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Cite this: Org. Biomol. Chem., 2014, 12, 406 Received 10th October 2013, Accepted 8th November 2013
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Ylide mediated carbonyl homologations for the preparation of isatin derivatives† Christina T. Lollar,a Katherine M. Krenek,a Kevin J. Bruemmera and Alexander R. Lippert*a,b
DOI: 10.1039/c3ob42024h www.rsc.org/obc
An exceptionally mild method for the preparation of isatin derivatives has been developed using a sulfur ylide mediated carbonyl homologation sequence starting from anthranilic acid precursors. This method proceeds at ambient temperature via a sulfur ylide intermediate without the need for protection of the amine or chromatographic isolation of the intermediate ylide. Gentle oxidation of the sulfur ylides provides isatin derivatives with N–H, N-alkyl, N-aryl substitution, electron-rich and electron-poor aromatic rings, and heterocyclic aromatic systems. We anticipate that this method will greatly expand the accessibility of complex isatin derivatives.
Isatin (1H-indol-2,3-dione) is an oxidized indole derivative that is endogenously present in mammalian blood, urine, and tissue.1–3 Isatin and its derivatives display rich biological activity,4,5 having been shown to inhibit monoamine oxidase enzymes,6 attenuate natriuretic peptide-stimulated7 and nitric oxide-stimulated cyclic guanosine monophosphate release,8 and act as sedatives,9 anti-inflammatory,10 antiviral,11 and anticancer,12–15 agents. In addition, isatin is endowed with versatile reactivity, and is often employed as a synthetic intermediate.16,17 The great potential of this important pharmacophore and synthetic building block is ultimately limited by the harsh conditions needed for its preparation. Classical methods for the synthesis of isatin and its derivatives, including the Sandmeyer,18–20 Stollé,21–23 Martinet,24,25 and the Gassman26 procedures, typically require harsh reagents, elevated temperatures, and non-ideal solvents. Additionally, most of these methods do not allow for easy control of regiochemistry, limiting the substrate scope of the reaction. Recently, several improved protocols have been put forth including copper-catalyzed C–H oxidations,27–29
a Department of Chemistry, Southern Methodist University, Dallas, TX 75275-0314, USA. E-mail: [email protected]; Fax: +1-214-768-4089; Tel: +1-214-768-2482 b Center for Drug Discovery, Design, and Delivery (CD4), Southern Methodist University, Dallas, TX 75275-0314, USA. E-mail: [email protected]; Fax: +1-214-768-4089; Tel: +1-214-768-2482 † Electronic supplementary information (ESI) available: Experimental procedures, 1H NMR, 13C NMR, and HRMS data. See DOI: 10.1039/c3ob42024h
406 | Org. Biomol. Chem., 2014, 12, 406–409
selenium-mediated oxidations,30 indole oxidations,31 arynebased methods,32 Sandmeyer modifications,33 and molecular elaboration of simple isatin synthons.34 Many of these methods, however, still display limited substrate scope or harsh reaction conditions. As such, there is a pressing need for safe, mild, and versatile strategies to prepare isatin derivatives. Sulfur ylides have received increasing attention due to their unique modes of reactivity, including epoxidations,35 aziridinations,36 cyclopropanations,37 and rearrangements.38 Resonance stabilized sulfur ylides can be readily acylated using a variety of coupling reagents, and oxidation of the carbon– sulfur bond leads to dicarbonyl derivatives,39,40 most notably α-ketoacids used in α-ketoacid-hydroxylamine peptide ligation reactions.41 We envisioned that the mild conditions used in sulfur ylide mediated carbonyl homologations of this type could provide ready access to isatin derivatives from anthranilic acid precursors. Herein, we report an efficient and mild preparation of the isatin moiety that utilizes an ylide acylation/ oxidation sequence to affect an overall carbonyl homologation with concomitant amide bond formation (Scheme 1). This procedure offers significant advantages over classical methods including ambient temperature, mild reagents, and perfect regiochemical control.
Scheme 1
Mild sulfur ylide mediated preparation of isatin derivatives.
