Chiral phosphine-squaramide-catalyzed Morita–Baylis–Hillman reaction: enantioselective synthesis of 3-hydroxy-2-oxindoles

Abstract

Phosphine-squaramide derivatives were developed to catalyze the enantioselective Morita–Baylis–Hillman reaction of acrylates with isatins to construct 3-hydroxy-2-oxindoles with quaternary stereocenters. In the presence of 2 mol% H–bonding catalyst 3e, the desired products were achieved in high yields and good-to-excellent enantioselectivities (up to 95% ee).

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Introduction

3-Substituted-3-hydroxy-2-oxindoles are important structural motifs found in many alkaloid natural products and pharma-ceutical molecules.¹ Over the past decade, organometallic and metal-free catalytic asymmetric methods have been developed for the construction of compounds bearing a quaternary stereocenter at the 3-position.^2–4 However, enantioselective organocatalysis mainly focused on the aldol additions to isatins.^4a–h The Morita–Baylis–Hillman (MBH) reaction is one of the most useful carbon–carbon bond forming reactions providing densely functionalized alcohols.⁵ The MBH reaction of electron-deficient olefins to isatin derivatives could obtain 3-substituted-3-hydroxy-2-oxindoles.⁶ Very recently, enantioselective versions were reported, using cinchona alkaloids⁷ or phosphinothiourea⁸ as chiral catalysts. Herein, we describe the first example of phosphine-squaramide catalyzed intermolecular MBH reaction with isatins as electrophiles, providing 3-substituted-3-hydroxy-2-oxindole derivatives in excellent yields with high enantioselectivities.

In our previous work, bifunctional phosphine was first used as a chiral organocatalyst to promote the enantioselective MBH reaction involving isatin as an electrophile.⁸ In the presence of phosphinothiourea 1 (Fig. 1), this MBH reaction was achieved in excellent chemical yields but moderate enantioselectivities. As a continuous work, we developed the novel chiral bifunctional phosphine organocatalysts bearing squaramide as H–bond donator. Compared with thiourea, the squaramide has a greater difference in duality, rigidity, H–bond length, H–bond angle, and pK_a, which endowed it with a unique catalophore for dual H–bonding catalysts.^9,10

Fig. 1 Structure of bifunctional phosphine 1 and 2.

Results and discussion

Phosphine-squaramides 3a–h were easily prepared by the condensation of (1R,2R)-2-amino-1-(diphenylphosphino)cyclo-hexane¹¹ with the corresponding squaramide derived from diethyl squarate in CH₂Cl₂ (Scheme 1).

Scheme 1 Synthetic route of the squaramide catalysts 3a–h.

With the new chiral bifunctional phosphines at hand, we initially conducted a MBH reaction of N-methyl isatin with methyl acrylate in dichloromethane at room temperature in the presence of 10 mol% of catalyst for 5 days (Table 1). The phosphine-squaramide 2 (Fig. 1), which was highly efficient for the intramolecular MBH reaction,¹² gave the MBH adduct with good yield but moderate enantioselectivity (entry 1). Pleasingly, phosphine-squaramide 3 with a dual H–bonding donator¹³ exhibited high catalytic activity, and more importantly, promising enantioselectivity (entries 2–9). Among the screened phosphine-squaramide organocatalysts, 3e was the best one, providing the desired product in 81% ee with 97% yield (entry 6). It is obvious that phosphine-squaramides 3 achieved better enantioselectivity than the phosphinothiourea 1 containing the same chiral backbone (entry 10).⁸

Table 1 Screening of phosphine-squaramides for the MBH reaction^a

Entry	Catalyst	Yield %^b	ee %^c
a The reactions were performed with 4a (0.2 mmol), 5a (1 mmol) and 10 mol% of catalyst 1–3 in 1 mL CH2Cl2 at 25 °C for 5 days. b Isolated yield. c Determined by chiral HPLC analysis using Chiralcel OD-H column.
1	2	74	42
2	3a	85	77
3	3b	89	74
4	3c	96	78
5	3d	94	77
6	3e	97	81
7	3f	90	77
8	3g	96	65
9	3h	97	58
10	1	91	45

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The effect of solvent was next explored with 10 mol% of catalyst 3e (Table 2). The MBH adducts were obtained in excellent yields in the screened aprotic polar solvents (entries 1–7). When a non-polar solvent such as toluene was involved, the MBH reaction became sluggish and resulted in lower yield (entry 8). In a protic polar solvent such as MeOH, a decrease of chemical yield resulted from the side-reaction, and the enantioselectivity was lower than other cases (entry 9 vs. 2–8). The solvent survey indicated that ethyl acetate was the optimal solvent, providing product 6a in 87% ee and 99% yield (entry 6).

Table 2 The survey of solvents for the MBH reaction of N-methyl isatin with methyl acrylate^a

Entry	Solvent	Time/d	Yield %^b	ee %^c
a Unless stated otherwise, the reactions were performed with 4a (0.2 mmol), 5a (0.4 mmol) and 10 mol% of catalyst 3e in 1 mL solvent at 25 °C. b Isolated yield. c Determined by chiral HPLC analysis using Chiralcel OD-H column. d 1 mmol scale.
1	CH2Cl2	5	97	81
2	CH2Cl2^d	5	97	81
3	CHCl3	5	95	83
4	THF	2	99	77
5	Ether	3	97	82
6	EtOAc	2	99	87
7	CH3CN	6	92	77
8	Toluene	6	79	85
9	CH3OH	3	85	74

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Further optimization of the reaction conditions was focused on the examination of substrate concentration, catalyst loading and reaction temperature (Table 3). The results indicated that the different substrate concentration has no effect on neither chemical yield nor stereoselectivity (entries 1–3). When the catalyst loading was reduced to 2 mol%, same results were obtained (entries 2, 4 and 5). In fact, the phosphine-squaramide catalyst has poor solubility in organic solvent. However, with 1 mol% catalyst 3e, the reaction rate decreased observably (entry 6). In the presence of 2 mol% 3e, the higher reaction temperature (40 °C) resulted in a decrease of reaction rate and enantioselectivity, probably due to the decomposition of catalyst (entry 8 vs. 5), while the lower reaction temperature (0 °C) resulted in slower reaction rate and better enantioselectivity (entry 9 vs. 5).

