Asymmetric synthesis of axially chiral anilides by Pd-catalyzed allylic substitutions with P/olefin ligands

Abstract

As an attractive class of non-biaryl atropisomeric compounds, C–N axially chiral anilides have received considerable attention, and several methods have been successfully developed for their synthesis. Pd-catalyzed asymmetric allylic amination was proved to be an effective approach for the chiral anilide synthesis, although only moderate enantioselectivity and relatively narrow substrate scope have been achieved in the previous work. Searching for highly efficient methods for the synthesis of axially chiral anilides is therefore of great interest in synthetic and pharmaceutical chemistry. In this paper, a palladium-catalyzed asymmetric allylic substitution of ortho-substituted anilides using phosphorus amidite–olefin ligands was successfully achieved to afford a variety of axially chiral anilides in high yields with up to 84% ee. The absolute configurations of chiral anilides were also determined from X-ray and CD spectra.

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Introduction

C–N axially chiral anilides as an attractive class of non-biaryl atropisomeric compounds have received considerable attention.¹ One of the most famous examples is the herbicide metolachlor,² although its axial chirality is found to have little effect on its biological activity. In 1994, Curran and coworkers reported their seminal work on the development of novel chiral auxiliaries based on axially chiral amides and imides.³ These axially chiral anilides gave high levels of asymmetric introduction in many types of important reactions, such as cycloaddition, alkylation, and aldol reaction.^3,4 The axially chiral anilides can be also incorporated in chiral organocatalysts for asymmetric Michael addition and Friedel–Crafts amination.⁵

Due to their highly potential applications, a variety of strategies for accessing enantioenriched axially chiral anilides have been successfully developed. For example, Uemura and Simpkins described a desymmetrization of prochiral anilides using chiral lithium reagents, respectively.⁶ Taguchi, Shimizu, and Curran reported the chiral resolution of racemic compounds.⁷ Kamikawa and Uemura reported the stereoselective synthesis of chiral anilides by nucleophilic aromatic substitution of planar chiral arene chromium complexes.⁸ In contrast to the aforementioned work, using a catalytic amount of the chiral catalyst seems to be more desirable. In 2005, Taguchi and coworkers described a Pd-catalyzed asymmetric N-arylation reaction for the chiral anilide synthesis.⁹ In 2006, Jørgensen reported an organocatalytic amination of 2-naphthols.⁵ Tanaka and Hsung developed a Rh-catalyzed asymmetric [2 + 2 + 2] cycloaddition, respectively.¹⁰ Recently, Maruoka and coworkers employed chiral phase-transfer catalysis for the synthesis of axially chiral o-iodoanilides.¹¹ As an extremely useful tool for the construction of C–N bonds, Pd-catalyzed asymmetric allylic aminations have also been employed for the chiral anilide synthesis to give a moderate enantioselectivity (30–56% ee) with a relatively narrow substrate scope.^12,13 Despite these advances, searching for highly efficient methods for the synthesis of axially chiral anilides is still of great interest in synthetic and pharmaceutical chemistry.^14,15

The lately emerging field of chiral olefin ligands has witnessed a rapid growth in recent years.¹⁶ As a novel type of ligand, chiral P/olefin hybrid ligands have been successfully developed for various transition-metal-catalyzed asymmetric reactions.¹⁷ Recently, our group has also described the application of chiral P/olefin ligands in Pd-catalyzed asymmetric allylic alkylations of indoles, pyrroles, and oximes.¹⁸ However, to the best of our knowledge, the construction of axial chirality using this type of ligand has not been reported.¹⁹ Herein, we wish to report our efforts on the asymmetric synthesis of axially chiral anilides through Pd-catalyzed allylic substitutions with phosphorus amidite–olefin ligands.

Results and discussion

At the outset, we examined the ability of phosphorus amidite–olefin ligands for the Pd-catalyzed asymmetric allylic alkylation of ortho-tert-butylanilide (1a) with cinnamyl ethyl carbonate (2a). It was found that the reaction using ligand 3a proceeded smoothly at room temperature to give the desired product 4aa in 86% yield with 20% ee (Scheme 1). In a control experiment, ligand 3b without the vinyl group gave product 4aa in a reverse absolute configuration with a very low ee (Scheme 1).

Scheme 1 Initial studies on Pd-catalyzed asymmetric allylic alkylation of ortho-tert-butylanilide 1a.

A variety of chiral P/olefin hybrid ligands 3c–i was next evaluated for this reaction (Fig. 1). Ligands 3c–d bearing methyl or diphenylmethyl on the nitrogen atom can only improve the enantioselectivity slightly. Ligands 3e–f containing different substituents on the carbon chiral center gave a lower ee. Using ligand 3g incorporated with an internal olefin led to an inverse configuration. Ligand 3h derived from H₈-BINOL gave 12% ee. When a chirality matched ligand 3i was subjected to this reaction, the enantioselectivity can be improved from 20% to 46%.

Fig. 1 Selective chiral P/olefin ligands for Pd-catalyzed asymmetric allylic alkylation of ortho-tert-butylanilide 1a.

The reaction conditions including bases and solvents were investigated to further improve the enantioselectivity. As shown in Table 1, bases were found to have a great impact on the enantioselectivity (entries 1–6). Significantly, the reaction with KOEt as a base can be accomplished in 0.5 h with 60% ee (Table 1, entry 6). Solvents can also influence the enantioselectivity, and toluene seems to be a better solvent (Table 1, entries 6–10). Decreasing the catalyst loading from 5 mol% to 2.5 mol% no loss of reactivity and enantioselectivity was observed (Table 1, entries 6 vs. 11). When anilide 1b containing one more tert-butyl group was used as a substrate, up to 79% ee was obtained (Table 1, entry 12).

