A mild, high yielding approach to C-3 hydroxylated oxindoles using catalytic quantities of
tetrabutylammonium fluoride and air as the stoicheiometric oxidant is reported over a wide
range of substitution patterns

Beatriz Fernandez D.-R. (7162838)

Benjamin Buckley (1249668)

Tetrahedron Letters

English

Benjamin R. Buckley

Beatriz Fernández D.-R.

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A catalytic, mild and efficient protocol for the C-3 aerial hydroxylation of oxindoles

Loughborough University Institutional Repository

   This item was submitted to Loughborough’s Institutional Repository (https://dspace.lboro.ac.uk/) by the author and is made available under the following Creative Commons Licence conditions.      For the full text of this licence, please go to: http://creativecommons.org/licenses/by-nc-nd/2.5/  Graphical Abstract To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered. A catalytic, mild and efficient protocol for the C-3 aerial hydroxylation of oxindoles  Benjamin R. Buckley,* Beatriz Fernández D.-R. NMeOHMeMeONMeOOHMeMeOTBAF (20 mol%)THF, air, rt, 20 h89%+ 15 other examplesNR'OOHRR''R = Me, Bn, allyl, arylR' = Me, Bn, Ts, BocR'' = H, Me, OMe, FHH HH Leave this area blank for abstract info.  ∗ Corresponding author. Tel.: +44 (0)1509228752; fax: +44 (0)1509 22 3925; e-mail: b.r.buckley@lboro.ac.uk 1   Tetrahedron Letters j ou rna l  homepage:  www.e lsev ie r .com   A catalytic, mild and efficient protocol for the C-3 aerial hydroxylation of oxindoles  Benjamin R. Buckley,* Beatriz Fernández D.-R. Department of Chemistry, Loughborough University, Loughborough, Leicestershire, LE11 3TU, UK.  Methods for functionalization of the oxindole nucleus are of significant value in medicinal chemistry and natural product synthesis.1 Due to their unprecedented structural diversity, biological activity and structural challenge, oxindoles continue to attract the interest of chemists and biologists alike. For example, the convolutamydines,2 and the 3-hydroxywelwitindolinones are part of a growing list of biologically active 3-hydroxyoxindoles (Figure 1).3 3-Hydroxyoxindoles with a quaternary benzylic centre are a useful class of compounds also found in several drug candidates, including the potent, orally active growth hormone  NOOHClCF3H2NOSM-130686NNHO ClciclazindolNHOHOBrBr RNHOHONHMeNHOHOHN SMeSconvolutamydine A, R = COMeconvolutamydine E, R = CH2OHdioxibrassine donaxaridine3-hydroxy-N-methylwelwitindolinone C isonitrileNEt2NMeOOHMeMeOClMeSCN Figure 1. Exemplar biologically active C-3 hydroxy oxindoles secretagogue SM-130686,4 a drug that currently is under investigation for the treatment of growth hormone deficiency and other medical conditions (Figure 1).5 There are a number of reports on the enantioselective formation of quaternary carbon centers at the 3-position of oxindoles.6 For example, Hartwig first reported the palladium-catalysed synthesis of oxindoles by amide α-arylation with ees of up to 67%;7 This was later improved upon by Kündig using modified N-heterocyclic carbenes8 and Marsden has reported several methods for the synthesis of 3-hydroxy- and 3-amino-oxindoles.9 Copper-mediated processes have also recently been employed to prepare quaternary C-3 oxindoles by both the Kündig10 and Taylor groups.11 Also of note are the recent reports by Franz,12 who has reported the asymmetric direct addition of nucleophiles to isatins using chiral Lewis acids, and Shibata and Toru who have reported the asymmetric C-3 hydroxylation of oxindoles also using chiral Lewis acids, with an oxaziridine as the stoicheiometric oxidant.13 Thus owing to the significance of the oxindole structural motif, the development of catalytic methods for the synthesis of oxindoles bearing a C-3 hydroxy quaternary centre is highly desirable.  