Table 3 Further optimization of reaction conditions^a

Entry	Conc./M	3e/mol (%)	Time/d	Yield %^b	ee %^c
a Unless stated otherwise, the reactions were performed with 4a (0.2 mmol), 5a (0.4 mmol) and catalyst 3e in EtOAc at 25 °C. b Isolated yield. c Determined by chiral HPLC analysis using Chiralcel OD-H column. d The reaction was conducted at 40 °C. e The reaction was conducted at 0 °C.
1	0.1	10	2	99	87
2	0.2	10	2	99	87
3	0.3	10	1.7	99	87
4	0.2	5	3	99	87
5	0.2	2	3	99	87
6	0.2	1	6.5	94	88
7	0.2	0.5	8	81	88
8^d	0.2	2	4.5	93	81
9^e	0.2	2	6.5	39	93

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Under the optimized reaction conditions (2 mol% 3e, 2 equiv. of acrylate, ethyl acetate as solvent, 25 °C), we examined the substrate scope of various acrylates (Table 4, entries 1–6). Almost the same level of enantioselectivities and chemical yields were observed when alkyl acrylates were used as nucleophiles (Table 4, entries 1–3, 6), except t-butyl acrylate due to its steric effect. However, the MBH reaction of phenyl acrylate exhibited poor reactivity under the typical reaction conditions, only 12% yield was obtained after reacting for one week (entry 5).

Table 4 Substrate scope of isatins with acrylates in the 3e-catalyzed MBH reaction^a

Entry	R^1	R^2		R^3	Product	Time/d	Yield %^b	ee %^c
a The reactions were performed with 4 (0.2 mmol), 5 (0.4 mmol) and 2 mol% of catalyst 3e in 1 mL EtOAc at 25 °C. b Isolated yield. c Determined by chiral HPLC analysis, and the data in parentheses were obtained after being recrystallized once from ethanol and petroleum ether.
1	H		Me	Me	6a	3	99	87
2	H		Me	Et	6b	2	98	86
3	H		Me	n-Bu	6c	2	99	83
4	H		Me	t-Bu	6d	3	77	71
5	H		Me	Ph	6e	7	12	80
6	H		Me	Bn	6f	2	99	89
7	H		n-Bu	Bn	6g	4.5	88	87
8	H		Bn	Bn	6h	3.5	92	88
9	4-Cl		Me	Bn	6i	3.5	92	94 (99)
10	4-Br		Me	Bn	6j	4.5	91	95 (99)
11	5-F		Me	Bn	6k	3.5	99	76 (99)
12	5-Cl		Me	Bn	6l	1.5	99	71
13	5-Br		Me	Bn	6m	1.5	98	72 (91)
14	6-Br		Me	Bn	6n	2.5	91	83 (99)
15	7-Br		Me	Bn	6o	3	81	82 (99)
16	5-Me		Me	Bn	6p	2.5	98	89 (98)
17	5-MeO		Me	Bn	6q	4.5	90	85
18	7-Me		Me	Bn	6r	3.5	80	89 (99)

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Next the substrate scope of different isatin derivatives was investigated by reacting them with benzyl acrylate (Table 4, entries 6–18). The N-alkyl groups of isatin affected the reaction rate rather than the enantioselectivity, and good results were attained (entries 6–8). For the MBH reaction of benzyl acrylate to N-methyl isatins with different aromatic moieties, good-to-excellent yields (80–99%) were achieved in all the examples examined, although different reaction times were required (entries 9–18 and 6). Regarding the enantioselectivity, the introduction of substituents at 4-position had a positive effect (entries 9 and 10 vs. 6), while the electron-attracting group at other position exhibited a negative effect, especially at 5-postion (entries 11–15 vs. 6). The presence of an electron-donating group at the phenyl unit affected the reactivity instead of the enantioselectivity (entries 16–18 vs. 6). For some of the solid products, their ee values could reach up to 99% after a simple recrystallization. The absolute configuration of product 6m was determined to be S by X-ray analysis (Fig. 2). And the configurations of other compounds were tentatively assigned by comparing to 6m.

Fig. 2 X-ray crystal structure of MBH product 6m.

In addition, we tried the MBH reaction of N-Ac isatin with benzyl acrylate. However, the isatin with an electron-withdrawing group at the 1-position was inert under the typical reaction conditions. Other nucleophiles were also examined. The MBH reaction between acrolein and N-methyl isatin was accomplished in 3 h, but the enantioselectivity was unsatisfied (6% ee and 74% yield). The methyl vinyl ketone resulted in complicated side-reactions.

Conclusions

In summary, we have developed phosphine-squaramide compounds as a novel class of chiral organocatalysts for the asymmetric Morita–Baylis–Hillman reaction using isatins as electrophiles. A variety of chiral 3-hydroxy-2-oxindoles were efficiently obtained in good-to-excellent yields (up to 99%) with high enantioselectivities (up to 99% ee after a simple recrystallization).

Experimental

General information

Melting points were taken without correction. Optical rotations were measured on a WZZ-2A digital polarimeter at the wavelength of the sodium D-line (589 nm). ¹H, ¹³C and ³¹P NMR spectra were recorded on Bruker 400 spectrometer. The chemical shifts of ¹H NMR and ¹³C NMR spectra were referenced to tetramethylsilane (δ 0.00 ppm) using CDCl₃ or (CD₃)₂SO as solvent. The chemical shifts of ³¹P NMR spectra were referenced to an external H₃PO₄ signal (0.00 ppm). IR spectra were recorded on Nicolet Magna-I 550 spectrometer. High Resolution Mass spectra (HRMS) were recorded on Micromass GCT with Electron Spray Ionization (ESI) resource. HPLC analysis was performed on Waters equipment using Daicel Chiralcel OD-H, Chiralpak AS-H or AD-H column.

Toluene, THF and ether were freshly distilled from sodium-benzophenone. Dichloromethane, chloroform, ethyl acetate and acetonitrile were freshly distilled from CaH₂. Methanol was distilled from magnesium. Thin-layer chromatography (TLC) was performed on 10–40 μm silica gel plates. Column chromatography was performed using silica gel (300–400 mesh) eluting with ethyl acetate, petroleum ether and CH₂Cl₂.

