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Cite this: Org. Biomol. Chem., 2014, 12, 5843 Received 4th June 2014, Accepted 24th June 2014
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Fluorous chiral bisoxazolines: application in copper-catalyzed asymmetric α-hydrophosphonylation† Tao Deng, Hongjun Wang and Chun Cai*
DOI: 10.1039/c4ob01144a www.rsc.org/obc
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 a great deal of attention as ligands in coordination chemistry and asymmetric catalysis.3 Bis-oxazoline-based complexes have been successfully applied to the asymmetric catalysis of a wide variety of key organic reactions (e.g. Friedel–Crafts reaction,4 Mukaiyama–Michael reaction5), either with concurrent or independent activation of both reagents.6,7 However, this kind of ligands are always expensive and difficult to recycle after the reactions. It is well known that the oxindole frameworks bearing the C3 quaternary stereocenter are widely distributed in many natural products,8 useful synthetic building blocks, and biologically active molecules9 (Fig. 1). Several different strategies have been reported to directly construct the 3-functionalized3-hydroxy-2-oxindole framework (Scheme 1). The most common protocol is the catalytic Aldol reactions of aldehydes or ketones with isatins.10–12 Another attractive strategy for the synthesis of 3-substituted-3-hydroxy oxindoles was nucleophilic additions to the 3-carbonyl of isatins. Meanwhile, the metal-mediated additions of carbon nucleophiles/equivalents, such as boronic acids,13–15 have been explored. Moreover, a catalytic Henry reaction of isatins with alkanes has also been applied for the construction of the medicinal scaffold.16 Notably, the oxidation of 3-substituted oxindoles itself was proved to be an efficient method to make this core structure.17 Recently, a catalytic decarboxylative [1,2]-addition of isatins has been reported to generate chiral 3-substituted oxindoles.18
Chemical Engineering College, Nanjing University of Science & Technology, Nanjing, Jiangsu 210094, P. R. China. E-mail: [email protected] † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c4ob01144a
This journal is © The Royal Society of Chemistry 2014
Fig. 1 Representative bioactive natural products built on a 3-hydroxy2-oxindole core scaffold.
Scheme 1 Routes framework.
for
the
preparation
of
3-hydoxy-2-oxindole
On the other hand, α-hydroxyphosphonates are an attractive class of biologically active compounds as well as useful synthetic intermediates of α-substituted phosphonyl compounds.19 They also showed potential biological activities and are widely used in pharmaceutical applications.20,21 Thus, it is suspected that quaternary α1-oxindole-α-hydroxy phosphonates, in which the PO(OR)2 and oxindolyl moieties are located at a tetra-substituted carbon atom, potentially have
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Fig. 2
Organic & Biomolecular Chemistry
Selected examples of chiral ligands examined.
some unique bioactivities. The increasing importance of unnatural hydroxyl acids in modification of natural and unnatural products to improve the bioactivity and stability makes the synthesis of hydroxyl phosphonates a significant subject. However, the synthesis of α1-oxindole-α-hydroxy phosphonates has been scarcely investigated.22 As a consequence, the development of environmentally benign practical synthetic routes under mild conditions for accessing these α-hydroxyphosphonates still remains a major goal. Herein, we disclose the copper-catalyzed α-hydrophosphonylation process of readily accessible dialkyl phosphites with isatins using a fluorous bis(oxazoline) ligand (L6) under mild reaction conditions to assemble the valuable 3-functionalized 3-hydroxy-2-oxindoles. Good to excellent enantioselectivities have been obtained under suitable conditions. These features render this synthetic protocol particularly attractive for practical application in drug discovery. The fluorous ligand used can be easily recovered with the F-SPE method.23 Initial optimization of the reaction conditions was carried out for a family of chiral bis(oxazoline) ligands (Fig. 2). Essential results observed for the α-hydrophosphonylation are collected in Table 1. Because of the solubility of the fluorous ligands, we choose DMSO for this reaction. The initial application of Ph-Box L1 resulted in poor enantioselectivity (14%
Table 1
Screening of chiral bis(oxazoline) ligandsa
Entry
Ligand
Yieldb/%
eec/%
1 2 3 4 5 6 7
L1 L2 L3 L4 L5 L6 L7
58 53 49 62 67 70 55
14 33 25 54 52 50 24
a Unless 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 chiral HPLC using a Venusil CA column.