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ð1Þ
We began by exploring the conversion of anthranilic acid into the α-keto-cyanosulfur ylide 2a (Table 1). Our strategy was to form a cyanosulfur ylide in situ from the corresponding sulfonium bromide salt 1. This salt is easily prepared from the neat reaction of dimethyl sulfide and bromoacetonitrile (eqn (1)). Stirring overnight at ambient temperature yields a pure white solid that is easily handled and stable for months when stored under nitrogen at 4 °C. Our initial concern was that the unprotected amine of the anthranilic acid would compete with the cyanosulfur ylide formed in situ from 1 in the acylation reaction. Indeed, we found that using 1.2 equivalents of the sulfonium bromide salt 1 lead to an unoptimized 60% yield of isatin due to formation of a dimerized side product (Table 1, entry 1). Fortunately, simply using three equivalents of 1 effectively suppressed this side reaction, providing the coupled α-keto-cyanosulfur ylide product 2a in an efficient manner (Table 1, entry 2). Using the appropriate work-up, the coupled ylide product 2a could be obtained essentially pure except for the presence of 2 equivalents of the unreacted cyanosulfur ylide derived from the sulfonium bromide salt 1. We found that, unlike other resonance-stabilized α-ketocyanosulfur ylides,36,37 these α-keto-γ-amino-cyanosulfur ylides spontaneously oxidized on silica gel forming a mixture of isatins and other fluorescent oxidation products. Hence, the ylides were directly oxidized without further chromatographic purification. Treatment with 1.5 equivalents of Oxone (2KOOSO3· KHSO4·K2SO4)42 for 10 minutes in 2 : 1 THF–H2O provided the isatin 3a in 85% yield over the two step protocol (Table 1,
Table 1 Reaction optimization of sulfur ylide mediated carbonyl homologation of anthranilic acid to isatin 3aa
Entry
Solvent A
Solvent B
Yieldb
1c 2 3 4 5 6 7 8 9 10
CH2Cl2 CH2Cl2 DMF THF CH3CN CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2
2 : 1 THF–H2O 2 : 1 THF–H2O 2 : 1 THF–H2O 2 : 1 THF–H2O 2 : 1 THF–H2O 2 : 1 acetone–H2O 4 : 1 H2O–DMF 9 : 1 H2O–DMF DMF 9 : 1 500 mM PBS pH 7–DMF
60% 85% 59% 75% 40% 68% 75% 81% 61% 26%
a Reactions were performed with anthranilic acid (1 mmol), 1 (3 mmol), HBTU (1.2 mmol), and DIPEA (3 mmol) in solvent A (10 mL), then Oxone (1.5 mmol) in solvent B (20 mL). b Isolated yields. c Reaction was performed with 1.2 mmol 1.
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entry 2). The ylide coupling reaction was found to be optimal in CH2Cl2, but also tolerated DMF, THF, and CH3CN (Table 1, entries 3–5), albeit with reduced yields at the measured time points. We next explored the conditions of the oxidation reaction using the sulfur ylide 2a formed in CH2Cl2. The oxidation reaction proceeded best in H2O and an organic co-solvent such as THF, DMF, or acetone, which effectively solubilized the Oxone salts and the ylide (Table 1, entries 1, 6–8). Even in the absence of added H2O, Oxone could still affect ylide oxidation in DMF, providing the isolated isatin in 61% (Table 1, entry 9). It is important to note that the pH of the reaction under these conditions is in the range of 2–3, due to the acidity of the Oxone salt mixture. Attempts to buffer to pH 7 resulted in a significant drop in yield (Table 1, entry 10). Having found optimal