General procedure for the synthesis of chiral phosphine-squaramide catalysts

To a solution of diethyl squarate (374 mg, 2.2 mmol) in EtOH (10 mL) was added amine (2 mmol) in EtOH (5 mL). The reaction mixture was stirring at room temperature or under reflux (monitoring by TLC), then the resulting solution was concentrated and purified by column chromatography to afford the corresponding squaramide. A solution of (1R,2R)-2-amino-1-(diphenylphosphino)-cyclohexane¹² (85 mg, 0.3 mmol) in CH₂Cl₂ (5 mL) was added to a solution of squaramide (0.33 mmol) in CH₂Cl₂ (5 mL). After stirring at room temperature for 4 days, the reaction mixture was filtered, and the precipitate was washed with CH₂Cl₂ (3 × 2 mL) to afford phosphine-squaramide 3 as solid.

3-((1R,2R)-2-(diphenylphosphino)cyclohexylamino)-4-(phenylamino)cyclobut-3-ene-1,2-dione (3a)

White solid, 47% yield. M.p.: > 300 °C. [α]²⁵_D +6.0 (c 0.54, DMSO). ¹H NMR (DMSO-d₆, 400 MHz): δ 9.13 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.56–7.40 (m, 4H), 7.40–7.20 (m, 9H), 7.15 (t, J = 7.1 Hz, 1H), 7.01 (t, J = 6.5 Hz, 1H), 3.94 (br s, 1H), 2.67 (t, J = 9.8 Hz, 1H), 2.09–1.91 (m, 1H), 1.84–1.46, (m, 4H), 1.42–1.20 (m, 2H), 1.07–0.86 (m, 1H); ¹³C NMR (DMSO-d₆, 100 MHz): δ 183.3, 179.8, 168.1, 163.2, 138.9, 136.7 (d, J = 13.3 Hz), 135.8 (d, J = 15.7 Hz), 134.0 (d, J = 21.0 Hz), 132.7 (d, J = 19.7 Hz), 129.2, 128.5, 128.4, 128.3 (×2), 128.2, 122.4, 117.8, 55.9 (d, J = 17.6 Hz), 40.4 (d, J = 14.2 Hz), 34.7 (d, J = 6.2 Hz), 27.7 (d, J = 6.5 Hz), 24.6 (d, J = 6.2 Hz), 24.3, 15.8; ³¹P NMR (DMSO-d₆, 162 MHz): δ −7.90; IR (KBr, cm⁻¹): ν 3423, 2972, 2935, 2852, 1796, 1658, 1604, 1568, 1479, 1433, 1089, 1050, 754, 735, 698, 513, 476; HRMS (ESI) Calcd for C₂₈H₂₈N₂O₂P ([M+H]⁺): 455.1888; Found: 455.1895.

3-((1R,2R)-2-(diphenylphosphino)cyclohexylamino)-4-(4-methoxyphenylamino)cyclobut-3-ene-1,2-dione (3b)

White solid, 40% yield. M.p.: > 300 °C. [α]²⁵_D +10.0 (c 0.56, DMSO). ¹H NMR (DMSO-d₆, 400 MHz): δ 9.04 (s, 1H), 7.51–7.14 (m, 13H), 6.88 (d, J = 8.9 Hz 2H), 3.92–3.89 (m, 1H), 3.71 (s, 3H), 2.65 (t, J = 10.0 Hz, 1H), 1.99–1.96 (m, 1H), 1.72–1.50 (m, 4H), 1.33–1.27 (m, 2H), 0.98–0.89 (m, 1H); ¹³C NMR (DMSO-d₆, 100 MHz): δ 182.7, 180.0, 167.7, 163.2, 155.1, 136.7 (d, J = 13.3 Hz), 135.8 (d, J = 15.9 Hz), 134.1 (d, J = 21.1 Hz), 132.7 (d, J = 19.6 Hz), 132.1, 129.0, 128.4, 128.3 (×2), 128.2, 119.4, 114.4, 55.8 (d, J = 17.7 Hz), 55.2, 40.3 (d, J = 14.3 Hz), 34.7 (d, J = 7.2 Hz), 27.7 (d, J = 5.4 Hz), 24.6 (d, J = 5.2 Hz), 24.3; ³¹P NMR (DMSO-d₆, 162 MHz): δ −8.01; IR (KBr, cm⁻¹): ν 3198, 3112, 3047, 2934, 2853, 1794, 1650, 1610, 1567, 1518, 1456, 1366, 1319, 1297, 1251, 1181, 1116, 1039, 828, 734, 697, 513; HRMS (ESI) Calcd for C₂₉H₃₀N₂O₃P ([M+H]⁺): 485.1994; Found: 485.1989.

3-((1R,2R)-2-(diphenylphosphino)cyclohexylamino)-4-(4-(trifluoromethyl)phenylamino)cyclobut-3-ene-1,2-dione (3c)

White solid, 51% yield. M.p.: > 300 °C. [α]²⁵_D +23.7 (c 0.47, DMSO). ¹H NMR (DMSO-d₆, 400 MHz): δ 9.37 (s, 1H), 7.66 (d, J = 8.6 Hz, 3H), 7.54–7.44 (m, 6H), 7.36–7.34 (m, 3H), 7.25 (t, J = 7.3 Hz, 2H), 7.20 (t, J = 7.3 Hz, 1H), 4.02–3.92 (m, 1H), 2.69 (t, J = 10.6 Hz, 1H), 2.02–1.99 (m, 1H), 1.76–1.53 (m, 4H), 1.33–1.24 (m, 2H), 1.00–0.97 (m, 1H); ¹³C NMR (DMSO-d₆, 100 MHz): δ 184.0, 179.7, 168.6, 162.5, 142.5, 136.7 (d, J = 13.5 Hz), 135.8 (d, J = 15.4 Hz), 134.0 (d, J = 21.0 Hz), 132.9 (d, J = 20.0 Hz), 129.1, 128.5, 128.4, 128.3 (×2), 128.2, 126.6 (d, J = 3.6 Hz), 117.8, 56.3 (d, J = 18.0 Hz), 40.3 (d, J = 14.3 Hz), 34.6 (d, J = 7.2 Hz), 27.8 (d, J = 6.6 Hz), 24.6 (d, J = 5.8 Hz), 24.4; ³¹P NMR (DMSO-d₆, 162 MHz): δ −3.08; IR (KBr, cm⁻¹): ν 3184, 2937, 1798, 1666, 1610, 1574, 1545, 1449, 1322, 1163, 1119, 1070, 838, 741, 697; HRMS (ESI) Calcd for C₂₉H₂₇N₂O₂F₃P ([M+H]⁺): 523.1762; Found: 523.1764.

