Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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In Situ Generation of Cyclopentadienol Intermediates from 2,4Dienals. Application to the Synthesis of Spirooxindoles via a Domino Polycyclization Anne-Sophie Marques,† Jérôme Marrot,† Isabelle Chataigner,‡ Vincent Coeffard,*,§ Guillaume Vincent,*,∥ and Xavier Moreau*,† †
Institut Lavoisier Versailles, UMR CNRS 8180, Université de Versailles-St-Quentin-en-Yvelines, Université Paris Saclay, 45 Avenue des États-Unis, Versailles 78035 Cedex, France ‡ Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA (UMR 6014), 76000 Rouen, France § Université de Nantes, CNRS, Chimie Et Interdisciplinarité: Synthèse, Analyse et Modélisation (CEISAM), UMR CNRS 6230, Faculté des Sciences et des Techniques, 2, rue de la Houssinière, BP 92208, Nantes 44322 Cedex 3, France ∥ Institut de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO), Université Paris-Sud, Université Paris-Saclay, CNRS UMR 8182, Orsay 91405 Cedex, France S Supporting Information *
ABSTRACT: An efficient domino polycyclization combining different classes of pericyclic reactions leads to complex spiroxindoles under mild conditions. This domino process represents a rare example of an in situ formation of cyclopentadienol derivatives from an interrupted iso-Nazarov electrocyclization of 2,4-dienals and their use in [4 + 2] cycloaddition reactions. According to the reaction conditions, different polycyclic architectures are obtained in good yields and excellent diastereoselectivities.
C
Scheme 1. Cascade Polycyclizations Involving an Interrupted Iso-Nazarov Cyclization
onstructing molecular complexity and diversity from simple and readily available substrates is still being pursued by the synthetic community. The development of domino polycyclizations1 is one of the most appealing strategies to generate intricate polycyclic scaffolds in a single operation. Besides cationic, nucleophilic, or radical processes, cascades that hinge upon different pericyclic reactions are a valuable tool that has been elegantly applied in synthetic methodologies2 or during total synthesis of natural products.3 In our continuous effort to explore efficient transformations of unsaturated aldehydes toward polycyclic architectures,4 we recently investigated this strategy by engaging 2,4-dienals5 in the interrupted iso-Nazarov cyclization.6 We have established that an oxyallyl cation, generated from the FeCl3-mediated 4πconrotatory cyclization of 2,4-dienals, could be engaged in [3 + 2] cycloadditions with N−Ac indoles (Scheme 1, previous work). Inspired by the large variety of oxindole scaffolds which are abundant in natural or synthetic bioactive molecules7 and in line with our interest in spirocyclic indolines,8 we envisaged applying our method in the formation of polyheterocyclic spirooxindole derivatives starting from alkylidene oxindoles.9 We were surprised to observe a different reaction outcome with an unexpected bridged spirooxindole being isolated (Scheme 1, this work). This unprecedented cascade polycyclization aroused our interest as the Diels−Alder cycloaddition reaction of cyclopentadienol derivatives has only been very rarely described © XXXX American Chemical Society