conditions, we next explored the scope of the reaction across a panel of anthranilic acid derivatives. The reaction proceeded efficiently with N–H, N-methyl, and N-phenyl substituents, providing the corresponding isatins in 85%, 60%, and 76% yields, respectively (Table 2, entries 1–3). Electron-poor aromatic rings, including 5-Br-, 4-Cl-, 4-F-, and 2-CF3- substituted anthranilic acids, were good substrates for this reaction sequence, cleanly affording the halogenated isatin products (Table 2, entries 4–7). Electron rich aromatic systems, including 6-Me- and 4-MeO- substituted anthranilic acids also yielded the corresponding isatins (Table 2, entries 8 and 10). We found, however, that 3-Meanthranilic acid produced isatin 3i in a reduced yield, indicating that steric hindrance at the 6-position attenuates the reaction efficiency, most likely during the ylide formation step (Table 2, entry 9). Finally, we utilized our ylide acylation/oxidation sequence on an amino nicotinic acid substrate (Table 2, entry 11) and were pleased to find that aza-isatin derivatives could be readily prepared using this method. In all cases, the two-step sequence proceeded without chromatographic purification of the ylides 2a–k, and most of the ylides were obtained in good purity after a simple aqueous work-up, with the most significant impurity being the unreacted cyanosulfur ylide derived from 1. However, some of the ylides, including the 3-Me- and 4-MeO- sulfur ylides 2i and 2j, provided mixtures after the sulfur ylide coupling step, indicating that activated carboxylates of anthranilic acids with steric congestion or electron rich aromatic systems are less efficacious as ylide acylating agents. In summary, we have developed a new, mild, and efficient preparation of isatin derivatives using a sulfur ylide mediated carbonyl homologation sequence. The sulfonium bromide 1 is readily prepared, easily handled, and the ylide formed in situ can be rapidly and efficiently coupled to anthranilic acid derivatives using mild reagents without the need for protection of the amino group. The sulfur ylides 2a–k can be directly oxidized without chromatographic purification. Treatment with Oxone for 10 minutes at room temperature provides the isatins 3a–k, highlighting a wide substrate scope for this easy and versatile isatin-forming process. We expect that this streamlined procedure will allow access to isatin derivatives that would be difficult to prepare using classical methods.
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Table 2 Substrate scope of sulfur ylide mediated carbonyl homologation of anthranilic acids to isatins 3a–3ka
Acknowledgements
1
85%
2
60%
We gratefully acknowledge Southern Methodist University (start-up funds to A.R.L.) for providing financial support for this project. We thank the Engaged Learning program at Southern Methodist University (research funds to C.T.L.) for providing additional funding. C.T.L. and K.J.B. are supported by a Hamilton Undergraduate Research Scholarship. We thank Maciej Kukula of the Shimadzu Center for Advanced Analytical Chemistry at the University of Texas at Arlington for acquiring high-resolution mass spectrometry data. Sara Merrikhihaghi provided experimental assistance for the characterization of compounds.
3
76%
Notes and references
Entry
Yield
Isatin
Yieldb,c
4
69%
5
60%
6
81%
