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Article

Spiro Indane-Based Phosphine-Oxazolines as Highly Efficient P,N Ligands for Enantioselective Pd-Catalyzed Allylic Alkylation of Indoles and Allylic Etherification

by
Zhongxuan Qiu
,
Rui Sun
,
Kun Yang
and
Dawei Teng
*
State Key laboratory Base of Eco-chemical Engineering, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
*
Author to whom correspondence should be addressed.
Molecules 2019, 24(8), 1575; https://doi.org/10.3390/molecules24081575
Submission received: 29 March 2019 / Revised: 17 April 2019 / Accepted: 20 April 2019 / Published: 21 April 2019
Browse Figures
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Abstract

:
A series of indane-based phosphine-oxazoline ligands with a spirocarbon stereogenic center were examined for palladium-catalyzed asymmetric allylic alkylation of indoles. Under optimized conditions, high yields (up to 98%) and enantioselectivities (up to 98% ee) were obtained with a broad scope of indole derivatives. The ligand was determined to be the most efficient P,N-ligand for this reaction. Moreover, the ligand was also efficient for Pd-catalyzed asymmetric allylic etherification with hard aliphatic alcohols as nucleophiles.

Graphical Abstract

1. Introduction

As a typical heterocyclic structural subunit, the indole scaffold is highly prevalent in biological compounds, pharmaceuticals, natural products and material science [1,2,3,4,5]. Notably, a variety of biologically active indole derivatives and indole-based drugs are enantiopure. Therefore, the synthesis and functionalization of chiral indole derivatives is meaningful. It is found that many 3-substitued indoles are important intermediates of natural products, such as (−)-agroclavine and (−)-aurantioclavine (Figure 1). Because of the biologically significant activities, including treatment of migraine headaches, antagonists, antiviral activity and agonist, functionalization of indoles on C-3 position has attracted much attention [6]. Enantioselective alkylation of indoles at the C-3 position by the Friedel–Crafts reaction with Lewis acid as the catalyst has been explored extensively [7,8,9,10]. However, high catalyst loading (10 %mol) is usually needed to obtain satisfactory yields and enantioselectivites.
Recently, palladium-catalyzed allylic alkylation has been proven to be an attractive strategy to achieve enantiopure 3-substituted indoles [11,12,13,14] and diligent efforts have been made to develop novel and efficient chiral palladium-complexes using the asymmetric allylic alkylation of indoles as the model reaction. Chan reported that chiral ferrocenyl P/S ligands demonstrated good catalytic performance [15]. Hoshi reported that high yields and good enantioselectivities were obtained with sulphur-MOP ligands [16]. A phosphine ligand developed by Mino afforded 89% yields and 80% enatioselectivities with narrow substrate scope [17]. Other ligands such as phosphoramidite-thioether [18], phosphoramidite-terminal olefin [19], phosphine olefin [20,21], and helicenylphosphine ligands [22] were also reported as efficient catalysts.
The P,N-ligands are an important class of ligands and have successfully been applied in a large scope of reactions because the steric and electronic characters of ligands can be finely tuned [23,24]. However, for the asymmetric allylic alkylation of indole, P,N ligands were not as effective as other ligands mentioned above. The reaction only afforded < 10% ee using iPr-phosphine-oxazoline (iPr-PHOX) as the ligand [15]. Hence, design of highly active and selective P/N ligands is still desirable.
Spiro phosphine-oxazoline ligands exhibit impressive catalytic performance in many cases by taking advantage of the chelating units of PHOX (phosphine-oxazoline ligands) and the spiro backbone. So far, there are four kinds of spiro phosphine-oxazoline ligands reported, including SIPHOX (spirobiindane-based phosphine-oxzoline ligands) by Zhou [25,26,27,28,29,30], SpinPHOX (spiro[4.4]-1,6-nonadiene-based phosphine-oxazoline ligands) by Ding [31,32,33,34], HMSI-PHOX (hexamethyl-1,1’-spirobiindane phosphine-oxazoline ligands) by Lin [35] and SMI-PHOX (an abbreviation for spiro mono-indane-based phosphine-oxazoline ligands L1–L4 in Scheme 1) by us [36,37]. Compared with the other three ligands, SMI-PHOX ligands possess potentially distinct features: (i) first spiro indane-based phosphine-oxazoline ligand with non-C2-symmetric skeleton in asymmetric metal catalysis; (ii) better stability and higher rigidity; (iii) only one chiral center avoiding the complex stereochemistry; (iv) modularity by changing easily accessible carboxylic acid and ClPR22 [36]. Because of the aforementioned properties, SMI-PHOX ligands have demonstrated excellent catalytic performance in several asymmetic reactions [36,37]. Therefore, we envisaged that they would be efficient chiral ligands for an indole C3-allylic alkylation reaction. As a result, high catalytic activities and enantioselectivities were obtained when these spiro phosphine-oxazoline ligands were used. We here disclose a detailed account of the Pd-catalyzed asymmetric allylic alkylation of indoles using a series of highly rigid spiro phosphine-oxazolines as chiral ligands.

2. Results and Discussion

The chiral phosphine-oxazoline ligands L1–L4 were synthesized according to the literature [36]. We investigated the ability of four representative spiro phosphine-oxazoline ligands L1–L4 for palladium-catalyzed asymmetric allylic alkylation of indole. The reaction of indole (1a) with 1,3-diphenyl-2-propenyl acetate (2a) as the model reaction was examined in the presence of [Pd(C3H5)Cl]2 (2.0 mol%) and ligand (4.0 mol%, Pd/ligand = 1/1) in toluene at room temperature using Cs2CO3 (2 equivalent) as the base. The results were summarized in Table 1. The reactions gave the corresponding product 3a in high yields (87%–95%) and enantioselectivities (87–96% ee) with the use of ligands L1, L2 and L4 (entry 1, 2, 4). However, yield and enantioselectivity slightly decreased in the presence of ligand L3 with a phenyl substitution on the oxazoline ring (entry 3). Taking into account the catalytic activity and enantioselectivity, ligand L1 was chosen as the optimal ligand for further intensive study.
The reaction was investigated under various conditions using the ligand L1. The results are summarized in Table 2. It was shown that solvents have a great influence on the reaction activity and enantioselectivity (entries 1–8). High yield (95%) and excellent enantioselectivity (96% ee) were obtained with toluene as the solvent (entry 1). When the reaction was carried out in xylenes and mesitylene, the enantioselectivities slightly decreased (entries 2 and 3). With dichloromethane and ethyl acetate as solvents, the entioselectivities decreased to around 80% ee (entries 4 and 5). Using acetonitrile, tetrahydrofuran or N,N-dimethylformamide as the solvents, low yields and entioselectivities were obtained (entries 6–8). Toluene was proved to be the best choice. We next changed the base for the reaction in toluene besides of Cs2CO3 (entries 9 and 10). Using K2CO3 as the base, product 3a was obtained with a slight decrease in enantioselectivity (89% ee) (entry 9). But the yield of 3a decreased to 65%. With Na2CO3, the enantioselectivity of the reaction dramatically decreased to 15% ee (entry 10). Subsequent optimization of temperature indicated that the reaction afforded lower yield of 3a at 0 °C and lower enantioselectivity at 40 °C than that at room temperature (entries 11 and 12). Compared to the results shown in entry 1, a slight decrease of yields and enantioselectivities was observed by changing the ratio of indole to 1,3-diphenyl-2-propenyl acetate from 1:1.2 to 1.2:1 (entries 13 and 14). Accordingly, the optimal reaction conditions were established as follows: 2 mol% [Pd(C3H5)Cl]2, 4 mol% of ligand L1, 2.0 equivalents of Cs2CO3 in toluene at room temperature with the molar ratio of 1a to 2a being 1:1.2.
With the optimized conditions in hand, we examined the substrate scope with various indoles 1a–1o and allylic acetates 2a–2e. As shown in Table 3, the reaction exhibited high tolerance of various substituted indoles. All reactions gave high yields and enantioselectivities either with substituents in the C2 position or in the phenyl ring. With 2-substituted indoles 1b–1c, the reactions proceeded smoothly to obtain the desired products 3b and 3c with 85–89% yields and 86–96% ee. C4, C5, C6 and C7-substituted indoles 1d–1o underwent the reactions smoothly to give the corresponding products 3d–3o in consistently high yields (86%–98%) and enantioselectivities (83–98% ee) with either electron-donating groups (Me, MeO, BnO) or electron-withdrawing (Cl, Br) groups in the phenyl ring. The electronic properties of the substituents in the phenyl ring of the indoles have no obvious effect on the reaction. As for the 1,3-diarylallyl acetate components, the substrates bearing either electron-donating (OMe) or electron-withdrawing (NO2) substituents at the para position of the benzene ring underwent the reaction smoothly to give the corresponding products in good yield with excellent ee values (Table 3, 3p–3s). To summarize Table 3, the ligand L1 exhibits superior catalytic performance for allylic alkylation reaction of 1,3-diaryl-2-propenyl acetate and indoles.
Encouraged by the excellent results achieved in the asymmetric allylic alkylation of indole, we successfully extended the current catalytic system to Pd-catalyzed asymmetric allylic etherification [38,39,40,41] by directly utilizing relatively hard aliphatic alcohols as nucleophiles (Table 4). We were pleased to find that the protocol is applicable to aromatic rings of benzylicalcohols with different electronic and steric natures. For example, a wide variety of benzylic alcohols bearing electron-donating (MeO) or electron-withdrawing (Br) groups at ortho-, meta-, or para-positions were well tolerated, and afforded the corresponding products 5a–5e in consistently high yields and enantioselectivities with dichloromethane (DCM) as the solvent (Table S1). When the aryl group was changed to naphthyl and aromatic heterocycle, good yields and ee values were also observed (5f and 5g). Notably, spiro phosphine-oxazoline ligand L1 also worked efficiency in the asymmetric allylic etherification of simple aliphatic alcohols, including primary and secondary alcohols, which led to the formation of the desired products in excellent enantioselectivities (5h–5j, 93–99% ee).