3-(3,5-Bis(trifluoromethyl)phenylamino)-4-((1R,2R)-2-(diphenylphosphino)cyclohexylamino)cyclobut-3-ene-1,2-dione (3d)

White solid, 64% yield. M.p.: > 300 °C. [α]²⁵_D +19.5 (c 0.41, DMSO). ¹H NMR (DMSO-d₆, 400 MHz): δ 9.66 (s, 1H), 7.91 (s, 2H), 7.70–7.66 (m, 2H), 7.54–7.43 (m, 4H), 7.48–7.43 (m, 3H), 7.25 (t, J = 7.3 Hz, 2H), 7.09 (t, J = 7.3 Hz, 1H), 4.00–3.94 (m, 1H), 2.70 (t, J = 10.8 Hz, 1H), 2.03–2.00 (m, 1H), 1.76–1.53 (m, 4H), 1.34–1.23 (m, 2H), 0.99–0.96 (m, 1H); ¹³C NMR (DMSO-d₆, 100 MHz): δ 184.1, 179.9, 168.8, 161.9, 141.0, 136.8 (d, J = 13.6 Hz), 135.7 (d, J = 15.6 Hz), 134.1 (d, J = 21.2 Hz), 132.9 (d, J = 19.8 Hz), 131.3 (d, J = 32.9 Hz), 129.1, 128.4, 128.3 (×2), 128.0, 124.5, 121.8, 117.7, 114.6–114.5 (m), 56.3 (d, J = 17.9 Hz), 40.3 (part in DMSO-d₆ residual peak), 34.5 (d, J = 7.4 Hz), 27.7 (d, J = 5.4 Hz), 24.6 (d, J = 4.0 Hz), 24.4; ³¹P NMR (162 MHz, DMSO-d₆): δ -8.03; IR (KBr, cm⁻¹): ν 3137, 3069, 2947, 1797, 1666, 1568, 1485, 1463, 1434, 1378, 1280, 1189, 1126, 749, 699, 684; HRMS (ESI) Calcd for C₃₀H₂₆N₂O₂PF₆ ([M+H]⁺): 591.1636; Found: 591.1637.

3-((1R,2R)-2-(diphenylphosphino)cyclohexylamino)-4-(4-nitrophenylamino)cyclobut-3-ene-1,2-dione (3e)

Yellow solid, 53% yield. M.p.: > 300 °C. The product 3e in DMSO is brown, and specific rotation data can not be obtained for its dark color. ¹H NMR (DMSO-d₆, 400 MHz): δ 9.60 (s, 1H), 8.20 (d, J = 8.9 Hz, 2H), 7.73 (d, J = 9.4 Hz, 1H), 7.55–7.45 (m, 6H), 7.36–7.35 (m, 3H), 7.23 (t, J = 7.4 Hz, 2H), 7.09 (t, J = 7.3 Hz, 1H), 4.04–3.94 (m, 1H), 2.71 (t, J = 10.8 Hz, 1H), 2.02–1.99 (m, 1H), 1.76–1.75 (m, 4H), 1.38–1.23 (m, 2H), 1.04–0.96 (m, 1H); ¹³C NMR (DMSO-d₆, 100 MHz): δ 184.6, 179.6, 169.0, 161.7, 145.2, 141.3, 136.8 (d, J = 13.3 Hz), 135.8 (d, J = 15.2 Hz), 134.1 (d, J = 21.1 Hz), 132.9 (d, J = 20.0 Hz), 129.1, 128.4, 128.3 (×2), 125.6, 117.4, 56.6 (d, J = 17.6 Hz), 40.4 (d, J = 14.4 Hz), 34.5 (d, J = 7.4 Hz), 27.8 (d, J = 6.7 Hz), 24.7 (d, J = 6.0 Hz), 24.4; ³¹P NMR (DMSO-d₆, 162 MHz): δ −7.8; IR (KBr, cm⁻¹): ν 3195, 3143, 3069, 2936, 2851, 1797, 1668, 1619, 1601, 1577, 1509, 1440, 1345, 1317, 1273, 1192, 1114, 847, 749, 702, 514; HRMS (ESI) Calcd for C₂₈H₂₇N₃O₄P ([M+H]⁺): 500.1739; Found: 500.1734.

3-((1R,2R)-2-(diphenylphosphino)cyclohexylamino)-4-(3-nitrophenylamino)cyclobut-3-ene-1,2-dione (3f)

Yellow solid, 35% yield. M.p.: > 300 °C. [α]²⁵_D +31.3 (c 0.32, DMSO). ¹H NMR (DMSO-d₆, 400 MHz): δ 9.47 (s, 1H), 8.28 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.66–7.44 (m, 7H), 7.36–7.35 (m, 3H), 7.25 (t, J = 7.4 Hz, 2H), 7.11 (t, J = 7.3 Hz, 1H), 4.02–3.92 (m, 1H), 2.70 (t, J = 10.6 Hz, 1H), 2.02–1.99 (m, 1H), 1.76–1.53 (m, 4H), 1.39–1.23 (m, 2H), 1.03–0.94 (m, 1H); ¹³C NMR (DMSO-d₆, 100 MHz): δ 183.9, 179.8, 163.5, 162.3, 148.6, 140.3, 136.8 (d, J = 13.3 Hz), 135.8 (d, J = 15.3 Hz), 134.0 (d, J = 21.2 Hz), 132.9 (d, J = 20.0 Hz), 130.7, 129.2, 128.5, 128.4, 128.3 (×2), 128.1, 123.7, 116.5, 112.1, 56.3 (d, J = 17.0 Hz), 40.3 (d, J = 14.3 Hz), 34.6 (d, J = 8.4 Hz), 27.8 (d, J = 5.8 Hz), 24.6 (d, J = 4.1 Hz), 24.4; ³¹P NMR (DMSO-d₆, 162 MHz): δ −7.90; IR (KBr, cm⁻¹): ν 3167, 3070, 2940, 2850, 1798, 1659, 1602, 1569, 1482, 1455, 1350, 1260, 1115, 1101, 999, 811, 797, 736, 698, 507, 490; HRMS (ESI) Calcd for C₂₈H₂₇N₃O₄P ([M+H]⁺): 500.1739; Found: 500.1735.