Table 1 Optimization of reaction conditions^a

Entry	Base	Solvent	Time (h)	Yield^b (%)	ee^c (%)
a All reactions were carried out with 1a (0.20 mmol), 2a (0.24 mmol), Pd/3i = 1/1 (5.0 mol% Pd), base (0.24 mmol), and solvent (3.0 mL) unless otherwise stated. b Isolated yield based on 1. c The ee was determined by chiral HPLC. d The reaction was carried out with 1 (0.40 mmol), 2a (0.48 mmol), Pd/3i = 1/1 (2.5 mol% Pd), KOEt (0.48 mmol), and toluene (3.0 mL).
1	LiO^tBu	Toluene	8	86	17
2	NaO^tBu	Toluene	5	91	12
3	KO^tBu	Toluene	5	93	46
4	KHMDS	Toluene	4	94	56
5	KH	Toluene	3.5	95	18
6	KOEt	Toluene	0.5	93	60
7	KOEt	THF	2	89	28
8	KOEt	DCM	2	88	56
9	KOEt	MeCN	4	93	26
10	KOEt	Benzene	3	95	61
11^d	KOEt	Toluene	1.5	92	61
12^d	KOEt	Toluene	3	91	79

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Under the optimal reaction conditions, the allyl carbonate scope was examined using anilide 1b as a substrate. As shown in Table 2, a wide range of allyl carbonates were well tolerated to give the corresponding axially chiral anilide products in 74–92% yields with 68–84% ees (Table 2, entries 1–9). When a simple allyl carbonate 2k was used as a substrate, the desired product 4bk can be obtained in 51% yield with 46% ee (Table 2, entry 10).

Table 2 Pd-catalyzed asymmetric allylic alkylation of ortho-tert-butylanilide 1b^a

Entry	Product (4)	Time (h)	Yield^b (%)	ee^c (%)
a All reactions were carried out with 1b (0.40 mmol), 2 (0.48 mmol), Pd/3i = 1/1 (2.5 mol% Pd), KOEt (0.48 mmol), and toluene (3.0 mL) unless otherwise stated. b Isolated yield based on 1b. c The ee was determined by chiral HPLC.
1	4bb: R = 4-CF3C6H4	3.5	92	68
2	4bc: R = 3-ClC6H4	2	80	75
3	4bd: R = 3-MeOC6H4	2.5	74	76
4	4be: R = 2-ClC6H4	1.5	80	80
5	4bf: R = 2-MeOC6H4	1.5	87	84
6	4bg: R = 2-BnOC6H4	2.5	76	80
7	4bh: R = 2-^iPrOC6H4	2	81	79
8	4bi: R = 2-MeC6H4	1.5	81	75
9	4bj: R = 1-naphthyl	2	76	83
10	4bk: R = H	4	51	46

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Subsequently, the asymmetric reaction of various N-acylanilides and allyl carbonate 2e was investigated. It was found that all these reactions went smoothly to furnish chiral anilides 4 in high yields with 43–83% ees (Table 3, entries 1–8). The substrate scope can be further extended to other anilides. The reaction of ortho-haloanilides 1k–m and allyl carbonate 2e can proceed well to give the desired products in high yields with relatively lower ees (Scheme 2), which can be used as chiral building blocks for further transformation.²⁰ Anilide 1n bearing an ortho-phenyl substituent was also a suitable substrate to give product 4ne in 78% yield with 33% ee (Scheme 2).

Scheme 2 Pd-catalyzed asymmetric synthesis of other types of axially chiral anilides.

Table 3 Pd-catalyzed asymmetric allylic alkylation of N-acylanilide^a

Entry	Product (4)	Time (h)	Yield^b (%)	ee^c (%)
a All reactions were carried out with 1 (0.40 mmol), 2e (0.48 mmol), Pd/3i = 1/1 (2.5 mol% Pd), KOEt (0.48 mmol), and toluene (3.0 mL) unless otherwise stated. b Isolated yield based on 1. c The ee was determined by chiral HPLC.
1	4ce: R = PhCH2CH2	2.5	83	47
2	4de: R = trans-PhCH=CH	4.5	79	44
3	4ee: R = Ph	4	71	46
4	4fe: R = 2-furyl	3.5	82	43
5	4ge: R = Cy	2	84	74
6	4he: R = 4-Cl-C6H4CH2	4	86	66
7	4ie: R = 2-Cl-C6H4CH2	4	90	75
8	4je: R = 2,5-Me2C6H4CH2	4	85	83

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The absolute configuration of product 4 was tentatively assigned as S by analogy with compounds (S)-4de and (S)-4ge, which was determined by their X-ray structures on the basis of the anomalous dispersion of the heavy chlorine atom (Fig. 2).²¹ To determine the absolute configurations of the other products, the CD spectra were measured in CH₃CN, and some typical ones are summarized in Fig. 3. As shown in Fig. 3, all of the compounds exhibited a similar (−)-Cotton effect in the CD spectra with compounds (S)-4de and (S)-4ge, which indicated that these compounds possess the same S configuration as (S)-4de and (S)-4ge.

Fig. 2 The X-ray structure of (S)-4de (above) and (S)-4ge (below).

Fig. 3 CD spectra of selected typical compounds 4 (c = 5 × 10⁻⁴ M in CH₃CN).

Experimental section

Representative procedure for 3i/Pd-catalyzed asymmetric allylic alkylation of ortho-tert-butylanilide (1a) (Table 1, entry 11)

To a dried Schlenk flask charged with [PdCl(C₃H₅)]₂ (0.0018 g, 0.005 mmol, 2.5 mol% Pd) and ligand 3i (0.0054 g, 0.010 mmol, 2.5 mol%) was added toluene (0.5 mL) under argon. After the mixture was stirred for 30 min at room temperature, cinnamyl ethyl carbonate 2a (0.0990 g, 0.48 mmol) and toluene (1.3 mL) were added sequentially, and the solution was stirred for 10 min. Meanwhile a suspension of ortho-tert-butylanilide (1a) (0.1070 g, 0.40 mmol) and KOEt (0.0404 g, 0.48 mmol) in toluene (1.2 mL) was stirred for 3 min at room temperature. Then the solution was added to the suspension with a syringe. After the resulting mixture was stirred at room temperature for 1.5 h, it was filtered by crude flash column chromatography with ethyl acetate, and evaporated under vacuum. The crude residue was purified by flash chromatography on silica gel (PE–EA = 10/1, v/v) to afford the desired product 4aa as a light yellow oil (0.1411 g, 92% yield, 61% ee).