7
91%
8
88%
9
49%
10
70%
11
54%
a Reactions were performed with anthranilic acid (1 mmol), 1 (3 mmol), HBTU (1.2 mmol), and DIPEA (3 mmol) in CH2Cl2 (10 mL), then Oxone (1.5 mmol) in 2 : 1 THF–H2O (20 mL). b Isolated yields. c Reported yields are the average of two independent experiments.
408 | Org. Biomol. Chem., 2014, 12, 406–409
1 N. Hamaue, N. Yamazaki, M. Minami, T. Endo, M. Hirahuji, Y. Monma and H. Togashi, Gen. Pharmacol., 1998, 30, 387. 2 P. J. Watkins, A. Clow, V. Glover, J. Halket, A. Przyborowska and M. Sandler, Neurochem. Int., 1990, 17, 321. 3 H. Xu, D. Wang, W. Zhang, W. Zhu, K. Yamamoto and L. Jin, Anal. Chim. Acta, 2006, 577, 207. 4 J. M. da Silva, S. J. Garden and A. C. Pinto, J. Braz. Chem. Soc., 2001, 12, 273. 5 A. Medvedev, N. Igosheva, M. Crumeyrolle-Arias and V. Glover, Stress, 2005, 8, 175. 6 V. Glover, J. M. Halket, P. J. Watkins, A. Clow, B. L. Goodwin and M. Sandler, J. Neurochem., 1988, 51, 656. 7 A. E. Medvedev, M. Sandler and V. Glover, Life Sci., 1998, 62, 2391. 8 A. Medvedev, O. Bussygyna, N. Pyatakova, V. Glover and I. Severina, Biochem. Pharmacol., 2002, 63, 763. 9 G. Zapata-Sudo, L. B. Pontes, D. Gabriel, T. C. F. Mendes, N. M. Ribeiro, A. C. Pinto, M. M. Trachez and R. T. Sudo, Pharmacol., Biochem. Behav., 2007, 86, 678. 10 M. E. Matheus, F. A. Violante, S. J. Garden, A. C. Pinto and P. D. Fernandes, Eur. J. Pharmacol., 2007, 556, 200. 11 P. Selvam, M. Chandramohan, E. De Clercq, M. Witvrouw and C. Pannecouque, Eur. J. Pharm. Sci., 2001, 14, 313. 12 K. L. Vine, J. M. Locke, M. Ranson, K. Benkendorff, S. G. Pyne and J. B. Bremner, Bioorg. Med. Chem., 2007, 15, 931. 13 M. D. Hall, N. K. Salam, J. L. Hellawell, H. M. Fales, C. B. Kensler, J. A. Ludwig, G. Szakács, D. E. Hibbs and M. M. Gottesman, J. Med. Chem., 2009, 52, 3191. 14 V. I. Chandran, L. Matesic, J. M. Locke, D. Skropeta, M. Ranson and K. L. Vine, Cancer Lett., 2012, 316, 151. 15 L. Matesic, J. M. Locke, K. L. Vine, M. Ranson, J. B. Bremner and D. Skropeta, Tetrahedron, 2012, 68, 6810. 16 W. C. Sumpter, Chem. Rev., 1943, 34, 393. 17 G. S. Singh and Z. Y. Desta, Chem. Rev., 2012, 112, 6104. 18 T. Sandmeyer, Helv. Chim. Acta, 1919, 2, 234.
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19 S. J. Garden, J. C. Torres, A. A. Ferreira, R. B. Silva and A. C. Pinto, Tetrahedron Lett., 1997, 38, 1501. 20 G. W. Rewcastle, H. S. Sutherland, C. A. Weir, A. G. Blackburn and W. A. Denny, Tetrahedron Lett., 2005, 46, 8719. 21 R. Stollé, R. Bergdoll, M. Luther, A. Auerhahn and W. Wacker, J. Prakt. Chem., 1930, 128, 1. 22 W. J. Welstead, H. W. Moran, H. F. Stauffer, L. B. Turnbull and L. F. Sancilio, J. Med. Chem., 1979, 22, 1074. 23 W. M. Bryant III, G. F. Huhn, J. H. Jensen, M. E. Pierce and C. Stammbach, Synth. Commun., 1993, 23, 1617. 24 K. C. Rice, B. J. Boone, A. B. Rubin and T. J. Rauls, J. Med. Chem., 1976, 19, 887. 25 P. Hewawasam and N. A. Meanwell, Tetrahedron Lett., 1994, 35, 7303. 26 P. G. Gassman, B. W. Cue Jr. and T. Y. Luh, J. Org. Chem., 1977, 42, 1344. 27 B. X. Tang, R. J. Song, C. Y. Wu, Y. Liu, M. B. Zhou, W. T. Wei, G. B. Deng, D. L. Yin and J. H. Li, J. Am. Chem. Soc., 2010, 132, 8900. 28 T. Liu, H. Yang, Y. Jiang and H. Fu, Adv. Synth. Catal., 2013, 355, 1169. 29 J. Sun, B. Liu and B. Xu, RSC Adv., 2013, 3, 5824. 30 Y. Liu, H. Chen, X. Hu, W. Zhou and G. J. Deng, Eur. J. Org. Chem., 2013, 4229.