3. Materials and Methods

3.1. General Information

All solvents were purified and dried according to standard methods prior to use. All air and moisture sensitive manipulations were carried out with standard Schlenk techniques under argon. Commercially available reagents were used without further purification. Melting points were recorded on a RY-1 microscopic melting apparatus and uncorrected. 1H- and 13C-nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance 500 spectrometer (Bruker, Rheinstetten, Germany). Chemical shifts were reported in parts per million (δ) relative to tetramethylsilane (TMS). High resolution mass spectrometry (HRMS) were performed on an Ultima Global spectrometer (Waters, Milford, MA, USA) with an electrospray ionization (ESI) source. HPLC was performed on a Shimadzu LC-20 Liquid Chromatograph ( Shimadzu, Kyoto, Japan) using chiralcel OD-H, AD-H and OJ-H columns. Ligands L1–L4 were prepared according to the reported procedure [36].

3.2. General Procedure for the Pd-Catalyzed Asymmetric Allylic Alkylation of Indoles

Ligand L1 (5.0 mg, 4 mol%) and [Pd(C3H5)Cl]2 (2.2 mg, 2 mol%) were dissolved in toluene (1.0 mL) in a Schlenk tube under Ar. After 0.5 h of stirring at room temperature, allylic acetate 2 (0.36 mmol) dissolved in toluene (0.5 mL) was added, followed by indole 1 (0.3 mmol), and Cs2CO3 (195 mg, 0.6 mmol). The mixture was stirred at room temperature for 12 h and then was diluted with CH2Cl2 and washed with saturated NH4Cl (aq). The organic layers were dried over MgSO4 and filtered, and the solvents were evaporated in vacuo. The residue was purified by flash column chromatography, eluting with petroleum ether and ethyl acetate to afford the corresponding product 3.
(S,E)-3-(1,3-diphenylallyl)-1H-indole (3a) [15]: Yellow solid (m.p. 121–123 °C), 95% yield. 1H-NMR (500 MHz, CDCl3) δ 7.98 (brs, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.39–7.19 (m, 12H), 7.04 (t, 7.4 Hz, 1H), 6.91 (s, 1H), 6.76 (dd, J = 15.8, 7.4 Hz, 1H), 6.47 (d, J = 15.8 Hz, 1H), 5.14 (d, J = 7.4 Hz, 1H); 13C-NMR (125 MHz, CDCl3) δ 143.3, 137.4, 136.6, 132.5, 130.5, 128.4, 128.3, 127.1, 126.7, 126.3, 126.2, 122.5, 122.0, 119.8, 119.3, 118.6, 111.0, 46,1.
(S,E)-3-(1,3-diphenylallyl)-2-methyl-1H-indole (3b) [15]: Yellow solid (m.p. 39–41 °C), 89% yield. 1H-NMR (500 MHz, CDCl3) δ 7.83 (brs, 1H), 7.40–7.36 (m, 5H), 7.31–7.28 (m, 5H), 7.23–7.21 (m, 2H), 7.12 (t, J = 7.3 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.88 (dd, J = 15.8, 7.2 Hz, 1H), 6.45 (d, J = 15.8 Hz, 1H), 5.17 (d, J = 7.2 Hz, 1H), 2.40 (s, 3H); 13C-NMR (125 MHz, CDCl3) δ 143.4, 137.5, 135.3, 132.1, 131.6, 130.5, 128.4, 128.3, 128.2, 127.9, 127.0, 126.2, 126.1, 120.9, 119.4, 119.2, 112.8, 110.2, 45.0, 12.4.
(S,E)-3-(1,3-diphenylallyl)-2-phenyl-1H-indole (3c) [15]: Yellow solid (m.p. 40–42 °C), 85% yield. 1H-NMR (500 MHz, CDCl3) δ 8.09 (brs, 1H), 7.53 (d, J = 7.4 Hz, 2H), 7.45–7.31 (m, 9H), 7.26–7.24 (m, 4H), 7.19–7.14 (m, 3H), 6.99 (t, J = 7.6 Hz, 1H), 6.90 (dd, J = 15.8, 7.3 Hz, 1H), 6.40 (d, J = 15.8 Hz, 1H), 5.27 (d, J = 8.4 Hz, 1H); 13C-NMR (125 MHz, CDCl3) δ 143.4, 137.4, 136.2, 135.5, 132.9, 132.2, 131.0, 128.7, 128.6, 128.5, 128.4, 128.2, 128.1, 128.0, 127.8, 127.0, 126.2, 126.0, 122.0, 121.1, 119.6, 113.8, 110.8, 45.1.
(S,E)-3-(1,3-diphenylallyl)-4-methyl-1H-indole (3d) [17]: White solid (m.p. 172–174 °C), 93% yield. 1H-NMR (500 MHz, CDCl3) δ 8.00 (brs, 1H), 7.35 (d, J = 7.4 Hz, 2H), 7.32–7.26 (m, 6H), 7.25–7.18 (m, 3H), 7.07 (t, J = 7.5 Hz, 1H), 6.86 (d, J = 2.2 Hz, 1H), 6.81 (d, J = 7.0 Hz, 1H), 6.75 (dd, J = 15.8, 6.6 Hz, 1H), 6.25 (d, J = 15.8 Hz, 1H), 5.46 (d, J = 6.4 Hz, 1H), 2.53 (s, 3H); 13C-NMR (125 MHz, CDCl3) δ 144.1, 137.6, 137.1, 134.0, 131.2, 130.8, 129.0, 128.6, 127.2, 126.4, 125.7, 123.6, 122.3, 121.4, 119.1, 109.1, 46.6, 20.5.
(S,E)-3-(1,3-diphenylallyl)-4-methoxy-1H-indole (3e): Yellow oil, 95% yield. 1H-NMR (500 MHz, CDCl3) δ 7.96 (brs, 1H), 7.36 (d, J = 7.6 Hz, 2H), 7.31–7.25 (m, 6H), 7.19–7.16 (m, 2H), 7.07 (t, J = 8.0 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.83 (d, J = 1.8 Hz, 1H), 6.77 (dd, J = 15.8, 7.2 Hz, 1H), 6.45 (d, J = 7.8 Hz, 1H), 6.35 (d, J = 15.8 Hz, 1H), 5.55 (d, J = 7.2 Hz, 1H), 3.73 (s, 3H); 13C-NMR (125 MHz, CDCl3) δ 154.8, 144.7, 138.1, 137.9, 134.0, 129.9, 128.5, 128.4, 128.0, 126.8, 126.2, 125.7, 122.9, 121.1, 119.3, 117.0, 104.3, 100.0, 55.0, 46.3. HRMS (ESI): calcd for C24H21NNaO [M + Na]+: 362.1515, found 362.1510.
(S,E)-3-(1,3-diphenylallyl)-5-methyl-1H-indole (3f) [15]: White solid (m.p. 113–114 °C), 96% yield. 1H-NMR (500 MHz, CDCl3) δ 7.90 (brs, 1H), 7.38–7.26 (m, 8H), 7.25–7.19 (m, 4H), 7.01 (d, 8.2 Hz, 1H), 6.86 (s, 1H), 6.73 (dd, J = 15.8, 7.3 Hz, 1H), 6.44 (d, J = 15.8 Hz, 1H), 5.11 (d, J = 7.2 Hz, 1H), 2.38 (s, 3H); 13C-NMR (125 MHz, CDCl3) δ 143.6, 137.7, 135.0, 132.8, 130.6, 128.6, 127.2, 126.4, 123.8, 122.9, 119.5, 118.2, 110.9, 46.1, 21.6.
(S,E)-3-(1,3-diphenylallyl)-5-methoxy-1H-indole (3g) [15]: Colorless oil, 98% yield. 1H-NMR (500 MHz, CDCl3) δ 7.90 (brs, 1H), 7.38–7.19 (m, 11H), 6.89–6.83 (m, 3H), 6.74 (dd, J = 15.8, 7.4 Hz, 1H), 6.47 (d, J = 15.8 Hz, 1H), 5.09 (d, J = 7.3 Hz, 1H), 3.72 (s, 3H); 13C-NMR (125 MHz, CDCl3) δ 154.0, 143.5, 137.7, 132.7, 132.0, 130.8, 128.7, 128.6, 127.4, 127.3, 126.6, 126.5, 123.6, 118.6, 112.4, 111.9, 102.0, 56.0, 46.4.