Gassman and Halweg reported the air oxidation of oxindoles to isatins (Scheme 1) through treatment of 3-methylthiooxindoles with a strong stoicheiometric base and air; strict anhydrous conditions were required in order to prevent degradation of the isatin to the corresponding anthranilic acid.14 We also noted the recent report from Curran and co-workers,15 where the attempted removal of the trimethylsilyl (TMS) group from 1 resulted in 3-hydroxy-1,3-dihydroindol-2-one 2 being the sole product of the reaction (Scheme 2). Careful investigation of Curran’s reaction A R T I C L E  I N F O  A B S T R A C T  Article history: Received Received in revised form Accepted Available online A mild, high yielding approach to C-3 hydroxylated oxindoles using catalytic quantities of tetrabutylammonium fluoride and air as the stoicheiometric oxidant is reported over a wide range of substitution patterns.  2009 Elsevier Ltd. All rights reserved.  Keywords: Oxindole TBAF Oxidation Catalysis welwitindoline  Tetrahedron 2 NHOH3CS HKOtBuTHFRNHOH3CSRO2NHOH3CSRO ONHORO Scheme 1. Gassman and Halweg’s route to isatins  conditions revealed the use of 1.1 equivalents of tetrabutylammonium fluoride (TBAF); as 1.0 equivalent was required to fully desilylate the aryl ring we postulated that in order for 3-hydroxy-1,3-dihydroindol-2-one to be the sole product of the reaction, base-catalysed aerial oxidation must occur. We believed that this interesting unwanted side reaction could be a practical, mild solution to the synthesis of 3-hydroxyoxindoles using a readily available organocatalyst (TBAF) and a benign oxidant (air). This is even more important when one considers that from both an economic and environmental viewpoint there is currently an urgent need for more atom efficient systems that employ environmentally benign oxidants such as H2O2 or more preferably O2.16 NOMeHMeMeTMSTBAF (1.1 equiv.)THF, 0ºCNOMeHMeMeNOMeOHMeMe2, 76%(racemic)not observed(R)-182% ee Scheme 2. Curran’s attempted removal of the trimethylsilyl group from 1.  We started our investigation by looking at the aerial oxidation of 1,3-dimethyl-1,3-dihydroindol-2-one 3a using varying equivalents of TBAF in tetrahydrofuran as the solvent.17 We were delighted to find that the reaction was extremely rapid at room temperature and excellent yields of the hydroxylated oxindole 4a were observed with catalyst loadings as low as 10 mol%. Below this level we observed poor conversion into the desired product perhaps due to the breakdown of catalyst–counterion pairs at low catalyst concentration.18 Using our optimized conditions (THF, 20 mol% TBAF)19 we screened a range of 3-alkyloxindoles, and again we were delighted to find that excellent yields of the corresponding 3-hydroxyoxindoles 4c-4j were achieved (Table 1). We were also interested to see if our system was able to oxidise 3-aryl oxindoles as this motif is present in a variety of natural products and biologically important molecules (see Figure 1 for example); again we observed excellent conversion into the hydroxylated products 4k-4p. These results are important when considering the recent report in which Itoh and co-workers described the asymmetric aerial phase-transfer oxidation of oxindoles (using aq. KOH as a stoicheiometric base): they noted that benzyl protected oxindoles gave poor yields