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Communication
31 R. Sriram, C. N. S. S. P. Kumar, N. Raghunandan, V. Ramesh, M. Sarangapani and V. J. Rao, Synth. Commun., 2012, 42, 3419. 32 D. C. Rogness and R. C. Larock, J. Org. Chem., 2011, 76, 4980. 33 L. L. Klein and M. D. Tufano, Tetrahedron Lett., 2013, 54, 1008. 34 Y. C. Liu, C. J. Ye, Q. Chen and G. F. Yang, Tetrahedron Lett., 2013, 54, 949. 35 V. K. Aggarwal and C. L. Winn, Acc. Chem. Res., 2004, 37, 611. 36 O. Illa, M. Namutebi, C. Saha, M. Ostovar, C. C. Chen, M. F. Haddow, S. Nocquet-Thibault, M. Lusi, E. M. McGarrigle and V. K. Aggarwal, J. Am. Chem. Soc., 2013, 135, 11951. 37 V. K. Aggarwal and E. Grange, Chem.–Eur. J., 2006, 12, 568. 38 V. Boyarskikh, A. Nyong and J. D. Rainier, Angew. Chem., Int. Ed., 2008, 47, 5374–5377. 39 A. R. Lippert, J. Kaeobamrung and J. W. Bode, J. Am. Chem. Soc., 2006, 128, 14738. 40 L. Ju, A. R. Lippert and J. W. Bode, J. Am. Chem. Soc., 2008, 130, 4253. 41 L. Ju and J. W. Bode, Org. Biomol. Chem., 2009, 7, 2259. 42 1.5 equivalents of Oxone corresponds to 3 equivalents of the active peroxymonosulfate.
Org. Biomol. Chem., 2014, 12, 406–409 | 409
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Cite this: Org. Biomol. Chem., 2014, 12, 406 Received 10th October 2013, Accepted 8th November 2013
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Ylide mediated carbonyl homologations for the preparation of isatin derivatives† Christina T. Lollar,a Katherine M. Krenek,a Kevin J. Bruemmera and Alexander R. Lippert*a,b
DOI: 10.1039/c3ob42024h www.rsc.org/obc
An exceptionally mild method for the preparation of isatin derivatives has been developed using a sulfur ylide mediated carbonyl homologation sequence starting from anthranilic acid precursors. This method proceeds at ambient temperature via a sulfur ylide intermediate without the need for protection of the amine or chromatographic isolation of the intermediate ylide. Gentle oxidation of the sulfur ylides provides isatin derivatives with N–H, N-alkyl, N-aryl substitution, electron-rich and electron-poor aromatic rings, and heterocyclic aromatic systems. We anticipate that this method will greatly expand the accessibility of complex isatin derivatives.
Isatin (1H-indol-2,3-dione) is an oxidized indole derivative that is endogenously present in mammalian blood, urine, and tissue.1–3 Isatin and its derivatives display rich biological activity,4,5 having been shown to inhibit monoamine oxidase enzymes,6 attenuate natriuretic peptide-stimulated7 and nitric oxide-stimulated cyclic guanosine monophosphate release,8 and act as sedatives,9 anti-inflammatory,10 antiviral,11 and anticancer,12–15 agents. In addition, isatin is endowed with versatile reactivity, and is often employed as a synthetic intermediate.16,17 The great potential of this important pharmacophore and synthetic building block is ultimately limited by the harsh conditions needed for its preparation. Classical methods for the synthesis of isatin and its derivatives, including the Sandmeyer,18–20 Stollé,21–23 Martinet,24,25 and the Gassman26 procedures, typically require harsh reagents, elevated temperatures, and non-ideal solvents. Additionally, most of these methods do not allow for easy control of regiochemistry, limiting the substrate scope of the reaction. Recently, several improved protocols have been put forth including copper-catalyzed C–H oxidations,27–29
a Department of Chemistry, Southern Methodist University, Dallas, TX 75275-0314, USA. E-mail: [email protected]; Fax: +1-214-768-4089; Tel: +1-214-768-2482 b Center for Drug Discovery, Design, and Delivery (CD4), Southern Methodist University, Dallas, TX 75275-0314, USA. E-mail: [email protected]; Fax: +1-214-768-4089; Tel: +1-214-768-2482 † Electronic supplementary information (ESI) available: Experimental procedures, 1H NMR, 13C NMR, and HRMS data. See DOI: 10.1039/c3ob42024h
406 | Org. Biomol. Chem., 2014, 12, 406–409
selenium-mediated oxidations,30 indole oxidations,31 arynebased methods,32 Sandmeyer modifications,33 and molecular elaboration of simple isatin synthons.34 Many of these methods, however, still display limited substrate scope or harsh reaction conditions. As such, there is a pressing need for safe, mild, and versatile strategies to prepare isatin derivatives. Sulfur ylides have received increasing attention due to their unique modes of reactivity, including epoxidations,35 aziridinations,36 cyclopropanations,37 and rearrangements.38 Resonance stabilized sulfur ylides can be readily acylated using a variety of coupling reagents, and oxidation of the carbon– sulfur bond leads to dicarbonyl derivatives,39,40 most notably α-ketoacids used in α-ketoacid-hydroxylamine peptide ligation reactions.41 We envisioned that the mild conditions used in sulfur ylide mediated carbonyl homologations of this type could provide ready access to isatin derivatives from anthranilic acid precursors. Herein, we report an efficient and mild preparation of the isatin moiety that utilizes an ylide acylation/ oxidation sequence to affect an overall carbonyl homologation with concomitant amide bond formation (Scheme 1). This procedure offers significant advantages over classical methods including ambient temperature, mild reagents, and perfect regiochemical control.
