Atroposelective Amination of Indoles via Chiral Center Induced Chiral Axis Formation

The construction of an N–C chiral axis for N-aryl indole derivatives is meaningful as they widely exist in functionalized molecules. This work provides a novel method for this purpose via amination of amino acid derivatives at the C2 position of the indole and chiral center induced chiral axis formation. The protocol of this transformation is easily accessible, not requiring metal or an organic chiral catalyst, endowing this method with great potential in the construction of axis chiral N-aryl indoles.


Introduction
Atropisomers around the C-N chiral axis, which have a typical chiral axis connecting a substituted nitrogen and the aryl-related hindrance, are one of the most important classes of axially chiral compounds. For example, Murrastifoline F was isolated from murraya alkaloid, which possesses anti-HIV activity [1][2][3]. Moreover, such skeletons have been used as chiral organocatalysts and ligands in enantioselective reactions, due to their specific electronic properties among biaryls (Scheme 1a) [4][5][6].
This study tackles this synthetic defiance considering the asymmetric catalysis free and easy formation of indole-based heterobiaryl axially chiral compounds, in line with strategies such as chiral center induced chiral axis formation and the central-to-axial chirality conversion [36][37][38]. It is worth noting that the Yu's group described a series of examples for atroposelective coupling of indoles at the C2 position with chiral amino acidbased sulfonamides via a central-to-axial chirality conversion strategy [39,40]. Encouraged by that, we rationalized that the construction of an N-C chiral axis for N-aryl indole derivatives possessing a sterically hindered N-phenyl group via amination at the C2 position of the indole and sequence chiral center induced chiral axis formation would represent a novel strategy for constructing indole-based N-C atropisomers (Scheme 1c). derivatives possessing a sterically hindered N-phenyl group via amination at the C2 sition of the indole and sequence chiral center induced chiral axis formation would repre a novel strategy for constructing indole-based N-C atropisomers (Scheme 1c). Scheme 1. Functionalized axially chiral indole-based molecules and outline for indole axially c construction.

Results and Discussion
To start this work, N-phenyl indole 1a and tert-butyl ((4-nitrophenyl)sulfony valinate 2a were used as the model substrate to test the feasibility for the C-N amina (Table 1). Product 3a was afforded using an aqueous NaClO solution with 1a in diffe solvents. The solvent was also crucial to both the yield and diastereoisomers (dr) va The optimal solvent was found to be DCM in 65% yield and 3.5/1 dr value (entry 1 Only a trace product was observed in the protic solvent (entry 4). The yield loss was to the formation of byproduct 4a and oxidative byproduct 5a. Interestingly, biaxial ch ity was observed as the chlorine atom brings steric hindrance at the C3 position. In work, excellent dr value was observed at the C-N axis chirality at the indole C2 posi Similar high dr was tracked for compound 4a (entry 1). Scheme 1. Functionalized axially chiral indole-based molecules and outline for indole axially chiral construction.

