Palladium-Catalyzed Stereoselective Construction of 1,3-Stereocenters Displaying Axial and Central Chirality via Asymmetric Alkylations

Abstract

The concurrent construction of 1,3-stereocenters remains a challenge. Herein, we report the development of stereoselective union of a point chiral center with allenyl axial chirality in 1,3-position by Pd-catalyzed asymmetric allenylic alkylation between racemic allenyl carbonates and indanone-derived β-ketoesters. Various target products bearing a broad range of functional groups were afforded in high yield (up to 99%) with excellent enantioselectivities (up to 98% ee) and good diastereoselectivities (up to 13:1 dr).

1. Introduction

Over the past decades, extensive demands for chiral non-racemic compounds from various fields have significantly motivated the development of asymmetric catalysis [1,2,3,4,5]. Hence numerous catalytic asymmetric methodologies have been developed for enantioselective construction of chiral structures [6,7,8,9]. Whereas many methods are available for the synthesis of chiral molecules containing one single stereocenter or even two adjacent stereocenters (Scheme 1a), much less efforts have been paid to the concurrent creation of nonadjacent stereocenters in an enantio- and diastereoselective manner, due in part to the difficulties in high levels of simultaneous stereocontrol posed by increased distance between the two chiral centers [10,11,12,13,14]. Of note, the limited reports on enantio- and diastereoselective construction of 1,3-stereocenters focused mostly on molecules bearing two point chiral centers, while those containing different types of chirality, for example, central and axial chiral motifs, have been rarely explored.

As a prominent example of axial chiral molecules, chiral allenes constitute an important structural motif widely present in a variety of organic molecules including natural products, pharmaceutical agents, chiral catalysts, and ligands for coordination chemistry etc., as represented by the selected compounds in Scheme 1b [15,16,17,18,19]. Interestingly, Enprostil [20], a prostaglandin analogue used for the treatment of acute duodenal ulcer disease, shows a distinct 1,3-stereocenters consisting of a point chiral center and allenyl axial chirality.

Functionalized alkynes are most commonly employed for the synthesis of chiral allenes by classic synthetic methods such as addition, elimination, substitution, and rearrangement (Scheme 1c) [5,21,22,23,24,25]. Moreover, transition metal-catalyzed 1,4-addition of enynes serves as a powerful strategy for the concise and efficient synthesis of multi-substituted chiral allenes [26,27,28,29,30]. It is worth noting that although great progress has been achieved for the enantioselective construction of allenyl axial chirality [31,32,33,34,35,36,37,38], only two reports documented the asymmetric concurrent creation of 1,3-stereocenters bearing allenyl axial chirality and central chirality, contributed by the Trost group [11] and the Ma/Zhang group [39], respectively. Both studies exploited the strategy of Pd-catalyzed asymmetric allenylic alkylation employing racemic allenyl acetate electrophile through dynamic kinetic transformation. In connection with our interest in the asymmetric functionalization of indanone derivatives [40,41], herein we report Pd-catalyzed asymmetric allenylic alkylation between racemic allenylic carbonates and indanone-derived β-ketoesters to construct 1,3-stereocenters bearing allenyl axial and central chirality (Scheme 1d), providing alkylation products in good yields (up to 99%) with excellent enantioselectivities (up to 98% ee) and good diastereoselectivities (up to 13:1 dr).

2. Results and Discussion

2.1. Optimization of the Reaction Conditions

In our preliminary investigation, allenylic carbonate 2a was selected as the model substrate for the asymmetric alkylation with β-ketoester 1a in the presence of Cs₂CO₃ using a palladium catalyst (

Table 1. Optimization of reaction conditions.

Entry a	Ligand	Base	Sol.	T [°C]	t [h]	Yield [%] b	dr c	ee [%] d
1	L1	Cs2CO3	DCM	25	0.5	84	10:1	−71/−39
2	L2	Cs2CO3	DCM	25	12	trace	-	-
3	L3	Cs2CO3	DCM	25	3	89	3:1	−67/−69
4	L4	Cs2CO3	DCM	25	12	55	15:1	−73/−17
5	L5	Cs2CO3	DCM	25	48	21	4:1	−23/−33
6	L6	Cs2CO3	DCM	25	24	20	11:1	−7/−5
7	L7	Cs2CO3	DCM	25	7.5	59	5:1	−69/−69
8	L8	Cs2CO3	DCM	25	24	29	5:1	−89/−51
9	L9	Cs2CO3	DCM	25	24	90	4:1	91/81
10 e	L9	Cs2CO3	DCM	25	6	97	4:1	93/77
11 e	L9	Cs2CO3	CHCl3	25	9	92	5:1	92/61
12 e	L9	Cs2CO3	DCE	25	12	92	4:1	91/75
13 e	L9	Cs2CO3	MeCN	25	12	96	5:1	92/81
14 e	L9	Cs2CO3	Tol.	25	9	98	5:1	92/73
15 e	L9	Cs2CO3	THF	25	6	97	6:1	92/65
16 e	L9	Cs2CO3	Dioxane	25	6	98	4:1	93/61
17 e	L9	Et3N	THF	25	10	70	6:1	94/71
18 e	L9	C4H9OK	THF	25	4	90	7:1	92/71
19 e	L9	C2H5ONa	THF	25	6	98	3:1	90/73
20 e	L9	NaHCO3	THF	25	6	98	7:1	93/67
21 e	L9	Na2CO3	THF	25	10	61	5:1	92/51
22 e	L9	K2CO3	THF	25	6	98	2:1	93/79
23 e	L9	NaHCO3	THF	0	24	98	6:1	95/79
24 e	L9	NaHCO3	THF	−10	42	98	7:1	95/70
25 e,f	L9	NaHCO3	THF	−10	12	98	7:1	96/71
26 e,g	L9	NaHCO3	THF	−10	48	98	8:1	96/77

^a The reaction was conducted with 1a (0.1 mmol), 2a (0.11 mmol), base (0.1 mmol), Pd₂dba₃ (2.5 mol%) and ligand (5 mol%) in solvent (1.0 mL). ^b Isolated yield. ^c Detected by ¹H NMR of the crude product. ^d Detected by chiral HPLC analysis. ^e 2a (0.12 mmol). ^f THF (0.5 mL) was used. ^g THF (2.0 mL) was used.

, entries 1–26). Initially, several classic biphosphine ligands were screened to explore the effect of the chiral ligands on the Pd-catalyzed allenylic alkylation reaction. With L1 or L3 as the ligand, product 3a could be afforded in high yields (84% and 89%) with good enantioselectivities (−71% ee and −67% ee) (entries 1 and 3). In the reaction with Trost ligand L2, no product was observed (entry 2), while L4 afforded product 3a in 55% yield with −73% ee and 15:1 dr (entry 4). Further screening led to the observation that ligands L5–L7 were sluggish for this allenylation, whereas ligand L6 afforded the product 3a with high diastereoselectivity (11:1) but low yield and enantioselectivity (20%, −7% ee) (entry 6). Then, the ligand (R)- and (S)-SegPhos were applied in this reaction. Interestingly, using ligand (S)-SegPhos (L9) the product 3a was obtained in 90% yield with 4:1 dr and 91% ee (entry 9). Subsequently, increasing the amount of 2a further increased the yield of 3a to 97%, and the enantioselectivity of 3a to 93%, respectively (entry 10). With L9 as the ligand, subsequent investigation on the solvent effect showed that THF was the best one, affording 97% yield 3a with 6:1 dr and 92% ee (entry 15). Next, we investigated the effect of base, and observed that the product 3a was formed in 98% yield, with 7:1 dr and 93% ee (entry 20), when the base of the reaction was NaHCO₃. Further optimization was performed and found that the reaction at 0.05 M could give product 3a in 98% yield with 8:1 dr and 96% ee at −10 °C.