Scheme 1
Mild sulfur ylide mediated preparation of isatin derivatives.
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ð1Þ
We began by exploring the conversion of anthranilic acid into the α-keto-cyanosulfur ylide 2a (Table 1). Our strategy was to form a cyanosulfur ylide in situ from the corresponding sulfonium bromide salt 1. This salt is easily prepared from the neat reaction of dimethyl sulfide and bromoacetonitrile (eqn (1)). Stirring overnight at ambient temperature yields a pure white solid that is easily handled and stable for months when stored under nitrogen at 4 °C. Our initial concern was that the unprotected amine of the anthranilic acid would compete with the cyanosulfur ylide formed in situ from 1 in the acylation reaction. Indeed, we found that using 1.2 equivalents of the sulfonium bromide salt 1 lead to an unoptimized 60% yield of isatin due to formation of a dimerized side product (Table 1, entry 1). Fortunately, simply using three equivalents of 1 effectively suppressed this side reaction, providing the coupled α-keto-cyanosulfur ylide product 2a in an efficient manner (Table 1, entry 2). Using the appropriate work-up, the coupled ylide product 2a could be obtained essentially pure except for the presence of 2 equivalents of the unreacted cyanosulfur ylide derived from the sulfonium bromide salt 1. We found that, unlike other resonance-stabilized α-ketocyanosulfur ylides,36,37 these α-keto-γ-amino-cyanosulfur ylides spontaneously oxidized on silica gel forming a mixture of isatins and other fluorescent oxidation products. Hence, the ylides were directly oxidized without further chromatographic purification. Treatment with 1.5 equivalents of Oxone (2KOOSO3· KHSO4·K2SO4)42 for 10 minutes in 2 : 1 THF–H2O provided the isatin 3a in 85% yield over the two step protocol (Table 1,
Table 1 Reaction optimization of sulfur ylide mediated carbonyl homologation of anthranilic acid to isatin 3aa
Entry
Solvent A
Solvent B
Yieldb
1c 2 3 4 5 6 7 8 9 10
CH2Cl2 CH2Cl2 DMF THF CH3CN CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2
2 : 1 THF–H2O 2 : 1 THF–H2O 2 : 1 THF–H2O 2 : 1 THF–H2O 2 : 1 THF–H2O 2 : 1 acetone–H2O 4 : 1 H2O–DMF 9 : 1 H2O–DMF DMF 9 : 1 500 mM PBS pH 7–DMF
60% 85% 59% 75% 40% 68% 75% 81% 61% 26%
a Reactions were performed with anthranilic acid (1 mmol), 1 (3 mmol), HBTU (1.2 mmol), and DIPEA (3 mmol) in solvent A (10 mL), then Oxone (1.5 mmol) in solvent B (20 mL). b Isolated yields. c Reaction was performed with 1.2 mmol 1.