Spectral data

(11bS)-N-Benzhydryl-N-((R)-1-phenylallyl)dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepin-4-amine (3d). White solid; mp 103–105 °C; [α]^D₂₀ = −70.3 (c 1.00, CH₂Cl₂); IR (film): 1468, 1232, 1050, 938 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 8.8 Hz, 2H), 7.43 (d, J = 7.2 Hz, 1H), 7.40–7.28 (m, 10H), 7.25–7.15 (m, 7H), 7.14–7.03 (m, 3H), 5.94 (ddd, J = 17.2, 10.0, 7.2 Hz, 1H), 5.72 (d, J = 11.2 Hz, 1H), 5.06 (dd, J = 12.0, 7.2 Hz, 1H), 4.87 (d, J = 10.0 Hz, 1H), 4.51(d, J = 17.2 Hz, 1H); ³¹P NMR (121 MHz, CDCl₃) δ 148.8; HRMS (ESI): calcd for C₄₂H₃₃NO₂P (M + H)⁺: 614.2243; Found: 614.2246.

(11bS)-N-Benzyl-N-((R)-1-phenylallyl)-8,9,10,11,12,13,14,15-octahydrodinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepin-4-amine (3h). White solid; mp 70–72 °C; [α]^D₂₀ = +108.6 (c 0.50, CH₂Cl₂); IR (film): 1468, 1232, 1050, 938 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.33–7.20 (m, 10H), 7.06–7.01 (m, 2H), 6.92 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.18 (ddd, J = 16.8, 10.0, 4.0 Hz, 1H), 5.25 (d, J = 10.0 Hz, 1H), 5.09 (d, J = 16.8 Hz, 1H), 4.62 (dd, J = 16.8, 8.0 Hz, 1H), 3.98 (dd, J = 14.8, 2.4 Hz, 1H), 3.45 (dd, J = 15.2, 3.2 Hz, 1H), 2.81–2.71 (m, 4H), 2.66–2.56 (m, 2H), 2.27–2.20 (m, 2H), 1.79–1.71 (m, 6H), 1.55–1.45 (m, 2H); ³¹P NMR (121 MHz, CDCl₃) δ 140.5; HRMS (ESI): calcd for C₃₆H₃₇NO₂P (M + H)⁺: 546.2556; Found: 546.2559.

(S)-N-(2-(tert-Butyl)phenyl)-N-cinnamyl-2-phenylacetamide (4aa). Light yellow oil; [α]²⁰_D = +18.9 (c 2.99, CH₂Cl₂) (61% ee); IR (film): 2959, 1650, 1490, 1392, 970 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J = 8.0 Hz, 1H), 7.35–7.17 (m, 9H), 7.10 (t, J = 7.2 Hz, 3H), 6.81 (d, J = 8.0 Hz, 1H), 6.42–6.31 (m, 2H), 5.14 (dd, J = 13.6, 4.4 Hz, 1H), 3.49 (dd, J = 13.6, 7.6 Hz, 1H), 3.36 (dd, J = 27.2, 15.2 Hz, 2H), 1.45 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 171.4, 146.5, 139.8, 136.9, 135.2, 134.0, 132.7, 130.1, 129.6, 128.9, 128.7, 128.4, 127.8, 127.0, 126.8, 126.7, 124.0, 53.9, 42.0, 36.4, 32.5; HRMS (TOF-EI): calcd for C₂₇H₂₉NO (M): 383.2249; Found: 383.2253.

(S)-N-Cinnamyl-N-(2,5-di-tert-butylphenyl)-2-phenylacetamide (4ba). Light yellow oil; [α]²⁰_D = −18.6 (c 1.72, CH₂Cl₂) (79% ee); IR (film): 2954, 1655, 1490, 1406, 970 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, J = 8.4 Hz, 1H), 7.32 (dd, J = 8.4, 2.0 Hz, 1H), 7.29–7.16 (m, 8H), 7.12 (d, J = 7.2 Hz, 2H), 6.72 (d, J = 2.4 Hz, 1H), 6.38 (ddd, J = 12.8, 8.0, 4.8 Hz, 1H), 6.30 (t, J = 16.0 Hz, 1H), 5.16 (dd, J = 14.0, 4.8 Hz, 1H), 3.45 (dd, J = 13.6, 8.0 Hz, 1H), 3.39 (dd, J = 27.2, 14.6 Hz, 2H), 1.44 (s, 9H), 1.07 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 171.4, 149.7, 143.0, 139.2, 136.9, 135.4, 134.4, 130.0, 129.6, 129.4, 128.6, 128.5, 127.7, 126.7, 126.5, 125.8, 124.0, 77.4, 53.6, 42.1, 35.9, 34.1, 32.5, 31.0; HRMS (TOF-EI): calcd for C₃₁H₃₇NO (M): 439.2875; Found: 439.2881.

(S)-N-(2,5-Di-tert-butylphenyl)-2-phenyl-N-(3-(4-(trifluoromethyl)phenyl)allyl)acetamide (4bb). Light yellow oil; [α]²⁰_D = +9.0 (c 4.18, CH₂Cl₂) (68% ee); IR (film): 2959, 1655, 1495, 1410, 1330, 1121, 970 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.53 (d, J = 8.4 Hz, 3H), 7.37–7.32 (m, 3H), 7.26–7.19 (m, 3H), 7.11 (d, J = 6.4 Hz, 2H), 6.69 (d, J = 2.0 Hz, 1H), 6.47 (ddd, J = 16.0, 8.4, 4.8 Hz, 1H), 6.34 (d, J = 16.0 Hz, 1H), 5.17 (dd, J = 14.0, 4.8 Hz, 1H), 3.48 (dd, J = 14.0, 8.4 Hz, 1H), 3.40 (dd, J = 28.0, 14.4 Hz, 2H), 1.44 (s, 9H), 1.08 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 171.5, 149.9, 143.1, 140.4, 139.2, 135.3, 132.9, 129.8, 129.4, 129.3 (q, J_C–F = 29.0 Hz), 128.6, 126.9, 126.7, 126.0, 125.8, 125.7, 125.6, 124.4 (q, J_C–F = 270.0 Hz), 53.5, 42.1, 36.0, 34.1, 32.5, 31.1; HRMS (TOF-EI): calcd for C₃₂H₃₇F₃NO (M + H)⁺: 508.2822; Found: 508.2818.