2.2. Substrate Scope for the Asymmetric Alkylations of β-Ketoester 1

Having established the optimized reaction conditions (Table 1, entry 26), the scope of β-ketoester 1 was then examined with allenylic carbonate 2a (Scheme 2). We evaluated the electronic nature and position of the substituents on the 1H-indanone backbone of the substrates. The products 3b, 3c, and 3g bearing electron-donating substituents were obtained in high yields (93–96% yield) with excellent enantioselectivities (95–96% ee) and good diastereoselectivities (6:1–9:1 dr). Furthermore, the disubstituted substrate 1d was also successfully transformed into 3d in 99% yield, with 97% ee and 9:1 dr. Meanwhile, substrates (1e, 1f, and 1h–1l) bearing halogen groups also engaged in the asymmetric alkylation reaction well and afforded products (3e, 3f, and 3h–3l) in 96–99% yields, with high enantioselectivities (95–97% ee) and diastereoselectivities (7:1–12:1 dr). Notably, the six-membered cyclic β-ketoester (1m) underwent the alkylation reaction smoothly to afford product 3m in high yield and excellent enantioselectivity (99%, 97% ee), though with a moderate dr (2:1).

2.3. Substrate Scope for the Asymmetric Alkylations of Allenylic Carbonates 2

Next, the substrate scope with respect to allenylic carbonates 2 were investigated (Scheme 3). The electronic nature and position of the substituents on the arylallenyl carbonates backbone of the substrates were also examined. When a chloro group was present at the C2 position in the aryl, high yield and enantioselectivity were observed for the formation of the alkylation product 3n (80% yield, 97% ee). The products (3o and 3p) bearing electron-donating substituents were obtained in 99% yield with 93–97% ee. Meanwhile, halogenation in the aryl C4 position of the substrates (2f and 2g) were well-tolerated, giving the corresponding products (3r and 3s) with 91–97% ee and a slight decrease in yield (84–87%). Moreover, 2-naphthyl-substituted allenylic carbonate also worked smoothly (73% yield, 97% ee). Compared to model substrate 2a, various substituted arylallenyl carbonates (2b–2h) could afford the target products (3n–3t) with relatively higher diastereoselectivities as expected. In addition, substrates 2i with an n-propyl group and 2j with isopropyl afforded products 3u and 3v with slightly decreased enantioselectivities and diastereoselectivities. The asymmetric alkylation of allenylic carbonate with symmetrical cyclohexyl substituent delivered the product 3w in moderate enantioselectivity and diastereoselectivity, albeit with a lower yield.

2.4. Gram-Scale Reaction and Product Derivatization

To demonstrate the practicality of the transformation, a gram-scale reaction was conducted and found that the reaction of β-ketoester 1j (2.5 mmol) with allenylic carbonate 2a (3.0 mmol) gave product 3j (1.01 g) in 98% yield, with 97% ee and 12:1 dr (Scheme 4). Target product 3x was found to undergo Suzuki coupling smoothly with phenyl boronic acid, affording compound 4a (Scheme 4) with a biphenyl motif (70% yield, 92% ee, 9:1 dr) [42].

2.5. Plausible Mechanism of the Palladium-Catalyzed Alkylation of β-Ketoester 1

A plausible mechanism for the palladium-catalyzed allenylic alkylation of indanone β-ketoester is depicted in Scheme 5 [43,44]. Oxidative addition of 2a with Pd(0) would immediately undergo delocalization to yield intermediate A. In the presence of NaHCO₃, the nucleophile 1a attacks the terminal carbon atom of intermediate A to afford the target product 3a and regenerate Pd(0).

3. Materials and Methods

3.1. General Information

Unless otherwise noted, materials were purchased from commercial suppliers and used without further purification. Column chromatography was performed on silica gel (200~300 mesh). Enantiomeric excesses (ee) were determined by HPLC (Agilent, Palo Alto, CA, USA) using corresponding commercial chiral columns as stated at 30 °C with UV detector at 254 nm. Optical rotations (JiaHang Instruments, Shanghai, China) were reported as follows: ${\left[\alpha \right]}_{\mathsf{D}}^{\mathsf{T}}$ (c g/100 mL, solvent). All ¹H NMR and ¹⁹F NMR spectra were recorded on a Bruker Avance II 400 MHz (Bruker, Karlsruhe, Germany) and Bruker Avance III 600 MHz (Bruker, Karlsruhe, Germany), respectively, ¹³C NMR spectra were recorded on a Bruker Avance II 101 MHz or Bruker Avance III 151 MHz with chemical shifts reported as ppm (in CDCl₃, TMS as an internal standard). Data for ¹H NMR are recorded as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, br = broad singlet, dd = double doublet, coupling constants in Hz, integration). HRMS (ESI) was obtained with a HRMS/MS instrument (LTQ Orbitrap XL TM, Agilent, Palo Alto, CA, USA). The characterization data is available in Supplementary Material.

3.2. Procedure for the Synthesis of Compounds 3

(S)-SegPhos (L9) (5 mol%) and Pd₂dba₃ (2.5 mol%) were stirred in THF (4 mL) in a Schlenk tube under a nitrogen atmosphere at room temperature for 10 min. To this Schlenk tube were added 1 (0.20 mmol, 1.0 equiv), NaHCO₃ (0.20 mmol, 1.0 equiv), and 2 (0.24 mmol, 1.2 equiv), then the reaction mixture was stirred at −10 °C. When compound 1 was consumed as checked by TLC, the reaction was stopped and purified by column chromatography (petroleum ether/ethyl acetate = 30:1) on silica gel directly to give product 3.

Ethyl 1-oxo-2-(4-phenylbuta-2,3-dien-1-yl)-2,3-dihydro-1H-indene-2-carboxylate (3a)

Prepared according to the procedure within 48 h as light yellow liquid (65.8 mg, 99% yield, dr = 8:1). ${\left[\alpha \right]}_{\mathsf{D}}^{17}$ = 84.324 (c 0.37, CH₂Cl₂); ¹H NMR (400 MHz, chloroform-d) δ 7.77 (d, J = 7.7 Hz, 1H), 7.06–7.55 (m, 1H), 7.51–7.33 (m, 3H), 7.31–7.27 (m, 1H), 7.21–7.16 (m, 3H), 6.08 (dt, J = 5.9, 2.7 Hz, 1H), 5.48 (q, J = 6.9 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.75 (d, J = 17.4 Hz, 1H), 3.24 (d, J = 17.4 Hz, 1H), 3.01 (ddd, J = 14.7, 7.0, 2.8 Hz, 1H), 2.68 (ddd, J = 14.7, 7.2, 2.7 Hz, 1H), 1.17 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 206.5, 201.8, 170.4, 153.2, 135.3, 135.3, 134.1, 128.5, 127.7, 127.0, 126.8, 126.4, 124.7, 95.5, 90.0, 61.8, 60.3, 36.5, 34.2, 14.0. HRMS (ESI) m/z Calcd. for C₂₂H₂₀NaO₃ ([M + Na]⁺) 335.1305, found 335.1298. Enantiomeric excess was determined to be 97% (determined by HPLC using chiral AD-H column, hexane/2-propanol = 50/1, λ = 254 nm, 30 °C, 0.8 mL/min, t_major = 26.2 min, t_minor = 24.5 min).

