Rhodium(III)-Catalyzed Addition of Indoles with Boc-Imines via C−H Bond Activation

Transition-metal-catalyzed aromatic C−H functionalization has been recognized to be a highly important synthetic tool for its atom-economical routes to functionalized aromatic molecules. Recently, it has been demonstrated that Rh catalysts are highly efficient for the activation of sp C−H bonds of aromatic compounds in the coupling with unsaturated molecules and with electrophilic reagents. Particularly, Rh catalytic C−H bond activation is an attractive strategy for preparing amino-containing aromatic compounds which are commonly found in pharmaceuticals as well as natural products and functional materials. Indoles derivatives are of great interest in organic synthesis because of their presence in numerous natural products and pharmaceuticals. Among them, 2-indolylmethanamine derivatives are particularly important because of their ubiquitous presence in numerous biologically active compounds. Therefore, methods for a general, rapid, and regioselective preparation of 2-indolyl-methanamines would be highly desirable. Zhou et al. successfully reported a Rh-catalyzed regioselective addition of indole C−H bonds to aryland alkyl-N-sulfonylimines for the preparation of 2-indolyl-methanamine derivatives with good functional group tolerance, but in relatively low yields (between 42 to 71%, see Scheme 1). Due to the importance of 2-indolyl methanamine derivatives, herein we report a rhodium(III)catalyzed direct and selective C-2 alkylation reaction of indoles with N-Boc-imines via C−H activation, affording a series of substituted 2-indolyl-methanamine derivatives with good functional group tolerance and in high yields under mild conditions. These compounds are potential building blocks for preparing biologically active compounds.


Introduction
Transition-metal-catalyzed aromatic C−H functionalization has been recognized to be a highly important synthetic tool for its atom-economical routes to functionalized aromatic molecules. 1 Recently, it has been demonstrated that Rh III catalysts are highly efficient for the activation of sp 2 C−H bonds of aromatic compounds in the coupling with unsaturated molecules and with electrophilic reagents. 2 Particularly, Rh III catalytic C−H bond activation is an attractive strategy for preparing amino-containing aromatic compounds which are commonly found in pharmaceuticals as well as natural products and functional materials. 3 Indoles derivatives are of great interest in organic synthesis because of their presence in numerous natural products and pharmaceuticals. 4 Among them, 2-indolylmethanamine derivatives are particularly important because of their ubiquitous presence in numerous biologically active compounds. [5][6][7][8][9] Therefore, methods for a general, rapid, and regioselective preparation of 2-indolyl-methanamines would be highly desirable. Zhou et al. 10 successfully reported a Rh III -catalyzed regioselective addition of indole C−H bonds to aryl-and alkyl-N-sulfonylimines for the preparation of 2-indolyl-methanamine derivatives with good functional group tolerance, but in relatively low yields (between 42 to 71%, see Scheme 1). Due to the importance of 2-indolyl methanamine derivatives, herein we report a rhodium(III)catalyzed direct and selective C-2 alkylation reaction of indoles with N-Boc-imines via C−H activation, affording a series of substituted 2-indolyl-methanamine derivatives with good functional group tolerance and in high yields under mild conditions. These compounds are potential building blocks for preparing biologically active compounds.