because of their highly favored isomerization into the corresponding cyclopentenones (Scheme 2). Only Woodward reported one example of the Diels−Alder cycloaddition of an acetoxycyclopentadiene generated via the thermolysis of acetoxydicyclopentadiene at 190 °C.10 Therefore, 5-silylated 1,3-cyclopentadienes 1 are generally used in Diels−Alder Received: December 18, 2017
A
DOI: 10.1021/acs.orglett.7b03934 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
excellent yield (73%, dr >20/1) along with compound 9a (10% yield) with a slight erosion of the diastereomeric purity (dr 10/ 1). Raising the reaction temperature to 45 °C led to the unique formation of 9a in 72% yield, but an epimerization still occurred (dr 10/1, entry 4). To circumvent this problem, we investigated the influence of the substituent borne by the alkylidene oxindole. Replacing the dienophile substituent by a ketone (entry 5), a nitrile (entry 6), or an electron-deficient aryl group (entry 7) did not afford any improvement. A mixture of 8b and 9b was obtained in the first case while a complex mixture of products or no reaction was observed in the other cases. Finally, using 3-(2,2,2-trifluoroethylidene)indolin-2-one 7e as a dienophile allowed the exclusive formation of 8e (60% yield, entry 8) at room temperature. When the reaction temperature was increased to 45 °C, the spiroxindole 9e was isolated as a single product in 86% yield without epimerization (dr >20/1, entry 9) (Table 1). As shown by the results gathered in Scheme 3, the position or the electronic nature of the substituent borne by the
Scheme 2. Cyclopentadienol and Surrogates in [4 + 2] Cycloaddition Reactions
cycloadditions as surrogates of uncontrollable cyclopentadienols in order to access 7-hydroxybicyclo[2.2.1]derivatives 5 after oxidation of the C−Si bond.11 Bridged structures 5 could also be accessed from cyclopentadienyl metal complexes 212 or from 1,3-cyclopentadienone derivatives 3 and 413 after reduction (Scheme 2). Herein, we would like to report an innovative access to ephemeral cyclopentadienols via the interrupted iso-Nazarov cyclization of 2,4-dienals and their use in Diels−Alder reactions with alkylidene oxindoles. Our exploratory studies focused on the reaction between 4phenylhexa-2,4-dienal 6a and isatin derived enoate 7a in the presence of FeCl3 (2 equiv).14 When the reaction was conducted in dichloromethane at room temperature, we were pleased to isolate the bridged spiroxindole 8a as a single regioand diastereomer15 in 54% yield (Table 1, entry 1).
Scheme 3. Scope of the Reaction for the Formation of Bridged Spirooxindoles 8
Table 1. Optimization of the Domino Polycyclization
entry
7
1 2 3 4 5 6 7 8c 9
7a 7a 7a 7a 7b 7c 7d 7e 7e
conditionsa CH2Cl2, rt HFIP, rt HFIP, H2O, HFIP, H2O, HFIP, H2O, HFIP, H2O, HFIP, H2O, HFIP, H2O, HFIP, H2O,
rt 45 °C rt rt rt rt 45 °C
yield of 8 (%)
yield of 9 (%), drb
54 (8a) 45 (8a) 73 (8a)
5, nd (9a) 10, 10:1 (9a) 72, 10:1 (9a) 31 (8b) 41, >20:1 (9b) complex mixture NR 60 (8e) 86%, >20:1 (9e)
a
Reaction conditions: 2 equiv of 6a, 1 equiv of 7, and 0 or 5 equiv of H2O in specified solvent (0.05 M) at the indicated temperature for 17 h. Isolated yield after column chromatography. NR: no reaction. b Diastereomeric ratio determined by 1H NMR of the crude mixture, nd: not determined. cReaction stirred for 24 h.
