standard conditions in 56% yield (Scheme 2).

To gain deeper insight into the transition-metal-free me- chanism, we isolated intermediate 6ad-2 and conducted an experiment under standard conditions, successfully achie- ving cyclization to yield the target product 6ad (Scheme 3).

Based on the experimental results and previous reports, we have proposed a possible mechanistic pathway. The t-BuOLi base initially deprotonates the aryl amine 2 to form an anionic intermediate A, then attacks the fluoro- arene 1, via an intermolecular nucleophilic aromatic substitution (S_NAr) to afford the arylated product B. Subsequently, the intermediate B undergoes further deprotonation to form an anionic intermediate C, which engages in an intramolecular S_NAr reaction through displacing a halide anion and restoring aromaticity to deliver the target compound 3 (Scheme 4).

In summary, we have established a novel base-promo- ted, transition-metal-free annulation strategy for the efficient construction of carboline derivatives. This method is characterized by mild reaction conditions, straightforward experimental operations, and broad substrate compatibility, enabling the versatile synthesis of α-, β-, γ- and δ- carboline architectures. Moreover, this method can also be applied to the synthesis of material molecules such as 2,6-CbPy. The developed protocol provides a practical, cost-effective and environmentally friendly approach for the synthesis of diversified carboline derivatives.