3-((1R,2R)-2-(diphenylphosphino)cyclohexylamino)-4-(octylamino)cyclobut-3-ene-1,2-dione (3g)

White solid, 36% yield. M.p.: 251–252 °C. [α]²⁵_D −11.2 (c 0.33, DMSO). ¹H NMR (DMSO-d₆, 400 MHz): δ 7.51–7.28 (m, 10H), 6.95 (br s 1H), 3.78 (br, 1H), 3.41 (m, 3H, part in water peak), 2.58 (t, J = 10.0 Hz, 1H, part in DMSO-d₆ residual peak), 1.95–1.92 (m, 1H), 1.70–1.26 (m, 18H), 0.89–0.83 (m, 4H); ¹³C NMR data can not be obtained for the poor solubility of 3g in organic solvent. ³¹P NMR (DMSO-d₆, 162 MHz): δ −8.09; IR (KBr, cm⁻¹): ν 3169, 3069, 2927, 2853, 1642, 1567, 1472, 1434, 1362, 1120, 742, 697; HRMS (ESI) Calcd for C₃₀H₄₀N₂O₂P ([M+H]⁺): 491.2827; Found: 491.2828.

3-(Cyclohexylamino)-4-((1R,2R)-2-(diphenylphosphino) cyclohexylamino)cyclobut-3-ene-1,2-dione (3h)

White solid, 38% yield. M.p.: > 300 °C. Specific rotation data can not be obtained for the poor solubility of 3h in organic solvent. ¹H NMR (DMSO-d₆, 400 MHz): δ 7.76 (br s, 1H), 7.49–7.31 (m, 10H), 6.98 (br s, 1H), 3.81 (s, 1H), 3.65 (s, 1H), 2.67–2.58 (m, 1H, part in DMSO-d₆ residual peak), 1.95–1.52 (m, 9H), 1.28–1.18 (m, 8H), 0.92–0.84 (m, 1H); ¹³C NMR data can not be obtained for the poor solubility of 3h in organic solvent. ³¹P NMR (DMSO-d₆, 162 MHz): δ −8.05; IR (KBr, cm⁻¹): ν 3187, 3052, 2926, 2852, 1797, 1644, 1562, 1480, 1433, 1346, 1314, 1261, 1101, 1029, 801, 737, 699; HRMS (ESI) Calcd for C₂₈H₃₄N₂O₂P ([M+H]⁺): 461.2358; Found: 461.2350.

General procedure for the enantioselective Morita–Baylis–Hillman reaction

To a solution of phosphine-squaramide 3e (0.004 mmol) in EtOAc (1.0 mL) was added acrylate (0.4 mmol) at 25 °C. After 10 min stirring at this temperature, isatin derivative (0.2 mmol) was added. The reaction mixture was stirred at 25 °C (monitoring by TLC). Then the resulting solution was concentrated under reduced pressure and the residue was purified by a flash column chromatography on silica gel to afford the desired adducts and the ee values were determined by HPLC analysis with chiral column.

(S)-methyl 2-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)acrylate (6a)

White solid, 99% yield, 87% ee, [α]²⁵_D +55.4 (c 0.35, CH₂Cl₂). ¹H NMR (CDCl₃, 400 MHz): δ 7.37–7.34 (m, 1H), 7.20 (d, J = 6.4 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 6.57 (s, 1H), 6.42 (s, 1H), 3.65 (s, 3H), 3.59 (s, 1H), 3.26 (s, 3H); HPLC analysis (OD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 1.0 mL min⁻¹): t_R = 12.12 min (minor), 19.81 min (major).

(S)-ethyl 2-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)acrylate (6b)

Amber syrup, 98% yield, 86% ee, [α]²⁵_D +41.4 (c 0.42, CH₂Cl₂). ¹H NMR (CDCl₃, 400 MHz): δ 7.37–7.34 (m, 1H), 7.20 (d, J = 6.8 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H),6.87 (d, J = 8.0 Hz, 1H), 6.59 (s, 1H), 6.41 (s, 1H), 4.10–4.01 (m, 2H), 3.56 (s, 1H), 3.26 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H); HPLC analysis (OD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 1.0 mL min⁻¹): t_R = 11.24 min (minor), 17.87 min (major).

(S)-butyl 2-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)acrylate (6c)

Amber syrup, 99% yield, 83% ee, [α]²⁵_D +29.5 (c 0.53, CH₂Cl₂). ¹H NMR (CDCl₃, 400 MHz): δ 7.34–7.30 (m, 1H), 7.17 (d, J = 6.4 Hz, 1H), 7.02 (t, J = 8.0 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.58 (s, 1H), 6.44 (s, 1H), 4.22 (s, 1H), 4.04–3.92 (m, 2H), 3.23 (s, 3H), 1.50–1.43 (m, 2H), 1.24–1.18 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H); HPLC analysis (OD-H column, λ = 254 nm, eluent: hexane/2-propanol = 95/5, flow rate: 1.0 mL min⁻¹): t_R = 10.46 min (minor), 13.55 min (major).

(S)-tert-butyl 2-(3-hydroxy-1-methyl-2-oxoindolin-3-yl) acrylate (6d)

Amber syrup, 77% yield, 71% ee, [α]²⁵_D +14.5 (c 0.45, CH₂Cl₂). ¹H NMR (CDCl₃, 400 MHz): δ 7.35–7.30 (m, 1H), 7.18 (d, J = 6.9 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.50 (s, 1H), 6.20 (s, 1H), 4.16 (s, 1H), 3.20 (s, 3H), 1.22 (s, 9H); HPLC analysis (AS-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 1.0 mL min⁻¹): t_R = 7.31 min (major), 11.29 min (minor).

