Organic &Biomolecular Chemistry

COMMUNICATION

Cite this: Org. Biomol. Chem., 2014,12, 5843

Received 4th June 2014,Accepted 24th June 2014

DOI: 10.1039/c4ob01144a

www.rsc.org/obc

Fluorous chiral bisoxazolines: applicationin copper-catalyzed asymmetricα-hydrophosphonylation†Tao Deng, Hongjun Wang and Chun Cai*

A copper-catalyzed asymmetric α-hydrophosphonylation of isatins

with a novel fluorous bis(oxazoline) as a ligand is presented. The

corresponding chiral α1-oxindole-α-hydroxyphosphonates were

obtained in 30–91% yield with enantioselectivities up to 92%.

The fluorous ligand can be easily recovered and reused at least

3 times without a significant loss in its activity.

Since 1991,1,2 bis(oxazoline) (BOX) ligands have received agreat deal of attention as ligands in coordination chemistryand asymmetric catalysis.3 Bis-oxazoline-based complexes havebeen successfully applied to the asymmetric catalysis of a widevariety of key organic reactions (e.g. Friedel–Crafts reaction,4

Mukaiyama–Michael reaction5), either with concurrent orindependent activation of both reagents.6,7 However, this kindof ligands are always expensive and difficult to recycle after thereactions.

It is well known that the oxindole frameworks bearing theC3 quaternary stereocenter are widely distributed in manynatural products,8 useful synthetic building blocks, and bio-logically active molecules9 (Fig. 1). Several different strategieshave been reported to directly construct the 3-functionalized-3-hydroxy-2-oxindole framework (Scheme 1). The mostcommon protocol is the catalytic Aldol reactions of aldehydesor ketones with isatins.10–12 Another attractive strategy for thesynthesis of 3-substituted-3-hydroxy oxindoles was nucleo-philic additions to the 3-carbonyl of isatins. Meanwhile, themetal-mediated additions of carbon nucleophiles/equivalents,such as boronic acids,13–15 have been explored. Moreover, acatalytic Henry reaction of isatins with alkanes has also beenapplied for the construction of the medicinal scaffold.16

Notably, the oxidation of 3-substituted oxindoles itself wasproved to be an efficient method to make this core structure.17

Recently, a catalytic decarboxylative [1,2]-addition of isatinshas been reported to generate chiral 3-substituted oxindoles.18

On the other hand, α-hydroxyphosphonates are an attractiveclass of biologically active compounds as well as usefulsynthetic intermediates of α-substituted phosphonyl com-pounds.19 They also showed potential biological activities andare widely used in pharmaceutical applications.20,21 Thus, it issuspected that quaternary α1-oxindole-α-hydroxy phospho-nates, in which the PO(OR)2 and oxindolyl moieties arelocated at a tetra-substituted carbon atom, potentially have

Fig. 1 Representative bioactive natural products built on a 3-hydroxy-2-oxindole core scaffold.

Scheme 1 Routes for the preparation of 3-hydoxy-2-oxindoleframework.

†Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ob01144a

Chemical Engineering College, Nanjing University of Science & Technology, Nanjing,

Jiangsu 210094, P. R. China. E-mail: c.cai@njust.edu.cn

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some unique bioactivities. The increasing importance of un-natural hydroxyl acids in modification of natural and unnaturalproducts to improve the bioactivity and stability makes thesynthesis of hydroxyl phosphonates a significant subject.However, the synthesis of α1-oxindole-α-hydroxy phosphonateshas been scarcely investigated.22 As a consequence, the develop-ment of environmentally benign practical synthetic routesunder mild conditions for accessing these α-hydroxyphos-phonates still remains a major goal.

Herein, we disclose the copper-catalyzed α-hydrophospho-nylation process of readily accessible dialkyl phosphites withisatins using a fluorous bis(oxazoline) ligand (L6) under mildreaction conditions to assemble the valuable 3-functionalized3-hydroxy-2-oxindoles. Good to excellent enantioselectivitieshave been obtained under suitable conditions. These featuresrender this synthetic protocol particularly attractive for practi-cal application in drug discovery. The fluorous ligand used canbe easily recovered with the F-SPE method.23

Initial optimization of the reaction conditions was carriedout for a family of chiral bis(oxazoline) ligands (Fig. 2). Essen-tial results observed for the α-hydrophosphonylation are col-lected in Table 1. Because of the solubility of the fluorousligands, we choose DMSO for this reaction. The initial appli-cation of Ph-Box L1 resulted in poor enantioselectivity (14%

ee, Table 1, entry 1), while the application of C2-Ph-Boxligands (L2 and L323) with diethyl phosphite turned out to befar more enantioselective (Table 1, entries 2 and 3). L3 andL7 have shown similar yields and ee values (Table 1, entries 3and 7). Although we observed better enantioselectivity in thepresence of commercial pybox ligand L4 when compared toother ligands, we still choose the fluorous bis(oxazoline)ligand L6 because of the recyclability. The slightly low level ofenantioselectivity still left much to be desired.

