chiral phosphine-squaramide-catalyzed morita–baylis–hillman reaction: enantioselective synthesis...

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

Jing-Ying Qian,a Ci-Ci Wang,a Feng Shaa and Xin-Yan Wu*ab

Received 21st March 2012, Accepted 20th April 2012

DOI: 10.1039/c2ra20521a

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).

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, enantiose-

lective 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-sub-

stituted-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 pKa, which endowed it with a unique catalophore for dual

H–bonding catalysts.9,10

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).

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, pro-

mising enantioselectivity (entries 2–9). Among the screened

phosphine-squaramide organocatalysts, 3e was the best one,

aKey Laboratory for Advanced Materials and Institute of Fine Chemicals,East China University of Science and Technology, Shanghai, 200237,P. R. China. E-mail: [email protected]; Fax: +86 21 64252758;Tel: +86 21 64252011bState Key Laboratory of Elemento-organic Chemistry, Nankai University,Tianjin, 300071, P. R. China{ Electronic supplementary information (ESI) available: NMR spectrafor the phosphine-squaramides 3a–h, HPLC spectra for the Morita–Baylis–Hillman products and the crystallographic data. See DOI:10.1039/c2ra20521a

Fig. 1 Structure of bifunctional phosphine 1 and 2.

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

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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

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 enantios-

electivity 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).

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 uC) resulted in a decrease of reaction rate and enantioselec-

tivity, probably due to the decomposition of catalyst (entry 8 vs.

5), while the lower reaction temperature (0 uC) resulted in slower

reaction rate and better enantioselectivity (entry 9 vs. 5).

Under the optimized reaction conditions (2 mol% 3e, 2 equiv.

of acrylate, ethyl acetate as solvent, 25 uC), 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).

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

Table 1 Screening of phosphine-squaramides for the MBH reactiona

Entry Catalyst Yield %b ee %c

1 2 74 422 3a 85 773 3b 89 744 3c 96 785 3d 94 776 3e 97 817 3f 90 778 3g 96 659 3h 97 58

10 1 91 45a The reactions were performed with 4a (0.2 mmol), 5a (1 mmol) and10 mol% of catalyst 1–3 in 1 mL CH2Cl2 at 25 uC for 5 days.b Isolated yield. c Determined by chiral HPLC analysis using ChiralcelOD-H column.

Table 2 The survey of solvents for the MBH reaction of N-methyl isatinwith methyl acrylatea

Entry Solvent Time/d Yield %b ee %c

1 CH2Cl2 5 97 812 CH2Cl2

d 5 97 813 CHCl3 5 95 834 THF 2 99 775 Ether 3 97 826 EtOAc 2 99 877 CH3CN 6 92 778 Toluene 6 79 859 CH3OH 3 85 74a Unless stated otherwise, the reactions were performed with 4a (0.2mmol), 5a (0.4 mmol) and 10 mol% of catalyst 3e in 1 mL solvent at25 uC. b Isolated yield. c Determined by chiral HPLC analysis usingChiralcel OD-H column. d 1 mmol scale.

Table 3 Further optimization of reaction conditionsa

Entry Conc./M 3e/mol (%) Time/d Yield %b ee %c

1 0.1 10 2 99 872 0.2 10 2 99 873 0.3 10 1.7 99 874 0.2 5 3 99 875 0.2 2 3 99 876 0.2 1 6.5 94 887 0.2 0.5 8 81 888d 0.2 2 4.5 93 819e 0.2 2 6.5 39 93a Unless stated otherwise, the reactions were performed with 4a (0.2mmol), 5a (0.4 mmol) and catalyst 3e in EtOAc at 25 uC. b Isolatedyield. c Determined by chiral HPLC analysis using Chiralcel OD-Hcolumn. d The reaction was conducted at 40 uC. e The reaction wasconducted at 0 uC.

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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.

In addition, we tried the MBH reaction of N-Ac isatin with

benzyl acrylate. However, the isatin with an electron-with-

drawing 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 com-

pounds 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 (d 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 mm 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 6 2 mL) to afford

phosphine-squaramide 3 as solid.