(S)-N-(2,5-Di-tert-butylphenyl)-2-phenyl-N-(3-(3-chlorophenyl)allyl)acetamide (4bc). Light yellow oil; [α]²⁰_D = +2.6 (c 5.07, CH₂Cl₂) (75% ee); IR (film): 2963, 1655, 1495, 1401, 1246, 970 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, J = 8.4 Hz, 1H), 7.33 (dd, J = 8.8, 2.4 Hz, 1H), 7.26–7.18 (m, 7H), 7.11 (d, J = 6.4 Hz, 2H), 6.68 (d, J = 2.4 Hz, 1H), 6.35 (ddd, J = 16.0, 8.8, 4.8 Hz, 1H), 6.25 (d, J = 16.0 Hz, 1H), 5.15 (dd, J = 14.0, 4.8 Hz, 1H), 3.43 (dd, J = 14.0, 8.8 Hz, 1H), 3.39 (dd, J = 28.0, 14.4 Hz, 2H), 1.44 (s, 9H), 1.08 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 171.5, 149.8, 143.0, 139.2, 135.4, 135.3, 133.4, 133.0, 129.9, 129.7, 129.4, 128.9, 128.5, 127.7, 126.8, 125.9, 124.8, 53.5, 42.1, 36.0, 34.1, 32.5, 31.1; HRMS (TOF-EI): calcd for C₃₁H₃₆NOCl (M): 473.2485; Found: 473.2491.

(S)-N-(2,5-Di-tert-butylphenyl)-2-phenyl-N-(3-(3-methyloxyphenyl)allyl)acetamide (4bd). Light yellow oil; [α]²⁰_D = +10.8 (c 4.58, CH₂Cl₂) (76% ee); IR (film): 2959, 1659, 1490, 1406, 1259, 965 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, J = 8.4 Hz, 1H), 7.32 (dd, J = 8.4, 2.4 Hz, 1H), 7.26–7.16 (m, 4H), 7.11 (d, J = 6.8 Hz, 2H), 6.86 (d, J = 7.6 Hz, 1H), 6.82 (s, 1H), 6.77 (dd, J = 8.0, 2.0 Hz, 1H), 6.72 (d, J = 2.0 Hz, 1H), 6.37 (ddd, J = 16.0, 8.8, 4.8 Hz, 1H), 6.28 (d, J = 16.0 Hz, 1H), 5.15 (dd, J = 14.0, 4.8 Hz, 1H), 3.78 (s, 3H), 3.44 (dd, J = 13.6, 8.4 Hz, 1H), 3.40 (dd, J = 27.6, 14.8 Hz, 2H), 1.44 (s, 9H), 1.09 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 171.4, 159.9, 149.8, 143.0, 139.2, 138.4, 135.4, 134.3, 130.0, 129.6, 129.4, 128.5, 126.8, 125.8, 124.3, 119.4, 113.8, 111.4, 55.4, 53.6, 42.1, 36.0, 34.1, 32.5, 31.1; HRMS (TOF-EI): calcd for C₃₂H₃₉NO₂ (M): 469.2981; Found: 469.2986.

(S)-N-(2,5-Di-tert-Butylphenyl)-2-phenyl-N-(3-(2-chlorophenyl)allyl)acetamide (4be). Light yellow oil; [α]²⁰_D = +35.4 (c 2.21, CH₂Cl₂) (80% ee); IR (film): 2963, 1655, 1495, 1406, 1263, 970 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, J = 8.8 Hz, 1H), 7.48 (dd, J = 7.6, 1.6 Hz, 1H), 7.34–7.28 (m, 2H), 7.26–7.16 (m, 4H), 7.15–7.11 (m, 3H), 6.71 (s, 1H), 6.69 (d, J = 13.6 Hz, 1H), 6.40 (ddd, J = 13.6, 8.8, 4.8 Hz, 1H), 5.15 (dd, J = 14.0, 4.8 Hz, 1H), 3.52 (dd, J = 14.0, 8.8 Hz, 1H), 3.40 (dd, J = 26.8, 14.4 Hz, 2H), 1.45 (s, 9H), 1.10 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 171.5, 149.9, 143.0, 139.3, 135.4, 135.0, 133.1, 130.1, 129.8, 129.7, 129.6, 129.4, 128.8, 128.5, 127.2, 127.1, 127.0, 126.8, 126.0, 53.8, 42.1, 36.0, 34.1, 32.5, 31.1; HRMS (TOF-EI): calcd for C₃₁H₃₆NOCl (M): 473.2485; Found: 473.2491.

(S)-N-(2,5-Di-tert-butylphenyl)-2-phenyl-N-(3-(2-methyloxyphenyl)allyl)acetamide (4bf). Light yellow oil; [α]²⁰_D = +18.3 (c 2.63, CH₂Cl₂) (84% ee); IR (film): 2965, 1651, 1486, 1242, 748 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.50 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 6.8 Hz, 1H), 7.31 (dd, J = 8.4, 2.0 Hz, 1H), 7.25–7.16 (m, 4H), 7.11 (d, J = 6.8 Hz, 2H), 6.88 (t, J = 7.6 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.62 (d, J = 16.0 Hz, 1H), 6.38 (ddd, J = 16.0, 8.8, 4.8 Hz, 1H), 5.15 (dd, J = 14.0, 4.4 Hz, 1H), 3.74 (s, 3H), 3.48 (dd, J = 13.6, 8.8 Hz, 1H), 3.39 (dd, J = 25.6, 14.8 Hz, 1H), 1.44 (s, 9H), 1.08 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 171.3, 156.8, 149.8, 143.0, 139.5, 135.6, 130.0, 129.5, 129.4, 129.1, 128.8, 128.5, 127.3, 126.7, 126.1, 125.7, 124.8, 120.8, 110.8, 55.4, 54.2, 42.2, 36.0, 34.1, 32.5, 31.0; HRMS (TOF-EI): calcd for C₃₂H₃₉NO₂ (M): 469.2981; Found: 469.2986.