5844 | Org. Biomol. Chem., 2014, 12, 5843–5846
ee, Table 1, entry 1), while the application of C2-Ph-Box ligands (L2 and L323) with diethyl phosphite turned out to be far more enantioselective (Table 1, entries 2 and 3). L3 and L7 have shown similar yields and ee values (Table 1, entries 3 and 7). Although we observed better enantioselectivity in the presence of commercial pybox ligand L4 when compared to other ligands, we still choose the fluorous bis(oxazoline) ligand L6 because of the recyclability. The slightly low level of enantioselectivity still left much to be desired. To address this issue, various bases and solvents were evaluated in association with different copper sources to identify 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 enantioselectivity was achieved for MeOH at room temperature (91% yield, 83% ee, Table 2, entry 16). Low enantioselectivities were observed in CH2Cl2 and isopropanol (Table 2, entries 11 and 13), although the yields were higher than in MeOH. No desired product was obtained with H2O or dioxane as the solvent (Table 2, entries 14 and 15).
Table 2 Optimization α-hydrophosphonylationa
of
the
conditions
for
the
Entry
Solvent
Base
Cu source
Yieldb/%
eec/%
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22d 23e 24 f
THF THF THF THF THF THF DMF DMSO EtOH MeCN i-PrOH EtOAc CH2Cl2 1,4-Dioxane H2O MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH
K3PO4 KOH Et3N DBU K2CO3 KF KF KF KF KF KF KF KF KF KF KF KF KF KF KF KF KF KF KF
Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 CuBr2 Cu(TFA)2 Cu(OTf)2 CuCl2 CuSO4 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2
nr 9 nr nr 14 22 69 70 83 72 92 74 93 nr nr 91 17 nr 26 31 19 23 16 11
— 29 — — 36 13 32 50 34 38 41 62 41 — — 83 39 — 60 75 68 80 85 88
a Unless 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) for 12 hours. b Isolated yield. c The ee value of the compound was checked by chiral HPLC using a Venusil CA column. d The reaction was carried out at 0 °C. e The reaction was carried out at −15 °C. f The reaction was carried out at −30 °C.
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To further explore this reaction, we tested the catalytic abilities of a series of cheap and readily available copper salts. We found that Cu(OAc)2 was the most efficient to catalyze the desired α-hydrophosphonylation in MeOH to provide 3a in 91% yield with enantioselectivity up to 83% (Table 2, entry 16). It was more striking that the product was readily separated by simple extraction of the reaction mixture with ethyl acetate. After removing the solvent, 3a was obtained in high purity, and no further isolation or purification steps were required. In the case of using CuBr2, low yield and enantioselectivity were obtained (Table 2, entry 17). The reaction did not occur with Cu(TFA)2 as the copper source (Table 2, entry 18). In order to minimize a possible nonenantioselective background reaction that could be detrimental to the enantioselectivity, 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 temperature also led to a decreases in yields (Table 2, entries 22–24). The ability to carry out the reaction at room temperature without unnecessary heating of the reaction mixture was an important feature of this catalytic system. Taking this consideration into account and encouraged by the high ee obtained in the synthesis of compound 3a, we studied the applicability of the reaction to other related substrates (Table 3). Having the best ligand and conditions in hand, we tested the scope of the α-hydrophosphonylation to other isatins. As shown in Table 3, a broad range of isatins was investigated to demonstrate the scope of our procedure and also clarify the influence of various substituents differently placed at the phenyl ring. The reaction was general no matter how isatins tolerate both electron-deficient and electron-rich substitutions. To our delight, for most of the substrates, the desired products (3a–3n) were achieved in moderate to high yields in the presence of 10 mol% of the Cu(OAc)2/L6 at room temperature. The isolated yields were substantial and besides such excellent efficiency, many of the studied substrates provided α1-oxindole-α-hydroxyphosphonates with high enantioselectivity (up to 92% ee). The best results in terms of high enantioselectivity have been observed for isatins that possess electron-donating groups (–Me or –OMe) placed at the phenyl ring (Table 3, entries 1, 3 and 7). For all of these substrates, the ee values exceeded 60%. Interestingly, 6-substituted isatins gave a lower enantiomeric excess of 60% and 61% (Table 3, entries 4 and 9). This phenomenon suggests that the Cu(OAc)2/L6 catalyst is the least selective for the 6-substituted substrates with lower electron density in the phenyl rings. Electron-withdrawing substituents (–F, –NO2 or –Cl) at the 5-position demonstrated a similar tendency in terms of enantioselectivity, although they underwent 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 yields was observed when using high temperature with lower enantiomeric excesses.
