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Ethyl (1R*,10S*,12R*,15S*)-4-Hydroxy-2-oxo-15- (2-oxo-1-pyrrolidinyl)-9-oxatetracyclo[10.2.2.01,10.03,8]hexadeca-3,5,7,13-tetraene-13-carboxylate

1
Centro de Investigación Biomédica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad Tecnológica Equinoccial, Av. Mariscal Sucre y Mariana de Jesús, Quito 170527, Ecuador
2
Instituto de Química de Recursos Naturales, Universidad de Talca, Av. Lircay s/n, Casilla 747, Talca 3460000, Chile
*
Authors to whom correspondence should be addressed.
Academic Editor: Norbert Haider
Molbank 2017, 2017(1), M928; https://doi.org/10.3390/M928
Received: 13 December 2016 / Revised: 11 January 2017 / Accepted: 13 January 2017 / Published: 18 January 2017
(This article belongs to the Section Organic Synthesis)

Abstract

N-Vinylpirrolidinone reacts with (E)-ethyl 5-hydroxy-3-(4-oxo-4H-chromen-3-yl) acrylate (1) through a domino reaction similar to that reported reaction for ethyl vinyl ether. Inverse electron demand Diels–Alder (IEDDA)–elimination-IEDDA generates isomeric tetracycles 5 and 6. The assignment of the relative stereochemistry of the products was made by comparing the proton couplings with those obtained by reaction with ethyl vinyl ether.
Keywords: domino-reaction; inverse electron demand Diels–Alder; N-vinylpyrrolidinone; chromone derivatives domino-reaction; inverse electron demand Diels–Alder; N-vinylpyrrolidinone; chromone derivatives

1. Introduction

Domino reactions, also known as cascade or tandem reactions, are an important type of chemical transformation in organic synthesis. These reactions have several benefits that are well established: high atom economy, shorter reaction time, and reduced waste generation, among others. Thus, they can be considered to fall under the banner of green chemistry. These reactions take advantage of the formation of several bonds in sequence without the workup and isolation of intermediates, changing the reaction conditions or adding reagents. This increases the structural complexity of the products obtained effectively in one step since each reaction that makes up the sequence occurs spontaneously [1,2,3].
The classification of domino reactions is sometimes difficult because of the diverse nature of the many steps involved in the transformation; however, it is generally done considering the major theme of the sequence. Most of these reactions consist of two or more nucleophilic, electrophilic, radical, pericyclic, or transition metal-catalyzed transformations [2,4]. The combination of reactions can be of the same (homo-domino) or different type (hetero-domino), for example, Knoevenagel-hetero-Diels–Alder [5], Knoevenagel-ene [6], or Sakurai-ene [7,8,9,10] reactions. Some examples showing inverse electron demand Diels–Alder reactions have also been reported, especially with dienes containing two electron-withdrawing groups at positions 1 and 3. These dienes react with enamines or enol ethers to provide functionalized 1-tetralones, benzocoumarines, 2-hydroxybenzophenones, bicyclic lactams, and xanthones [11,12,13,14].
In this field, we have described the reactions of (E)-ethyl-3-(4-oxo-4H-chromen-3-yl)acrylate (1), (E)-3-(4-oxo-4H-chromen-3-yl)-2-acrylonitrile, and their 5-hydroxy-derivatives with ethyl vinyl ether. For example, 1 undergoes competitive, solvent-dependent, domino reactions. In toluene, inverse electron demand Diels–Alder (IEDDA)–elimination-IEDDA generates isomeric tetracycles 3 and 4. Alternatively, IEDDA followed by elimination and oxidation provide xanthone 2 [15] (Scheme 1). 2D NMR experiments along with X-ray crystal crystallography, allowed for the unequivocal assignment of these structures. In this communication, we describe the use of N-vinylpyrrolidinone as a useful dienophile for obtaining highly functionalized tetracyclic compounds analogues to 3 and 4.

2. Results

The starting chromone derivative 1 was obtained by Wittig reaction of 5-hydroxy-3-formylchromone with carboethoxymethylenetriphenylphosphorane in toluene under reflux. The E/Z product mixture has a 55/40 E/Z ratio and an overall yield of 95% [16]. When N-vinylpyrrolidinone, a dienophile already used in inverse electron demand Diels–Alder reactions [17], reacted with 1 in toluene at 140 °C in a sealed tube, a mixture of isomeric tetracyclic compounds 5 and 6, along with the xanthone 2, were obtained in yields of 35%, 15% and 2%, respectively (Scheme 2). NMR spectra are provided as supplementary materials.

