Asymmetric Friedel–Crafts Alkylation of Indoles Catalyzed by Chiral Aziridine-Phosphines

: Over the course of the present studies, a series of optically pure phosphines functionalized by chiral aziridines was synthesized in reasonable / good chemical yields. Their catalytic activity was checked in the enantioselective Friedel–Crafts alkylation of indoles by β -nitrostyrene in the presence of a copper(I) triﬂuoromethanesulfonate benzene complex. The corresponding Friedel–Crafts products were achieved e ﬃ ciently in terms of chemical yield and enantioselectivity (up to 85% in some cases).


Introduction
The synthesis of various organic molecules in an asymmetric manner remains one of the most important trends in modern synthetic organic chemistry. The desired chiral products of asymmetric transformations may be obtained using such approaches as organocatalysis [1,2], the use of chiral ligands or chiral auxiliary [3]. Additionally, more sophisticated methods like stereodivergent [4][5][6] or stereoconvergent synthesis [7][8][9] have been applied successfully in order to obtain various chiral systems.
Chiral phosphoroorganic compounds containing a three-membered ring of aziridine that act as ligands/organocatalysts in asymmetric synthesis are only rarely mentioned in the literature [28][29][30][31][32]. It should be pointed out that the successful application of phosphinoyl-aziridines as organocatalysts in the asymmetric Michael [33] and Mannich reaction [34] was reported in our department. Based on our experience in the field of asymmetric catalysis [35][36][37] and continuing our studies on phosphorus-containing chiral aziridines [33,34], we have attempted the synthesis of chiral aziridine-phosphines. Their catalytic ability was then checked in the asymmetric Friedel-Crafts alkylation of indoles using β-nitrostyrene in the presence of a copper(I) triflate benzene complex.
Their catalytic ability was then checked in the asymmetric Friedel-Crafts alkylation of indoles using β-nitrostyrene in the presence of a copper(I) triflate benzene complex.
Catalysts 2020, 10, x FOR PEER REVIEW 2 of 10 Their catalytic ability was then checked in the asymmetric Friedel-Crafts alkylation of indoles using β-nitrostyrene in the presence of a copper(I) triflate benzene complex.

Asymmetric Friedel-Crafts Alkylation of Indole Catalyzed by Aziridine Phosphines 1-8
Having enantiomerically pure aziridine-phosphines 1-8, we decided to test their catalytic ability in the asymmetric Friedel-Crafts alkylation of indole with β-nitrostyrene in the presence of a (CuOTf) 2 ·C 6 H 6 complex and triethylamine in chloroform at −15 • C (Scheme 2) [16]. Chemical yields, enantiomeric excess (ee) values and absolute configurations of product 9 from the model asymmetric Friedel-Crafts alkylation reactions are summarized in Table 1. Inspection of Table 1 reveals that aziridine-phosphines 1-4 bearing a methylene subunit between the aromatic ring and a nitrogen atom of aziridine exhibited relatively low catalytic activity leading to the Friedel-Crafts product 9 in yields from 33 to 40% and with enantioselectivity ranging from 26 to 30% of ee (Table 1, entries 1-4). Moreover, as previously observed in the case of the asymmetric Michael addition [33] and the enantioselective Mannich reaction [34], the application of enantiomeric forms of the catalyst allowed for product 9 to be obtained in both enantiomeric forms ( Table 1, entries 1 and 2). In turn, aziridine-phosphines 5-8 catalyzed the title reaction more effectively (Table 1, entries 5-8), leading to 3-substituted indole 9 in 65-75% yields and with 68-84% ee's. As previously, both enantiomeric products 9 can be achieved by the use of opposite enantiomers of the catalyst ( Table 1, entries 5 and 6).

Asymmetric Friedel-Crafts Reaction Catalyzed by Aziridine-Phosphine 6
After screening the catalysts, we decided to check the influence of various additives on the course of the title asymmetric reaction (Scheme 3).  Additives:
Inspection of Table 1 reveals that aziridine-phosphines 1-4 bearing a methylene subunit between the aromatic ring and a nitrogen atom of aziridine exhibited relatively low catalytic activity leading to the Friedel-Crafts product 9 in yields from 33 to 40% and with enantioselectivity ranging from 26 to 30% of ee (Table 1, entries 1-4). Moreover, as previously observed in the case of the asymmetric Michael addition [33] and the enantioselective Mannich reaction [34], the application of enantiomeric forms of the catalyst allowed for product 9 to be obtained in both enantiomeric forms ( Table 1, entries 1 and 2). In turn, aziridine-phosphines 5-8 catalyzed the title reaction more effectively (Table 1, entries 5-8), leading to 3-substituted indole 9 in 65-75% yields and with 68-84% ee's. As previously, both enantiomeric products 9 can be achieved by the use of opposite enantiomers of the catalyst ( Table 1, entries 5 and 6).