Results and Discussion
To explore the optimum reaction conditions, 1-(N,N-dimethylcarbamoyl) indole (1a) and benzaldehyde N-(tert-butoxycarbonyl)imine (2a) were chosen as model substrates for the synthesis of 2-indolylmethanamine derivative (3a) ( Table 1). Initially, we applied [RhCp*Cl 2 ] 2 (5 mol%) as a catalyst without any additive. However, no desired product was detected after 6 h, and 1a was mostly recovered (Table 1, entry 1). Then we chose AgCO 2 CF 3 as an additive and partial conversion of 1a was observed after 6 h at 75 o C with a low yield of 30% ( Strong solvent effects have also been observed, such as the reaction proceeded well in 1,2-dichloroethane (DCE) and dichloromethane (DCM), whereas toluene (PhMe) and tert-butyl alcohol (t-BuOH) were not suitable for this reaction, in which we could not observe the full conversion of starting materials despite prolonging the reaction time to 24 h (Table 1, entries [6][7][8]. Reducing the amount of either catalyst or additive led to decreased yields ( Table 1, entries 9-10).
Further investigations revealed that the reaction could occur at a milder temperature (Table 1, entry 11). When the temperature was raised to 50 o C, the yield dropped down to 68% (Table 1, entry 12) and many side products were detected. Altogether, the optimal result was obtained by treating 1a and 1.5 equivalent of 2a in DCE using catalyst [RhCp*Cl 2 ] 2 (5 mol%) and additive AgSbF 6 (20 mol%) at 75 o C for 6 h under an inert nitrogen atmosphere.
Under the aforementioned optimized reaction condition, we examined the substrate scope of this reaction with various substituted 1-(N,N-dimethylcarbamoyl) indoles and imines (Table 2). In general, a range of substituted Scheme 1. Synthetic strategies to produce 2-indolyl-methanamines.  1-(N,N-dimethylcarbamoyl) indole derivatives and imines with electron-withdrawing or electron-donating groups were all successfully transformed into the corresponding adducts in good to excellent yields (68-95%, 3a-3o).
Introduction of electron-donating groups (-Me, and -OMe) to the indole ring gave high yields (3b and 3c).
The chloro (3d) and bromo (3e) atoms were highly compatible with this addition reaction. Tolerance to the chloro and bromo is especially noteworthy since they are useful for subsequent cross-coupling reactions. However, the substrates substituted by a fluoro and cyano moiety at the 5-position of the indole resulted in slightly decreased yields, respectively (3f and 3g). Substitution with methyl or chloro at 6-position of indole also gave good yields (3h and 3i). The results also indicated that the electronic property of the substitutes and the positions of substitution on the benzene ring of imines have no significant influence on the yields of these adducts (3j-3o). Nathphyl, thiofuran and 3-amyl groups were also introduced to the imines and good yields were obtained (3p-3r). Furthermore, a gram-scale reaction was conducted to evaluate the reaction efficacy on a preparative scale. The reaction of 1-(N,N-dimethylcarbamoyl)indole (1a) with benzaldehyde N-(tert-butoxycarbonyl)imine (2a) under the standard conditions provided the target product in 87% yield (Scheme 2). Therefore, the present method is very effective for the synthesis of 3a.
Based on the previous work, 3,11,12 we proposed the following mechanism (Scheme 3). First, an active catalyst is generated through anion exchange with AgSbF 6 , then a N,N-dimethylcarbamoyl-directed C−H bond activation occur through deprotonation-metalation to give A, coordination of the N-Boc-imine (B) would then activate the imine for migratory insertion to form the N-Rh species C. In the last step, C is protonated to provide the desired indole derivative 3 accompanied by the regeneration of the active catalyst.

Conclusions
In summary, we have developed an efficient methodology for the addition of 1-(N,N-dimethylcarbamoyl) indoles with tert-butyloxy carbonyl protected imines via Rh III -catalyzed C−H activation reaction to afford biologically relevant 2-indolylmethanamines with good functional group tolerance and selectivity in good to excellent yields. In view of the potential use of these 2-indolylmethanamines, we expect this method to be widely used in the pharmaceutical field.

General synthesis procedures of 3a to 3r
In a reaction tube, [Cp*RhCl 2 ] 2 (0.01 mmol, 6.2 mg), AgSbF 6 (0.04 mmol, 13.7 mg), substrate 1a (0.20 mmol, 1.0 equiv), and 2a (0.30 mmol, 1.5 equiv) were added followed by addition of DCE (2.0 mL). The vessel was sealed and heated at 75 °C (oil bath temperature) for 6 h under an inert nitrogen atmosphere. The resulting mixture was cooled to room temperature, filtered through a short silica gel pad and transferred to silica gel column directly to give the product. Following general procedure, compound 3a was purified by column chromatography on silica gel using petroleum ether:ethyl acetate (5:1) in 85% isolated yield as an off-white solid.