(S)-phenyl 2-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)acrylate (6e)

Amber syrup, 12% yield, 80% ee, [α]²⁰_D +12.6 (c 0.26, CH₂Cl₂). ¹H NMR (CDCl₃, 400 MHz): δ 7.38–7.27 (m, 4H), 7.19 (t, J = 7.6 Hz, 1H), 7.11–7.07 (m, 1H), 6.93–6.90 (m, 2H), 6.86–6.84 (m, 2H), 6.66 (s, 1H), 3.47 (s, 1H), 3.22 (s, 3H); HPLC analysis (OD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 1.0 mL min⁻¹): t_R = 19.21 min (minor), 31.34 min (major).

(S)-benzyl 2-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)acrylate (6f)

Amber syrup, 99% yield, 89% ee, [α]²⁵_D +34.0 (c 0.53, CH₂Cl₂). ¹H NMR (CDCl₃, 400 MHz): δ 7.36–7.32 (m, 4H), 7.19 (d, J = 6.8 Hz, 1H), 7.13–7.10 (m, 2H), 7.05 (t, J = 7.5 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.67 (s, 1H), 6.47 (s, 1H), 5.00 (d, J = 12.4 Hz, 1H), 4.96 (d, J = 12.3 Hz, 1H), 3.43 (s, 1H), 2.98 (s, 3H); HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 1.0 mL min⁻¹): t_R = 25.00 min (minor), 29.50 min (major).

(S)-benzyl 2-(1-butyl-3-hydroxy-2-oxoindolin-3-yl)acrylate (6g)

Amber syrup, 88% yield, 87% ee, [α]¹⁸_D +38.0 (c 0.65, CH₂Cl₂). ¹H NMR (CDCl₃, 400 MHz): δ 7.31–7.25 (m, 4H), 7.12–7.16 (m, 1H), 7.09–7.06 (m, 2H), 7.03–7.00 (m, 1H), 6.75 (d, J = 7.8 Hz, 1H), 6.61 (s, 1H), 6.45 (s, 1H), 5.05–5.02 (m, 1H), 4.92–4.89 (m, 1H), 4.12 (s, 1H), 3.60–3.54 (m, 1H), 3.45–3.37 (m, 1H), 1.62–1.54 (m, 2H), 1.41–1.31 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz): δ 176.2, 164.4, 144.0, 139.1, 135.2, 130.0, 129.7, 128.5, 128.2 (×2), 123.9, 122.7, 109.0, 76.1, 66.8, 39.9, 29.1, 20.1, 13.8; IR (KBr, cm⁻¹): ν 3333, 2961, 2929, 1728, 1698, 1613, 1495, 1470, 1456, 1382, 1280, 1175, 951, 744; HRMS (ESI) calcd for C₂₂H₂₃NO₄Na ([M+Na]⁺): 388.1525; Found: 388.1529. HPLC analysis (OD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 1.0 mL min⁻¹): t_R = 8.96 min (minor), 12.33 min (major).

(S)-benzyl 2-(1-benzyl-3-hydroxy-2-oxoindolin-3-yl)acrylate (6h)

Amber syrup, 92% yield, 88% ee, [α]¹⁵_D +37.0 (c 0.73, CH₂Cl₂). ¹H NMR (CDCl₃, 400 MHz): δ 7.31–7.16 (m, 10H), 7.12–7.09 (m, 2H), 6.70–6.96 (m, 1H), 6.63 (s, 1H), 6.60 (d, J = 7.8 Hz, 1H), 6.47 (s, 1H), 5.06–5.03 (m, 1H), 4.91–4.83 (m, 2H), 4.52–4.48 (m, 1H), 3.98 (s, 1H); ¹³C NMR (CDCl₃, 100 MHz): δ 176.5, 164.4, 143.6, 139.0, 135.5, 135.1, 130.1, 129.5, 128.8, 128.6 (×2), 128.4, 128.3, 127.6, 127.3, 123.9, 123.0, 109.9, 76.2, 66.9, 43.8; IR (KBr, cm⁻¹): ν 3339, 1705, 1615, 1492, 1460, 1373, 1357, 1317, 1176, 1163, 1057, 972, 939, 758, 694; HRMS (ESI) calcd for C₂₅H₂₁NO₄Na ([M+Na]⁺): 422.1368; Found: 422.1370. HPLC analysis (OD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 1.0 mL min⁻¹): t_R = 14.33 min (minor), 19.08 min (major).

(R)-benzyl 2-(4-chloro-3-hydroxy-1-methyl-2-oxoindolin-3-yl) acrylate (6i)

White solid, 92% yield, 94% ee, [α]²⁴_D +39.3 (c 0.66, CH₂Cl₂). After recrystallization: 99% ee. ¹H NMR (CDCl₃, 400 MHz): δ 7.32–7.30 (m, 3H), 7.23 (t, J = 8.0 Hz, 1H), 7.13–7.11 (m, 2H), 6.96–6.94 (m, 1H), 6.79 (s, 1H), 6.60–6.57 (m, 2H), 4.99–4.92 (m, 2H), 4.00 (s, 1H), 2.94 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz): δ 175.3, 164.3, 146.2, 136.9, 134.9, 131.4, 131.1, 130.9, 128.6, 128.4 (×2), 125.7, 124.1, 107.2, 76.5, 67.0, 26.4; IR (KBr, cm⁻¹): ν 3338, 1709, 1608, 1591, 1460, 1325, 1174, 1119, 1065, 777, 732; HRMS (ESI) calcd for C₁₉H₁₆NO₄NaCl ([M+Na]⁺): 380.0666; Found: 380.0662. HPLC analysis (OD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 1.0 mL min⁻¹): t_R = 19.17 min (minor), 28.07 min (major).