To address this issue, various bases and solvents wereevaluated in association with different copper sources to ident-ify the most enantioselective and reliable catalytic system(Table 2). KF was proved to be the best choice for this reaction(Table 2, entry 6). Among the tested solvents, the best enantio-selectivity was achieved for MeOH at room temperature (91%yield, 83% ee, Table 2, entry 16). Low enantioselectivities wereobserved in CH2Cl2 and isopropanol (Table 2, entries 11 and13), although the yields were higher than in MeOH. No desiredproduct was obtained with H2O or dioxane as the solvent(Table 2, entries 14 and 15).

Fig. 2 Selected examples of chiral ligands examined.

Table 2 Optimization of the conditions for theα-hydrophosphonylationa

Entry Solvent Base Cu source Yieldb/% eec/%

1 THF K3PO4 Cu(OAc)2 nr —2 THF KOH Cu(OAc)2 9 293 THF Et3N Cu(OAc)2 nr —4 THF DBU Cu(OAc)2 nr —5 THF K2CO3 Cu(OAc)2 14 366 THF KF Cu(OAc)2 22 137 DMF KF Cu(OAc)2 69 328 DMSO KF Cu(OAc)2 70 509 EtOH KF Cu(OAc)2 83 3410 MeCN KF Cu(OAc)2 72 3811 i-PrOH KF Cu(OAc)2 92 4112 EtOAc KF Cu(OAc)2 74 6213 CH2Cl2 KF Cu(OAc)2 93 4114 1,4-Dioxane KF Cu(OAc)2 nr —15 H2O KF Cu(OAc)2 nr —16 MeOH KF Cu(OAc)2 91 8317 MeOH KF CuBr2 17 3918 MeOH KF Cu(TFA)2 nr —19 MeOH KF Cu(OTf)2 26 6020 MeOH KF CuCl2 31 7521 MeOH KF CuSO4 19 6822d MeOH KF Cu(OAc)2 23 8023e MeOH KF Cu(OAc)2 16 8524 f MeOH KF Cu(OAc)2 11 88

aUnless otherwise specified, all reactions were carried out with isatin(1.0 mmol), diethyl phosphite (1.2 mmol), L6 (0.1 mmol), base(0.1 mmol) and Cu source (0.1 mmol) in the solvent (1 mL) for12 hours. b Isolated yield. c The ee value of the compound was checkedby chiral HPLC using a Venusil CA column. d The reaction was carriedout at 0 °C. e The reaction was carried out at −15 °C. f The reaction wascarried out at −30 °C.

Table 1 Screening of chiral bis(oxazoline) ligandsa

Entry Ligand Yieldb/% eec/%

1 L1 58 142 L2 53 333 L3 49 254 L4 62 545 L5 67 526 L6 70 507 L7 55 24

aUnless otherwise specified, all reactions were carried out with isatin(1.0 mmol), diethyl phosphite (1.2 mmol), ligand (0.1 mmol),KF (0.1 mmol) and Cu(OAc)2 (0.1 mmol) in DMSO (1 mL) for 12 hours.b Isolated yield. c The ee value of the compounds was checked by chiralHPLC using a Venusil CA column.

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To further explore this reaction, we tested the catalyticabilities of a series of cheap and readily available coppersalts. We found that Cu(OAc)2 was the most efficient tocatalyze the desired α-hydrophosphonylation in MeOH toprovide 3a in 91% yield with enantioselectivity up to 83%(Table 2, entry 16). It was more striking that the product wasreadily separated by simple extraction of the reaction mixturewith ethyl acetate. After removing the solvent, 3a was obtainedin high purity, and no further isolation or purification stepswere required. In the case of using CuBr2, low yield andenantioselectivity were obtained (Table 2, entry 17). The reac-tion did not occur with Cu(TFA)2 as the copper source (Table 2,entry 18).

In order to minimize a possible nonenantioselective back-ground reaction that could be detrimental to the enantio-selectivity, we carried out the reaction at low temperature.A slight increase of enantioselectivity was observed at −15 °C(Table 2, entries 16 and 23). But the use of low temperaturealso led to a decreases in yields (Table 2, entries 22–24). Theability to carry out the reaction at room temperature withoutunnecessary heating of the reaction mixture was an importantfeature of this catalytic system.