Results and Discussion
To start this work, N-phenyl indole 1a and tert-butyl ((4-nitrophenyl)sulfonyl)-Lvalinate 2a were used as the model substrate to test the feasibility for the C-N amination (Table 1). Product 3a was afforded using an aqueous NaClO solution with 1a in different solvents. The solvent was also crucial to both the yield and diastereoisomers (dr) value. The optimal solvent was found to be DCM in 65% yield and 3.5/1 dr value (entry 1-6). Only a trace product was observed in the protic solvent (entry 4). The yield loss was due to the formation of byproduct 4a and oxidative byproduct 5a. Interestingly, biaxial chirality was observed as the chlorine atom brings steric hindrance at the C3 position. In Yu's work, excellent dr value was observed at the C-N axis chirality at the indole C2 position. Similar high dr was tracked for compound 4a (entry 1). In should be mentioned that the protecting group of valinate also s fected the yield and dr ( Table 2). The p-nitrobenzene sulfonyl group (Ns) for this transformation (entry 2). Other sulfonyl protecting groups yielded in less than 5% yield. The benzyl protecting group (Bn) and tert-butoxyc (Boc) were conductive to produce byproduct 5a. In should be mentioned that the protecting group of valinate also significantly affected the yield and dr ( Table 2). The p-nitrobenzene sulfonyl group (Ns) was favorable for this transformation (entry 2). Other sulfonyl protecting groups yielded the product 3a in less than 5% yield. The benzyl protecting group (Bn) and tert-butoxycarbonyl group (Boc) were conductive to produce byproduct 5a. In should be mentioned that the protecting group of valinate also significantl fected the yield and dr ( Table 2). The p-nitrobenzene sulfonyl group (Ns) was favor for this transformation (entry 2). Other sulfonyl protecting groups yielded the produ in less than 5% yield. The benzyl protecting group (Bn) and tert-butoxycarbonyl gr (Boc) were conductive to produce byproduct 5a. In order to show the generality of this strategy, the couplings of various indoles N-Ns protected amino acid derivatives were investigated under the optimal conditi Entry Protecting Group Yield/% a Dr In order to show the generality of this strategy, the couplings of various indoles with N-Ns protected amino acid derivatives were investigated under the optimal conditions. First, a series of substituted indole derivatives at different positions reacted with 2a to give product 3a-3j in moderate yield (Scheme 2, 3a-3h). The electron-donating group bearing indoles at the C4-C5 position had lower yields but improved dr value (3d, 3e vs. 3a, 3b, 3i). For substrate 3j, the C-3 chlorination product 4j was produced at the same time. The dr value of 3j was around 5/1, but its side product 4j had excellent dr value. A similar dr value with the model substrate 3a was obtained for C-6 substituted indoles (3h, 3i). One example using the heterocyclic indole analogue with 1-(2-methoxyphenyl)-1H-pyrrolo [2,3b]pyridine was also conducted with 43% yield and good dr value (3k). Next, we explored the variations at the N-aryl ring of the indole. A less bulky ortho-substituted substrate resulted in lower dr value (3l). In the case of substitutions at the meta position, 1:1 of two diastereomers were observed (3m). First, a series of substituted indole derivatives at different positions reacted with 2a to give product 3a-3j in moderate yield (scheme 2, 3a-3h). The electron-donating group bearing indoles at the C4-C5 position had lower yields but improved dr value (3d, 3e vs. 3a, 3b, 3i). For substrate 3j, the C-3 chlorination product 4j was produced at the same time. The dr value of 3j was around 5/1, but its side product 4j had excellent dr value. A similar dr value with the model substrate 3a was obtained for C-6 substituted indoles (3h, 3i). One example using the heterocyclic indole analogue with 1-(2-methoxyphenyl)-1H-pyrrolo [2,3-b]pyridine was also conducted with 43% yield and good dr value (3k). Next, we explored the variations at the N-aryl ring of the indole. A less bulky ortho-substituted substrate resulted in lower dr value (3l). In the case of substitutions at the meta position, 1:1 of two diastereomers were observed (3m). After that, we continued to investigate the reactivity and stereoselectivity of the reactions of N-phenylindole (1a) with various amino acid derivatives (Scheme 3). Generally, the steric hindrance of amino acid derivatives had a positive influence on the stereoselectivity. To our delight, excellent dr value was shown with amino acid derivatives such as L-Isoleucine (3p), L-Norvaline (3q). But the yield was slightly decreased with bulker amino acid. As for the L-Cyclohexyl glycine derivative 3s and 2-Amino-1-propanol derivative 3t, byproducts 4s and 4t were tracked, respectively. After that, we continued to investigate the reactivity and stereoselectivity of the reactions of N-phenylindole (1a) with various amino acid derivatives (Scheme 3). Generally, the steric hindrance of amino acid derivatives had a positive influence on the stereoselectivity. To our delight, excellent dr value was shown with amino acid derivatives such as L-Isoleucine (3p), L-Norvaline (3q). But the yield was slightly decreased with bulker amino acid. As for the L-Cyclohexyl glycine derivative 3s and 2-Amino-1-propanol derivative 3t, byproducts 4s and 4t were tracked, respectively. Scheme 3. Substrates scope for various amino acid for construction of C-N axially chirality. reaction conditions: indoles (0.2 mmol), amino acid (0.6 mmol), 5% NaClO (0. 6 mmol), DCM (4 mL), rt, 24 h.
The absolute configuration of axially chiral product 3a was determined to be (Ra,S) by single-crystal X-ray diffraction analysis (Scheme 4) (CCDC 2222365 for the major diastereomer of 3a, see the Supporting Information for details). Thus, the absolute configurations of other axially chiral products were assigned to be (Ra,S) by analogy with 3a. Next, we investigated the configurational stability and the rotational barrier of product 3a and other isomers (S1-S4, Scheme 4) via DFT calculations (Scheme 4). It was discovered that the indole C2-N axis was unstable (the rotate barrier was 24.1 kcal/mol and 23.5 kcal/mol, respectively, for TS2 and TS4), which will rapidly disappear under room temperature. However, the N-Caryl axis had good configurational stability due to the fact that the rotational barrier was high (28.5 kcal/mol for TS3, 27.6 kcal/mol for TS1). As the amino acid was optically pure, the diastereo ratio may come from the atropisomerism of an N-Caryl axis.
In summary, we present here an atroposelective coupling of indoles with chiral amino acid-based sulfonamides mediated by hypo-halides through chiral center induced chiral axis formation strategy. The reaction delivers 2-amido-N-arylindoles with an N-C chiral axis in a moderate to good dr value. The substrates and reaction protocol of this The absolute configuration of axially chiral product 3a was determined to be (Ra,S) by single-crystal X-ray diffraction analysis (Scheme 4) (CCDC 2222365 for the major diastereomer of 3a, see the Supporting Information for details). Thus, the absolute configurations of other axially chiral products were assigned to be (Ra,S) by analogy with 3a. Next, we investigated the configurational stability and the rotational barrier of product 3a and other isomers (S1-S4, Scheme 4) via DFT calculations (Scheme 4). It was discovered that the indole C2-N axis was unstable (the rotate barrier was 24.1 kcal/mol and 23.5 kcal/mol, respectively, for TS2 and TS4), which will rapidly disappear under room temperature. However, the N-C aryl axis had good configurational stability due to the fact that the rotational barrier was high (28.5 kcal/mol for TS3, 27.6 kcal/mol for TS1). As the amino acid was optically pure, the diastereo ratio may come from the atropisomerism of an N-C aryl axis.
In summary, we present here an atroposelective coupling of indoles with chiral amino acid-based sulfonamides mediated by hypo-halides through chiral center induced chiral axis formation strategy. The reaction delivers 2-amido-N-arylindoles with an N-C chiral axis in a moderate to good dr value. The substrates and reaction protocol of this transformation are easily accessible, not requiring chiral catalyst, endowing this method with great potential in the construction of axis chiral N-arylindoles. transformation are easily accessible, not requiring chiral catalyst, endowing this method with great potential in the construction of axis chiral N-arylindoles. Scheme 4. DFT calculations for rotate barrier for C-N axis and N-aryl axis and absolute configuration of 3a.