aromatic moiety of the indolin-2-one has almost no influence regarding to the reactivity and stereoselectivity of the cycloaddition reaction. Indeed, when 3-alkylidene oxindoles substituted at the C5 position by an electron-withdrawing (halogen atoms 7f−i or trifluoromethyl 7j) or electrondonating (methyl 7k, methoxy 7l) group were reacted with dienal 6a, the bridged spirooxindoles 8f−8l were obtained in moderate to good yield (45−77%) for this three-bond-forming reaction and excellent level of selectivity (single product, dr >20/1, within all cases). Of note, the lower yield observed in the case of 5-iodo-3-(2,2,2-trifluoroethylidene)indolin-2-one 7i
Recent reports highlighting the beneficial role of fluorinated solvents in the enhancement of reactivity when ionic intermediates are involved16 prompted us to investigate the use of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as solvent for this transformation. Interestingly, the compound 8a was obtained in a disappointing 45% yield along with a new spirooxindole 9a (5% yield) generated from 8a by a ringopening reaction (entry 2).17 Using H2O (5 equiv) as an additive (entry 3), the same product 8a was obtained with an B
DOI: 10.1021/acs.orglett.7b03934 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
in HFIP depicted in Figure 1 begins with coordination of FeCl3 to (2Z,4E)-4-methylhexa-2,4-dienal formed by double-bond
is probably due to its low solubility in HFIP. Different halogenated oxindoles at the C6 or C7 position were tested in this transformation and afforded the polycyclic architectures 8m−r with the same level of reactivity (62−70% yield) and selectivity. Finally, dienophile 7p, with an ester group at the C6 position, led to formation of the cycloadduct 8p in a slightly better yield (75%). This method was also applicable to a set of dienals. A methyl or phenyl group at the C4 and phenyl or alkyl groups (Me, Et, iBu) at C5 in the unsaturated aldehyde was well tolerated, and the products 8s−w were isolated in moderate to excellent yields (47−85%). We then turned our attention to the formation of spirooxindoles 9. As noted in Table 1, these novel architectures were obtained selectively by carrying out the reaction at 45 °C. The cascade iso-Nazarov cyclization/[4 + 2] cycloaddition reaction/ring opening rearrangement was followed by reduction of the aldehydes 9 to the alcohols 10 with NaBH4, in order to facilitate the isolation and purification. As depicted in Scheme 4, 3-alkylidene oxindoles 7, decorated with a range of substituents on the aromatic part, underwent a cascade transformation to give the corresponding spirocyclic compounds 10.
Figure 1. DFT-computed energy surface for the formation of cyclopentadienol intermediate and the water-assisted process.
isomerization of the corresponding (2E,4E)-dienal. Such a process has already been reported in FeCl3-promoted isoNazarov cyclization.18 The coordination process leading to A is exergonic by 6.7 kcal/mol in HFIP. The complex A then undergoes a conrotatory 4π electrocyclization to give the intermediate B via TS1 with an activation energy of 12.3 kcal/ mol. Previous works have shown that the zwitterion B featuring two adjacent stereocenters with a trans relationship can be trapped through a dearomative [3 + 2]-cycloaddition with indoles6 (Scheme 1, previous work). Under the reaction conditions, intermediate B could evolve to the cyclopentadienol intermediate via a concerted mechanism. Calculations indicate that an activation energy of 29.7 kcal/mol is required. The high energy barrier would be explained by the formation of a strained four-membered cyclic transition state TS2 for the proton transfer leading to C. In TS2, the breaking C−H bond is 1.33 Å, while the length of the forming O−H bond is 1.38 Å (Figure 2). The high energy
Scheme 4. Scope of the Reaction for the Formation of Spirooxindoles 9
Figure 2. DFT-optimized transition states.
barrier could explain the lower yields when dry solvents were used for the reaction (Table 1, entries 1 and 2). The reaction optimization presented in Table 1 showed that addition of water was beneficial to the reaction yield, and therefore, these results prompted us to investigate the role of water in the formation of cyclopentadienol intermediate. In light of the ability of water to act as a proton shuttle in catalytic processes,19 we surmised that addition of one molecule of water (structure D) could lead to a more energetically favorable six-membered transition state. Starting from D, the cyclopentadienol structure E would be formed via TS3. In TS3, the hydrogen atom connected with the carbon is transferred to the water molecule (H−O = 1.28 Å), while water’s hydrogen is transferred to the oxygen atom (H−O = 1.45 Å). This water-assisted [1,3]-proton shift requires an activation energy of 11.1 kcal/mol, which is much lower than the nonwater process. IRC calculations showed that TS3 would allow the formation of cyclopentadienol E which would further react with 3-alkylidene oxindoles via a [4 + 2] cycloaddition.