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Scope of substratesa
Entry
R1
R2
R3
Product
Yieldb/%
eec/%
1
H
H
Et
3a
2 3 4 5
H 5-Me 6-Br 5-F
Bn H H H
Et Et Et Et
3b 3c 3d 3e
6h
5-NO2
H
Et
3f
7h
5-MeO
H
Et
3g
8 9 10 11 12 13 14
5-Cl 6-Cl H 5-Me 6-Br 5-F 6-Cl
H H H H H H H
Et Et i-Pr i-Pr i-Pr i-Pr i-Pr
3h 3i 3j 3k 3l 3m 3n
91 87d 85e 81 f 69 63 73 31 60g 30 54g 37 59g 68 62 76 82 40 61 59
83 82d 80e 77 f 89 82 61 78 71g 74 66g 92 78g 80 60 92 92 90 88 82
a Unless otherwise specified, all reactions were carried out at room temperature 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 ee value of the compounds was checked by chiral HPLC using a Venusil CA column. d First reuse of ligand recovered by F-SPE. e Second reuse of ligand recovered by F-SPE. f Third reuse of ligand recovered by F-SPE. g 50 °C needed. h For 24 hours.
More importantly, dialkyl hydrogen phosphates with different steric hindrances underwent the reaction, giving better enantioselectivities (Table 3, entries 10–15). The bulky diisopropyl phosphite was less reactive and gave compound 3j with a 76% yield and ee up to 92% (Table 3, entry 10). Isatins bearing a 5-substituted phenyl group with an electron-donating (–Me) or an electron-withdrawing (–F) group, respectively, gave similar results providing the expected products with higher yields and better ee values (Table 3, entries 11 and 13). More consistent results were obtained with the 6-substituted isatin derivatives (–Br, –Cl) reacting with diisopropyl phosphite to give compounds 3l and 3n (Table 3, entries 12 and 14) in moderate yields and enantiomeric excesses above 82%.
Conclusions In summary, we have presented an efficient protocol for the asymmetric α-hydrophosphonylation of isatins in the presence of a novel fluorous bis(oxazoline). This process was carried out under mild conditions and gave the corresponding α1-oxindole-α-hydroxyphosphonates bearing a quaternary stereocenter with moderate to high yields and good enantiomeric excesses. The reaction expands the scope of the asymmetric
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addition with a variety of isatin derivatives. The fluorous ligand can be easily recovered and reused at least 3 times without significant loss in its activity.
Acknowledgements Published on 04 July 2014. Downloaded by University of Illinois - Urbana on 23/08/2014 07:36:01.
We are grateful for financial support from the Jiangsu National Science Foundation of China (BK 20131346).
Notes and references 1 D. A. Evans, K. A. Woerpel, M. M. Hinman and M. M. Faul, J. Am. Chem. Soc., 1991, 113, 726. 2 E. J. Corey, N. Imai and H. Y. Zhang, J. Am. Chem. Soc., 1991, 113, 728. 3 H. A. McManusn and P. J. Guiry, Chem. Rev., 2004, 104, 4151. 4 (a) J. R. Gao, H. Wu, B. Xiang, W. B. Yu, L. Han and Y. X. Jia, J. Am. Chem. Soc., 2013, 135, 2983; (b) J. George and B. V. S. Reddy, Org. Biomol. Chem., 2012, 10, 4731. 5 J. George and B. V. S. Reddy, Adv. Synth. Catal., 2013, 355, 383. 6 T. Risgaard, K. V. Gothelf and K. A. Jørgensen, Org. Biomol. Chem., 2003, 1, 153–156. 7 K. Lang, J. Park and S. Hong, J. Org. Chem., 2010, 75, 6424. 8 (a) Y. Kamano, H. P. Zhang, Y. Kchihara, H. Kizu, K. Komiyama and G. R. Pettit, Tetrahedron Lett., 1995, 36, 2783; (b) J. Kohno, Y. Koguchi, M. Nishio, K. Nakao, M. Kuroda, R. Shimizu, T. Ohnuki and S. Komatsubara, J. Org. Chem., 2000, 65, 990; (c) Y. Q. Tang, I. Sattler, R. Thiericke, S. Grabley and X. Z. Feng, Eur. J. Org. Chem., 2001, 261; (d) C. Y. Gan and T. Kam, Tetrahedron Lett., 2009, 50, 1059. 