(S,E)-5-(benzyloxy)-3-(1,3-diphenylallyl)-1H-indole (3h) [15]: Colorless oil, 97% yield. 1H-NMR (500 MHz, CDCl3) δ 7.82 (brs, 1H), 7.37–7.17 (m, 16H), 6.92–6.88 (m, 2H), 6.82 (s, 1H), 6.70 (dd, J = 15.8, 7.4 Hz, 1H), 6.43 (d, J = 15.8 Hz, 1H), 5.04 (d, J = 7.3 Hz, 1H), 4.93 (s, 2H); 13C-NMR (125 MHz, CDCl3) δ 152.9, 143.3, 137.6, 137.5, 132.4, 131.9, 130.5, 128.5, 127.7, 127.6, 127.2, 126.4, 126.3, 123.5, 118.3, 112.9, 111.8, 103.4, 70.8, 46.2.
(S,E)-5-chloro-3-(1,3-diphenylallyl)-1H-indole (3i) [15]: Yellow oil, 95% yield. 1H-NMR (500 MHz, CDCl3) δ 8.01 (brs, 1H), 7.38–7.20 (m, 12H), 7.13–7.11 (m, 1H), 6.94 (s, 1H), 6.69 (dd, J = 15.8, 7.3 Hz, 1H), 6.43 (d, J = 15.8 Hz, 1H), 5.07 (d, J = 7.3 Hz, 1H); 13C-NMR (125 MHz, CDCl3) δ 143.0, 137.4, 135.0, 132.1, 130.9, 128.6, 128.5, 128.0, 127.3, 126.6, 126.4, 125.2, 124.0, 122.5, 119.3, 118.6, 112.2, 46.0.
(S,E)-5-bromo-3-(1,3-diphenylallyl)-1H-indole (3j) [15]: Colorless oil, 92% yield. 1H-NMR (500 MHz, CDCl3) δ 8.00 (brs, 1H), 7.53 (s, 1H), 7.36 (d, J = 7.6 Hz, 2H), 7.32–7.28 (m, 5H), 7.26–7.19 (m, 5H), 6.90 (d, J = 2.2 Hz, 1H), 6.69 (dd, J = 15.8, 7.3 Hz, 1H), 6.42 (d, J = 15.8 Hz, 1H), 5.05 (d, J = 7.3 Hz, 1H); 13C-NMR (125 MHz, CDCl3) δ 142.8, 137.2, 135.2, 132.0, 130.7, 128.4, 128.3, 127.2, 126.5, 126.3, 125.0, 123.8, 122.2, 118.4, 112.7, 112.5, 45.8.
(S,E)-3-(1,3-diphenylallyl)-6-methyl-1H-indole (3k) [20]: Yellow oil, 90% yield. 1H-NMR (500 MHz, CDCl3) δ 7.85 (brs, 1H), 7.37–7.17 (m, 11H), 7.14 (s, 1H), 6.86–6.83 (m, 2H), 6.74 (dd, J = 15.8, 7.4 Hz, 1H), 6.45 (d, J = 15.8 Hz, 1H), 5.09 (d, J = 7.4 Hz, 1H), 2.43 (s, 3H); 13C-NMR (125 MHz, CDCl3) δ 143.4, 137.5, 137.1, 132.6, 131.8, 130.4, 128.4, 128.3, 127.1, 126.3, 124.6, 121.9, 121.1, 119.5, 118.4, 111.0, 46.2, 21.6.
(S,E)-6-chloro-3-(1,3-diphenylallyl)-1H-indole (3l) [20]: Yellow oil, 94% yield. 1H-NMR (500 MHz, CDCl3) δ 8.01 (brs, 1H), 7.38–7.28 (m, 10H), 7.26–7.20 (m, 2H), 7.00 (dd, J = 8.5, 1.8 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 6.72 (dd, J = 15.8, 7.4 Hz, 1H), 6.44 (d, J = 15.8 Hz, 1H), 5.09 (d, J = 7.4 Hz, 1H); 13C-NMR (125 MHz, CDCl3) δ 143.0, 137.2, 137.0, 132.1, 130.8, 128.5, 128.4, 128.0, 127.3, 126.6, 126.3, 125.4, 123.3, 120.8, 120.2, 118.9, 111.1, 46.1.
(S,E)-3-(1,3-diphenylallyl)-7-methyl-1H-indole (3m) [19]: Yellow oil, 90% yield. 1H-NMR (500 MHz, CDCl3) δ 7.89 (brs, 1H), 7.41–7.30 (m, 9H), 7.28-7.22 (m, 2H), 7.03–6.98 (m, 2H), 6.92 (s, 1H), 6.78 (dd, J = 15.8, 7.3 Hz, 1H), 6.49 (d, J = 15.8 Hz, 1H), 5.16 (d, J = 7.2 Hz, 1H), 2.50 (s, 3H); 13C-NMR (125 MHz, CDCl3) δ 143.4, 137.5, 136.2, 132.5, 130.5, 128.4, 128.3, 127.1, 126.3, 122.6, 122.3, 120.2, 119.6, 119.1, 117.6, 46.2, 16.5.
(S,E)-3-(1,3-diphenylallyl)-7-methoxy-1H-indole (3n): Yellow oil, 86% yield. 1H-NMR (500 MHz, CDCl3) δ 8.21 (brs, 1H), 7.37–7.17 (m, 10H), 7.03 (d, J = 8.0 Hz, 1H), 6.95-6.88 (m, 2H), 6.74 (dd, J = 15.8, 7.4 Hz, 1H), 6.63 (d, J = 7.6 Hz, 1H), 6.44 (d, J = 15.8 Hz, 1H), 5.10 (d, J = 7.4 Hz, 1H), 3.94 (s, 3H); 13C-NMR (125 MHz, CDCl3) δ 146.1, 143.5, 137.5, 132.6, 130.5, 128.4, 128.2, 127.1, 122.2, 119.8, 119.1, 112.7, 101.9, 55.3, 46.3. HRMS (ESI): calcd for C24H21NNaO [M+Na]+: 362.1515, found 362.1516.
(S,E)-7-chloro-3-(1,3-diphenylallyl)-1H-indole (3o): Yellow solid (m.p. 81–82 °C), 90% yield. 1H-NMR (500 MHz, CDCl3) δ 8.23 (brs, 1H), 7.38–7.28 (m, 9H), 7.24–7.17 (m, 3H), 6.98–6.94 (m, 2H), 6.73 (dd, J = 15.8, 7.3 Hz, 1H), 6.45 (d, J = 15.8 Hz, 1H), 5.11 (d, J = 7.3 Hz, 1H); 13C-NMR (125 MHz, CDCl3) δ 143.0, 137.3, 133.9, 132.1, 130.9, 128.5, 128.4, 128.3, 127.3, 126.6, 126.4, 123.3, 121.5, 120.3, 119.9, 118.6, 116.6, 46.2. HRMS (ESI): calcd for C23H18ClNNa [M + Na]+: 366.1020, found 366.1018.
(S,E)-3-(1,3-di-p-tolylallyl)-1H-indole (3p) [19]: Yellow oil, 92% yield. 1H-NMR (500 MHz, CDCl3) δ 7.97 (brs, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.28–7.02 (m, 10H), 6.91 (s, 1H), 6.70 (dd, J = 15.8, 7.4 Hz, 1H), 6.44 (d, J = 15.8 Hz, 1H), 5.09 (d, J = 7.2 Hz, 1H), 2.35 (s, 3H), 2.33 (s, 3H); 13C-NMR (125 MHz, CDCl3) δ 140.7, 137.0, 136.8, 136.0, 135.0, 132.0, 130.4, 129.4, 129.3, 128.6, 127.0, 126.4, 122.8, 122.2, 120.1, 119.6, 119.2, 111.3, 46.0, 21.3.
(S,E)-3-(1,3-bis(4-methoxyphenyl)allyl)-1H-indole (3q) [43]: Yellow oil, 85% yield. 1H-NMR (500 MHz, CDCl3) δ 7.98 (s, 1H), 7.43–7.28 (m, 4H), 7.24 (d, J = 8.2 Hz, 2H), 7.16 (t, J = 7.6 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.89 (s, 1H), 6.85–6.81 (m, 4H), 6.56 (dd, J = 15.8, 7.3 Hz, 1H), 6.36 (d, J = 15.8 Hz, 1H), 5.05 (d, J = 7.3 Hz, 1H), 3.78 (s, 6H); 13C-NMR (125 MHz, CDCl3) δ 158.9, 158.1, 136.7, 135.8, 130.8, 130.4, 129.7, 129.5, 127.5, 126.9, 122.6, 122.0, 120.0, 119.4, 119.2, 113.9, 113.8, 111.2, 55.3, 55.2, 45.4.
(S,E)-3-(1,3-bis(4-chlorophenyl)allyl)-1H-indole (3r) [19]: Yellow oil, 91% yield. 1H-NMR (500 MHz, CDCl3) δ 8.05 (brs, 1H), 7.39 (d, J = 8.2 Hz, 2H), 7.30–7.19 (m, 9H), 7.06 (t, J = 7.5 Hz, 1H), 6.92 (s, 1H), 6.69 (dd, J = 15.8, 7.2 Hz, 1H), 6.38 (d, J = 15.8 Hz, 1H), 5.11 (d, J = 7.2 Hz, 1H); 13C-NMR (125 MHz, CDCl3) δ 141.8, 136.9, 135.9, 133.1, 132.8, 132.4, 130.0, 129.9, 128.9, 128.8, 127.7, 126.7, 122.8, 122.5, 119.9, 119.8, 118.2, 111.4, 45.7.
(S,E)-3-(1,3-bis(4-nitrophenyl)allyl)-1H-indole (3s): Yellow oil, 87% yield. 1H-NMR (500 MHz, CDCl3) δ 8.23–8.11 (m, 5H), 7.50–7.32 (m, 6H), 7.22 (t, J = 7.4 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.98 (s, 1H), 6.90 (dd, J = 15.8, 7.2 Hz, 1H), 6.5 (d, J = 15.8 Hz, 1H), 5.28 (d, J = 8.0 Hz, 1H); 13C-NMR (125 MHz, CDCl3) δ 150.2, 146.8, 143.4, 136.7, 135.7, 130.0, 129.4, 127.0, 126.2, 124.0, 123.9, 122.8, 122.7, 119.9, 119.2, 116.2, 111.6, 46.1. HRMS (ESI): calcd for C23H17N3NaO4 [M + Na]+: 422.1111, found 422.1110.