Ethyl 6-methyl-1-oxo-2-(4-phenylbuta-2,3-dien-1-yl)-2,3-dihydro-1H-indene-2-carboxylate (3b)

Prepared according to the procedure within 60 h as light yellow liquid (64.4 mg, 93% yield, dr = 9:1). ${\left[\alpha \right]}_{\mathsf{D}}^{17}$ = 77.698 (c 0.56, CH₂Cl₂); ¹H NMR (400 MHz, chloroform-d) δ 7.58 (s, 1H), 7.45–7.39 (m, 1H), 7.36–7.26 (m, 3H), 7.24–7.18 (m, 3H), 6.10 (dt, J = 6.1, 2.7 Hz, 1H), 5.49 (q, J = 6.8 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.71 (d, J = 17.2 Hz, 1H), 3.21 (d, J = 17.2 Hz, 1H), 3.01 (ddd, J = 14.6, 7.1, 2.8 Hz, 1H), 2.70 (ddd, J = 14.5, 7.2, 2.6 Hz, 1H), 2.42 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 206.5, 202.0, 170.6, 150.7, 137.7, 136.7, 135.4, 134.1, 128.5, 127.0, 126.8, 126.1, 124.6, 95.4, 90.1, 61.7, 60.6, 36.2, 34.2, 21.1, 14.0. HRMS (ESI) m/z Calcd. for C₂₃H₂₂NaO₃ ([M + Na]⁺) 369.1461, found 369.1456. Enantiomeric excess was determined to be 95% (determined by HPLC using chiral AD-H column, hexane/2-propanol = 50/1, λ = 254 nm, 30 °C, 0.8 mL/min, t_major = 27.9 min, t_minor = 22.4 min).

Ethyl 6-methoxy-1-oxo-2-(4-phenylbuta-2,3-dien-1-yl)-2,3-dihydro-1H-indene-2-carboxylate (3c)

Prepared according to the procedure within 48 h as light yellow liquid (68.8 mg, 95% yield, dr = 8:1). ${\left[\alpha \right]}_{\mathsf{D}}^{17}$ = 71.161 (c 0.27, CH₂Cl₂); ¹H NMR (400 MHz, chloroform-d) δ 7.40–7.32 (m, 4H), 7.27 (d, J = 1.9 Hz, 2H), 7.25–7.15 (m, 2H), 6.16 (dt, J = 5.8, 2.7 Hz, 1H), 5.55 (q, J = 6.9 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 3.72 (d, J = 17.0 Hz, 1H), 3.24 (d, J = 17.0 Hz, 1H), 3.06 (ddd, J = 14.6, 7.1, 2.8 Hz, 1H), 2.78 (ddd, J = 14.6, 7.2, 2.7 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 206.5, 201.9, 170.5, 159.7, 146.2, 136.5, 134.1, 128.5, 127.1, 127.0, 126.8, 124.9, 105.7, 95.4, 90.0, 61.7, 61.0, 55.6, 35.8, 34.2, 14.0. HRMS (ESI) m/z Calcd. for C₂₃H₂₂NaO₄ ([M + Na]⁺) 385.1410, found 385.1404. Enantiomeric excess was determined to be 95% (determined by HPLC using chiral OD-H column, hexane/2-propanol = 50/1, λ = 254 nm, 30 °C, 0.8 mL/min, t_major = 31.3 min, t_minor = 35.8 min).

Ethyl 5,6-dimethoxy-1-oxo-2-(4-phenylbuta-2,3-dien-1-yl)-2,3-dihydro-1H-indene-2-carboxylate (3d)

Prepared according to the procedure within 72 h as light yellow liquid (77.6 mg, 99% yield, dr = 9:1). ${\left[\alpha \right]}_{\mathsf{D}}^{17}$ = 100.27 (c 0.74, CH₂Cl₂); ¹H NMR (400 MHz, chloroform-d) δ 7.32–7.22 (m, 2H), 7.20–7.10 (m, 4H), 6.79 (s, 1H), 6.05 (dt, J = 6.1, 2.8 Hz, 1H), 5.48 (q, J = 6.9 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.92 (s, 3H), 3.89 (s, 3H), 3.63 (d, J = 17.1 Hz, 1H), 3.20–3.09 (m, 1H), 2.97 (ddd, J = 14.8, 7.1, 2.7 Hz, 1H), 2.71 (ddd, J = 14.7, 7.0, 2.8 Hz, 1H), 1.18 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 206.3, 200.3, 170.7, 156.0, 149.7, 148.8, 134.1, 128.5, 128.0, 126.9, 126.8, 107.3, 104.9, 95.4, 90.1, 61.7, 60.6, 56.2, 56.1, 36.1, 34.0, 14.0. HRMS (ESI) m/z Calcd. for C₂₄H₂₄NaO₅ ([M + Na]⁺) 415.1516, found 415.1507. Enantiomeric excess was determined to be 97% (determined by HPLC using chiral OD-H column, hexane/2-propanol = 7/3, λ = 254 nm, 30 °C, 0.8 mL/min, t_major = 25.3 min, t_minor = 33.9 min).

Ethyl 6-fluoro-1-oxo-2-(4-phenylbuta-2,3-dien-1-yl)-2,3-dihydro-1H-indene-2-carboxylate (3e)

Prepared according to the procedure within 72 h as light yellow liquid (69.3 mg, 99% yield, dr = 7:1). ${\left[\alpha \right]}_{\mathsf{D}}^{18}$ = 76.074 (c 0.65, CH₂Cl₂); ¹H NMR (600 MHz, chloroform-d) δ 7.37 (dd, J = 7.4, 2.5 Hz, 1H), 7.33 (dd, J = 8.5, 4.3 Hz, 1H), 7.29–7.22 (m, 3H), 7.20–7.13 (m, 3H), 6.05 (dt, J = 6.0, 2.7 Hz, 1H), 5.47 (q, J = 6.7 Hz, 1H), 4.08 (qd, J = 7.1, 1.2 Hz, 2H), 3.67 (d, J = 17.1 Hz, 1H), 3.19 (d, J = 17.1 Hz, 1H), 2.97 (ddd, J = 14.9, 7.0, 2.8 Hz, 1H), 2.73 (ddd, J = 14.9, 7.0, 2.8 Hz, 1H), 1.16 (t, J = 7.2 Hz, 3H); ¹³C NMR (151 MHz, Chloroform-d) δ 206.3, 201.1, 170.1, 162.4 (d, J = 166.7 Hz), 148.6, 137.0, 133.9, 128.6, 127.9 (d, J = 5.1 Hz), 127.1, 126.8, 122.9, 110.3 (d, J = 15.2 Hz), 95.8, 89.9, 61.9, 61.2, 35.9, 34.0, 14.0; ¹⁹F NMR (376 MHz, Chloroform-d) δ −104.2–−123.6 (m). HRMS (ESI) m/z Calcd. for C₂₂H₁₉FNaO₃ ([M + Na]⁺) 373.1210, found 373.1202. Enantiomeric excess was determined to be 96% (determined by HPLC using chiral IC-IB-H column, hexane/2-propanol = 9/1, λ = 254 nm, 30 °C, 0.6 mL/min, t_major = 33.4 min, t_minor = 32.0 min).