9 (a) C. V. Galliford and K. A. Scheidt, Angew. Chem., Int. Ed., 2007, 46, 8748; (b) J. Kohno, Y. Koguchi, M. Nishio, K. Nakao, M. Juroda, R. Shimizu, T. Ohnuki and S. Komatsubara, J. Org. Chem., 2000, 65, 990; (c) K. A. Brian and M. W. Robert, Org. Lett., 2003, 5, 197; (d) N. Basse, S. Piguel, D. Papapostolou, A. Ferrier-Berthelot, N. Richy, M. Pagano, P. Sarthou, J. Sobczak-Thépot, M. ReboudRavaux and J. Vidal, J. Med. Chem., 2007, 50, 2842; (e) K. Stratmann, R. E. Moore, R. Bonjouklian, J. B. Deeter, G. M. L. Patterson, S. Shaffer, C. D. Smith and T. A. Smitka, J. Am. Chem. Soc., 1994, 116, 9935; (f) J. L. Jimenez, U. Huber, R. E. Moore and G. M. L. Patterson, J. Nat. Prod., 1999, 62, 569; (g) A. Fréchard, N. Fabre, C. Péan, S. Montaut, M. T. Fauvel, P. Rollin and I. Fourasté, Tetra-
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10 11
12 13 14 15 16 17
18 19 20
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Cite this: Org. Biomol. Chem., 2014, 12, 5843 Received 4th June 2014, Accepted 24th June 2014
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Fluorous chiral bisoxazolines: application in copper-catalyzed asymmetric α-hydrophosphonylation† Tao Deng, Hongjun Wang and Chun Cai*
DOI: 10.1039/c4ob01144a www.rsc.org/obc
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 a great deal of attention as ligands in coordination chemistry and asymmetric catalysis.3 Bis-oxazoline-based complexes have been successfully applied to the asymmetric catalysis of a wide variety of key organic reactions (e.g. Friedel–Crafts reaction,4 Mukaiyama–Michael reaction5), either with concurrent or independent activation of both reagents.6,7 However, this kind of ligands are always expensive and difficult to recycle after the reactions. It is well known that the oxindole frameworks bearing the C3 quaternary stereocenter are widely distributed in many natural products,8 useful synthetic building blocks, and biologically active molecules9 (Fig. 1). Several different strategies have been reported to directly construct the 3-functionalized3-hydroxy-2-oxindole framework (Scheme 1). The most common protocol is the catalytic Aldol reactions of aldehydes or ketones with isatins.10–12 Another attractive strategy for the synthesis of 3-substituted-3-hydroxy oxindoles was nucleophilic additions to the 3-carbonyl of isatins. Meanwhile, the metal-mediated additions of carbon nucleophiles/equivalents, such as boronic acids,13–15 have been explored. Moreover, a catalytic Henry reaction of isatins with alkanes has also been applied for the construction of the medicinal scaffold.16 Notably, the oxidation of 3-substituted oxindoles itself was proved to be an efficient method to make this core structure.17 Recently, a catalytic decarboxylative [1,2]-addition of isatins has been reported to generate chiral 3-substituted oxindoles.18
Chemical Engineering College, Nanjing University of Science & Technology, Nanjing, Jiangsu 210094, P. R. China. E-mail: [email protected] † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c4ob01144a
This journal is © The Royal Society of Chemistry 2014
Fig. 1 Representative bioactive natural products built on a 3-hydroxy2-oxindole core scaffold.
Scheme 1 Routes framework.
for
the
preparation
of
3-hydoxy-2-oxindole
On the other hand, α-hydroxyphosphonates are an attractive class of biologically active compounds as well as useful synthetic intermediates of α-substituted phosphonyl compounds.19 They also showed potential biological activities and are widely used in pharmaceutical applications.20,21 Thus, it is suspected that quaternary α1-oxindole-α-hydroxy phosphonates, in which the PO(OR)2 and oxindolyl moieties are located at a tetra-substituted carbon atom, potentially have
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Fig. 2
Organic & Biomolecular Chemistry
Selected examples of chiral ligands examined.