of C-3 hydroxylated products, also that the Boc protecting group is not tolerated under their reaction conditions; further they did not report the oxidation of oxindoles with aromatic groups at C-3.20 Jiang and Tan have also reported the molecular oxygen oxidation of oxindoles employing a stoichieometric base and a chiral pentadinium salt, but the substrate screen was narrow with the only group at nitrogen studied being p-methoxybenzyl.21 Our procedure appears quite general with the protecting group on nitrogen having little influence on the reaction, however, a group at nitrogen is essential for the reaction to occur (see 4b, Table 1 for example, this is presumably due to deprotonation of the nitrogen in preference to enolate formation). Table 1. Application to a range of substratesa,b NHOORNHOONHOTBAF (20 mol%)THF, open vessel, r.t.4a R =Me 96%4b R = H 0%NHOOPhRNHOOOO NHOOOORaliphaticsaromaticsNHOOR4c R = Me 90%4d R = Bn 86%4e R = Ts 92%4f R = Boc 94%4g R = H 88%4h R = Br 90%4i R = OMe 97%4j R = tBu 93%4k R = H 96%4l R = OMe 88%4m R = F 84%4n R = Me 90%4o R = Me 81%4p R = F 93%R3a-p 4a-p a General conditions: TBAF (1 M in THF, 0.2 equiv.), THF (2 mL), open vessel, r.t., 24 h19; b Percentage yields shown refer to the isolated yield after chromatography. Intrigued by these findings we also carried out a competition experiment through the addition of an electrophile to the reaction. For example, when 3g is treated with TBAF (0.2 equiv.) in THF the oxidized oxindole 4g is the sole product (Table 1), however, if 1,3-Dichloro-5,5-dimethylhydantoin (DCDMH) is added prior to the addition of TBAF then chlorination at C-3 is observed (to afford 5 along with recovered starting material 3g, Scheme 3) with no C-3 hydroxylated product 4g being detectable by 1H NMR spectroscopy or TLC analysis. Suggesting that quenching of the enolate with an electrophile other than O2 is more facile and that the reagent used inhibits formation of the enolate after 1 turnover of the system, thus only 15% of chlorinated product is observed from the use of 20 mol% TBAF. When 1 equivalent of TBAF is employed complete conversion into 5 is observed. NNOOClClNOBnHBnNOBnClBnTBAF (0.2 equiv.)THF, r.t., 24 h(DCDMH 1.1 equiv.)NOBnOHBn4g not observed 5 15% Conversion3g  Scheme 3. Competition experiment by addition of DCDMH to the reaction.  A proposed catalytic cycle is outlined in Scheme 4. Treatment of the oxindole 3 with TBAF affords the tetrabutylammonium enolate 6 plus HF, following Path A addition of O2 affords the peroxide anion 7 and recombination with a molecule of HF affords the peroxide 8 plus TBAF which can re-enter the catalytic  ∗ Corresponding author. Tel.: +44 (0)1509228752; fax: +44 (0)1509 22 3925; e-mail: b.r.buckley@lboro.ac.uk 3 cycle.22 In order to break down the peroxide 8 we propose that another molecule of the enolate 6 intercepts 8 (Path B) and affords two molecules of the hydroxylated product 4 plus another molecule of TBAF. Recently Garg23 and Rawal24 both independently described their routes to (−)-3-hydroxy-N-methylwelwitindolinone C isothiocyanate employing a strong base, and in the case of Garg, air and Rawal an oxaziridine as oxygen source for the C-3 hydroxylation reaction (Scheme 5). Employing our TBAF conditions to a model substrate 9, shown in Scheme 6, which was prepared by analogy to that reported previously by Garg,17,25 we were able to establish that excellent yield of the C-3 hydroxylated product 10 could be achieved. F  NBu4NORR'HNORR'NBu4HF +aerial O2NORR'OO NBu4NORR'OOHNORR'HOHFF  NBu4 6Path APath B3478 Scheme 