Asymmetric Friedel-Crafts Reaction Catalyzed by Aziridine-Phosphine 6
After screening the catalysts, we decided to check the influence of various additives on the course of the title asymmetric reaction (Scheme 3). Chemical yields, enantiomeric excess (ee) values and absolute configurations of product 9 from the model asymmetric Friedel-Crafts alkylation reactions are summarized in Table 1. Inspection of Table 1 reveals that aziridine-phosphines 1-4 bearing a methylene subunit between the aromatic ring and a nitrogen atom of aziridine exhibited relatively low catalytic activity leading to the Friedel-Crafts product 9 in yields from 33 to 40% and with enantioselectivity ranging from 26 to 30% of ee (Table 1, entries 1-4). Moreover, as previously observed in the case of the asymmetric Michael addition [33] and the enantioselective Mannich reaction [34], the application of enantiomeric forms of the catalyst allowed for product 9 to be obtained in both enantiomeric forms (Table 1, entries 1 and 2). In turn, aziridine-phosphines 5-8 catalyzed the title reaction more effectively (Table 1, entries 5-8), leading to 3-substituted indole 9 in 65-75% yields and with 68-84% ee's. As previously, both enantiomeric products 9 can be achieved by the use of opposite enantiomers of the catalyst ( Table 1, entries 5 and 6).

Asymmetric Friedel-Crafts Reaction Catalyzed by Aziridine-Phosphine 6
After screening the catalysts, we decided to check the influence of various additives on the course of the title asymmetric reaction (Scheme 3).  Thus, zinc trifluoromethanesulfonate (instead of (CuOTf) 2 ·C 6 H 6 complex), triflimide 10 [43] and (S)-1,1 -binaphthyl-2,2 -diyl hydrogenphosphate 11 [44] were used in the asymmetric Friedel-Crafts alkylation of indole. The results are summarized in Table 2. As can be seen in Table 2, the use of zinc triflate resulted in a lowering of both the yield and enantiomeric excess of product 9 ( Table 2, entry 1). The Friedel-Crafts alkylations performed in the presence of triflimide 10 and chiral acid 11 ran with slightly higher enantioselectivity; however, their chemical yields were lower in comparison with the process promoted by the (CuOTf) 2 ·C 6 H 6 complex ( Table 2, entries 2 and 3).
Finally, we decided to expand the range of substrates. For this purpose, the asymmetric Friedel-Crafts alkylations were carried out using variously substituted indoles and β-nitrostyrenes in the presence of aziridine-phosphine 6 and the (CuOTf) 2 ·C 6 H 6 complex (Scheme 4). The results are collected in Table 3.
Catalysts 2020, 10, x FOR PEER REVIEW 4 of 10 Thus, zinc trifluoromethanesulfonate (instead of (CuOTf)2•C6H6 complex), triflimide 10 [43] and (S)-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate 11 [44] were used in the asymmetric Friedel-Crafts alkylation of indole. The results are summarized in Table 2. As can be seen in Table 2, the use of zinc triflate resulted in a lowering of both the yield and enantiomeric excess of product 9 ( Table 2, entry 1). The Friedel-Crafts alkylations performed in the presence of triflimide 10 and chiral acid 11 ran with slightly higher enantioselectivity; however, their chemical yields were lower in comparison with the process promoted by the (CuOTf)2•C6H6 complex ( Table 2, entries 2 and 3).
Finally, we decided to expand the range of substrates. For this purpose, the asymmetric Friedel-Crafts alkylations were carried out using variously substituted indoles and β-nitrostyrenes in the presence of aziridine-phosphine 6 and the (CuOTf)2•C6H6 complex (Scheme 4). The results are collected in Table 3.  The results in Table 3 clearly indicate that chiral aziridine-phosphine 6 worked well as a catalyst in the asymmetric Friedel-Crafts alkylation of indoles with β-nitrostyrenes in the presence of the (CuOTf)2•C6H6 complex and triethylamine, affording the corresponding chiral products 12-17 in yields and with enantioselectivity around 80%. The best results were obtained in the reaction of 5bromoindole with β-nitrostyrene (88% yield and 92% of ee, respectively). In our opinion, the possible transition state comprises the formation of an orthogonal system of catalyst-substrates analogous to the model proposed previously [16]. In this proposed mechanistic model, a minimalization of steric interactions takes place: the steric effect between the methylene CH2  The results in Table 3 clearly indicate that chiral aziridine-phosphine 6 worked well as a catalyst in the asymmetric Friedel-Crafts alkylation of indoles with β-nitrostyrenes in the presence of the (CuOTf) 2 ·C 6 H 6 complex and triethylamine, affording the corresponding chiral products 12-17 in yields and with enantioselectivity around 80%. The best results were obtained in the reaction of 5-bromoindole with β-nitrostyrene (88% yield and 92% of ee, respectively). In our opinion, the possible transition state comprises the formation of an orthogonal system of catalyst-substrates analogous to the model proposed previously [16]. In this proposed mechanistic model, a minimalization of steric interactions takes place: the steric effect between the methylene CH 2 Catalysts 2020, 10, 971 5 of 10 group (C-2) of the aziridine ring and the phenyl ring of indole is almost insignificant in comparison with the steric hindrance induced in this place by the presence of a fragment of the ring containing an isopropyl group in the favorable trans-configuration relative to the substituent on the nitrogen atom (R-enantiomer) ( Figure 2). Moreover, the Si-attack of indole on the double bond of styrene is more favorable, which is due to the quasi-trans orientation of the phenyl substituent of styrene to indole with respect to the bond being formed (Figure 2).
Catalysts 2020, 10, x FOR PEER REVIEW 5 of 10 group (C-2) of the aziridine ring and the phenyl ring of indole is almost insignificant in comparison with the steric hindrance induced in this place by the presence of a fragment of the ring containing an isopropyl group in the favorable trans-configuration relative to the substituent on the nitrogen atom (R-enantiomer) ( Figure 2). Moreover, the Si-attack of indole on the double bond of styrene is more favorable, which is due to the quasi-trans orientation of the phenyl substituent of styrene to indole with respect to the bond being formed (Figure 2).