Excellent results were obtained with halogen atoms (F (10f), Cl (10g), Br (9h, isolated as an aldehyde, before reduction)) or electron-donating groups (Me (10k), OMe (10l)) at the C5 position of the oxindole unit as these products were isolated in yields between 60 and 67%. The outcome of the reaction was divergent when 6-substituted indolin-2-ones were engaged in the sequence. When 6-bromo-3-(2,2,2-trifluoroethylidene)indolin-2-one 7m was used in the reaction, the synthesis of tricycle scaffold 10m was achieved in 60% yield. Replacing the bromine with a fluorine atom (10o) or an ester group (10p) led to lower yields (respectively 45% and 31% yield). Finally, a 3-alkylidene oxindole bearing a fluorine atom at C7 position was also amenable to the reaction affording the polycycle 10q in 59% yield. Based on the above results, DFT calculations at the B3LYP level were performed to account for the cyclopentadienol intermediate formation.14 The DFT computed energy surface C
DOI: 10.1021/acs.orglett.7b03934 Org. Lett. XXXX, XXX, XXX−XXX
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(f) Riveira, M. J.; La-Venia, A.; Mischne, M. P. J. Org. Chem. 2016, 81, 7977. (3) (a) Beaudry, C. M.; Malerich, J. P.; Trauner, D. Chem. Rev. 2005, 105, 4757. (b) Poulin, J.; Grisé-Bard, C. M.; Barriault, L. Chem. Soc. Rev. 2009, 38, 3092. (4) (a) Portalier, F.; Bourdreux, F.; Marrot, J.; Moreau, X.; Coeffard, V.; Greck, C. Org. Lett. 2013, 15, 5642. (b) Pantaine, L.; Coeffard, V.; Moreau, X.; Greck, C. Org. Lett. 2015, 17, 3674. (c) Giardinetti, M.; Moreau, X.; Coeffard, V.; Greck, C. Adv. Synth. Catal. 2015, 357, 3501. (5) Marques, A.-S.; Coeffard, V.; Chataigner, I.; Vincent, G.; Moreau, X. Org. Lett. 2016, 18, 5296. (6) For a review dealing with iso-Nazarov cyclization, see: (a) Riveira, M. J.; Marsili, L. A.; Mischne, M. P. Org. Biomol. Chem. 2017, 15, 9255. For selected reviews dealing with the Nazarov cyclization, see: (b) West, F. G.; Scadeng, O.; Wu, Y.-W.; Fradette, R. J.; Joy, S. The Nazarov Cyclization. In Comprehensive Organic Synthesis, 2nd ed; Knochel, P., Molander, G. A., Eds.; Elsevier: Amsterdam, 2014; Vol. 5, pp 827−866. (c) Spencer, W. T., III; Vaidya, T.; Frontier, A. J. Eur. J. Org. Chem. 2013, 2013, 3621. (d) Tius, M. A. Chem. Soc. Rev. 2014, 43, 2979. (e) Di Grandi, M. J. Org. Biomol. Chem. 2014, 12, 5331. (7) (a) Zheng, Y.; Tice, C. M.; Singh, S. B. Bioorg. Med. Chem. Lett. 2014, 24, 3673. (b) Yu, B.; Yu, D.-Q.; Liu, H.-M. Eur. J. Med. Chem. 2015, 97, 673. (c) Pavlovska, T. L.; Redkin, R. G.; Lipson, V. V.; Atamanuk, D. V. Mol. Diversity 2016, 20, 299. (8) (a) Nandi, R. K.; Guillot, R.; Kouklovsky, C.; Vincent, G. Org. Lett. 2016, 18, 1716. (b) Tomakinian, T.; Hamdan, H. A.; Denizot, N.; Guillot, R.; Baltaze, J.-P.; Kouklovsky, C.; Vincent, G. Eur. J. Org. Chem. 2017, 2017, 2757. (c) Ryzhakov, D.; Jarret, M.; Guillot, R.; Kouklovsky, C.; Vincent, G. Org. Lett. 2017, 19, 6336. (9) For selected reviews dealing with the syntheses of spiroxindoles, see: (a) Hong, W.; Wang, R. Adv. Synth. Catal. 2013, 355, 1023. (b) Cheng, D.; Ishihara, Y.; Tan, B.; Barbas, C. F., III ACS Catal. 