4. Proposed catalytic cycle NMeOHMeMeOClMeSCNNMeOOHMeMeOClMeSCNRef.23 LiHMDS, airTHF, 23 ºC, 48%.orRef.24 KHMDS, THF,–78 ºC, then 67%.Ph NSO2PhOH H Scheme 5. Garg and Rawal’s independent routes to the 3-hydroxywelwitindoline NMeOHMeMeONMeOOHMeMeOTBAF (0.2 equiv.)THF, r.t., 5 min,89% yield, 2:1 d.r.HH HH9 10  Scheme 6. Application towards the 3-hydroxywelwitindolines  In conclusion, we have developed a mild catalytic process for the hydroxylation of oxindoles at the C-3 position using an environmentally benign terminal oxidant that appears to be of general use to a wide range of protected oxindoles. The protocol is also effective for hindered substrates such as the welwitindolinone model 9. In addition stoicheiometric TBAF is an effective base for halogenation at the C-3 position of oxindoles. Acknowledegments The authors would like to thank Eli Lilly Co. for a generous equipment donation, Research Councils UK for a RCUK fellowship (to B.R.B.), the EU Lifelong Learning Programme for support (to B.F.D.-R.), the Royal Society for a Research Grant (RG100494) and Loughborough University for funding. References and notes 1. (a) Tokunaga, T.; Hume, W. E.; Umezome, T.; Okazaki, K.; Ueki, Y.; Kumagai, K.; Hourai, S.; Nagamine, J.; Seki, H.; Taiji, M.; Noguchi, H.; Nagata, R. J. Med. Chem. 2001, 44, 4641; (b) Woodward, C. L.; Li, Z.; Kathcart, A. K.; Terrell, J.; Gerena, L.; Lopez-Sanchez, M.; Kyle, D. E.; Bhattacharjee, A. K.; Nichols, D. A.; Ellis, W.; Prigge, S. T.; Geyer, J. A.; Waters, N. C. J. Med. Chem. 2003, 46, 3877; (c) Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Wang, G.; Qiu, S.; Shangary, S.; Gao, W.; Qin, D.; Stuckey, J.; Krajewski, K.; Roller, P. P.; Wang, S. J. Med. Chem. 2006, 49, 3432; (d) Yeoh, G. B.; Chan, K. C.; Morsingh, F. Rev. Pure Appl. Chem. 1967, 17, 49; (e) Bindra, J. S. Oxindole Alkaloids. In Alkaloid Chemistry and Physiology; Manske, R. H. F., Ed.; Academic Press: New York, 1973; Vol. 14, pp 83–121. 2. Kamano, Y.; Zhang, H.-P.; Ichihara, Y.; Kizu, H.; Komiyamac, K. Pettit, G. R. Tetrahedron Lett. 1995, 36 2783. 3. Jimenez, J. I.; Huber, U.; Moore, R. E.; Patterson, G. M. L. J. Nat. Prod. 1999, 62, 569. 4. Tokunaga, T.; Hume, W. E.; Nagamine, J.; Kawamura, T.; Taiji, M.; Nagata, R. Bioorg. Med. Chem. Lett. 2005, 15, 1789. 5. Nagamine, J.; Kawamura, T.; Tokunaga, T.; Hume, W. E.; Nagata, R.; Nakagawa, T.; Taiji, M. Combinatorial Chem. & High Throughput Screening 2006, 9, 187.  6. (a) Freund, R.; Mederski, W. W. K. R. Helv. Chim. Acta 2000, 83, 1247; (b) Zhang, T. Y.; Zhang, H. Tetrahedron Lett. 2002, 43, 1363; (c) Glorius, F.; Altenhoff, G.; Goddard, R.; Lehmann, C. Chem. Commun. 2002, 2704; (d) Bonnet, L. G.; Douthwaite, R. E.; Hodgson, R. Organometallics 2003, 22, 4384; (e) Trost, B. M.; Frederiksen, M. U. Angew. Chem. Int. Ed. 2005, 44, 308; (f) Bignan, G. C.; Battista, K.; Connolly, P. J.; Orsini, M. J.; Liu, J.; Middleton, S. A.; Reitz, A. B. Bioorg. Med. Chem. Lett. 2005, 15, 5022;(g) Arao, T.; Sato, K.; Kondo, K.; Aoyama, T. Chem. Pharm. Bull. 2006, 54, 1576; (h) Arao, T.; Kondo, K.; Aoyama, T. Chem. Pharm. Bull. 2006, 54, 1743; (i) Arao, T.; Kondo, K.; Aoyama, T. Tetrahedron Lett. 2006, 47, 1417; (j) Reisman, S. E.; Ready, J. M.; Weiss, M. M.; Hasuoka, A.; Hirata, M.; Tamaki, K.; Ovaska, T. V.; Smith, C. J.; Wood, J. L. J. Am. Chem. Soc. 2008, 130, 2087; (k) Malkov, A. V.; Stewart-Liddon, A. J. P.; Teply, F.; Kobr, L.; Muir, K. W.; Haigh, D.; Kocovsky, P. Tetrahedron 2008, 64, 4011. 7. (a) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem. 1998, 63, 6546; (b) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402. 