3.3. General Procedure for the N-Boc Protection of Alkylated Indoles

To a solution of 3 (0.15 mmol) and DMAP (0.9 mg, 0.0075 mmol) in CH2Cl2 (3 mL) was added (Boc)2O (49 mg, 0.225 mmol), and the solution was stirred for 0.5 h at room temperature. The resulting mixture was evaporated under reduced pressure and purified by flash column chromatography (elution with n-hexane/EtOAc = 30:1) to afford the N-Boc-protected alkylated indole (Boc-3).
(S,E)-tert-butyl 3-(1,3-diphenylallyl)-1H-indole-1-carboxylate (Boc-3a) [15]: Colorless oil. 99% yield and 96% ee, determined by chiral HPLC analysis (Chiralcel OD-H hexane/isopropanol, 99:1 v/v, 0.4 mL/min, 25 °C, UV 254 nm), Retention times: tr = 13.2 min for (S)-isomer (major), tr = 16.0 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 8.12 (brs, 1H), 7.39–7.21 (m, 13H), 7.14 (t, J = 7.6 Hz, 1H), 6.72 (dd, J = 15.8, 7.4 Hz, 1H), 6.46 (d, J = 15.8 Hz, 1H), 5.06 (d, J = 7.4 Hz, 1H), 1.68 (s, 9H); 13C-NMR (125 MHz, CDCl3) δ 150.0, 142.1, 137.3, 135.8, 131.4, 131.3, 129.9, 128.6, 128.5, 128.4, 127.4, 126.8, 126.4, 124.4, 123.8, 123.1, 122.5, 120.2, 115.3, 83.7, 46.0, 28.3.
(S,E)-tert-butyl 3-(1,3-diphenylallyl)-2-methyl-1H-indole-1-carboxylate (Boc-3b) [15]: Colorless oil. 99% yield and 96% ee, determined by chiral HPLC analysis (Chiralcel OJ-H hexane/isopropanol, 99:1 v/v, 0.3 mL/min, 25 °C, UV 254 nm), Retention times: tr = 37.2 min for (R)-isomer (minor), tr = 50.1 min for (S)-isomer (major). 1H-NMR (500 MHz, CDCl3) δ 8.14 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 7.5 Hz, 2H), 7.34–7.27 (m, 7H), 7.23–7.19 (m, 3H), 7.07 (t, J = 7.5 Hz, 1H), 6.83 (dd, J = 15.8, 7.4 Hz, 1H), 6.48 (d, J = 16.0 Hz, 1H), 5.20 (d, J = 7.4 Hz, 1H), 2.62 (s, 3H), 1.70 (s, 9H); 13C-NMR (125 MHz, CDCl3) δ 150.7, 142.3, 137.2, 136.0, 134.0, 131.5, 130.5, 128.9, 128.5, 128.3, 128.0, 127.2, 126.3, 123.1, 122.2, 119.5, 119.1, 115.3, 83.6, 44.5, 28.3, 14.3.
(S,E)-tert-butyl 3-(1,3-diphenylallyl)-2-phenyl-1H-indole-1-carboxylate (Boc-3c) [15]: White solid (m.p. 153–155 °C). 98% yield and 86% ee, determined by chiral HPLC analysis (Chiralcel AD-H hexane/isopropanol, 99:1 v/v, 0.8 mL/min, 25 °C, UV 254 nm), Retention times: tr = 5.1 min for (S)-isomer (major), tr = 13.4 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 8.29 (d, J = 8.6 Hz, 1H), 7.42–7.36 (m, 5H), 7.33–7.17 (m, 12H), 7.10 (t, J = 7.8 Hz, 1H), 6.77 (dd, J = 15.8, 7.6 Hz, 1H), 6.32 (d, J = 15.8 Hz, 1H), 4.85 (d, J = 7.6 Hz, 1H), 1.22 (s, 9H); 13C-NMR (125 MHz, CDCl3) δ 150.4, 142.8, 137.6, 137.2, 136.9, 134.5, 131.9, 130.9, 130.3, 128.7, 128.5, 128.4, 128.2, 128.1, 127.5, 126.6, 124.5, 122.8, 121.5, 121.2, 115.6, 83.3, 45.1, 27.8.
(S,E)-tert-butyl 3-(1,3-diphenylallyl)-4-methyl-1H-indole-1-carboxylate (Boc-3d) [18]: White solid (m.p. 137–139 °C). 98% yield and 84% ee, determined by chiral HPLC analysis (Chiralcel OD-H hexane/isopropanol, 99:1 v/v, 0.7 mL/min, 25 °C, UV 254 nm), Retention times: tr = 7.1 min for (S)-isomer (major), tr = 8.5 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 8.07 (brs, 1H), 7.38 (d, J = 7.4 Hz, 2H), 7.35–7.25 (m, 8H), 7.24–7.19 (m, 2H), 6.94 (d, J = 7.3 Hz, 1H), 6.73 (dd, J = 15.8, 6.6 Hz, 1H), 6.31 (d, J = 15.8 Hz, 1H), 5.37 (d, J = 6.6 Hz, 1H), 2.50 (s, 3H), 1.68 (s, 9H); 13C-NMR (125 MHz, CDCl3) δ 149.9, 142.8, 137.4, 136.4, 132.7, 131.3, 131.2, 128.9, 128.6, 127.4, 126.7, 126.5, 125.0, 124.9, 124.4, 123.5, 113.2, 83.7, 46.6, 28.3, 27.5, 20.4.
(S,E)-tert-butyl 3-(1,3-diphenylallyl)-4-methoxy-1H-indole-1-carboxylate (Boc-3e): Colorless oil. 99% yield and 92% ee, determined by chiral HPLC analysis (Chiralcel OD-H hexane/isopropanol, 99:1 v/v, 0.7 mL/min, 25 °C, UV 254 nm), Retention times: tr = 7.8 min for (S)-isomer (major), tr = 11.6 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 7.73 (brs, 1H), 7.37 (d, J = 7.5 Hz, 2H), 7.30–7.27 (m, 7H), 7.20 (t, J = 7.8 Hz, 3H), 6.73 (dd, J = 15.8, 7.4 Hz, 1H), 6.60 (d, J = 8.0 Hz, 1H), 6.37 (d, J = 15.8 Hz, 1H), 5.46 (d, J = 7.4 Hz, 1H), 3.70 (s, 3H), 1.66 (s, 9H); 13C-NMR (125 MHz, CDCl3) δ 154.3, 150.0, 143.5, 137.7, 137.3, 132.9, 130.5, 128.5, 128.2, 127.1, 126.4, 126.1, 125.3, 123.4, 122.6, 119.6, 108.3, 103.8, 93.7, 55.2, 46.5, 28.3. HRMS (ESI): calcd for C29H29NNaO3 [M + Na]+: 462.2040, found 462.2033.
(S,E)-tert-butyl 3-(1,3-diphenylallyl)-5-methyl-1H-indole-1-carboxylate (Boc-3f) [15]: White solid (m.p. 151–152 °C). 98% yield and 95% ee, determined by chiral HPLC analysis (Chiralcel OD-H hexane/isopropanol, 99:1 v/v, 0.7 mL/min, 25 °C, ultraviolet (UV) 254 nm), Retention times: tr = 7.5 min for (S)-isomer (major), tr = 8.9 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 7.96 (brs, 1H), 7.37–7.27 (m, 9H), 7.25–7.19 (m, 2H), 7.12–7.09 (m, 2H), 6.68 (dd, J = 15.8, 7.3 Hz, 1H), 6.42 (d, J = 15.8 Hz, 1H), 5.01 (d, J = 7.3 Hz, 1H), 2.35 (s, 3H), 1.65 (s, 9H); 13C-NMR (125 MHz, CDCl3) δ 150.0, 142.2, 137.3, 134.0, 131.9, 131.4, 131.3, 130.1, 128.6, 128.5, 127.4, 126.7, 126.4, 125.8, 123.9, 122.8, 119.9, 114.9, 83.5, 45.9, 28.3, 21.5.