2014, 4, 743. For a review on the synthesis of related spiroindolenines, see: (c) James, M. J.; O’Brien, P.; Taylor, R. J. K.; Unsworth, W. P. Chem. Eur. J. 2016, 22, 2856. (10) Winstein, S.; Shatavsky, M.; Norton, C.; Woodward, R. B. J. Am. Chem. Soc. 1955, 77, 4183. (11) For selected examples, see: (a) Fleming, I.; Michael, J. P. J. Chem. Soc., Chem. Commun. 1978, 6, 245. (b) Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem., Int. Ed. 2000, 39, 4073. (c) Breder, A.; Chinigo, G. M.; Waltman, A. W.; Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47, 8514. (12) (a) Merlic, C. A.; Bendorf, H. D. Organometallics 1993, 12, 559. (b) Allen, S. K.; Lathrop, T. E.; Patel, S. B.; Harrell Moody, D. M.; Sommer, R. D.; Coombs, T. C. Tetrahedron Lett. 2015, 56, 6038. (13) (a) Srikrishna, A.; Viswajanani, R.; Reddy, T. J.; Vijaykumar, D.; Kumar, P. P. J. Org. Chem. 1997, 62, 5232. (b) Šála, M.; Hřebabecký, H.; Dračínský, M.; Masojídková, M.; De Palma, A. M.; Neyts, J.; Holý, A. Tetrahedron 2009, 65, 9291. (14) See the Supporting Information for details. (15) The heteroatom-directed π-facial selectivity in such Diels−Alder reactions is well established even if its origin is still controversial. For a review, see: Mehta, G.; Uma, R. Acc. Chem. Res. 2000, 33, 278. (16) Colomer, I.; Chamberlain, A. E. R.; Haughey, M. B.; Donohoe, T. J. Nat. Rev. Chem. 2017, 1, 0088. (17) When submitted to the reaction conditions at 45 °C, 8 led to 9. See the Supporting Information for a proposed mechanism. (18) Kuroda, C.; Koshio, H. Chem. Lett. 2000, 29, 962−963. (19) For selected references, see: (a) Shi, F.-Q.; Li, X.; Xia, Y.; Zhang, L.; Yu, Z.-X. J. Am. Chem. Soc. 2007, 129, 15503. (b) Liang, Y.; Liu, S.; Xia, Y.; Li, Y.; Yu, Z.-X. Chem. - Eur. J. 2008, 14, 4361. (c) Wang, Y.; Yu, Z.-X. Org. Biomol. Chem. 2017, 15, 7439.
In summary, a new cascade polycyclization leading to original spirooxindole-based scaffolds has been developed. The sequence, based on an interrupted iso-Nazarov cyclization followed by a [4 + 2] cycloaddition reaction, is a scarce example of the formation and trapping of cyclopentadienol derivatives. According to the reaction conditions, different polycyclic architectures are obtained in good yields and excellent diastereoselectivities. Moreover, DFT calculations highlighted the important role of H2O in the formation of the substituted cyclopentadienol.
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03934. Experimental procedures and compound characterization data including NMR spectra (PDF) Accession Codes
CCDC 1585821−1585822 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
* E-mail: vincent.coeff
[email protected]. * E-mail:
[email protected]. * E-mail:
[email protected]. ORCID
Guillaume Vincent: 0000-0003-3162-1320 Xavier Moreau: 0000-0002-6737-9671 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by a public grant overseen by the French National Research Agency (ANR) as part of the “Investissements d’Avenir” program (Nos. ANR-11-IDEX0003-02, CHARMMMAT ANR-11-LABX-0039, and Labex SynOrg (ANR-11-LABX-0029)). We also thank the Université de Versailles Saint Quentin and the Centre National de la Recherche Scientifique (CNRS) for financial support.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b03934 Org. Lett. XXXX, XXX, XXX−XXX