some unique bioactivities. The increasing importance of unnatural hydroxyl acids in modification of natural and unnatural products to improve the bioactivity and stability makes the synthesis of hydroxyl phosphonates a significant subject. However, the synthesis of α1-oxindole-α-hydroxy phosphonates has been scarcely investigated.22 As a consequence, the development of environmentally benign practical synthetic routes under mild conditions for accessing these α-hydroxyphosphonates still remains a major goal. Herein, we disclose the copper-catalyzed α-hydrophosphonylation process of readily accessible dialkyl phosphites with isatins using a fluorous bis(oxazoline) ligand (L6) under mild reaction conditions to assemble the valuable 3-functionalized 3-hydroxy-2-oxindoles. Good to excellent enantioselectivities have been obtained under suitable conditions. These features render this synthetic protocol particularly attractive for practical application in drug discovery. The fluorous ligand used can be easily recovered with the F-SPE method.23 Initial optimization of the reaction conditions was carried out for a family of chiral bis(oxazoline) ligands (Fig. 2). Essential results observed for the α-hydrophosphonylation are collected in Table 1. Because of the solubility of the fluorous ligands, we choose DMSO for this reaction. The initial application of Ph-Box L1 resulted in poor enantioselectivity (14%
Table 1
Screening of chiral bis(oxazoline) ligandsa
Entry
Ligand
Yieldb/%
eec/%
1 2 3 4 5 6 7
L1 L2 L3 L4 L5 L6 L7
58 53 49 62 67 70 55
14 33 25 54 52 50 24
a Unless 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 chiral HPLC using a Venusil CA column.
5844 | Org. Biomol. Chem., 2014, 12, 5843–5846
ee, Table 1, entry 1), while the application of C2-Ph-Box ligands (L2 and L323) with diethyl phosphite turned out to be far more enantioselective (Table 1, entries 2 and 3). L3 and L7 have shown similar yields and ee values (Table 1, entries 3 and 7). Although we observed better enantioselectivity in the presence of commercial pybox ligand L4 when compared to other ligands, we still choose the fluorous bis(oxazoline) ligand L6 because of the recyclability. The slightly low level of enantioselectivity still left much to be desired. To address this issue, various bases and solvents were evaluated in association with different copper sources to identify 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 enantioselectivity was achieved for MeOH at room temperature (91% yield, 83% ee, Table 2, entry 16). Low enantioselectivities were observed in CH2Cl2 and isopropanol (Table 2, entries 11 and 13), although the yields were higher than in MeOH. No desired product was obtained with H2O or dioxane as the solvent (Table 2, entries 14 and 15).
Table 2 Optimization α-hydrophosphonylationa
of
the
conditions
for
the
Entry
Solvent
Base
Cu source
Yieldb/%
eec/%
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22d 23e 24 f
THF THF THF THF THF THF DMF DMSO EtOH MeCN i-PrOH EtOAc CH2Cl2 1,4-Dioxane H2O MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH
K3PO4 KOH Et3N DBU K2CO3 KF KF KF KF KF KF KF KF KF KF KF KF KF KF KF KF KF KF KF
Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 CuBr2 Cu(TFA)2 Cu(OTf)2 CuCl2 CuSO4 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2
nr 9 nr nr 14 22 69 70 83 72 92 74 93 nr nr 91 17 nr 26 31 19 23 16 11
— 29 — — 36 13 32 50 34 38 41 62 41 — — 83 39 — 60 75 68 80 85 88
a Unless 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) for 12 hours. b Isolated yield. c The ee value of the compound was checked by chiral HPLC using a Venusil CA column. d The reaction was carried out at 0 °C. e The reaction was carried out at −15 °C. f The reaction was carried out at −30 °C.