8. (a) Kündig, E. P.; Seidel, T. M.; Jia, Y.-X.; Bernardinelli, G. Angew. Chem. Int. Ed. 2007, 46, 8484; (b) Jia, Y.-X.; Hillgren, J. M.; Watson, E. L.; Marsden, S. P.; Kündig, E. P. Chem. Commun. 2008, 4040. 9. (a) Hillgren, J. M.; Marsden, S. P. J. Org. Chem. 2008, 73, 6459; (b) Marsden, S. P.; Watson, E. L.; Raw, S. A. Org. Lett. 2008, 10, 2905; (c) Watson, E. L.; Marsden, S. P.; , Raw, S. A. Tetrahedron Lett. 2009, 50, 3318; (d) Jia, Y.-X.; Hillgren, J. M.; Watson, E. L.; Marsden, S. P.; Kündig, E. P. Chem. Commun. 2008, 4040. 10. Jia, Y.-X.; Kündig, E. P. Angew. Chem. Int. Ed. 2009, 48, 1636. 11. (a) Perry, A.; Taylor, R. J. K. Chem. Commun. 2009, 3249; (b) Pugh, D. S.; Klein, J. E. M. N.; Perry, A.; Taylor, R. J. K. Synlett 2010, 934; (c) Franckevičius, V.; Cuthbertson, J. D.; Pickworth, M.; Pugh, D. S.; Taylor, R. J. K. Org. Lett. 2011, 13, 4264; (d) Klein, J. E. M. N.; Perry, A.; Pugh, D. S.; Taylor, R. J. K. Org. Lett. 2010, 12, 3446. 12. Hanhan, N. V.; Sahin, A. H.; Chang, T. W.; Fettinger, J. C.; Franz, A. K. Angew. Chem. 2010, 122, 756.  13. Ishimaru, T.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.; Kanemasa, S. J. Am. Chem. Soc. 2006, 128, 16488. 14. Gassman, P. G.; Halweg, K. M. J. Org. Chem. 1979, 44, 628. 15. Petit, M.; Geib, S. J.; Curran, D. P. Tetrahedron 2004, 60, 7543. 16. Carey, J. S.; Laffan, D.; Thomsonc, D.; Williams, M. T. Org. Biomol. Chem. 2006, 4, 2337. 17. See Supplementary Information for Table S1 and the synthesis of compound 9. 18. Page, P. C. B.; Rassias, G. A.; Barros, D.; Bethell, D.; Schilling, M. B. J. Chem. Soc. Perkin Trans. 1. 2000, 3325. 19. Representative method for the C-3 hydroxylation of oxindoles: 3-hydroxy-1,3-dimethylindolin-2-one 4a: Tetrahedron 4 To a solution of 3a (0.16 g; 1.0 mmol) in THF (10 mL) was added TBAF (0.2 mL; 1 M in THF; 0.20 mmol) in a Carousel 12 reaction vial. The reaction was followed by tlc analysis. Once complete the reaction mixture was then quenched with a saturated solution of ammonium chloride (5 mL) and extracted with ether (3 x 30 mL). The organic layer was washed twice with brine (10 mL), dried with MgSO4 and concentrated under reduced pressure. Flash chromatography on silica gel (light petroleum/ethyl acetate; 10:1) afforded the title compound as a colorless oil (0.17 g, 96%) with almost identical spectroscopic data to that reported in the literature, see Thomson, J. E.; Kyle, A. F.; Gallagher, K. A.; Lenden, P.; Concellón, C.; Morrill, L. C.; Miller, A. J.; Joannesse, C.; Slawin, A. M. Z.; Smith, A. D. Synthesis 2008, 2805. 20. Sano, D.; Nagata, K.; Itoh, T. Org. Lett. 2008, 10, 1593. 21. Yang, Y.; Moinodeen, F.; Chin, W.; Ma, T.; Jiang, Z.; Tan, C.-H. Org. Lett., 2012, 14, 4762. 22.    A plausible route to intermediates of type 7 can be found in: (a) Heaney, H.; Taha, M. O.; Slawin, A. M. Z. Tetrahedron Lett. 1997, 38, 3051; (b) Heaney, H, Taha, M. O. Arkivoc 2000, i, 343. 23. Quasdorf, K. W.; Huters, A. D.; Lodewyk, M. W.; Tantillo, D. J.; Garg, N. K. J. Am. Chem. Soc. 2012, 134, 1396. 24. Allan, K. M.; Kobayashi, K.; Rawal, V. H. J. Am. Chem. Soc. 2012, 134, 1392. 25. Tian, X.; Huters, A. D.; Douglas, C. J.; Garg, N. K. Org. Lett. 2009, 11, 2349. Supplementary Material Synthetic details along with 1H and 13C NMR spectra for all novel compounds are presented in the Supplementary Data file. 

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A catalytic, mild and efficient protocol for the C-3 aerial hydroxylation of oxindoles

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