(R)-benzyl 2-(4-bromo-3-hydroxy-1-methyl-2-oxoindolin-3-yl) acrylate (6j)

White solid, 91% yield, 95% ee, [α]²³_D +28.9 (c 0.73, CH₂Cl₂). After recrystallization: 99% ee. ¹H NMR (CDCl₃, 400 MHz): δ 7.32–7.30 (m, 3H), 7.18–7.11 (m, 4H), 6.82 (s, 1H), 6.62 (d, J = 7.0 Hz, 1H), 6.59 (s, 1H), 4.99–4.92 (m, 2H), 3.92 (s, 1H), 2.94 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz): δ 175.1, 164.3, 146.4, 136.8, 135.0, 131.3 (×2), 128.6, 128.4 (×2), 127.4, 127.2, 119.4, 107.7, 77.2, 67.0, 26.3; IR (KBr, cm⁻¹): ν 3435, 1712, 1605, 1582, 1460, 1315, 1159, 1113, 1045, 988, 951, 787, 761, 697; HRMS (ESI) calcd for C₁₉H₁₇NO₄Br ([M+H]⁺): 402.0341; Found: 402.0347. HPLC analysis (OD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 1.0 mL min⁻¹): t_R = 16.53 min (minor), 25.60 min (major).

(S)-benzyl 2-(5-fluoro-3-hydroxy-1-methyl-2-oxoindolin-3-yl)acrylate (6k)

White solid, 99% yield, 76% ee, [α]¹⁷_D +50.0 (c 0.68, CH₂Cl₂). After recrystallization: 99% ee. ¹H NMR (CDCl₃, 400 MHz): δ 7.32–7.30 (m, 3H), 7.12–7.10 (m, 2H), 7.00 (td, J = 2.5 Hz, J = 8.8 Hz, 1H), 6.92 (dd, J = 2.6 Hz, J = 7.4 Hz, 1H), 6.65 (s, 1H), 6.61 (dd, J = 4.0 Hz, J = 8.3 Hz, 1H), 6.48 (s, 1H), 5.00–4.92 (m, 2H), 4.26 (s, 1H), 2.94 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz): δ 176.1, 164.1, 159.4 (d, J = 242.1 Hz), 140.3, 138.7, 134.8, 131.0 (d, J = 8.1 Hz), 129.0, 128.6, 128.5 (×2), 116.1 (d, J = 23.5 Hz), 112.1 (d, J = 29.4 Hz), 109.3 (d, J = 8.1 Hz), 76.2, 67.1, 26.2; IR (KBr, cm⁻¹): ν 3331, 1726, 1706, 1619, 1491, 1459, 1365, 1287, 1186, 1106, 1050, 966, 819, 699; HRMS (ESI) calcd for C₁₉H₁₇NO₄F ([M+H]⁺): 342.1142; Found: 342.1140. HPLC analysis (OD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 1.0 mL min⁻¹): t_R = 14.67 min (minor), 18.18 min (major).

(S)-benzyl 2-(5-chloro-3-hydroxy-1-methyl-2-oxoindolin-3-yl) acrylate (6l)

White solid, 99% yield, 71% ee, [α]¹⁷_D +26.2 (c 0.71, CH₂Cl₂). ¹H NMR (CDCl₃, 400 MHz): δ 7.33–7.26 (m, 4H), 7.14–7.10 (m, 3H), 6.66 (s, 1H), 6.62 (d, J = 8.3 Hz, 1H), 6.48 (s, 1H), 5.01–4.92 (m, 2H), 4.02 (s, 1H), 2.94 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz): δ 175.9, 164.1, 143.0, 138.6, 134.8, 131.0, 129.9, 129.0, 128.6, 128.5, 128.3, 124.4, 109.7, 76.0, 67.1, 26.2; IR (KBr, cm⁻¹): ν 3335, 1727, 1705, 1608, 1487, 1359, 1288, 1188, 1105, 1049, 967, 818, 751, 697; HRMS (ESI) calcd for C₁₉H₁₆NO₄NaCl ([M+Na]⁺): 380.0666; Found: 380.0668. HPLC analysis (OD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 1.0 mL min⁻¹): t_R = 16.00 min (minor), 19.53 min (major).

(S)-benzyl 2-(5-bromo-3-hydroxy-1-methyl-2-oxoindolin-3-yl) acrylate (6m)

White solid, 98% yield, 72% ee, [α]¹⁷_D +17.2 (c 0.78, CH₂Cl₂), After recrystallization: 91% ee. ¹H NMR (CDCl₃, 400 MHz): δ 7.43 (dd, J = 2.0 Hz, J = 8.3 Hz, 1H), 7.33–7.31 (m, 3H), 7.28–7.27 (m, 1H), 7.13–7.11 (m, 2H), 6.64 (s, 1H), 6.58 (d, J = 8.3 Hz, 1H), 6.48 (s, 1H), 5.02–4.92 (m, 2H), 3.87 (s, 1H), 2.94 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz): δ 175.7, 164.1, 143.5, 138.6, 134.8, 132.9, 131.3, 129.0, 128.6, 128.5, 127.1, 155.5, 110.2, 75.9, 67.1, 26.2; IR (KBr, cm⁻¹): ν 3329, 2937, 1704, 1630, 1484, 1456, 1421, 1357, 1287, 1185, 1103, 1051, 966, 814, 755, 696; HRMS (ESI) calcd for C₁₉H₁₆NO₄NaBr ([M+Na]⁺): 424.0160; Found: 424.0161. HPLC analysis (OD-H column, λ = 254 nm, eluent: hexane/2-propanol = 95/5, flow rate: 1.0 mL min⁻¹): t_R = 33.38 min (minor), 39.82 min (major).

(S)-benzyl 2-(6-bromo-3-hydroxy-1-methyl-2-oxoindolin-3-yl) acrylate (6n)

White solid, 91% yield, 83% ee, [α]²³_D +31.4 (c 0.72, CH₂Cl₂), After recrystallization: 99% ee. ¹H NMR (CDCl₃, 400 MHz): δ 7.35–7.32 (m, 3H), 7.17–7.15 (m, 1H), 7.08–7.06 (m, 2H), 7.01–6.99 (m, 1H), 6.78 (d, J = 1.8 Hz, 1H), 6.65 (s, 1H), 6.47 (s, 1H), 5.00–4.98 (m, 1H), 4.89–4.86 (m, 1H), 4.06 (s, 1H), 2.88 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz): δ 176.1, 164.1, 145.6, 138.6, 134.7, 129.0, 128.6 (×2), 128.3, 125.7, 125.0, 123.8, 112.4, 75.7, 67.1, 26.2; IR (KBr, cm⁻¹): ν 3301, 1732, 1712, 1602, 1373, 1286, 1180, 1098, 1053, 984, 962, 763; HRMS (ESI) calcd for C₁₉H₁₆NO₄NaBr ([M+Na]⁺): 424.0160; Found: 424.0157. HPLC analysis (OD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 0.8 mL min⁻¹): t_R = 17.61 min (minor), 22.45 min (major).