Ethyl 6-chloro-1-oxo-2-(4-phenylbuta-2,3-dien-1-yl)-2,3-dihydro-1H-indene-2-carboxylate (3f)

Prepared according to the procedure within 96 h as light yellow liquid (72.5 mg, 99% yield, dr = 8:1). ${\left[\alpha \right]}_{\mathsf{D}}^{16}$ = 104.13 (c 0.70, CH₂Cl₂); ¹H NMR (600 MHz, chloroform-d) δ 7.69 (d, J = 2.1 Hz, 1H), 7.47 (dd, J = 8.1, 2.1 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.28–7.24 (m, 2H), 7.20–7.16 (m, 1H), 7.15–7.12 (m, 2H), 6.04 (dt, J = 6.0, 2.7 Hz, 1H), 5.46 (q, J = 6.7 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.67 (d, J = 17.4 Hz, 1H), 3.18 (d, J = 17.4 Hz, 1H), 2.96 (ddd, J = 15.0, 7.0, 2.7 Hz, 1H), 2.74 (ddd, J = 14.9, 6.9, 2.8 Hz, 1H), 1.15 (t, J = 7.1 Hz, 3H); ¹³C NMR (151 MHz, Chloroform-d) δ 206.2, 200.7, 170.1, 151.3, 136.9, 135.2, 134.1, 133.8, 128.5, 127.6, 127.1, 126.8, 124.3, 95.9, 89.8, 62.0, 60.8, 36.0, 34.0, 14.0. HRMS (ESI) m/z Calcd. for C₂₂H₁₉ClNaO₃ ([M + Na]⁺) 389.0915, found 389.0911. Enantiomeric excess was determined to be 97% (determined by HPLC using chiral AD-H column, hexane/2-propanol = 50/1, λ = 254 nm, 30 °C, 0.8 mL/min, t_major = 37.9 min, t_minor = 30.4 min).

Ethyl 5-methyl-1-oxo-2-(4-phenylbuta-2,3-dien-1-yl)-2,3-dihydro-1H-indene-2-carboxylate (3g)

Prepared according to the procedure within 72 h as light yellow liquid (66.5 mg, 96% yield, dr = 6:1); ${\left[\alpha \right]}_{\mathsf{D}}^{16}$ = 69.372 (c 0.38, CH₂Cl₂); ¹H NMR (400 MHz, chloroform-d) δ 7.65 (d, J = 7.8 Hz, 1H), 7.30–7.23 (m, 2H), 7.18 (d, J = 7.1 Hz, 5H), 6.06 (dt, J = 5.9, 2.8 Hz, 1H), 5.47 (q, J = 6.9 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.68 (d, J = 17.4 Hz, 1H), 3.17 (d, J = 17.3 Hz, 1H), 2.98 (ddd, J = 14.7, 7.0, 2.8 Hz, 1H), 2.67 (ddd, J = 14.6, 7.2, 2.7 Hz, 1H), 2.40 (s, 3H), 1.16 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 206.4, 201.3, 170.6, 153.8, 146.8, 143.3, 134.1, 133.0, 129.1, 128.5, 127.0, 126.8, 124.5, 95.4, 90.1, 61.7, 60.4, 36.3, 34.2, 22.1, 14.0. HRMS (ESI) m/z Calcd. for C₂₃H₂₂NaO₃ ([M + Na]⁺) 369.1461, found 369.1455. Enantiomeric excess was determined to be 96% (determined by HPLC using chiral AD-H column, hexane/2-propanol = 50/1, λ = 254 nm, 30 °C, 0.8 mL/min, t_major = 33.3 min, t_minor = 30.3 min).

Ethyl 5-fluoro-1-oxo-2-(4-phenylbuta-2,3-dien-1-yl)-2,3-dihydro-1H-indene-2-carboxylate (3h)

Prepared according to the procedure within 96 h as light yellow liquid (67.2 mg, 96% yield, dr = 10:1). ${\left[\alpha \right]}_{\mathsf{D}}^{17}$ = 84.648 (c 0.47, CH₂Cl₂); ¹H NMR (600 MHz, chloroform-d) δ 7.75 (dd, J = 8.4, 5.2 Hz, 1H), 7.31–7.25 (m, 2H), 7.22–7.15 (m, 3H), 7.08–7.01 (m, 2H), 6.06 (dt, J = 6.0, 2.8 Hz, 1H), 5.47 (q, J = 6.8 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.71 (d, J = 17.5 Hz, 1H), 3.20 (d, J = 17.6 Hz, 1H), 2.98 (ddd, J = 14.9, 7.0, 2.8 Hz, 1H), 2.70 (ddd, J = 14.9, 6.9, 2.7 Hz, 1H), 1.17 (t, J = 7.1 Hz, 3H); ¹³C NMR (151 MHz, Chloroform-d) δ 206.3, 199.9, 170.1, 167.5 (d, J = 257.6 Hz), 156.2 (d, J = 9.9 Hz), 133.9, 131.7, 128.6, 127.1, 127.0 (d, J = 10.8 Hz), 126.8, 116.2 (d, J = 23.9 Hz), 113.2 (d, J = 22.7 Hz), 95.7, 89.9, 61.9, 60.6, 36.2, 34.0, 14.0; ¹⁹F NMR (377 MHz, Chloroform-d) δ -101.5 (t, J = 9.4 Hz). HRMS (ESI) m/z Calcd. for C₂₂H₁₉FNaO₃ ([M + Na]⁺) 373.1210, found 373.1202. Enantiomeric excess was determined to be 96% (determined by HPLC using chiral AD-H column, hexane/2-propanol = 50/1, λ = 254 nm, 30 °C, 0.8 mL/min, t_major = 26.1 min, t_minor = 24.0 min).

Ethyl 5-chloro-1-oxo-2-(4-phenylbuta-2,3-dien-1-yl)-2,3-dihydro-1H-indene-2-carboxylate (3i)

Prepared according to the procedure within 48 h as light yellow liquid (72.5 mg, 99% yield, dr = 11:1). ${\left[\alpha \right]}_{\mathsf{D}}^{18}$ = 69.762 (c 0.51, CH₂Cl₂); ¹H NMR (400 MHz, chloroform-d) δ 7.70 (d, J = 8.1 Hz, 1H), 7.51–7.41 (m, 1H), 7.35 (dd, J = 10.2, 2.0 Hz, 2H), 7.28 (d, J = 1.8 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 7.20–7.15 (m, 2H), 6.07 (dt, J = 6.0, 2.9 Hz, 1H), 5.49 (q, J = 6.6 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.71 (d, J = 17.5 Hz, 1H), 3.22 (d, J = 17.5 Hz, 1H), 2.99 (ddd, J = 14.9, 7.0, 2.8 Hz, 1H), 2.75 (ddd, J = 14.9, 6.8, 2.8 Hz, 1H), 1.19 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 206.3, 200.4, 170.1, 154.6, 141.9, 133.9, 133.8, 128.6, 128.6, 127.2, 126.7, 126.7, 125.7, 95.9, 89.8, 61.9, 60.5, 36.1, 33.9, 14.0. HRMS (ESI) m/z Calcd. for C₂₂H₁₉ClNaO₃ ([M + Na]⁺) 389.0915, found 389.0908. Enantiomeric excess was determined to be 95% (determined by HPLC using chiral AD-H column, hexane/2-propanol = 50/1, λ = 254 nm, 30 °C, 0.8 mL/min, t_major = 25.3 min, t_minor = 22.8 min).