Materials
The drying of tetrahydrofurane was accomplished using the sodium benzophenone ketyl radical. Chloroform was distilled over phosphorus pentoxide. 1 H, 13 C and 31 P NMR spectra were recorded on a Bruker instrument at 600, 150 and 243 MHz, respectively, with CDCl3 as solvent and TMS as the internal standard. Data are reported as s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br. s = broad singlet. Column chromatography was conducted using Merck 60 silica gel. TLC was performed on Merck 60 F254 silica gel plates. The plates were visualized using UV light (254 nm) or iodine vapors. The enantiomeric excess (ee) values were determined by HPLC with chiral support (Chiralcel OD-H column). The corresponding chiral phosphinoyl-aziridines were synthesized according to general protocols reported by our group [33,34].

Reduction of Phosphinoyl-Aziridines to Aziridine-Phosphines 1-8-General Procedure [38]
To a stirred mixture of phosphine oxide (1 mmol) and triethoxysilane (3 mmol) in dry THF (5 mL), titanium isopropoxide (0.1 mmol) was added. The reaction mixture was refluxed until the completion of the reaction (TLC monitored) and cooled to room temperature. A solution of NaOH (1 M, 10 mL) was added. The resulting mixture was stirred for 2 h at room temperature and then extracted with ethyl acetate (4 × 15 mL). The organic layer was dried with MgSO4 and evaporated in vacuo. The crude product was purified via column chromatography on silica gel (hexane:ethyl acetate 7:1). (

Materials
The drying of tetrahydrofurane was accomplished using the sodium benzophenone ketyl radical. Chloroform was distilled over phosphorus pentoxide. 1 H, 13 C and 31 P NMR spectra were recorded on a Bruker instrument at 600, 150 and 243 MHz, respectively, with CDCl 3 as solvent and TMS as the internal standard. Data are reported as s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br. s = broad singlet. Column chromatography was conducted using Merck 60 silica gel. TLC was performed on Merck 60 F 254 silica gel plates. The plates were visualized using UV light (254 nm) or iodine vapors. The enantiomeric excess (ee) values were determined by HPLC with chiral support (Chiralcel OD-H column). The corresponding chiral phosphinoyl-aziridines were synthesized according to general protocols reported by our group [33,34].

Reduction of Phosphinoyl-Aziridines to Aziridine-Phosphines 1-8-General
Procedure (Coumbe, et al., 1994) To a stirred mixture of phosphine oxide (1 mmol) and triethoxysilane (3 mmol) in dry THF (5 mL), titanium isopropoxide (0.1 mmol) was added. The reaction mixture was refluxed until the completion of the reaction (TLC monitored) and cooled to room temperature. A solution of NaOH (1 M, 10 mL) was added. The resulting mixture was stirred for 2 h at room temperature and then extracted with ethyl acetate (4 × 15 mL). The organic layer was dried with MgSO 4 and evaporated in vacuo. The crude product was purified via column chromatography on silica gel (hexane:ethyl acetate 7:1).

Conclusions
The chiral aziridine-phosphines proved to be an effective catalyst for the asymmetric Friedel-Crafts alkylation of indoles with β-nitrostyrenes in the presence of the copper(I) complex and triethylamine. The appropriate Friedel-Crafts products were formed in satisfactory chemical yields and with high enantiomeric excess values. The absolute configuration of the carbon atom of aziridine has a decisive influence on the stereochemical course of the title reaction.