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entry 2). The ylide coupling reaction was found to be optimal in CH2Cl2, but also tolerated DMF, THF, and CH3CN (Table 1, entries 3–5), albeit with reduced yields at the measured time points. We next explored the conditions of the oxidation reaction using the sulfur ylide 2a formed in CH2Cl2. The oxidation reaction proceeded best in H2O and an organic co-solvent such as THF, DMF, or acetone, which effectively solubilized the Oxone salts and the ylide (Table 1, entries 1, 6–8). Even in the absence of added H2O, Oxone could still affect ylide oxidation in DMF, providing the isolated isatin in 61% (Table 1, entry 9). It is important to note that the pH of the reaction under these conditions is in the range of 2–3, due to the acidity of the Oxone salt mixture. Attempts to buffer to pH 7 resulted in a significant drop in yield (Table 1, entry 10). Having found optimal conditions, we next explored the scope of the reaction across a panel of anthranilic acid derivatives. The reaction proceeded efficiently with N–H, N-methyl, and N-phenyl substituents, providing the corresponding isatins in 85%, 60%, and 76% yields, respectively (Table 2, entries 1–3). Electron-poor aromatic rings, including 5-Br-, 4-Cl-, 4-F-, and 2-CF3- substituted anthranilic acids, were good substrates for this reaction sequence, cleanly affording the halogenated isatin products (Table 2, entries 4–7). Electron rich aromatic systems, including 6-Me- and 4-MeO- substituted anthranilic acids also yielded the corresponding isatins (Table 2, entries 8 and 10). We found, however, that 3-Meanthranilic acid produced isatin 3i in a reduced yield, indicating that steric hindrance at the 6-position attenuates the reaction efficiency, most likely during the ylide formation step (Table 2, entry 9). Finally, we utilized our ylide acylation/oxidation sequence on an amino nicotinic acid substrate (Table 2, entry 11) and were pleased to find that aza-isatin derivatives could be readily prepared using this method. In all cases, the two-step sequence proceeded without chromatographic purification of the ylides 2a–k, and most of the ylides were obtained in good purity after a simple aqueous work-up, with the most significant impurity being the unreacted cyanosulfur ylide derived from 1. However, some of the ylides, including the 3-Me- and 4-MeO- sulfur ylides 2i and 2j, provided mixtures after the sulfur ylide coupling step, indicating that activated carboxylates of anthranilic acids with steric congestion or electron rich aromatic systems are less efficacious as ylide acylating agents. In summary, we have developed a new, mild, and efficient preparation of isatin derivatives using a sulfur ylide mediated carbonyl homologation sequence. The sulfonium bromide 1 is readily prepared, easily handled, and the ylide formed in situ can be rapidly and efficiently coupled to anthranilic acid derivatives using mild reagents without the need for protection of the amino group. The sulfur ylides 2a–k can be directly oxidized without chromatographic purification. Treatment with Oxone for 10 minutes at room temperature provides the isatins 3a–k, highlighting a wide substrate scope for this easy and versatile isatin-forming process. We expect that this streamlined procedure will allow access to isatin derivatives that would be difficult to prepare using classical methods.
Org. Biomol. Chem., 2014, 12, 406–409 | 407
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Table 2 Substrate scope of sulfur ylide mediated carbonyl homologation of anthranilic acids to isatins 3a–3ka
Acknowledgements
1
85%
2
60%
We gratefully acknowledge Southern Methodist University (start-up funds to A.R.L.) for providing financial support for this project. We thank the Engaged Learning program at Southern Methodist University (research funds to C.T.L.) for providing additional funding. C.T.L. and K.J.B. are supported by a Hamilton Undergraduate Research Scholarship. We thank Maciej Kukula of the Shimadzu Center for Advanced Analytical Chemistry at the University of Texas at Arlington for acquiring high-resolution mass spectrometry data. Sara Merrikhihaghi provided experimental assistance for the characterization of compounds.
3
76%
Notes and references
Entry
Yield
Isatin
Yieldb,c
4
69%
5
60%
6
81%
7
91%
8
88%
9
49%
10
70%
11
54%
a Reactions were performed with anthranilic acid (1 mmol), 1 (3 mmol), HBTU (1.2 mmol), and DIPEA (3 mmol) in CH2Cl2 (10 mL), then Oxone (1.5 mmol) in 2 : 1 THF–H2O (20 mL). b Isolated yields. c Reported yields are the average of two independent experiments.
408 | Org. Biomol. Chem., 2014, 12, 406–409
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