3. Discussion

The analysis of 1D and 2D NMR spectra (1H, 13C, HMBC and HSQC) of 5 and 6 allowed unequivocal structure assignments. The relative stereochemistry of these cycloadducts was made analyzing the cis and trans coupling constants between H-10 and H-15 with H-11 and H-16, respectively, and by comparing them with analogs 3 and 4 obtained in the reaction with ethyl vinyl ether [15]. The spectra of 5 and 6 show a very similar coupling pattern in the bicyclic moiety compared to that of 3 and 4 respectively, including a similar 4JH,H coupling through a W coupling path between the H-16 and H-11 protons in 5. Selected coupling constants are shown in Table 1.
Molbank 2017 m928 i001

4. Materials and Methods

The 1H and 13C-NMR spectra were recorded at 300.13 MHz and 75.47 MHz, respectively, on a AVANCE DRX 300 Spectrometer (Bruker BioSpin GmbH, Rheinstetten, Germany) using CDCl3 as a solvent. The chemical shifts are reported in ppm downfield from TMS for 1H-NMR and relative to the central CDCl3 resonance (77.0 ppm) for 13C-NMR. Melting points are uncorrected and were taken with a Gallenkamp melting point apparatus. Infrared spectra were recorded with a NICOLET 510P FT-IR spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA). High resolution mass spectrum was obtained on a MAT 95XP, Thermo Finnigan spectrometer(Thermo Fisher Scientific, Waltham, MA, USA). Commercial N-vinylpyrrolidinone was used without purification. The domino reactions were done in an Ace pressure tube (Aldrich catalogue number: Z564605-1EA). The separations and purifications were performed by column chromatography on silica gel 60 (Merck, Darmstadt, Germany, 70-230 mesh). The reported yields of the cycloadducts were calculated based on the integration of the 1H-NMR spectrum.