(S)-N-(2,5-Di-tert-butylphenyl)-2-phenyl-N-(3-(2-benzyloxyphenyl)allyl)acetamide (4bg). Light yellow oil; [α]²⁰_D = +26.3 (c 2.54, CH₂Cl₂) (80% ee); IR (film): 2963, 1650, 1495, 1401, 1241, 752 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.50 (d, J = 8.4 Hz, 1H), 7.40 (dd, J = 7.6, 1.2 Hz, 1H), 7.34–7.27 (m, 6H), 7.24–7.11 (m, 6H), 6.89 (t, J = 7.6 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.72 (s, 1H), 6.72 (d, J = 15.6 Hz, 1H), 6.38 (ddd, J = 15.6, 8.8, 4.8 Hz, 1H), 5.16 (ddd, J = 13.2, 9.2, 8.0 Hz, 1H), 5.05–4.99 (m, 2H), 3.51 (dd, J = 13.6, 4.8 Hz, 1H), 3.39 (dd, J = 26.4, 14.4 Hz, 2H), 1.43 (s, 9H), 1.06 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 171.4, 155.9, 149.7, 143.1, 139.2, 137.3, 135.5, 130.0, 129.5, 129.4, 128.9, 128.8, 128.7, 128.5, 127.9, 127.2, 127.0, 126.7, 126.5, 125.8, 124.7, 121.1, 112.6, 70.3, 54.0, 42.2, 36.0, 34.1, 32.5, 31.1; HRMS (TOF-EI): calcd for C₃₈H₄₃NO₂ (M): 545.3294; Found: 545.3299.

(S)-N-(2,5-Di-tert-butylphenyl)-2-phenyl-N-(3-(2-isopropoxyphenyl)allyl)acetamide (4bh). Light yellow solid; mp 77–79 °C; [α]²⁰_D = +21.7 (c 4.11, CH₂Cl₂) (79% ee); IR (film): 2963, 1646, 1486, 1410, 1237, 952 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 6.4 Hz, 1H), 7.30 (dd, J = 8.8, 2.0 Hz, 1H), 7.25–7.11 (m, 6H), 6.87–6.80 (m, 2H), 6.74 (d, J = 2.4 Hz, 1H), 6.61 (d, J = 16.0 Hz, 1H), 6.38 (ddd, J = 16.0, 8.8, 5.2 Hz, 1H), 5.15 (dd, J = 14.0, 5.2 Hz, 1H), 4.50–4.43 (m, 1H), 3.51 (dd, J = 13.6, 8.8 Hz, 1H), 3.39 (dd, J = 26.4, 14.4 Hz, 1H), 1.44 (s, 9H), 1.25 (t, J = 5.6 Hz, 6H), 1.07 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 171.3, 155.2, 149.7, 143.0, 139.4, 135.5, 129.9, 129.4, 129.4, 129.3, 128.6, 128.5, 127.3, 127.0, 126.7, 125.7, 124.4, 120.6, 114.0, 70.7, 54.1, 42.2, 35.9, 34.1, 32.5, 31.1, 22.3, 22.3; HRMS (TOF-EI): calcd for C₃₄H₄₃NO₂ (M): 497.3294; Found: 497.3299.

(S)-N-(2,5-Di-tert-butylphenyl)-2-phenyl-N-(3-(2-methylphenyl)allyl)acetamide (4bi). Light yellow oil; [α]²⁰_D = +25.2 (c 2.91, CH₂Cl₂) (75% ee); IR (film): 2958, 1654, 1494, 1401, 1249, 969 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, J = 8.4 Hz, 1H), 7.37 (dd, J = 5.2, 4.0 Hz, 1H), 7.32 (dd, J = 8.4, 2.0 Hz, 1H), 7.24–7.16 (m, 3H), 7.14–7.07 (m, 5H), 6.72 (d, J = 2.0 Hz, 1H), 6.54 (d, J = 15.6 Hz, 1H), 6.25 (ddd, J = 15.6, 8.8, 5.2 Hz, 1H), 5.16 (dd, J = 14.0, 5.2 Hz, 1H), 3.52 (dd, J = 14.0, 8.8 Hz, 1H), 3.39 (dd, J = 28.8, 14.4 Hz, 2H), 2.19 (s, 3H), 1.45 (s, 9H), 1.09 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 171.3, 149.8, 143.0, 139.3, 136.0, 135.4, 135.4, 132.0, 130.3, 129.7, 129.6, 129.3, 128.5, 127.6, 126.8, 126.2, 126.1, 125.9, 125.5, 53.9, 42.1, 36.0, 34.1, 32.5, 31.1, 19.9; HRMS (TOF-EI): calcd for C₃₂H₃₉NO (M): 453.3032; Found: 453.3038.

(S)-N-(2,5-Di-tert-butylphenyl)-2-phenyl-N-(3-(1-naphthyl)allyl)acetamide (4bj). Light yellow solid; mp 96–98 °C; [α]²⁰_D = +46.9 (c 3.69, CH₂Cl₂) (83% ee); IR (film): 2963, 1637, 1490, 1406, 1174, 974 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.89 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.47–7.38 (m, 3H), 7.35 (dd, J = 8.4, 2.0 Hz, 1H), 7.25–7.18 (m, 3H), 7.17–7.07 (m, 3H), 6.77 (d, J = 2.0 Hz, 1H), 6.41 (ddd, J = 15.6, 8.8, 5.2 Hz, 1H), 5.24 (dd, J = 14.0, 5.2 Hz, 1H), 3.63 (dd, J = 14.0, 8.8 Hz, 1H), 3.42 (dd, J = 30.0, 14.4 Hz, 2H), 1.47 (s, 9H), 1.05 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 171.4, 149.9, 143.0, 139.4, 135.4, 134.7, 133.7, 131.4, 131.2, 129.7, 129.4, 128.59, 128.57, 128.1, 127.4, 126.8, 126.1, 126.0, 125.9, 125.8, 124.3, 124.1, 54.0, 42.1, 36.0, 34.1, 32.5, 31.1; HRMS (TOF-EI): calcd for C₃₅H₃₉NO (M): 489.3032; Found: 489.3038.