Materials and Methods
Unless otherwise noted, all reactants or reagents including dry solvents were obtained from commercial suppliers and used as received. NaClO (Sodium hypochlorite solution reagent grade, available chlorine 4.00-4.99%) was purchased from Lingfeng reagent company, Shanghai, China. All the reactions were conducted using reaction tube (10 mL) under argon atmosphere. Analytical thin layer chromatography (TLC) was performed using Silica Gel 60 F25 plates. Column chromatograph was performed on silica gel 100~200 mesh. 1 H and 13 C NMR spectra were obtained in CDCl3 or DMSO using 300 MHz, 400 MHz Varian NMR spectrometer. Chemical shifts in 1 H NMR spectra are reported in parts per million (ppm) on the δ scale from an internal standard of residual CDCl3 (7.26 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), integration, and coupling constant in Hertz (Hz). Chemical shifts in 13 C NMR spectra are reported in ppm on the δ scale from the central peak of residual CDCl3 (77.16 ppm).

General Procedures for Indole C2 Amination with N-Ns Protected Amino Acid
A 10 mL round bottom flask was equipped with a rubber septum and magnetic stir bar and was charged with 1 (0.2 mmol), 2 (0.6 mmol), NaClO (0.6 mmol, 774 μL, 5% in water) in DCM (4 mL) at room temperature for 24 h. Upon completion of the reaction, the mixture was washed with saturated Na2CO3 aqueous solution (4 mL), water, and saturated brine (4 mL) in sequence. The organic layer was concentrated and purified via a flash column (PE/EA from 50/1 to 30/1).

Materials and Methods
Unless otherwise noted, all reactants or reagents including dry solvents were obtained from commercial suppliers and used as received. NaClO (Sodium hypochlorite solution reagent grade, available chlorine 4.00-4.99%) was purchased from Lingfeng reagent company, Shanghai, China. All the reactions were conducted using reaction tube (10 mL) under argon atmosphere. Analytical thin layer chromatography (TLC) was performed using Silica Gel 60 F25 plates. Column chromatograph was performed on silica gel 100~200 mesh. 1 H and 13 C NMR spectra were obtained in CDCl 3 or DMSO using 300 MHz, 400 MHz Varian NMR spectrometer. Chemical shifts in 1 H NMR spectra are reported in parts per million (ppm) on the δ scale from an internal standard of residual CDCl3 (7.26 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), integration, and coupling constant in Hertz (Hz). Chemical shifts in 13 C NMR spectra are reported in ppm on the δ scale from the central peak of residual CDCl3 (77.16 ppm).