(S,E)-tert-butyl 3-(1,3-diphenylallyl)-5-methoxy-1H-indole-1-carboxylate (Boc-3g) [15]: Yellow oil. 98% yield and 98% ee, determined by chiral HPLC analysis (Chiralcel OD-H hexane/isopropanol, 99:1 v/v, 0.7 mL/min, 25 °C, UV 254 nm), Retention times: tr = 8.0 min for (S)-isomer (major), tr = 10.2 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 7.99 (brs, 1H), 7.39–7.22 (m, 11H), 6.91 (dd, J = 9.0, 2.4 Hz, 1H), 6.78 (d, J = 2.3 Hz, 1H), 6.69 (dd, J = 15.8, 7.4 Hz, 1H), 6.46 (d, J = 15.8 Hz, 1H), 5.00 (d, J = 7.3 Hz, 1H), 3.73 (s, 3H), 1.67 (s, 9H); 13C-NMR (125 MHz, CDCl3) δ 155.8, 155.0, 142.2, 137.4, 131.5, 131.3, 130.9, 128.8, 128.7, 128.6, 127.6, 126.9, 126.6, 124.7, 123.0, 116.1, 112.9, 103.3, 83.7, 55.8, 46.2, 28.4, 27.6.
(S,E)-tert-butyl 5-(benzyloxy)-3-(1,3-diphenylallyl)-1H-indole-1-carboxylate (Boc-3h) [15]: Colorless oil. 99% yield and 96% ee, determined by chiral HPLC analysis (Chiralcel OD-H hexane/isopropanol, 99:1 v/v, 0.35 mL/min, 25 °C, UV 254 nm), Retention times: tr = 34.3 min for (S)-isomer (major), tr = 38.3 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 8.00 (brs, 1H), 7.38–7.30 (m, 13H), 7.28–7.22 (m, 3H), 6.99 (dd, J = 9.0, 2.2 Hz, 1H), 6.86 (d, J = 2.2 Hz, 1H), 6.69 (dd, J = 15.8, 7.4 Hz, 1H), 6.45 (d, J = 15.8 Hz, 1H), 4.98 (d, J = 5.0 Hz, 3H), 1.67 (s, 9H); 13C-NMR (125 MHz, CDCl3) δ 154.9, 150.0, 142.2, 137.4, 131.5, 131.3, 130.9, 128.8, 128.7, 128.6, 128.0, 127.7, 127.6, 126.9, 126.6, 124.7, 123.0, 116.2, 113.9, 104.7, 83.7, 70.8, 46.2, 28.4.
(S,E)-tert-butyl 5-chloro-3-(1,3-diphenylallyl)-1H-indole-1-carboxylate (Boc-3i) [15]: White solid (m.p. 54–56 °C). 99% yield and 92% ee, determined by chiral HPLC analysis (Chiralcel OD-H hexane/isopropanol, 99:1 v/v, 0.7 mL/min, 25 °C, UV 254 nm), Retention times: tr = 8.2 min for (S)-isomer (major), tr = 9.0 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 8.02 (brs, 1H), 7.37–7.27 (m, 10H), 7.24–7.20 (m, 2H), 6.64 (dd, J = 15.8, 7.3 Hz, 1H), 6.42 (d, J = 15.8 Hz, 1H), 4.98 (d, J = 7.3 Hz, 1H), 1.65 (s, 9H); 13C-NMR (125 MHz, CDCl3) δ 149.6, 141.7, 137.1, 134.2, 131.6, 131.1, 130.8, 128.7, 128.6, 128.4, 128.2, 127.5, 127.0, 126.4, 125.1, 124.6, 122.5, 119.6, 116.4, 84.2, 45.8, 28.2.
(S,E)-tert-butyl 5-bromo-3-(1,3-diphenylallyl)-1H-indole-1-carboxylate (Boc-3j) [15]: White solid (m.p. 72–73 °C). 96% yield and 93% ee, determined by chiral HPLC analysis (Chiralcel OD-H hexane/isopropanol, 99:1 v/v, 0.7 mL/min, 25 °C, UV 254 nm), Retention times: tr = 8.2 min for (S)-isomer (major), tr = 8.8 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 7.99 (brs, 1H), 7.46 (s, 1H), 7.38–7.36 (m, 4H), 7.33–7.27 (m, 6H), 7.26–7.21 (m, 2H), 6.67 (dd, J = 15.8, 7.3 Hz, 1H), 6.43 (d, J = 15.8 Hz, 1H), 4.99 (d, J = 7.3 Hz, 1H), 1.65 (s, 9H); 13C-NMR (125 MHz, CDCl3) δ 149.4, 141.5, 137.0, 134.5, 131.5, 131.4, 130.7, 128.6, 128.4, 128.2, 127.4, 127.2, 126.8, 126.3, 124.8, 122.5, 122.3, 116.6, 115.8, 84.1, 45.6, 28.1.
(S,E)-tert-butyl 3-(1,3-diphenylallyl)-6-methyl-1H-indole-1-carboxylate (Boc-3k): White solid (m.p. 121–123 °C). 99% yield and 93% ee, determined by chiral HPLC analysis (Chiralcel OD-H hexane/isopropanol, 99:1 v/v, 0.7 mL/min, 25 °C, UV 254 nm), Retention times: tr = 7.2 min for (S)-isomer (major), tr = 8.2 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 7.97 (brs, 1H), 7.37–7.18 (m, 12H), 6.96 (d, J = 8.0 Hz, 1H), 6.69 (dd, J = 15.8, 7.4 Hz, 1H), 6.44 (d, J = 15.8 Hz, 1H), 5.01 (d, J = 7.4 Hz, 1H), 2.44 (s, 3H), 1.65 (s, 9H); 13C-NMR (125 MHz, CDCl3) δ 150.0, 142.2, 137.3, 136.3, 134.4, 131.3, 131.2, 128.6, 128.5, 128.4, 127.6, 127.4, 126.7, 126.4, 123.9, 123.1, 123.0, 119.7, 115.6, 83.5, 46.0, 28.2, 22.0. HRMS (ESI): calcd for C29H29NNaO2 [M + Na]+: 446.2091, found 446.2093.
(S,E)-tert-butyl 6-chloro-3-(1,3-diphenylallyl)-1H-indole-1-carboxylate (Boc-3l): Colorless oil. 98% yield and 93% ee, determined by chiral HPLC analysis (Chiralcel OD-H hexane/isopropanol, 99:1 v/v, 0.7 mL/min, 25 °C, UV 254 nm), Retention times: tr = 8.5 min for (S)-isomer (major), tr = 9.2 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 8.14 (brs, 1H), 7.36–7.19 (m, 12H), 7.10 (dd, J = 8.3, 1.7 Hz, 1H), 6.67 (dd, J = 15.8, 7.4 Hz, 1H), 6.43 (d, J = 15.8 Hz, 1H), 5.00 (d, J = 7.3 Hz, 1H), 1.66 (s, 9H); 13C-NMR (125 MHz, CDCl3) δ 171.2, 149.5, 141.8, 137.1, 136.2, 131.5, 130.9, 130.4, 128.7, 128.6, 128.4, 127.5, 126.9, 126.4, 124.3, 123.0, 122.9, 120.9, 115.6, 84.3, 60.4, 45.9, 28.2, 21.1, 14.2. HRMS (ESI): calcd for C28H26ClNNaO2 [M + Na]+: 466.1544, found 466.1547.
(S,E)-tert-butyl 3-(1,3-diphenylallyl)-7-methyl-1H-indole-1-carboxylate (Boc-3m) [19]: White solid (m.p. 123–124 °C). 99% yield and 83% ee, determined by chiral HPLC analysis (Chiralcel OD-H hexane/isopropanol, 99:1 v/v, 0.7 mL/min, 25 °C, UV 254 nm), Retention times: tr = 7.6 min for (S)-isomer (major), tr = 8.9 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 7.39–7.28 (m, 9H), 7.26–7.18 (m, 3H), 7.09–7.04 (m, 2H), 6.71 (dd, J = 15.8, 7.4 Hz, 1H), 6.45 (d, J = 15.8 Hz, 1H), 5.03 (d, J = 7.4 Hz, 1H), 2.64 (s, 3H), 1.63 (s, 9H); 13C-NMR (125 MHz, CDCl3) δ 149.6, 142.0, 137.2, 135.4, 131.2, 131.1, 131.0, 128.4, 128.3, 127.6, 127.2, 126.5, 126.3, 125.9, 125.3, 122.8, 122.4, 117.6, 83.2, 45.8, 28.0, 22.1.