(S)-N-Allyl-N-(2,5-di-tert-butylphenyl)-2-phenylacetamide (4bk). Light yellow oil; [α]²⁰_D = +49.6 (c 1.69, CH₂Cl₂) (46% ee); IR (film): 2963, 1655, 1490, 1401, 1259, 925 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.50 (d, J = 8.4 Hz, 1H), 7.32 (dd, J = 8.4, 2.0 Hz, 1H), 7.26–7.17 (m, 3H), 7.10 (d, J = 7.2 Hz, 2H), 6.72 (d, J = 2.0 Hz, 1H), 5.99 (dddd, J = 16.8, 10.0, 6.4, 4.8 Hz, 1H), 5.12 (d, J = 10.0 Hz, 1H), 5.01 (d, J = 16.8 Hz, 1H), 4.96 (d, J = 4.8 Hz, 1H), 3.37 (dd, J = 25.6, 14.4 Hz, 2H), 3.31 (dd, J = 13.6, 8.4 Hz, 1H), 1.41 (s, 9H), 1.17 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 171.3, 149.7, 142.9, 139.5, 135.4, 133.1, 129.8, 129.6, 129.4, 128.5, 126.7, 125.8, 118.8, 54.3, 42.1, 35.9, 34.2, 32.4, 31.1; HRMS (TOF-EI): calcd for C₂₅H₃₃NO (M): 363.2562; Found: 363.2566.

(S)-N-(3-(2-Chlorophenyl)allyl)-N-(2,5-di-tert-butylphenyl)-3-phenylpropanamide (4ce). Light yellow oil; [α]²⁰_D = −8.0 (c 2.89, CH₂Cl₂) (47% ee); IR (film): 2963, 1650, 1472, 1401, 1272, 965 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.55 (dd, J = 7.6, 1.2 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.32–7.28 (m, 2H), 7.25–7.11 (m, 5H), 7.07 (d, J = 6.8 Hz, 2H), 6.80 (d, J = 2.0 Hz, 1H), 6.72 (d, J = 15.6 Hz, 1H), 6.44 (ddd, J = 15.6, 9.2, 5.2 Hz, 1H), 5.15 (dd, J = 14.0, 5.2 Hz, 1H), 3.48 (dd, J = 14.0, 9.2 Hz, 1H), 3.01–2.87 (m, 2H), 2.37–2.25 (m, 2H), 1.35 (s, 9H), 1.16 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 172.9, 150.2, 143.1, 141.6, 139.4, 135.0, 133.1, 130.0, 129.8, 129.6, 129.1, 128.8, 128.7, 128.6, 127.2, 127.2, 127.0, 126.2, 125.7, 53.8, 37.6, 35.8, 34.2, 32.3, 31.8, 31.2; HRMS (TOF-EI): calcd for C₃₂H₃₈NOCl (M): 487.2642; Found: 487.2647.

(S)-N-(3-(2-Chlorophenyl)allyl)-N-(2,5-di-tert-butylphenyl)-cinnamamide (4de). Light yellow solid; mp 95–97 °C; [α]²⁰_D = −12.8 (c 2.99, CH₂Cl₂) (44% ee); IR (film): 2963, 1655, 1468, 1379, 1232, 970 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.71 (d, J = 15.6 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.32–7.27 (m, 6H), 7.23–7.14 (m, 2H), 6.95 (s, 1H), 6.77 (d, J = 16.0 Hz, 1H), 6.56 (ddd, J = 16.0, 9.2, 5.2 Hz, 1H), 6.21 (d, J = 15.6 Hz, 1H), 5.25 (dd, J = 14.0, 5.2 Hz, 1H), 3.62 (dd, J = 14.0, 9.2 Hz, 1H), 1.40 (s, 9H), 1.19 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 166.6, 150.4, 143.9, 141.9, 139.2, 135.5, 135.0, 133.1, 130.1, 129.8, 129.7, 129.4, 128.9, 128.8, 128.0, 127.2, 127.0, 125.8, 119.5, 54.2, 35.9, 34.3, 32.4, 31.2; HRMS (TOF-EI): calcd for C₃₂H₃₆NOCl (M): 485.2485; Found: 485.2491.

(S)-N-(3-(2-Chlorophenyl)allyl)-N-(2,5-di-tert-butylphenyl)-benzamide (4ee). Light yellow oil; [α]²⁰_D = −16.7 (c 3.16, CH₂Cl₂) (46% ee); IR (film): 2963, 1633, 1468, 1410, 1281, 965 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.48 (d, J = 6.0 Hz, 1H), 7.36–7.29 (m, 4H), 7.26–7.15 (m, 4H), 7.10 (t, J = 7.2 Hz, 2H), 7.04 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 16.0 Hz, 1H), 6.60 (ddd, J = 16.0, 8.8, 4.8 Hz, 1H), 5.33 (dd, J = 14.0, 4.8 Hz, 1H), 3.72 (dd, J = 14.0, 8.8 Hz, 1H), 1.25 (s, 9H), 1.16 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 169.3, 149.5, 142.9, 139.4, 136.3, 135.0, 133.1, 130.3, 130.2, 130.1, 129.8, 129.7, 129.4, 128.9, 127.6, 127.2, 127.2, 127.0, 125.3, 55.5, 35.9, 34.1, 32.5, 31.1; HRMS (TOF-EI): calcd for C₃₀H₃₄NOCl (M): 459.2329; Found: 459.2335.

(S)-N-(3-(2-Chlorophenyl)allyl)-N-(2,5-di-tert-butylphenyl)-2-furylamide (4fe). Light yellow oil; [α]²⁰_D = −22.4 (c 3.53, CH₂Cl₂) (43% ee); IR (film): 2954, 1642, 1472, 1410, 1188, 970 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.58 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.23–7.14 (m, 2H), 7.00 (d, J = 2.0 Hz, 1H), 6.80 (d, J = 15.6 Hz, 1H), 6.59 (ddd, J = 15.6, 9.2, 4.8 Hz, 1H), 6.14 (d, J = 2.0 Hz, 1H), 5.32 (dd, J = 13.6, 4.8 Hz, 1H), 5.26 (d, J = 3.2 Hz, 1H), 3.64 (dd, J = 13.6, 9.2 Hz, 1H), 1.31 (s, 9H), 1.17 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 159.4, 150.4, 147.4, 144.7, 143.7, 139.1, 134.9, 133.1, 130.4, 129.9, 129.79, 129.77, 128.9, 127.2, 127.0, 126.8, 126.0, 116.6, 111.2, 54.9, 35.9, 34.2, 32.3, 31.1; HRMS (TOF-EI): calcd for C₂₈H₃₂NO₂Cl (M): 449.2122; Found: 449.2126.