Table 4 Substrate scope of isatins with acrylates in the 3e-catalyzedMBH reactiona

Entry R1 R2 R3 Product Time/d Yield %b ee %c

1 H Me Me 6a 3 99 872 H Me Et 6b 2 98 863 H Me n-Bu 6c 2 99 834 H Me t-Bu 6d 3 77 715 H Me Ph 6e 7 12 806 H Me Bn 6f 2 99 897 H n-Bu Bn 6g 4.5 88 878 H Bn Bn 6h 3.5 92 889 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 7113 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 8518 7-Me Me Bn 6r 3.5 80 89 (99)a The reactions were performed with 4 (0.2 mmol), 5 (0.4 mmol) and 2mol% of catalyst 3e in 1 mL EtOAc at 25 uC. b Isolated yield.c Determined by chiral HPLC analysis, and the data in parentheseswere obtained after being recrystallized once from ethanol andpetroleum ether.

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


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3-((1R,2R)-2-(diphenylphosphino)cyclohexylamino)-4-

(phenylamino)cyclobut-3-ene-1,2-dione (3a)

White solid, 47% yield. M.p.: . 300 uC. [a]25D +6.0 (c 0.54,

DMSO). 1H NMR (DMSO-d6, 400 MHz): d 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): d

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 (62), 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): d 27.90; IR (KBr, cm21): n 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)


DMSO). 1H NMR (DMSO-d6, 400 MHz): d 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): d 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 (62), 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): d 28.01; IR (KBr, cm21):

n 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.


(trifluoromethyl)phenylamino)cyclobut-3-ene-1,2-dione (3c)

White solid, 51% yield. M.p.: . 300 uC. [a]25D +23.7 (c 0.47, DMSO).

1H NMR (DMSO-d6, 400 MHz): d 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): d 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 (62),

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): d 23.08; IR (KBr,

cm21): n 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)


DMSO). 1H NMR (DMSO-d6, 400 MHz): d 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): d 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 (62),

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): d -8.03; IR (KBr, cm21): n 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.


nitrophenylamino)cyclobut-3-ene-1,2-dione (3e)

Yellow solid, 53% yield. M.p.: . 300 uC. 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): d 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): d 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 (62), 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): d 27.8; IR (KBr, cm21): n 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.


nitrophenylamino)cyclobut-3-ene-1,2-dione (3f)

Yellow solid, 35% yield. M.p.: . 300 uC. [a]25D +31.3 (c 0.32,

DMSO). 1H NMR (DMSO-d6, 400 MHz): d 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): d 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

(62), 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): d 27.90; IR

(KBr, cm21): n 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 uC. [a]25D 211.2 (c 0.33,

DMSO). 1H NMR (DMSO-d6, 400 MHz): d 7.51–7.28 (m, 10H),


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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): d 28.09; IR (KBr,

cm21): n 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 uC. Specific rotation data

can not be obtained for the poor solubility of 3h in organic

solvent. 1H NMR (DMSO-d6, 400 MHz): d 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): d 28.05; IR (KBr, cm21): n 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 uC. After

10 min stirring at this temperature, isatin derivative (0.2 mmol)

was added. The reaction mixture was stirred at 25 uC(monitoring by TLC). Then the resulting solution was concen-

trated 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, [a]25D +55.4 (c 0.35, CH2Cl2). 1H

NMR (CDCl3, 400 MHz): d 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, l = 254 nm, eluent: hexane/

2-propanol = 90/10, flow rate: 1.0 mL min21): tR = 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, [a]25D +41.4 (c 0.42, CH2Cl2). 1H


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,

l = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate:

1.0 mL min21): tR = 11.24 min (minor), 17.87 min (major).

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



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, l = 254 nm, eluent: hexane/



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

(6d)



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, l = 254 nm, eluent: hexane/


(major), 11.29 min (minor).

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


NMR (CDCl3, 400 MHz): d 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, l = 254 nm, eluent: hexane/2-propanol = 90/10, flow

rate: 1.0 mL min21): tR = 19.21 min (minor), 31.34 min (major).

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



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, l = 254 nm, eluent: hexane/2-propanol

= 90/10, flow rate: 1.0 mL min21): tR = 25.00 min (minor),

29.50 min (major).

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


NMR (CDCl3, 400 MHz): d 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): d 176.2, 164.4, 144.0, 139.1, 135.2,

130.0, 129.7, 128.5, 128.2 (62), 123.9, 122.7, 109.0, 76.1, 66.8,

39.9, 29.1, 20.1, 13.8; IR (KBr, cm21): n 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, l = 254 nm, eluent:

hexane/2-propanol = 90/10, flow rate: 1.0 mL min21): tR =

8.96 min (minor), 12.33 min (major).