Taking this consideration into account and encouraged bythe high ee obtained in the synthesis of compound 3a, westudied the applicability of the reaction to other related sub-strates (Table 3). Having the best ligand and conditions inhand, we tested the scope of the α-hydrophosphonylation toother isatins. As shown in Table 3, a broad range of isatins wasinvestigated to demonstrate the scope of our procedure andalso clarify the influence of various substituents differentlyplaced at the phenyl ring. The reaction was general no matterhow isatins tolerate both electron-deficient and electron-richsubstitutions. To our delight, for most of the substrates, thedesired products (3a–3n) were achieved in moderate to highyields in the presence of 10 mol% of the Cu(OAc)2/L6 at roomtemperature. The isolated yields were substantial and besidessuch excellent efficiency, many of the studied substrates pro-vided α1-oxindole-α-hydroxyphosphonates with high enantio-selectivity (up to 92% ee).

The best results in terms of high enantioselectivity havebeen observed for isatins that possess electron-donatinggroups (–Me or –OMe) placed at the phenyl ring (Table 3,entries 1, 3 and 7). For all of these substrates, the ee valuesexceeded 60%. Interestingly, 6-substituted isatins gave a lowerenantiomeric excess of 60% and 61% (Table 3, entries 4 and9). This phenomenon suggests that the Cu(OAc)2/L6 catalyst isthe least selective for the 6-substituted substrates with lowerelectron density in the phenyl rings. Electron-withdrawing sub-stituents (–F, –NO2 or –Cl) at the 5-position demonstrated asimilar tendency in terms of enantioselectivity, although theyunderwent α-hydrophosphonylation more selectively (Table 3,entries 5, 6 and 8). We also found that the introduction of R2

obviously affected this reaction with lower yield and higher ee(Table 3, entry 2). Additionally, an obvious increase of yieldswas observed when using high temperature with lower enantio-meric excesses.

More importantly, dialkyl hydrogen phosphates withdifferent steric hindrances underwent the reaction, givingbetter enantioselectivities (Table 3, entries 10–15). The bulkydiisopropyl phosphite was less reactive and gave compound 3jwith a 76% yield and ee up to 92% (Table 3, entry 10). Isatinsbearing a 5-substituted phenyl group with an electron-donat-ing (–Me) or an electron-withdrawing (–F) group, respectively,gave similar results providing the expected products withhigher yields and better ee values (Table 3, entries 11 and 13).More consistent results were obtained with the 6-substitutedisatin derivatives (–Br, –Cl) reacting with diisopropyl phosphiteto give compounds 3l and 3n (Table 3, entries 12 and 14) inmoderate yields and enantiomeric excesses above 82%.

Conclusions

In summary, we have presented an efficient protocol for theasymmetric α-hydrophosphonylation of isatins in the presenceof a novel fluorous bis(oxazoline). This process was carried outunder mild conditions and gave the corresponding α1-oxi-ndole-α-hydroxyphosphonates bearing a quaternary stereo-center with moderate to high yields and good enantiomericexcesses. The reaction expands the scope of the asymmetric

Table 3 Scope of substratesa

Entry R1 R2 R3 Product Yieldb/% eec/%

1 H H Et 3a 91 8387d 82d

85e 80e

81 f 77 f

2 H Bn Et 3b 69 893 5-Me H Et 3c 63 824 6-Br H Et 3d 73 615 5-F H Et 3e 31 78

60g 71g

6h 5-NO2 H Et 3f 30 7454g 66g

7h 5-MeO H Et 3g 37 9259g 78g

8 5-Cl H Et 3h 68 809 6-Cl H Et 3i 62 6010 H H i-Pr 3j 76 9211 5-Me H i-Pr 3k 82 9212 6-Br H i-Pr 3l 40 9013 5-F H i-Pr 3m 61 8814 6-Cl H i-Pr 3n 59 82

aUnless otherwise specified, all reactions were carried out at roomtemperature with isatin (1.0 mmol), diethyl phosphite (1.2 mmol), L6(0.1 mmol), KF (0.1 mmol) and Cu(OAc)2 (0.1 mmol) in MeOH (1 mL)for 12 hours. b Isolated yield after column chromatography. c The eevalue of the compounds was checked by chiral HPLC using a VenusilCA column. d First reuse of ligand recovered by F-SPE. e Second reuseof ligand recovered by F-SPE. f Third reuse of ligand recovered byF-SPE. g 50 °C needed. h For 24 hours.

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addition with a variety of isatin derivatives. The fluorousligand can be easily recovered and reused at least 3 timeswithout significant loss in its activity.

Acknowledgements

We are grateful for financial support from the Jiangsu NationalScience Foundation of China (BK 20131346).

Notes and references

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