(S)-N-(3-(2-Chlorophenyl)allyl)-N-(2,5-di-tert-butylphenyl)-2-cyclohexanylamide (4ge). Light yellow oil; [α]²⁰_D = +9.3 (c 3.22, CH₂Cl₂) (74% ee); IR (film): 2937, 1650, 1468, 1424, 1268, 970 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.55 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.33–7.30 (m, 2H), 7.23–7.14 (m, 2H), 6.95 (d, J = 2.0 Hz, 1H), 6.73 (d, J = 16.0 Hz, 1H), 6.45 (ddd, J = 16.0, 8.8, 4.8 Hz, 1H), 5.11 (dd, J = 14.0, 4.8 Hz, 1H), 3.47 (dd, J = 14.0, 8.8 Hz, 1H), 1.99–1.94 (m, 1H), 1.75–1.64 (m, 4H), 1.62–1.44 (m, 3H), 1.39 (s, 9H), 1.19 (s, 9H), 1.03–0.78 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 176.9, 149.7, 143.1, 139.5, 135.1, 133.1, 129.8, 129.7, 129.4, 129.3, 128.7, 127.5, 127.2, 127.0, 125.3, 53.7, 42.9, 35.8, 34.2, 32.4, 31.1, 28.3, 25.9, 25.4; HRMS (TOF-EI): calcd for C₃₀H₄₀NOCl (M): 465.2798; Found: 465.2804.

(S)-N-(2,5-Di-tert-butylphenyl)-2-(4-chlorophenyl)-N-(3-(2-chlorophenyl)allyl)acetamide (4he). Light yellow oil; [α]²⁰_D = +50.2 (c 2.19, CH₂Cl₂) (66% ee); IR (film): 2959, 1655, 1490, 1094, 1023, 965 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.53 (d, J = 8.8 Hz, 1H), 7.48 (dd, J = 8.0, 1.6 Hz, 1H), 7.34 (dd, J = 8.4, 2.0 Hz, 1H), 7.30 (dd, J = 8.0, 1.2 Hz, 1H), 7.22–7.13 (m, 4H), 7.06 (d, J = 8.0 Hz, 2H), 6.71 (d, J = 2.0 Hz, 1H), 6.70 (d, J = 15.2 Hz, 1H), 6.38 (ddd, J = 15.2, 8.8, 4.0 Hz, 1H), 5.13 (dd, J = 14.4, 4.0 Hz, 1H), 3.53 (dd, J = 14.4, 8.8 Hz, 1H), 3.40–3.31 (m, 2H), 1.44 (s, 9H), 1.12 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 171.0, 150.1, 143.0, 139.2, 134.9, 133.8, 133.1, 132.7, 130.8, 130.3, 129.81, 129.77, 129.5, 128.9, 128.6, 127.2, 127.0, 126.9, 126.1, 53.8, 41.3, 36.0, 34.2, 32.5, 31.1; HRMS (ESI): calcd for C₃₁H₃₆NOCl₂ (M + H)⁺: 508.2169; Found: 508.2169.

(S)-N-(2,5-Di-tert-butylphenyl)-2-(2-chlorophenyl)-N-(3-(2-chlorophenyl)allyl)acetamide (4ie). Light yellow oil; [α]²⁰_D = +21.0 (c 3.05, CH₂Cl₂) (75% ee); IR (film): 2965, 1657, 1470, 1407, 1249, 970 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.54–7.50 (m, 2H), 7.36 (dd, J = 7.6, 1.2 Hz, 1H), 7.33–7.27 (m, 3H), 7.24–7.13 (m, 4H), 6.83 (d, J = 2.0 Hz, 1H), 6.74 (d, J = 15.6 Hz, 1H), 6.48 (ddd, J = 15.6, 8.8, 4.8 Hz, 1H), 5.17 (dd, J = 14.0, 4.8 Hz, 1H), 3.71 (d, J = 16.0 Hz, 1H), 3.55 (dd, J = 14.0, 8.8 Hz, 1H), 3.36 (d, J = 16.0 Hz, 1H), 1.47 (s, 9H), 1.10 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 170.7, 150.2, 143.2, 139.0, 135.1, 134.5, 133.9, 133.1, 131.3, 130.3, 129.9, 129.8, 129.6, 129.3, 128.8, 128.3, 127.2, 127.06, 127.05, 126.9, 126.0, 54.0, 39.9, 36.0, 34.1, 32.6, 31.1; HRMS (ESI): calcd for C₃₁H₃₆NOCl₂ (M + H)⁺: 508.2169; Found: 508.2169.

(S)-N-(2,5-Di-tert-butylphenyl)-2-(2,5-dimethylphenyl)-N-(3-(2-chlorophenyl)allyl)acetamide (4je). Light yellow oil; [α]²⁰_D = +29.9 (c 3.07, CH₂Cl₂) (83% ee); IR (film): 2963, 1655, 1472, 1406, 1254, 974 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.53 (dd, J = 7.6, 1.2 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.32–7.28 (m, 2H), 7.23–7.14 (m, 2H), 7.08 (s, 1H), 6.92–6.88 (m, 2H), 6.73 (d, J = 16.0 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 6.50 (ddd, J = 16.0, 8.8, 4.0 Hz, 1H), 5.18 (dd, J = 13.6, 4.0 Hz, 1H), 3.51 (dd, J = 13.6, 8.8 Hz, 1H), 3.44 (d, J = 15.2 Hz, 1H), 3.27 (d, J = 15.2 Hz, 1H), 2.25 (s, 3H), 1.83 (s, 3H), 1.45 (s, 9H), 1.02 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 171.8, 149.9, 143.0, 139.3, 135.5, 135.1, 133.9, 133.3, 133.1, 130.3, 130.1, 129.8, 129.6, 129.3, 128.8, 127.5, 127.2, 127.2, 127.0, 125.9, 53.8, 39.5, 36.0, 34.0, 32.5, 30.9, 21.1, 19.3; HRMS (ESI): calcd for C₃₃H₄₁NOCl (M + H)⁺: 502.2871; Found: 502.2866.