(S,E)-tert-butyl 3-(1,3-diphenylallyl)-7-methoxy-1H-indole-1-carboxylate (Boc-3n): Colorless oil. 95% yield and 84% ee, determined by chiral HPLC analysis (Chiralcel OD-H hexane/isopropanol, 99:1 v/v, 0.7 mL/min, 25 °C, UV 254 nm), Retention times: tr = 21.4 min for (S)-isomer (major), tr = 49.0 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 7.37 (d, J = 7.5 Hz, 2H), 7.32–7.26 (m, 7H), 7.25–7.21 (m, 2H), 7.07 (t, J = 7.9 Hz, 1H), 6.96 (d, J = 7.8 Hz, 1H), 6.80 (d, J = 7.9 Hz, 1H), 6.69 (dd, J = 15.8, 7.4 Hz, 1H), 6.43 (d, J = 15.8 Hz, 1H), 5.01 (d, J = 7.4 Hz, 1H), 3.93 (s, 3H), 1.62 (s, 9H); 13C-NMR (125 MHz, CDCl3) δ 150.0, 148.4, 142.2, 137.3, 132.8, 131.4, 131.3, 128.6, 127.4, 126.7, 126.5, 126.4, 125.2, 123.5, 122.4, 112.8, 106.9, 83.3, 55.8, 46.0, 28.1. HRMS (ESI): calcd for C29H29NNaO3 [M+Na]+: 462.2040, found 462.2043.
(S,E)-tert-butyl 7-chloro-3-(1,3-diphenylallyl)-1H-indole-1-carboxylate (Boc-3o): Colorless oil. 99% yield and 94% ee, determined by chiral HPLC analysis (Chiralcel OD-H hexane/isopropanol, 99:1 v/v, 0.7 mL/min, 25 °C, UV 254 nm), Retention times: tr = 11.6 min for (S)-isomer (major), tr = 17.3 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 7.36–7.27 (m, 10H), 7.26–7.21 (m, 3H), 7.06 (t, J = 7.8 Hz, 1H), 6.67 (dd, J = 15.8, 7.4 Hz, 1H), 6.43 (d, J = 15.8 Hz, 1H), 5.00 (d, J = 7.4 Hz, 1H), 1.63 (s, 9H); 13C-NMR (125 MHz, CDCl3) δ 149.1, 141.7, 137.0, 133.2, 132.7, 131.5, 130.8, 128.6, 128.5, 128.4, 127.4, 127.3, 126.8, 126.5, 126.4, 123.4, 122.4, 120.4, 118.7, 84.5, 45.8, 27.9. HRMS (ESI): calcd for C28H26ClNNaO2 [M + Na]+: 466.1544, found 466.1539.
(S,E)-tert-butyl 3-(1,3-di-p-tolylallyl)-1H-indole-1-carboxylate (Boc-3p) [19]: Colorless oil. 99% yield and 94% ee, determined by chiral HPLC analysis (Chiralcel AD-H hexane/isopropanol, 99:1 v/v, 0.5 mL/min, 25 °C, UV 254 nm), Retention times: tr = 12.0 min for (S)-isomer (major), tr = 14.1 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 8.13 (brs, 1H), 7.38 (d, J = 8.2 Hz, 2H), 7.31–7.27 (m, 3H), 7.24–7.22 (m, 2H), 7.16–7.11 (m, 5H), 6.67 (dd, J = 15.8, 7.4 Hz, 1H), 6.43 (d, J = 15.8 Hz, 1H), 5.01 (d, J = 7.7 Hz, 1H), 2.35 (s, 3H), 2.34 (s, 3H), 1.69 (s, 9H); 13C-NMR (125 MHz, CDCl3) δ 150.1, 139.4, 137.2, 136.3, 136.0, 134.7, 131.1, 130.6, 130.1, 129.4, 129.3, 128.5, 126.4, 124.5, 123.9, 123.5, 122.6, 120.4, 115.4, 83.8, 45.7, 28.4, 21.3.
(S,E)-tert-butyl 3-(1,3-bis(4-methoxyphenyl)allyl)-1H-indole-1-carboxylate (Boc-3q): Yellow oil. 85% yield and 90% ee, determined by chiral HPLC analysis (Chiralcel OD-H hexane/isopropanol, 99:1 v/v, 0.7 mL/min, 25 °C, UV 254 nm), Retention times: tr = 17.5 min for (S)-isomer (major), tr = 19.3 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 8.08 (s, 1H), 7.33–7.74 (m, 5H), 7.22 (d, J = 8.6 Hz, 2H), 7.11 (t, J = 7.5 Hz, 1H), 6.82 (t, J = 9.2 Hz, 4H), 6.51 (dd, J = 15.8, 7.2 Hz, 1H), 6.34 (d, J = 15.8 Hz, 1H), 4.95 (d, J = 7.2 Hz, 1H), 3.78 (s, 6H), 1.65 (s, 9H); 13C-NMR (125 MHz, CDCl3) δ 159.1, 158.3, 150.0, 134.4, 130.4, 130.1, 130.0, 129.4, 127.5, 124.3, 123.7, 123.6, 122.4, 120.2, 115.3, 113.9, 83.7, 55.3, 55.2, 45.1, 28.3. HRMS (ESI): calcd for C30H31NNaO4 [M + Na]+: 492.2145, found 492.2150.
(S,E)-tert-butyl 3-(1,3-bis(4-chlorophenyl)allyl)-1H-indole-1-carboxylate (Boc-3r) [19]: White solid (m.p. 65–67 °C). 99% yield and 95% ee, determined by chiral HPLC analysis (Chiralcel OD-H hexane/isopropanol, 99:1 v/v, 0.7 mL/min, 25 °C, UV 254 nm), Retention times: tr = 8.6 min for (S)-isomer (major), tr = 11.7 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 8.11 (brs, 1H), 7.36 (s, 1H), 7.32–7.23 (m, 10H), 7.14 (t, J = 7.5 Hz, 1H), 6.64 (dd, J = 15.8, 7.2 Hz, 1H), 6.37 (d, J = 15.8 Hz, 1H), 5.01 (d, J = 7.2 Hz, 1H), 1.68 (s, 9H); 13C-NMR (125 MHz, CDCl3) δ 150.0, 140.5, 136.0, 135.6, 133.3, 132.8, 131.5, 130.7, 129.9, 129.7, 129.0, 128.9, 127.8, 124.7, 124.0, 122.7, 122.4, 120.1, 115.5, 84.1, 45.4, 28.4.
(S,E)-tert-butyl 3-(1,3-bis(4-nitrophenyl)allyl)-1H-indole-1-carboxylate (Boc-3s): Yellow oil. 87% yield and 97% ee, determined by chiral HPLC analysis (Chiralcel AD-H hexane/isopropanol, 93:7 v/v, 1.0 mL/min, 25 °C, UV 254 nm), Retention times: tr = 43.5 min for (R)-isomer (minor), tr = 54.4 min for (S)-isomer (major). 1H-NMR (500 MHz, CDCl3) δ 8.21–8.12 (m, 5H), 7.50 (d, J = 7.2 Hz, 4H), 7.42 (s, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.24–7.14 (m, 2H), 6.85 (dd, J = 15.8, 7.2 Hz, 1H), 6.51 (d, J = 15.8 Hz, 1H), 5.21 (d, J = 7.2 Hz, 1H), 1.68 (s, 9H); 13C-NMR (125 MHz, CDCl3) δ 148.7, 147.1, 142.9, 134.3, 130.7, 129.3, 129.0, 127.0, 124.9, 124.1, 122.8, 120.6, 119.5, 115.6, 84.3, 45.8, 28.2. HRMS (ESI): calcd for C28H25N3NaO6 [M + Na]+: 522.1636, found 522.1632.