(S)-benzyl 2-(7-bromo-3-hydroxy-1-methyl-2-oxoindolin-3-yl) acrylate (6o)

White solid, 81% yield, 82% ee, [α]²⁴_D +74.5 (c 0.65, CH₂Cl₂), After recrystallization: 99% ee. ¹H NMR (CDCl₃, 400 MHz): δ 7.40 (dd, J = 1.3 Hz, J = 8.3 Hz, 1H), 7.34–7.31 (m, 3H), 7.12–7.05 (m, 3H), 6.88–6.85 (m, 1H), 6.66 (s, 1H), 6.49 (s, 1H), 5.00–4.91 (m, 2H), 4.16 (s, 1H), 3.33 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz): δ 176.8, 164.1, 138.8, 135.7, 134.7, 132.4, 129.0, 128.7, 128.5, 128.4, 124.2, 122.9, 102.9, 75.3, 67.2, 29.7; IR (KBr, cm⁻¹): ν 3374, 1711, 1608, 1579, 1461, 1313, 1165, 1113, 1045, 965, 782, 747, 703; HRMS (ESI) calcd for C₁₉H₁₆NO₄NaBr ([M+Na]⁺): 424.0160; Found: 424.0163. HPLC analysis (OD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 1.0 mL min⁻¹): t_R = 10.62 min (minor), 13.15 min (major).

(S)-benzyl 2-(3-hydroxy-1,5-dimethyl-2-oxoindolin-3-yl) acrylate (6p)

White solid, 99% yield, 89% ee, [α]¹⁶_D +28.4 (c 0.67, CH₂Cl₂), After recrystallization: 98% ee. ¹H NMR (CDCl₃, 400 MHz): δ 7.31–7.29 (m, 3H), 7.11–7.08 (m, 3H), 6.99 (s, 1H), 6.63 (s, 1H), 6.60 (d, J = 8.0 Hz, 1H), 6.46 (s, 1H), 5.00–4.91 (m, 2H), 3.82 (s, 1H), 2.93 (s, 3H), 2.29 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz): δ 176.1, 164.4, 142.0, 139.2, 135.0, 132.6, 130.3, 129.3, 128.5 (×2), 128.4 (×2), 124.6, 108.5, 76.2, 67.0, 26.1, 21.0; IR (KBr, cm⁻¹): ν 3322, 1727, 1700, 1622, 1497, 1367, 1288, 1187, 1106, 1049, 962, 807, 698; HRMS (ESI) calcd for C₂₀H₁₉NO₄Na ([M+Na]⁺): 360.1212; Found: 360.1212. HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 1.0 mL min⁻¹): t_R = 27.54 min (minor), 31.92 min (major).

(S)-benzyl 2-(3-hydroxy-5-methoxy-1-methyl-2-oxoindolin-3-yl)acrylate (6q)

White solid, 90% yield, 85% ee, [α]²⁷_D +21.2 (c 0.64, CH₂Cl₂), ¹H NMR (CDCl₃, 400 MHz): δ 7.23–7.22 (m, 3H), 7.03–7.01 (m, 2H), 6.76–6.70 (m, 2H), 6.56–6.52 (m, 2H), 6.40 (s, 1H), 4.92–4.83 (m, 2H), 4.19 (s, 1H), 3.67 (s, 3H), 2.83 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz): δ 176.0, 164.3, 156.2, 139.0, 137.7, 134.9, 130.6, 128.7, 128.5 (×2), 128.4, 114.6, 110.9, 109.2, 76.4, 67.0, 55.8, 26.1; IR (KBr, cm⁻¹): ν 3342, 3266, 1722, 1691, 1500, 1465, 1373, 1282, 1186, 1029, 961, 810, 754, 698; HRMS (ESI) calcd for C₂₀H₁₉NO₅Na ([M+Na]⁺): 376.1161; Found: 376.1159. HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 1.0 mL min⁻¹): t_R = 38.07 min (minor), 48.60 min (major).

(S)-benzyl 2-(3-hydroxy-1,7-dimethyl-2-oxoindolin-3-yl) acrylate (6r)

White solid, 80% yield, 89% ee, [α]²⁷_D +54.8 (c 0.55, CH₂Cl₂), After recrystallization: 99% ee. ¹H NMR (CDCl₃, 400 MHz): δ 7.31–7.29 (m, 3H), 7.09–7.01 (m, 2H), 7.03–6.98 (m, 2H), 6.92–6.89 (m, 1H), 6.64 (s, 1H), 6.48 (s, 1H), 4.99–4.88 (m, 2H), 4.01 (s, 1H), 3.18 (s, 3H), 2.39 (s, 3H); ¹³C NMR (CDCl₃, 100 MHz): δ 177.0, 164.4, 142.0, 139.3, 135.0, 133.9, 130.0, 128.6. 128.5, 128.4 (×2), 122.9, 121.8, 120.3, 75.4, 67.0, 29.5, 18.9; IR (KBr, cm⁻¹): ν 3374, 1706, 1602, 1456, 1369, 1288, 1184, 1111, 1071, 1025, 962, 744, 700; HRMS (ESI) calcd for C₂₀H₁₉NO₄Na ([M+Na]⁺): 360.1212; Found: 360.1205. HPLC analysis (AD-H column, λ = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate: 1.0 mL min⁻¹): t_R = 29.48 min (minor), 37.65 min (major).

Acknowledgements

We are grateful for the financial support from National Natural Science Foundation of China (20772029), and the Fundamental Research Funds for the Central Universities.

References

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Footnote

† Electronic supplementary information (ESI) available: NMR spectra for the phosphine-squaramides 3a–h, HPLC spectra for the Morita–Baylis–Hillman products and the crystallographic data. See DOI: 10.1039/c2ra20521a

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