(S)-N-(2,4-Di-methyl-6-iodophenyl)-2-phenyl-N-(3-(2-chloro-phenyl)allyl)acetamide (4ke). Light yellow oil; [α]²⁰_D = +11.6 (c 2.71, CH₂Cl₂) (48% ee); IR (film): 2923, 1664, 1468, 1383, 1263, 965 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.63 (s, 1H), 7.43 (dd, J = 7.6, 1.6 Hz, 1H), 7.32–7.18 (m, 5H), 7.16–7.13 (m, 1H), 7.12–7.09 (m, 1H), 7.03 (s, 1H), 6.71 (d, J = 15.6 Hz, 1H), 6.39 (dt, J = 15.6, 7.6 Hz, 1H), 4.53 (dd, J = 14.0, 6.4 Hz, 1H), 4.23 (dd, J = 14.0, 8.0 Hz, 1H), 3.43 (d, J = 14.8 Hz, 1H), 3.24 (d, J = 14.8 Hz, 1H), 2.31 (s, 3H), 2.04 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 171.0, 140.5, 140.5, 138.7, 138.4, 135.0, 134.7, 133.1, 132.5, 129.84, 129.80, 129.7, 129.2, 128.8, 128.4, 127.5, 127.2, 127.0, 126.9, 102.2, 51.8, 41.6, 20.7, 19.6; HRMS (ESI): calcd for C₂₅H₂₄ONClI (M + H)⁺: 516.0586; Found: 516.0583.

(S)-N-(2,4-Di-methyl-6-bromophenyl)-2-phenyl-N-(3-(2-chloro-phenyl)allyl)acetamide (4le). Light yellow oil; [α]²⁰_D = +7.0 (c 4.52, CH₂Cl₂) (53% ee); IR (film): 2919, 1659, 1468, 1388, 1263, 974 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.43 (d, J = 7.2 Hz, 1H), 7.36 (s, 1H), 7.29–7.11 (m, 6H), 7.07 (d, J = 7.2 Hz, 2H), 7.00 (s, 1H), 6.70 (d, J = 15.6 Hz, 1H), 6.35 (dt, J = 15.6, 7.6 Hz, 1H), 4.43 (dd, J = 14.0, 6.8 Hz, 1H), 4.34 (dd, J = 14.0, 7.2 Hz, 1H), 3.44 (d, J = 14.8 Hz, 1H), 3.26 (d, J = 14.8 Hz, 1H), 2.33 (s, 3H), 2.02 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 171.2, 140.2, 138.9, 137.2, 135.1, 134.8, 133.0, 132.1, 131.5, 129.8, 129.7, 128.8, 128.4, 127.4, 127.2, 127.0, 126.9, 124.8, 51.3, 41.3, 21.0, 19.1; HRMS (ESI): calcd for C₂₅H₂₄ONBrCl (M + H)⁺: 468.0724; Found: 468.0723.

(S)-N-(6-Bromo-2-methyl-phenyl)-2-phenyl-N-(3-(2-chlorophenyl)allyl)acetamide (4me). Light yellow oil; [α]²⁰_D = +5.9 (c 2.91, CH₂Cl₂) (46% ee); IR (film): 2927, 1664, 1464, 1388, 1263, 970 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.55 (dd, J = 7.6, 1.2 Hz, 1H), 7.42 (dd, J = 7.6, 1.6 Hz, 1H), 7.29 (dd, J = 7.6, 1.6 Hz, 1H), 7.25–7.12 (m, 7H), 7.05 (dd, J = 7.6, 1.6 Hz, 2H), 6.70 (d, J = 16.0 Hz, 1H), 6.35 (dt, J = 16.0, 7.6 Hz, 1H), 4.47–4.34 (m, 2H), 3.45 (d, J = 14.8 Hz, 1H), 3.26 (d, J = 14.8 Hz, 1H), 2.05 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 171.0, 139.8, 139.7, 135.1, 134.6, 133.1, 131.7, 130.8, 130.0, 129.9, 129.7, 129.7, 128.8, 128.5, 127.3, 127.3, 127.0, 127.0, 125.4, 51.3, 41.6, 19.1; HRMS (TOF-EI): calcd for C₂₄H₂₁NOClBr (M): 453.0495; Found: 453.0500.

(S)-N-(3-(2-Chlorophenyl)allyl)-N-(3,5-dimethyl-[1,1′-biphenyl]-2-yl)-2-phenylacetamide (4ne). Light yellow oil; [α]²⁰_D = +4.3 (c 1.46, CH₂Cl₂) (33% ee); IR (film): 2954, 1655, 1468, 1392, 1263, 965 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.32–7.21 (m, 11H), 7.16–7.12 (m, 4H), 7.10 (d, J = 4.4 Hz, 1H), 6.59 (d, J = 16.0 Hz, 1H), 6.05 (dt, J = 16.0, 8. 4 Hz, 1H), 4.32 (dd, J = 14.4, 6.4 Hz, 1H), 3.74 (dd, J = 14.4, 8.0 Hz, 1H), 3.47 (dd, J = 25.6, 15.2 Hz, 2H), 2.40 (s, 3H), 2.12 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 171.5, 140.6, 139.6, 138.5, 136.8, 136.5, 135.1, 135.0, 133.0, 131.6, 130.4, 129.9, 129.7, 129.1, 129.0, 128.7, 128.6, 128.5, 127.67, 127.66, 127.2, 126.94, 126.89, 52.4, 41.1, 21.3, 19.0; HRMS (TOF-EI): calcd for C₃₁H₂₈NOCl (M): 465.1859; Found: 465.1864.

Conclusions

In summary, a Pd-catalyzed asymmetric allylic alkylation of anilides using chiral phosphorus amidite–olefin ligands is successfully developed, and a wide range of highly desirable optically active C–N axially chiral anilides were obtained in high yields with up to 84% ee. The absolute configurations of the corresponding chiral anilide products were determined from X-ray and CD spectra.

Acknowledgements

The authors are thankful for the financial support from the National Natural Science Foundation of China (21072194, 21172222, 21222207), and the 973 program (2010CB833300).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: The procedure for palladium-catalyzed asymmetric alkylation of N-nonsubstituted anilides, characterization of ligands and products, X-ray structural data, and data for the determination of enantiomeric excesses. CCDC 1005254 and 1025346. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ob01087f

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