3.4. General Procedure for the Pd-Catalyzed Asymmetric Allylic Etherification

Ligand L1 (5.0 mg, 4 mol%) and [Pd(C3H5)Cl]2 (2.2 mg, 2 mol%) were dissolved in DCM (1.0 mL) in a Schlenk tube under Ar. After 0.5 h of stirring at room temperature, allylic acetate 2a (0.3 mmol) dissolved in DCM (0.5 mL) was added, followed by alcohol 4 (0.9 mmol) dissolved in DCM (0.5 mL) and Cs2CO3 (195 mg, 0.9 mmol). The mixture was stirred at 0 °C for 5 h and then was diluted with CH2Cl2 and washed with saturated NH4Cl (aq). The organic layers were dried over MgSO4 and filtered, and the solvents were evaporated in vacuo. The residue was purified by flash column chromatography, eluting with petroleum ether and ethyl acetate to afford the corresponding product 5.
(S,E)-(3-(benzyloxy)prop-1-ene-1,3-diyl)dibenzene (5a) [44]: Colorless oil. 99% yield and 98% ee, determined by chiral HPLC analysis (Chiralcel OD-H hexane/isopropanol, 99:1 v/v, 0.5 mL/min, 25 °C, UV 254 nm), Retention times: tr = 12.2 min for (S)-isomer (major), tr = 13.4 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 7.46–7.30 (m, 14H), 7.27–7.23 (m, 1H), 6.66 (d, J = 15.9 Hz, 1H), 6.38 (dd, J = 15.9, 7.0 Hz, 1H), 5.04 (d, J = 7.0 Hz, 1H), 4.62-4.57 (m, 2H); 13C-NMR (125 MHz, CDCl3) δ 141.0, 138.2, 136.5, 131.4, 130.2, 129.6, 128.4, 128.3, 127.6, 127.4, 126.9, 126.5, 81.5, 70.0.
(S,E)-(3-((4-methoxybenzyl)oxy)prop-1-ene-1,3-diyl)dibenzene (5b) [44]: Colorless oil. 97% yield and 97% ee, determined by chiral HPLC analysis (Chiralcel OD-H hexane/isopropanol, 99:1 v/v, 0.5 mL/min, 25 °C, UV 254 nm), Retention times: tr = 18.0 min for (S)-isomer (major), tr = 23.8 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 7.44 (d, J = 7.6 Hz, 2H), 7.38 (t, J = 7.6 Hz, 4H), 7.32–7.29 (m, 5H), 7.23 (t, J = 7.2 Hz, 1H), 6.91 (d, J = 8.5 Hz, 2H), 6.63 (d, J = 15.9 Hz, 1H), 6.36 (dd, J = 15.9, 7.0 Hz, 1H), 5.01 (d, J = 7.0 Hz, 1H), 4.51 (s, 2H), 3.82 (s, 3H); 13C-NMR (125 MHz, CDCl3) δ 159.1, 141.2, 136.6, 131.4, 130.4, 130.3, 129.3, 128.5, 127.6, 126.9, 126.5, 113.7, 81.2, 69.7, 55.2.
(S,E)-(3-((4-bromobenzyl)oxy)prop-1-ene-1,3-diyl)dibenzene (5c) [44]: Colorless oil. 93% yield and 91% ee, determined by chiral HPLC analysis (Chiralcel OD-H hexane/isopropanol, 95:5 v/v, 0.5 mL/min, 25 °C, UV 254 nm), Retention times: tr = 10.2 min for (S)-isomer (major), tr = 11.2 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 7.47 (d, J = 8.3 Hz, 2H), 7.42-7.36 (m, 6H), 7.31–7.27 (m, 3H), 7.25–7.23 (m, 3H), 6.61 (d, J = 15.9 Hz, 1H), 6.32 (dd, J = 15.9, 7.1 Hz, 1H), 4.97 (d, J = 7.1 Hz, 1H), 4.55–4.48 (m, 2H); 13C-NMR (125 MHz, CDCl3) δ 140.9, 137.5, 136.5, 131.8, 131.5, 130.1, 129.4, 128.7, 128.6, 127.9, 127.0, 126.7, 121.4, 81.9, 69.4.
(S,E)-(3-((3-bromobenzyl)oxy)prop-1-ene-1,3-diyl)dibenzene (5d) [45]: Colorless oil. 95% yield and 94% ee, determined by chiral HPLC analysis (Chiralcel OD-H hexane/isopropanol, 99:1 v/v, 0.5 mL/min, 25 °C, UV 254 nm), Retention times: tr = 14.3 min for (S)-isomer (major), tr = 15.9 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 7.54 (s, 1H), 7.44–7.39 (m, 7H), 7.33–7.29 (m, 4H), 7.26–7.21 (m, 2H), 6.65 (d, J = 15.9 Hz, 1H), 6.36 (dd, J = 15.9, 7.1 Hz, 1H), 5.02 (d, J = 7.0 Hz, 1H), 4.58 (q, J = 12.2 Hz, 2H); 13C-NMR (125 MHz, CDCl3) δ 140.9, 136.5, 131.8, 130.6, 130.0, 128.6, 127.9, 127.0, 126.7, 126.1, 122.6, 82.1, 69.4.
(S,E)-(3-((2-bromobenzyl)oxy)prop-1-ene-1,3-diyl)dibenzene (5e) [46]: Colorless oil. 93% yield and 93% ee, determined by chiral HPLC analysis (Chiralcel OJ-H hexane/isopropanol, 99:1 v/v, 0.3 mL/min, 25 °C, UV 254 nm), Retention times: tr = 73.1 min for (S)-isomer (major), tr = 81.9 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 7.69 (d, J = 7.7 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.57–7.47 (m, 6H), 7.45–7.39 (m, 4H), 7.35–7.24 (m, 2H), 6.80 (d, J = 15.9 Hz, 1H), 6.47 (dd, J = 15.9, 7.0 Hz, 1H), 5.17 (d, J = 7.1 Hz, 1H), 4.76 (q, J = 13.1 Hz, 2H); 13C-NMR (125 MHz, CDCl3) δ 141.0, 137.9, 136.6, 132.9, 132.5, 131.8, 130.0, 129.2, 128.9, 128.6, 127.8, 127.4, 126.9, 126.7, 82.4, 69.8.
(S,E)-2-(((1,3-diphenylallyl)oxy)methyl)naphthalene (5f) [40]: Colorless oil. 97% yield and 94% ee, determined by chiral HPLC analysis (Chiralcel OD-H hexane/isopropanol, 98:2 v/v, 1.0 mL/min, 25 °C, UV 254 nm), Retention times: tr = 7.3 min for (S)-isomer (major), tr = 10.2 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 7.84–7.79 (m, 4H), 7.51–7.45 (m, 5H), 7.40–7.37 (m, 4H), 7.32–7.28 (m, 3H), 7.23 (t, J = 7.3 Hz, 1H), 6.66 (d, J = 15.9 Hz, 1H), 6.39 (dd, J = 15.9, 7.0 Hz, 1H), 5.06 (d, J = 7.0 Hz, 1H), 4.74 (s, 2H); 13C-NMR (125 MHz, CDCl3) δ 141.2, 136.7, 136.0, 133.4, 133.1, 131.7, 130.3, 128.6, 128.2, 128.0, 127.8, 127.7, 127.1, 126.7, 126.5, 126.1, 125.9, 125.8, 81.7, 70.3.
(S,E)-2-(((1,3-diphenylallyl)oxy)methyl)pyridine (5g) [44]: Colorless oil. 86% yield and 94% ee, determined by chiral HPLC analysis (Chiralcel OD-H hexane/isopropanol, 99:1 v/v, 0.8 mL/min, 25 °C, UV 254 nm), Retention times: tr = 25.0 min for (S)-isomer (major), tr = 36.8 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 8.56 (d, J = 4.6 Hz, 1H), 7.74–7.71 (m, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 7.4 Hz, 2H), 7.40 (t, J = 7.4 Hz, 4H), 7.32 (t, J = 7.6 Hz, 3H), 7.25 (t, J = 7.3 Hz, 1H), 7.21–7.19 (m, 1H), 6.72 (d, J = 15.8 Hz, 1H), 6.40 (dd, J = 15.8, 7.1 Hz, 1H), 5.11 (d, J = 7.1 Hz, 1H), 4.78 (dd, J = 34.2, 13.5 Hz, 2H); 13C-NMR (125 MHz, CDCl3) δ 158.7, 148.9, 140.7, 136.4, 131.7, 129.8, 128.4, 127.7, 126.8, 126.5, 122.1, 121.2, 82.5, 71.1.
(S,E)-(3-ethoxyprop-1-ene-1,3-diyl)dibenzene (5h) [44]: Colorless oil. 98% yield and 99% ee, determined by chiral HPLC analysis (Chiralcel OD-H hexane/isopropanol, 99:1 v/v, 0.5 mL/min, 25 °C, UV 254 nm), Retention times: tr = 9.2 min for (S)-isomer (major), tr = 10.4 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 7.42–7.35 (m, 6H), 7.31–7.27 (m, 3H), 7.22 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 15.9 Hz, 1H), 6.34 (dd, J = 15.9, 7.1 Hz, 1H), 4.93 (d, J = 7.1 Hz, 1H), 3.61–3.56 (m, 1H), 3.52–3.48 (m, 1H), 1.27 (t, J = 7.0 Hz, 3H); 13C-NMR (125 MHz, CDCl3) δ 141.6, 136.7, 131.2, 130.7, 128.5, 127.7, 127.6, 126.9, 126.6, 82.6, 64.0, 15.4.
(S,E)-(3-(but-3-en-1-yloxy)prop-1-ene-1,3-diyl)dibenzene (5i) [44]: Colorless oil. 97% yield and 95% ee, determined by chiral HPLC analysis (Chiralcel OD-H hexane/isopropanol, 99.2:0.8 v/v, 0.4 mL/min, 25 °C, UV 254 nm), Retention times: tr = 10.3 min for (S)-isomer (major), tr = 12.1 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 7.40–7.34 (m, 6H), 7.30–7.26 (m, 3H), 7.22 (t, J = 7.4 Hz, 1H), 6.62 (d, J = 15.9 Hz, 1H), 6.31 (dd, J = 15.9, 7.0 Hz, 1H), 5.90–5.81 (m, 1H), 5.11–5.02 (m, 2H), 4.92 (d, J = 7.0 Hz, 1H), 3.60–3.56 (m, 1H), 3.50–3.46 (m, 1H), 2.43 (q, J = 6.8 Hz, 2H); 13C-NMR (125 MHz, CDCl3) δ 141.4, 136.6, 135.3, 131.3, 130.5, 128.5, 127.7, 127.6, 126.8, 126.6, 116.3, 82.7, 68.0, 34.4.
(S,E)-2-((1,3-diphenylallyl)oxy)-2,3-dihydro-1H-indene (5j) [41]: Colorless oil. 96% yield and 93% ee, determined by chiral HPLC analysis (Chiralcel OD-H hexane/isopropanol, 99:1 v/v, 0.5 mL/min, 25 °C, UV 254 nm), Retention times: tr = 13.7 min for (S)-isomer (major), tr = 14.8 min for (R)-isomer (minor). 1H-NMR (500 MHz, CDCl3) δ 7.45–7.36 (m, 6H), 7.32–7.30 (m, 3H), 7.26–7.15 (m, 5H), 6.65 (d, J = 15.9 Hz, 1H), 6.37 (dd, J = 15.9, 7.0 Hz, 1H), 5.12 (d, J = 6.9 Hz, 1H), 4.55–4.51 (m, 1H), 3.25–3.02 (m, 4H); 13C-NMR (125 MHz, CDCl3) δ 141.4, 140.8, 136.5, 131.1, 130.6, 128.4, 127.5, 126.8, 126.5, 126.3, 124.5, 80.9, 77.9, 39.5.