Ethyl 5-bromo-1-oxo-2-(4-phenylbuta-2,3-dien-1-yl)-2,3-dihydro-1H-indene-2-carboxylate (3j)

Prepared according to the procedure within 48 h as light yellow liquid (81.2 mg, 99% yield, dr = 12:1). ${\left[\alpha \right]}_{\mathsf{D}}^{16}$ = 48.041 (c 0.69, CH₂Cl₂); ¹H NMR (400 MHz, chloroform-d) δ 7.59 (d, J = 8.2 Hz, 1H), 7.54–7.46 (m, 2H), 7.30–7.24 (m, 2H), 7.22–7.12 (m, 3H), 6.03 (dt, J = 6.1, 2.8 Hz, 1H), 5.46 (q, J = 6.7 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.68 (d, J = 17.5 Hz, 1H), 3.19 (d, J = 17.5 Hz, 1H), 2.96 (ddd, J = 14.9, 6.9, 2.8 Hz, 1H), 2.73 (ddd, J = 14.9, 6.8, 2.9 Hz, 1H), 1.16 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 206.2, 200.7, 170.0, 154.7, 134.3, 133.8, 131.4, 130.8, 129.8, 128.6, 127.2, 126.7, 125.7, 95.9, 89.8, 62.0, 60.4, 36.0, 33.9, 14.0. HRMS (ESI) m/z Calcd. for C₂₂H₁₉BrNaO₃ ([M + Na]⁺) 433.0410, found 433.0403. Enantiomeric excess was determined to be 97% (determined by HPLC using chiral AD-H column, hexane/2-propanol = 50/1, λ = 254 nm, 30 °C, 0.8 mL/min, t_major = 27.2min, t_minor = 24.8 min).

Ethyl 4-chloro-1-oxo-2-(4-phenylbuta-2,3-dien-1-yl)-2,3-dihydro-1H-indene-2-carboxylate (3k)

Prepared according to the procedure within 60 h as light yellow liquid (72.5 mg, 99% yield, dr = 9:1). ${\left[\alpha \right]}_{\mathsf{D}}^{15}$ = 227.30 (c 0.67, CH₂Cl₂); ¹H NMR (600 MHz, chloroform-d) δ 7.65 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.33–7.30 (m, 1H), 7.29–7.23 (m, 2H), 7.20–7.13 (m, 3H), 6.06 (dt, J = 6.0, 2.7 Hz, 1H), 5.48 (q, J = 6.8 Hz, 1H), 4.10 (qd, J = 7.2, 2.4 Hz, 2H), 3.69 (d, J = 17.8 Hz, 1H), 3.23 (d, J = 17.8 Hz, 1H), 3.00 (ddd, J = 14.8, 6.7, 2.8 Hz, 1H), 2.70 (ddd, J = 14.9, 7.2, 2.7 Hz, 1H), 1.17 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 206.4, 201.1, 170.0, 150.7, 137.3, 134.8, 133.8, 132.8, 129.3, 128.5, 127.1, 126.8, 122.8, 95.9, 89.8, 62.0, 60.2, 35.6, 34.1, 14.0. HRMS (ESI) m/z Calcd. for C₂₂H₁₉ClNaO₃ ([M + Na]⁺) 389.0915, found 389.0908. Enantiomeric excess was determined to be 95% (determined by HPLC using chiral AD-OD-H column, hexane/2-propanol = 50/1, λ = 254 nm, 30 °C, 0.6 mL/min, t_major = 47.7 min, t_minor = 51.0 min).

Ethyl 4-bromo-1-oxo-2-(4-phenylbuta-2,3-dien-1-yl)-2,3-dihydro-1H-indene-2-carboxylate (3l)

Prepared according to the procedure within 72 h as light yellow liquid (81.2 mg, 99% yield, dr = 8:1). ${\left[\alpha \right]}_{\mathsf{D}}^{16}$ = 76.255 (c 0.74, CH₂Cl₂); ¹H NMR (400 MHz, chloroform-d) δ 7.69 (d, J = 7.7 Hz, 2H), 7.29–7.22 (m, 3H), 7.21–7.14 (m, 3H), 6.06 (dt, J = 6.1, 2.8 Hz, 1H), 5.48 (q, J = 6.8 Hz, 1H), 4.11 (qd, J = 7.1, 1.5 Hz, 2H), 3.64 (d, J = 17.9 Hz, 1H), 3.18 (d, J = 17.9 Hz, 1H), 3.00 (ddd, J = 14.8, 6.7, 2.9 Hz, 1H), 2.69 (ddd, J = 14.8, 7.3, 2.7 Hz, 1H), 1.18 (t, J = 7.2 Hz, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 206.4, 201.2, 170.0, 152.8, 138.0, 137.3, 133.8, 129.5, 128.6, 127.1, 126.8, 123.5, 122.0, 95.9, 89.8, 62.0, 60.3, 37.6, 34.2, 14.0. HRMS (ESI) m/z Calcd. for C₂₂H₁₉BrNaO₃ ([M + Na]⁺) 433.0410, found 433.0404. Enantiomeric excess was determined to be 97% (determined by HPLC using chiral AD-OD-H column, hexane/2-propanol = 50/1, λ = 254 nm, 30 °C, 0.6 mL/min, t_major = 48.8 min, t_minor = 52.0 min).

Ethyl 1-oxo-2-(4-phenylbuta-2,3-dien-1-yl)-1,2,3,4-tetrahydronaphthalene-2-carboxylate (3m)

Prepared according to the procedure within 48 h as light yellow liquid (68.5 mg, 99% yield, dr = 2:1). ${\left[\alpha \right]}_{\mathsf{D}}^{16}$ = 9.667 (c 0.30, CH₂Cl₂); ¹H NMR (400 MHz, chloroform-d) δ 8.05 (dd, J = 7.9, 1.5 Hz, 1H), 7.51–7.38 (m, 1H), 7.35–7.21 (m, 5H), 7.21–7.17 (m, 2H), 6.12 (dt, J = 6.5, 2.3 Hz, 1H), 5.60 (q, J = 7.4 Hz, 1H), 4.16 (qt, J = 7.1, 1.4 Hz, 2H), 3.11–2.86 (m, 2H), 2.79 (ddd, J = 8.1, 5.5, 2.4 Hz, 2H), 2.62 (dt, J = 13.9, 5.5 Hz, 1H), 2.34 (ddd, J = 14.1, 9.5, 5.0 Hz, 1H), 1.17 (t, J = 7.1Hz, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 207.0, 195.0, 171.5, 143.2, 134.3, 133.6, 131.9, 128.8, 128.6, 128.4, 128.1, 127.0, 126.8, 94.7, 90.2, 61.5, 57.5, 33.8, 30.4, 25.7, 14.1. HRMS (ESI) m/z Calcd. for C₂₃H₂₂NaO₃ ([M + Na]⁺) 369.1461, found 369.1454. Enantiomeric excess was determined to be 97%/75% (determined by HPLC using chiral OJ-H column, hexane/2-propanol = 50/1, λ = 254 nm, 30 °C, 0.8 mL/min, t_major = 76.9/68.2 min, t_minor = 57.7/82.0 min).