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


NMR (CDCl3, 400 MHz): d 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


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(m, 1H), 3.98 (s, 1H); 13C NMR (CDCl3, 100 MHz): d 176.5,

164.4, 143.6, 139.0, 135.5, 135.1, 130.1, 129.5, 128.8, 128.6 (62),

128.4, 128.3, 127.6, 127.3, 123.9, 123.0, 109.9, 76.2, 66.9, 43.8; IR

(KBr, cm21): n 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, l = 254 nm, eluent: hexane/2-propanol


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, [a]24D +39.3 (c 0.66, CH2Cl2).

After recrystallization: 99% ee. 1H NMR (CDCl3, 400 MHz): d

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): d

175.3, 164.3, 146.2, 136.9, 134.9, 131.4, 131.1, 130.9, 128.6, 128.4

(62), 125.7, 124.1, 107.2, 76.5, 67.0, 26.4; IR (KBr, cm21): n

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, l = 254 nm,

eluent: hexane/2-propanol = 90/10, flow rate: 1.0 mL min21): tR

= 19.17 min (minor), 28.07 min (major).

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

acrylate (6j)



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): d 175.1, 164.3, 146.4, 136.8,

135.0, 131.3 (62), 128.6, 128.4 (62), 127.4, 127.2, 119.4, 107.7,

77.2, 67.0, 26.3; IR (KBr, cm21): n 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, l = 254 nm, eluent: hexane/



(S)-benzyl 2-(5-fluoro-3-hydroxy-1-methyl-2-oxoindolin-3-

yl)acrylate (6k)



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,


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 (62), 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, cm21): n 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, l = 254 nm, eluent: hexane/2-propanol


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, [a]17D +26.2 (c 0.71, CH2Cl2). 1H

NMR (CDCl3, 400 MHz): d 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):

d 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, cm21): n

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, l = 254 nm, eluent: hexane/2-propanol = 90/10, flow


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

acrylate (6m)

White solid, 98% yield, 72% ee, [a]17D +17.2 (c 0.78, CH2Cl2),


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): d 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, cm21): n 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, l = 254 nm, eluent:

hexane/2-propanol = 95/5, flow rate: 1.0 mL min21): tR =

33.38 min (minor), 39.82 min (major).


acrylate (6n)



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): d 176.1, 164.1, 145.6, 138.6, 134.7,

129.0, 128.6 (62), 128.3, 125.7, 125.0, 123.8, 112.4, 75.7, 67.1,

26.2; IR (KBr, cm21): n 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, l = 254 nm, eluent: hexane/2-

propanol = 90/10, flow rate: 0.8 mL min21): tR = 17.61 min



acrylate (6o)



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): d 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,

cm21): n 3374, 1711, 1608, 1579, 1461, 1313, 1165, 1113, 1045,

965, 782, 747, 703; HRMS (ESI) calcd for C19H16NO4NaBr


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([M+Na]+): 424.0160; Found: 424.0163. HPLC analysis (OD-H



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

(6p)



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,


176.1, 164.4, 142.0, 139.2, 135.0, 132.6, 130.3, 129.3, 128.5 (62),

128.4 (62), 124.6, 108.5, 76.2, 67.0, 26.1, 21.0; IR (KBr, cm21): n

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,

l = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate:


(S)-benzyl 2-(3-hydroxy-5-methoxy-1-methyl-2-oxoindolin-3-

yl)acrylate (6q)


1H

NMR (CDCl3, 400 MHz): d 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): d 176.0, 164.3, 156.2, 139.0, 137.7, 134.9, 130.6, 128.7,

128.5 (62), 128.4, 114.6, 110.9, 109.2, 76.4, 67.0, 55.8, 26.1; IR

(KBr, cm21): n 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, l = 254 nm, eluent: hexane/2-propanol = 90/10, flow rate:


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

(6r)



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):

d 177.0, 164.4, 142.0, 139.3, 135.0, 133.9, 130.0, 128.6. 128.5,

128.4 (62), 122.9, 121.8, 120.3, 75.4, 67.0, 29.5, 18.9; IR (KBr,

cm21): n 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



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.

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chiral phosphine-squaramide-catalyzed morita–baylis–hillman reaction: enantioselective synthesis...

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