4. Conclusions

SMI-PHOX ligand exhibited good catalytic performance in Pd-catalyzed asymmetric allylic alkylation reactions of indoles with 1,3-diaryl-2-propenyl acetate. The reactions afforded the corresponding products with high yields (up to 98%) and enantioselectivities (up to 98% ee) for a broad scope of indole derivatives. SMI-PHOX ligand was determined to be the most efficient P,N-ligand for this reaction. Furthermore, SMI-PHOX ligand was also efficient for Pd-catalyzed asymmetric allylic etherification with hard aliphatic alcohols as nucleophiles. Up to 99% yield and 99% ee were obtained. Further applications of these ligands in other asymmetric transformations are currently under development in our laboratory.

Supplementary Materials

The supplementary materials including NMR spectra and HPLC traces of the compounds are available online.

Author Contributions

Conceptualization, D.T. and Z.Q.; methodology, Z.Q. and R.S.; formal analysis, Z.Q. and K.Y.; investigation, Z.Q. and R.S.; resources, D.T.; data curation, Z.Q.; writing—original draft preparation, D.T. and Z.Q.; writing—review and editing, D.T.; supervision, D.T. and Z.Q. All authors read and approved the final manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds are available from the authors.
Molecules 24 01575 g001 550
Figure 1. Selected natural products containing the indole moieties.
Figure 1. Selected natural products containing the indole moieties.
Molecules 24 01575 g001
Molecules 24 01575 sch001 550
Scheme 1. Spiro-backbone-based phosphine-oxazoline ligands.
Scheme 1. Spiro-backbone-based phosphine-oxazoline ligands.
Molecules 24 01575 sch001
Table
Table 1. Evaluation of ligands for Pd-catalyzed allylic alkylation of indoles. a
Table 1. Evaluation of ligands for Pd-catalyzed allylic alkylation of indoles. a
Molecules 24 01575 i001
EntryLigandT (°C)Time (h)Yield b (%)ee c,d (%)
1L125129596
2L225128791
3L325247080
4L425129487
a Unless otherwise noted, reactions were performed with 1a (0.3 mmol), 2a (0.36 mmol), [Pd(C3H5)Cl]2 (2 mol%), Ligand (4 mol%), Cs2CO3 (0.6 mmol) in toluene (1.5 mL) at room temperature (r.t.). b Isolated yield. c The ee values were determined by chiral high-performance liquid chromatography (HPLC) with the N-Boc-protected derivative of 3a. d The absolute configurations were assigned as S via comparison of specific rotations with the literature data [20].
Table
Table 2. Optimization of reaction conditions for Pd-catalyzed allylic alkylation of indoles. a
Table 2. Optimization of reaction conditions for Pd-catalyzed allylic alkylation of indoles. a
Molecules 24 01575 i002
EntrySolventBaseTime (h)T (°C)Yield b (%)ee c,d (%)
1tolueneCs2CO312259596
2xylenesCs2CO312258694
3mesityleneCs2CO312258490
4CH2Cl2Cs2CO312257683
5EtOAcCs2CO312257484
6CH3CNCs2CO324254719
7THFCs2CO32425493
8DMFCs2CO34825N.R. eN.D. f
9tolueneK2CO312256589
10tolueneNa2CO312257615
11tolueneCs2CO31207090
12tolueneCs2CO312408479
13 gtolueneCs2CO312259194
14 htolueneCs2CO312259095
a Unless otherwise noted, reactions were performed with 1a (0.3 mmol), 2a (0.36 mmol), [Pd(C3H5)Cl]2 (2 mol%), L1 (4 mol%), base (0.6 mmol) in solvent (1.5 mL) at a certain temperature. b Isolated yield. c The ee values were determined by chiral HPLC with the N-Boc-protected derivative of 3a. d The absolute configurations were assigned as S via comparison of specific rotations with the literature data [20]. e No reaction. f Not detected. g The molar ratio of 1a to 2a was 1:1. h The molar ratio of 1a to 1b was 1.2:1.
Table
Table 3. Substrate scope of asymmetric allylic alkylation of indoles. a
Table 3. Substrate scope of asymmetric allylic alkylation of indoles. a
Molecules 24 01575 i003
EntryR1R2ArProductYield b (%)Ee c,d (%)
1HHPh3a9596
2HMePh3b8996
3HPhPh3c8586
44-MeHPh3d9384
54-MeOHPh3e9592
65-MeHPh3f9695
75-MeOHPh3g9898
85-BnOHPh3h9796
95-ClHPh3i9592
105-BrHPh3j9293
116-MeHPh3k9093
126-ClHPh3l9493
137-MeHPh3m9083
147-MeOHPh3n8684
157-ClHPh3o9094
16HH4-MePh3p9294
17HH4-MeOPh3q8590
18HH4-ClPh3r9195
19HH4-NO2Ph3s8797
a Unless otherwise noted, reactions were performed with 1 (0.3 mmol), 2 (0.36 mmol), [Pd(C3H5)Cl]2 (2 mol%), L1 (4 mol%), Cs2CO3 (0.6 mmol) in toluene (1.5 mL) at room temperature. b Isolated yield. c The ee values were determined by chiral HPLC with the N-Boc-protected derivative of 3. d The absolute configurations were assigned as S via comparison of specific rotations with the literature data [20].
Table
Table 4. Substrate scope of asymmetric allylic etherification. a
Table 4. Substrate scope of asymmetric allylic etherification. a
Molecules 24 01575 i004
Entry4ProductYield b (%)ee c,d (%)
14a5a9998
24b5b9797
34c5c9391
44d5d9594
54e5e9393
64f5f9794
74g5g8694
84h5h9899
94i5i9795
104j5j9693
a Unless otherwise noted, reactions were performed with 2a (0.3 mmol), 4 (0.9 mmol), [Pd(C3H5)Cl]2 (2 mol%), L1 (4 mol%), Cs2CO3 (0.9 mmol) in DCM (2 mL) at 0oC. b Isolated yield. c Determined by HPLC using a chiral column. d The absolute configurations were assigned as S via comparison of specific rotations with the literature data [42].

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Qiu, Z.; Sun, R.; Yang, K.; Teng, D. Spiro Indane-Based Phosphine-Oxazolines as Highly Efficient P,N Ligands for Enantioselective Pd-Catalyzed Allylic Alkylation of Indoles and Allylic Etherification. Molecules 2019, 24, 1575. https://doi.org/10.3390/molecules24081575

AMA Style

Qiu Z, Sun R, Yang K, Teng D. Spiro Indane-Based Phosphine-Oxazolines as Highly Efficient P,N Ligands for Enantioselective Pd-Catalyzed Allylic Alkylation of Indoles and Allylic Etherification. Molecules. 2019; 24(8):1575. https://doi.org/10.3390/molecules24081575

Chicago/Turabian Style

Qiu, Zhongxuan, Rui Sun, Kun Yang, and Dawei Teng. 2019. "Spiro Indane-Based Phosphine-Oxazolines as Highly Efficient P,N Ligands for Enantioselective Pd-Catalyzed Allylic Alkylation of Indoles and Allylic Etherification" Molecules 24, no. 8: 1575. https://doi.org/10.3390/molecules24081575

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