Ethyl 2-(4-(2-chlorophenyl) buta-2,3-dien-1-yl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3n)

Prepared according to the procedure within 72 h as light yellow liquid (58.6 mg, 80% yield, dr = 10:1). ${\left[\alpha \right]}_{\mathsf{D}}^{15}$ = 300.81 (c 0.25, CH₂Cl₂); ¹H NMR (400 MHz, chloroform-d) δ 7.78–7.76 (m, 1H), 7.61–7.57 (m, 1H), 7.46–7.33 (m, 3H), 7.29 (dd, J = 8.0, 1.4 Hz, 1H), 7.21–7.16 (m, 1H), 7.13–7.08 (m, 1H), 6.54 (dt, J = 6.5, 2.7 Hz, 1H), 5.50 (q, J = 7.0 Hz, 1H), 4.09 (qd, J = 7.1, 1.4 Hz, 2H), 3.73 (d, J = 17.4 Hz, 1H), 3.22 (d, J = 17.3 Hz, 1H), 2.99 (ddd, J = 14.7, 7.2, 2.8 Hz, 1H), 2.73 (ddd, J = 14.6, 7.1, 2.8 Hz, 1H), 1.16 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 207.3, 201.8, 170.4, 153.2, 135.4, 135.3, 132.1, 131.8, 129.7, 128.3, 128.0, 127.8, 126.7, 126.4, 124.8, 91.8, 90.2, 61.8, 60.2, 36.5, 33.9, 14.0. HRMS (ESI) m/z Calcd. for C₂₂H₁₉ClNaO₃ ([M + Na]⁺) 389.0915, found 389.0912. Enantiomeric excess was determined to be 97% (determined by HPLC using chiral OJ-H column, hexane/2-propanol = 50/1, λ = 254 nm, 30 °C, 0.8 mL/min, t_major = 48.5 min, t_minor = 38.6 min).

Ethyl 2-(4-(3-methoxyphenyl) buta-2,3-dien-1-yl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3o)

Prepared according to the procedure within 48 h as light yellow liquid (71.6 mg, 99% yield, dr = 9:1). ${\left[\alpha \right]}_{\mathsf{D}}^{21}$ = 64.833 (c 0.51, CH₂Cl₂); ¹H NMR (400 MHz, chloroform-d) δ 7.76 (d, J = 7.7 Hz, 1H), 7.59–7.55 (m, 1H), 7.45–7.33 (m, 2H), 7.20–7.16 (m, 1H), 6.86–6.68 (m, 3H), 6.05 (dt, J = 6.1, 2.8 Hz, 1H), 5.48 (q, J = 6.8 Hz, 1H), 4.09 (qd, J = 7.2, 1.1 Hz, 2H), 3.81 (s, 3H), 3.74 (d, J = 17.3 Hz, 1H), 3.24 (d, J = 17.4 Hz, 1H), 3.00 (ddd, J = 14.7, 6.9, 2.9 Hz, 1H), 2.67 (ddd, J = 14.7, 7.2, 2.6 Hz, 1H), 1.16 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 206.5, 201.9, 170.4, 159.9, 153.2, 135.5, 135.4, 135.2, 129.5, 127.8, 126.5, 124.8, 119.5, 113.0, 111.8, 95.5, 90.2, 61.8, 60.3, 55.2, 36.5, 34.2, 14.0. HRMS (ESI) m/z Calcd. for C₂₃H₂₂NaO₄ ([M + Na]⁺) 385.1410, found 385.1407. Enantiomeric excess was determined to be 97% (determined by HPLC using chiral IB-H column, hexane/2-propanol = 50/1, λ = 254 nm, 30 °C, 0.8 mL/min, t_major = 30.8 min, t_minor = 26.8 min).

Ethyl 1-oxo-2-(4-(p-tolyl) buta-2,3-dien-1-yl)-2,3-dihydro-1H-indene-2-carboxylate (3p)

Prepared according to the procedure within 72 h as light yellow liquid (68.5 mg, 99% yield, dr = 13:1). ${\left[\alpha \right]}_{\mathsf{D}}^{13}$ = 64.270 (c 0.45, CH₂Cl₂); ¹H NMR (400 MHz, chloroform-d) δ 7.77 (d, J = 7.6 Hz, 1H), 7.65–7.52 (m, 1H), 7.48–7.33 (m, 3H), 7.09 (s, 3H), 6.05 (dt, J = 6.4, 2.7 Hz, 1H), 5.45 (q, J = 6.8 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.74 (d, J = 17.4 Hz, 1H), 3.24 (d, J = 17.4 Hz, 1H), 3.00 (ddd, J = 14.6, 7.0, 2.8 Hz, 1H), 2.66 (ddd, J = 14.5, 7.2, 2.6 Hz, 1H), 2.32 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 206.3, 201.9, 170.4, 153.3, 136.8, 135.4, 135.2, 131.0, 129.3, 127.7, 126.7, 126.5, 124.8, 95.3, 89.9, 61.8, 60.4, 36.5, 34.3, 21.2, 14.0. HRMS (ESI) m/z Calcd. for C₂₃H₂₂NaO₃ ([M + Na]⁺) 369.1461, found 369.1455. Enantiomeric excess was determined to be 93% (determined by HPLC using chiral AD-OD-H column, hexane/2-propanol = 50/1, λ = 254 nm, 30 °C, 0.6 mL/min, t_major = 59.1 min, t_minor = 54.5 min).

Ethyl 2-(4-(4-cyanophenyl) buta-2,3-dien-1-yl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3q)

Prepared according to the procedure within 72 h as light yellow liquid (57.9 mg, 81% yield, dr = 12:1). ${\left[\alpha \right]}_{\mathsf{D}}^{15}$ = 88.378 (c 0.37, CH₂Cl₂); ¹H NMR (400 MHz, chloroform-d) δ 7.69 (d, J = 7.7 Hz, 1H), 7.51 (dd, J = 7.5, 1.2 Hz, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.39–7.28 (m, 2H), 7.23–7.14 (m, 2H), 6.01 (dt, J = 6.0, 2.8 Hz, 1H), 5.50 (q, J = 6.9 Hz, 1H), 4.01 (q, J = 7.1 Hz, 2H), 3.65 (d, J = 17.3 Hz, 1H), 3.11 (d, J = 17.3 Hz, 1H), 2.90 (ddd, J = 14.8, 7.0, 2.9 Hz, 1H), 2.69 (ddd, J = 14.8, 7.3, 2.7 Hz, 1H), 1.08 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 207.6, 201.6, 170.3, 153.0, 139.3, 135.5, 135.3, 132.3, 127.9, 127.2, 126.4, 124.8, 119.0, 110.2, 94.8, 91.0, 61.9, 60.0, 36.5, 33.6, 14.0. HRMS (ESI) m/z Calcd. for C₂₃H₁₉NNaO₃ ([M + Na]⁺) 380.1257, found 380.1248. Enantiomeric excess was determined to be 97% (determined by HPLC using chiral OD-H column, hexane/2-propanol = 95/5, λ = 254 nm, 30 °C, 0.8 mL/min, t_major = 41.0 min, t_minor = 36.8 min).

Ethyl 2-(4-(4-fluorophenyl) buta-2,3-dien-1-yl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3r)

Prepared according to the procedure within 48 h as light yellow liquid (60.9 mg, 87% yield, dr = 10:1). ${\left[\alpha \right]}_{\mathsf{D}}^{17}$ = 79.750 (c 0.40, CH₂Cl₂); ¹H NMR (400 MHz, chloroform-d) δ 7.76 (d, J = 7.7 Hz, 1H), 7.60–7.56 (m, 1H), 7.44–7.35 (m, 2H), 7.17–7.10 (m, 2H), 7.01–6.93 (m, 2H), 6.04 (dt, J = 6.3, 2.8 Hz, 1H), 5.47 (q, J = 6.8 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.73 (d, J = 17.4 Hz, 1H), 3.21 (d, J = 17.3 Hz, 1H), 2.98 (ddd, J = 14.8, 6.9, 2.8 Hz, 1H), 2.70 (ddd, J = 14.7, 7.1, 2.7 Hz, 1H), 1.16 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 206.2, 201.8, 170.4, 162.0 (d, J = 247.5 Hz), 153.2, 135.3 (d, J = 6.1 Hz), 130.0, 128.3, 128.2, 127.8, 126.4, 124.7, 115.5 (d, J = 21.2 Hz), 94.6, 90.3, 61.8, 60.2, 36.5, 34.1, 14.0. ¹⁹F NMR (376 MHz, Chloroform-d) δ -102.3 (q, J = 6.5 Hz); HRMS (ESI) m/z Calcd. for C₂₂H₁₉FNaO₃ ([M + Na]⁺) 373.1210, found 373.1203. Enantiomeric excess was determined to be 97% (determined by HPLC using chiral AD-OD-H column, hexane/2-propanol = 50/1, λ = 254 nm, 30 °C, 0.6 mL/min, t_major = 64.5 min, t_minor = 61.0 min).