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To further explore this reaction, we tested the catalytic abilities of a series of cheap and readily available copper salts. We found that Cu(OAc)2 was the most efficient to catalyze the desired α-hydrophosphonylation in MeOH to provide 3a in 91% yield with enantioselectivity up to 83% (Table 2, entry 16). It was more striking that the product was readily separated by simple extraction of the reaction mixture with ethyl acetate. After removing the solvent, 3a was obtained in high purity, and no further isolation or purification steps were required. In the case of using CuBr2, low yield and enantioselectivity were obtained (Table 2, entry 17). The reaction did not occur with Cu(TFA)2 as the copper source (Table 2, entry 18). In order to minimize a possible nonenantioselective background reaction that could be detrimental to the enantioselectivity, 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 temperature also led to a decreases in yields (Table 2, entries 22–24). The ability to carry out the reaction at room temperature without unnecessary heating of the reaction mixture was an important feature of this catalytic system. Taking this consideration into account and encouraged by the high ee obtained in the synthesis of compound 3a, we studied the applicability of the reaction to other related substrates (Table 3). Having the best ligand and conditions in hand, we tested the scope of the α-hydrophosphonylation to other isatins. As shown in Table 3, a broad range of isatins was investigated to demonstrate the scope of our procedure and also clarify the influence of various substituents differently placed at the phenyl ring. The reaction was general no matter how isatins tolerate both electron-deficient and electron-rich substitutions. To our delight, for most of the substrates, the desired products (3a–3n) were achieved in moderate to high yields in the presence of 10 mol% of the Cu(OAc)2/L6 at room temperature. The isolated yields were substantial and besides such excellent efficiency, many of the studied substrates provided α1-oxindole-α-hydroxyphosphonates with high enantioselectivity (up to 92% ee). The best results in terms of high enantioselectivity have been observed for isatins that possess electron-donating groups (–Me or –OMe) placed at the phenyl ring (Table 3, entries 1, 3 and 7). For all of these substrates, the ee values exceeded 60%. Interestingly, 6-substituted isatins gave a lower enantiomeric excess of 60% and 61% (Table 3, entries 4 and 9). This phenomenon suggests that the Cu(OAc)2/L6 catalyst is the least selective for the 6-substituted substrates with lower electron density in the phenyl rings. Electron-withdrawing substituents (–F, –NO2 or –Cl) at the 5-position demonstrated a similar tendency in terms of enantioselectivity, although they underwent 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 yields was observed when using high temperature with lower enantiomeric excesses.
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Communication Table 3
Scope of substratesa
Entry
R1
R2
R3
Product
Yieldb/%
eec/%
1
H
H
Et
3a
2 3 4 5
H 5-Me 6-Br 5-F
Bn H H H
Et Et Et Et
3b 3c 3d 3e
6h
5-NO2
H
Et
3f
7h
5-MeO
H
Et
3g
8 9 10 11 12 13 14
5-Cl 6-Cl H 5-Me 6-Br 5-F 6-Cl
H H H H H H H
Et Et i-Pr i-Pr i-Pr i-Pr i-Pr
3h 3i 3j 3k 3l 3m 3n
91 87d 85e 81 f 69 63 73 31 60g 30 54g 37 59g 68 62 76 82 40 61 59
83 82d 80e 77 f 89 82 61 78 71g 74 66g 92 78g 80 60 92 92 90 88 82
a Unless otherwise specified, all reactions were carried out at room temperature 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 ee value of the compounds was checked by chiral HPLC using a Venusil CA column. d First reuse of ligand recovered by F-SPE. e Second reuse of ligand recovered by F-SPE. f Third reuse of ligand recovered by F-SPE. g 50 °C needed. h For 24 hours.
More importantly, dialkyl hydrogen phosphates with different steric hindrances underwent the reaction, giving better enantioselectivities (Table 3, entries 10–15). The bulky diisopropyl phosphite was less reactive and gave compound 3j with a 76% yield and ee up to 92% (Table 3, entry 10). Isatins bearing a 5-substituted phenyl group with an electron-donating (–Me) or an electron-withdrawing (–F) group, respectively, gave similar results providing the expected products with higher yields and better ee values (Table 3, entries 11 and 13). More consistent results were obtained with the 6-substituted isatin derivatives (–Br, –Cl) reacting with diisopropyl phosphite to give compounds 3l and 3n (Table 3, entries 12 and 14) in moderate yields and enantiomeric excesses above 82%.
Conclusions In summary, we have presented an efficient protocol for the asymmetric α-hydrophosphonylation of isatins in the presence of a novel fluorous bis(oxazoline). This process was carried out under mild conditions and gave the corresponding α1-oxindole-α-hydroxyphosphonates bearing a quaternary stereocenter with moderate to high yields and good enantiomeric excesses. The reaction expands the scope of the asymmetric
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Organic & Biomolecular Chemistry
addition with a variety of isatin derivatives. The fluorous ligand can be easily recovered and reused at least 3 times without significant loss in its activity.
Acknowledgements Published on 04 July 2014. Downloaded by University of Illinois - Urbana on 23/08/2014 07:36:01.
We are grateful for financial support from the Jiangsu National Science Foundation of China (BK 20131346).
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