Ethyl 2-(4-(4-chlorophenyl) buta-2,3-dien-1-yl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3s)

Prepared according to the procedure within 48 h as light yellow liquid (61.5 mg, 84% yield, dr = 11:1). ${\left[\alpha \right]}_{\mathsf{D}}^{17}$ = 72.922 (c 0.42, CH₂Cl₂); ¹H NMR (400 MHz, chloroform-d) δ 7.76 (d, J = 7.7 Hz, 1H), 7.60–7.56 (m, 1H), 7.46–7.34 (m, 2H), 7.30–7.19 (m, 2H), 7.15–7.06 (m, 2H), 6.03 (dt, J = 6.2, 2.8 Hz, 1H), 5.49 (q, J = 6.9 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.73 (d, J = 17.4 Hz, 1H), 3.20 (d, J = 17.3 Hz, 1H), 2.98 (ddd, J = 14.7, 6.9, 2.9 Hz, 1H), 2.70 (ddd, J = 14.7, 7.2, 2.7 Hz, 1H), 1.16 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 206.5, 201.8, 170.4, 153.1, 135.4, 135.3, 132.6, 132.6, 128.7, 128.0, 127.8, 126.4, 124.7, 94.7, 90.5, 61.8, 60.2, 36.5, 34.0, 14.0. HRMS (ESI) m/z Calcd. for C₂₂H₁₉ClNaO₃ ([M + Na]⁺) 389.0915, found 389.0907. Enantiomeric excess was determined to be 91% (determined by HPLC using chiral IC-IB-H column, hexane/2-propanol = 9/1, λ = 254 nm, 30 °C, 0.6 mL/min, t_major = 41.9 min, t_minor = 37.0 min).

Ethyl 2-(4-(naphthalen-2-yl) buta-2,3-dien-1-yl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3t)

Prepared according to the procedure within 72 h as light yellow liquid (55.8 mg, 73% yield, dr = 9:1). ${\left[\alpha \right]}_{\mathsf{D}}^{16}$ = 94.309 (c 0.25, CH₂Cl₂); ¹H NMR (400 MHz, chloroform-d) δ 7.84–7.70 (m, 4H), 7.54 (d, J = 7.9 Hz, 2H), 7.44 (d, J = 6.0 Hz, 2H), 7.40–7.35 (m, 3H), 6.24 (dd, J = 6.7, 3.1 Hz, 1H), 5.55 (d, J = 6.9 Hz, 1H), 4.10 (q, J = 7.4 Hz, 2H), 3.76 (d, J = 17.4 Hz, 1H), 3.27 (d, J = 17.3 Hz, 1H), 3.04 (dd, J = 15.3, 6.7 Hz, 1H), 2.73 (dd, J = 15.3, 7.6 Hz, 1H), 1.16 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, chloroform-d) δ 207.0, 201.8, 170.4, 153.2, 135.4, 135.3, 133.7, 132.7, 131.6, 128.5, 128.2, 127.7, 126.4, 126.2, 125.7, 125.7, 125.5, 124.7, 124.7, 95.9, 90.3, 61.8, 60.4, 36.5, 34.2, 14.0. HRMS (ESI) m/z Calcd. for C₂₆H₂₂NaO₃ ([M + Na]⁺) 405.1461, found 405.1455. Enantiomeric excess was determined to be 97% (determined by HPLC using chiral AD-H column, hexane/2-propanol = 50/1, λ = 254 nm, 30 °C, 0.8 mL/min, t_major = 49.1 min, t_minor = 45.2 min).

Ethyl 2-(hepta-2,3-dien-1-yl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3u)

Prepared according to the procedure within 84 h as light yellow liquid (50.74 mg, 85% yield, dr = 2:1). ${\left[\alpha \right]}_{\mathsf{D}}^{16}$ = 49.275 (c 0.14, CH₂Cl₂); ¹H NMR (400 MHz, chloroform-d) δ 7.76 (d, J = 7.7 Hz, 1H), 7.65–7.57 (m, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.40–7.37 (m, 1H), 5.14–4.83 (m, 2H), 4.24–4.07 (m, 2H), 3.68 (dd, J = 17.3, 2.6 Hz, 1H), 3.23 (d, J = 17.3 Hz, 1H), 2.83 (dtd, J = 15.1, 7.6, 2.5 Hz, 1H), 2.54 (dddd, J = 14.5, 7.4, 5.2, 2.6 Hz, 1H), 1.87 (qd, J = 7.1, 3.6 Hz, 2H), 1.36 (qd, J = 7.4, 2.1 Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H), 0.88 (t, J = 7.4, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 205.7, 202.1, 170.6, 153.4, 135.4, 135.3, 127.6, 126.4, 124.7, 91.4, 85.6, 61.6, 60.6, 36.2, 34.6, 30.9, 22.3, 14.1, 13.6. HRMS (ESI) m/z Calcd. for C₁₉H₂₂NaO₃ ([M + Na]⁺) 321.1461, found 321.1453. Enantiomeric excess was determined to be 79%/71% (determined by HPLC using chiral AS-AD-H column, hexane/2-propanol = 50/1, λ = 254 nm, 30 °C, 0.6 mL/min, t_major = 30.5/26.7 min, t_minor = 25.6/28.2 min).

Ethyl 2-(5-methylhexa-2,3-dien-1-yl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3v)

Prepared according to the procedure within 84 h as light yellow liquid (49.5 mg, 83% yield, dr = 2:1). ${\left[\alpha \right]}_{\mathsf{D}}^{16}$ = 67.677 (c 0.20, CH₂Cl₂); ¹H NMR (600 MHz, chloroform-d) δ 7.76 (dd, J = 7.7, 3.9 Hz, 1H), 7.65–7.59 (m, 1H), 7.48 (dd, J = 7.8, 2.9 Hz, 1H), 7.44–7.35 (m, 1H), 5.15–4.89 (m, 2H), 4.32–4.08 (m, 2H), 3.68 (d, J = 17.2 Hz, 1H), 3.24 (dd, J = 17.3, 3.7 Hz, 1H), 2.94–2.77 (m, 1H), 2.55 (ddt, J = 14.2, 7.6, 2.0 Hz, 1H), 2.20 (dp, J = 9.7, 3.1 Hz, 1H), 1.20 (t, J = 7.1 Hz, 3H), 0.94 (ddd, J = 6.5, 4.6, 1.6 Hz, 6H); ¹³C NMR (151 MHz, Chloroform-d) δ 204.2, 202.2, 170.7, 153.4, 135.3, 129.0, 127.7, 126.4, 124.8, 98.9, 86.8, 61.7, 60.6, 36.2, 34.8, 27.9, 22.4, 14.1. HRMS (ESI) m/z Calcd. for C₁₉H₂₂NaO₃ ([M + Na]⁺) 321.1461, found 321.1453. Enantiomeric excess was determined to be 77%/55% (determined by HPLC using chiral AS-AD-H column, hexane/2-propanol = 50/1, λ = 254 nm, 30 °C, 0.6 mL/min, t_major = 27.5/24.7 min, t_minor = 23.8/26.2 min).

Ethyl 2-(4-cyclohexylbuta-2,3-dien-1-yl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3w)

Prepared according to the procedure within 84 h as light yellow liquid (52.8 mg, 78% yield, dr = 2:1). ${\left[\alpha \right]}_{\mathsf{D}}^{16}$ = 43.017 (c 0.18, CH₂Cl₂); ¹H NMR (400 MHz, chloroform-d) δ 7.80–7.72 (m, 1H), 7.64–7.6 (m, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.44–7.34 (m, 1H), 4.99 (dtt, J = 23.8, 6.8, 3.1 Hz, 2H), 4.15 (qd, J = 7.1, 1.5 Hz, 2H), 3.68 (d, J = 17.4 Hz, 1H), 3.24 (d, J = 17.3 Hz, 1H), 2.83 (dddd, J = 14.1, 6.9, 4.1, 2.6 Hz, 1H), 2.56 (dddd, J = 14.9, 7.9, 5.5, 2.7 Hz, 1H), 1.86 (dddd, J = 11.2, 8.7, 5.9, 3.1 Hz, 1H), 1.66 (tt, J = 18.8, 7.4 Hz, 5H), 1.39–1.10 (m, 6H), 1.00 (tdd, J = 13.6, 7.7, 3.7 Hz, 2H); ¹³C NMR (101 MHz, Chloroform-d) δ 204.5, 202.2, 170.7, 153.4, 135.4, 129.0, 128.4, 127.7, 126.4, 124.8, 97.5, 86.4, 61.7, 60.6, 37.2, 36.2, 34.8, 32.9, 26.1, 14.1. HRMS (ESI) m/z Calcd. for C₂₂H₂₆NaO₃ ([M + Na]⁺) 361.1774, found 361.1765. Enantiomeric excess was determined to be 73%/55% (determined by HPLC using chiral AS-AD-H column, hexane/2-propanol = 50/1, λ = 254 nm, 30 °C, 0.6 mL/min, t_major = 29.9/26.9 min, t_minor = 26.3/27.9 min).

Ethyl4-bromo-2-(4-(4-chlorophenyl) buta-2,3-dien-1-yl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3x)

Prepared according to the procedure within 48 h as light yellow liquid (87.9 mg, 99% yield, dr = 10:1). ${\left[\alpha \right]}_{\mathsf{D}}^{16}$ = 101.589 (c 1.20, CH₂Cl₂); ¹H NMR (600 MHz, chloroform-d) δ 7.72–7.69 (m, 2H), 7.26–7.21 (m, 3H), 7.07 (d, J = 8.3 Hz, 2H), 6.01 (dt, J = 6.0, 2.8 Hz, 1H), 5.50 (q, J = 6.8 Hz, 1H), 4.11 (qd, J = 7.1, 3.2 Hz, 2H), 3.62 (d, J = 17.8 Hz, 1H), 3.14 (d, J = 17.8 Hz, 1H), 2.98 (ddd, J = 14.9, 6.7, 2.9 Hz, 1H), 2.72 (ddd, J = 14.9, 7.1, 2.8 Hz, 1H), 1.18 (t, J = 7.1 Hz, 3H). ¹³C NMR (101 MHz, Chloroform-d) δ 206.4, 201.2, 170.0, 152.7, 138.0, 137.3, 132.7, 132.4, 129.6, 128.7, 127.9, 123.4, 122.0, 95.1, 90.2, 62.0, 60.2, 37.6, 33.9, 14.0. HRMS (ESI) m/z Calcd. for C₂₂H₁₈BrClNaO₃ ([M + Na]⁺) 467.0020, found 467.0022. Enantiomeric excess was determined to be 96% (determined by HPLC using chiral AD-OJ-H column, hexane/2-propanol = 50/1, λ = 254 nm, 30 °C, 0.6 mL/min, t_major = 92.3 min, t_minor = 83.9 min).

3.3. Procedure for the Synthesis of Compounds 4a

A Schlenk flask under a nitrogen atmosphere was charged with compound 3x (222 mg, 0.50 mmol, 1.0 eq), phenylboronic acid (73.2 mg, 0.60 mmol, 1.2 eq), Cs₂CO₃ (244 mg, 0.75 mmol, 1.5 eq), and Pd(PPh₃)₄ (28.9 mg, 25.0 µmol, 5 mol%). THF (5 mL) was added and the mixture was heated to 80 °C for 18 h, when compound 3x was consumed as checked by TLC, the mixture was cooled to rt and diluted with Et₂O (15 mL). The mixture was washed with water (15 mL). The aq. layer was extracted with Et₂O (2 × 25 mL) and the combined org. layers were dried, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether/ethyl acetate = 20:1) yielding the title compound 4a as a slightly yellow oil.

Ethyl2-(4-(4-chlorophenyl)buta-2,3-dien-1-yl)-1-oxo-4-phenyl-2,3-dihydro-1H-indene-2-carboxylate (4a)

Prepared according to the procedure within 18 h as slightly yellow oil (154 mg, 70% yield, dr = 9:1). ${\left[\alpha \right]}_{\mathsf{D}}^{16}$ = 23.014 (c 0.37, CH₂Cl₂); ¹H NMR (400 MHz, chloroform-d) δ 7.79 (dd, J = 18.7, 7.5 Hz, 1H), 7.63 (dd, J = 16.9, 7.2 Hz, 1H), 7.55–7.42 (m, 5H), 7.38 (dd, J = 6.6, 3.1 Hz, 1H), 7.32–7.27 (m, 1H), 7.16 (dd, J = 8.6, 2.1 Hz, 2H), 7.07–7.03 (m, 1H), 6.10–5.91 (m, 1H), 5.61–5.48 (m, 1H), 4.30–4.12 (m, 2H), 3.81 (dd, J = 17.5, 11.5 Hz, 1H), 3.22 (dd, J = 17.5, 9.8 Hz, 1H), 3.01 (tdd, J = 11.7, 7.0, 3.0 Hz, 1H), 2.70 (dddd, J = 30.5, 14.6, 7.2, 2.7 Hz, 1H), 1.23 (t, J = 7.1 Hz, 3H). ¹³C NMR (101 MHz, Chloroform-d) δ 206.5, 201.8, 170.4, 150.6, 140.2, 138.7, 135.6, 132.6, 128.8, 128.7, 128.4, 128.4, 128.4, 127.9, 127.8, 123.8, 115.3, 94.5, 90.5, 61.9, 60.5, 36.5, 34.2, 14.1. HRMS (ESI) m/z Calcd. for C₂₈H₂₃ClNaO₃ ([M + Na]⁺) 465.1228, found 465.1225. Enantiomeric excess was determined to be 92% (determined by HPLC using chiral IF-OD-H column, hexane/2-propanol = 95/5, λ = 254 nm, 30 °C, 0.6 mL/min, t_major = 41.3 min, t_minor = 44.3 min).

4. Conclusions

In conclusion, we have developed Pd(0)-catalyzed asymmetric allenylic alkylation of indanone-derived β-ketoesters by allenyl carbonates. This reaction provides a contribution toward the construction of 1,3-stereocenters bearing allenyl axial and central chirality with high levels of stereocontrol. This work features a broad substrate scope, mild reaction conditions, high efficiency, excellent enantioselectivities, and good diastereoselectivities.