4.1. Domino Reaction

The reaction was performed in a pressure tube by adding 0.9 mL of N-vinylpyrrolidinone (0.9 g, 8.3 mmol) to a solution of 107 mg of 5-hydroxy-(E)-ethyl-3-(4-oxo-4H-chromen-3-yl)acrylate (1) (0.41 mmol) in toluene (5.0 mL). The mixture was stirred for 3 days at 140 °C, the solvent was removed at reduced pressure, and the crude product was dissolved in 5.0 mL of EtOAc. The solution was washed with a large excess of water to remove the unreacted N-vinylpyrrolidinone, dried over MgSO4 and evaporated to dryness in vacuum. The crude product was purified by column chromatography on silica gel using hexane/EtOAc 4:1 as an eluent to afforded fractions with almost pure products. Recrystallizations in EtOAC/hexane afford pure compound 5 in a 13.4% yield and 6 as an analytical sample.
Ethyl (1R*,10S*,12R*,15S*)-4-hydroxy-2-oxo-15-(2-oxo-1-pyrrolidinyl)-9-oxatetracyclo[10.2.2.01,10.03,8] hexadeca-3,5,7,13-tetraene-13-carboxylate (5). Crystallized from EtOAc/hexane as colorless crystals; 1H-NMR (CDCl3) δ: 1.30 (dddd, 1H, J1 = 13.4 Hz, J2 = 5.6 Hz, J3 = 2.9 Hz, J4 = 2.9 Hz, H-16β), 1.35 (t, 3H, J = 7.1 Hz, CO2CH2CH3), 1.75 (ddd, 1H, J1 = 13.9 Hz, J2 = 3.8 Hz, J3 = 2.2 Hz, H-11α), 1.80–1.88 (m, 1H, H-4′), 1.90–2.01 (m, 1H. H-4′), 2.09 (dddd, 1H, J1 = 13.9 Hz, J2 = 10.3 Hz, J3 = 3.3 Hz, J4 = 2.9 Hz, H-11β), 2.16–2.26 (m, 2H, H-3′), 2.25 (ddd, 1H, J1 = 13.4 Hz, J2 = 9.8 Hz, J3 = 2.9 Hz, H-16α), 3.00 (ddd, 1H, J1 = 9.0 Hz, J2 = 8.6 Hz, J3 = 4.5 Hz, H-5′), 3.16 (dt, 1H, J1 = 9.0 Hz, J2 = 7.5 Hz, H-5′), 3.40 (m, 1H, H-12), 4.22–4.33 (m, 3H, H-10 and CO2CH2CH3), 5.44 (dd, 1H, J1 = 9.7 Hz, J2 = 5.6 Hz, H-15), 6.49 (dd, 1H, J1 = 8.3 Hz, J2 = 0.8 Hz, H-7), 6.54 (dd, 1H, J1 = 8.4 Hz, J2 = 0.8 Hz, H-5), 7.38 (dd, 1H, J1 = 8.4 Hz, J2 = 8.3 Hz, H-6), 7.39 (m, 1H, H-14), 11.55 (s, 1H, OH); 13C-NMR (CDCl3) δ: 14.2 (CO2CH2CH3), 18.2 (C-4′), 29.7 (C-12), 30.6 (C-16), 30.8 (C-3′), 31.1 (C-11), 44.6 (C-5′), 45.7 (C-15), 53.3 (C-1), 61.1 (CO2CH2CH3), 77.33 (C-10), 107.6 (C-7), 107.7 (C-3), 110.3 (C-5), 134.9 (C-14), 138.4 (C-6), 139.6 (C-13), 160.9 (C-8), 162.5 (C-4), 163.9 (CO2Et), 175.2 (C-2), 198.1 (C-2); mp 181.5−183 °C; IR (KBr) 2971, 1714, 1690, 1642, 1221 cm−1; HREIMS [M]+ m/z calcd. for C22H23NO6 397.1525: found 397.1524.
Ethyl (1R*,10S*,12R*,15R*)-4-hydroxy-2-oxo-15-(2-oxo-1-pyrrolidinyl)-9-oxatetracyclo[10.2.2.01,10.03,8] hexadeca-3,5,7,13-tetraene-13-carboxylate (6). Crystallized from EtOAc/hexane as colorless crystals; 1H-NMR (CDCl3) δ 1.13 (ddt, 1H, J1 = 13.5 Hz, J2 = 5.6 Hz, J3 = 3.0 Hz, H-16α), 1.31 (t, 3H, J = 7.1 Hz, CO2CH2CH3), 1.65 (dddd, 1H, J1 = 14.2 Hz, J2 = 3.5 Hz, J3 = 3.5 Hz, J4 = 2.4 Hz, H-11α), 1.82–1.95 (m, 1H, H-4′), 2.04–2.11 (m, 1H, H-16β), 2.08–2.16 (m, 1H, H-4′), 2.24 (ddd, 1H, J1 = 14.2 Hz, J2 = 8.3 Hz, J3 = 2.4 Hz, H-11β), 2.37 (ddd, 1H, J1 = 16.6 Hz, J2 = 9.5 Hz, J3 = 3.6 Hz, H-3′), 2.53 (dt, 1H, J1 = 16.8 Hz, J2 = 9.5 Hz, H-3′), 3.06 (ddd, 1H, J1 = 9.2 Hz, J2 = 8.8 Hz, J3 = 3.0 Hz, H-5′), 3.08–3.16 (m, 1H, H-5′), 3.42 (m, 1H, H-12), 4.24 (q, 2H, J1 = 7.1 Hz, CO2CH2CH3), 4.68 (ddd, 1H, J1 = 8.3 Hz, J2 = 2.4 Hz, J3 = 1.2 Hz, H-10), 4.82 (dd, 1H, J1 = 9.6 Hz, J2 = 5.6 Hz, H-15), 6.34 (dd, 1H, J1 = 8.3 Hz, J2 = 1.2 Hz, H-7), 6.54 (d, 1H, J = 8.3 Hz, H-5), 6.77 (m, 1H, H-14), 7.35 (t, 1H, J = 8.3 Hz, H-6), 11.72 (s, 1H, OH); 13C-NMR (CDCl3) δ 14.2 (CO2CH2CH3), 18.3 (C-4′), 28.1 (C-12), 31.0 (C-16), 31.2 (C-3′), 33.5 (C-11), 45.5 (C-5′), 48.1 (C-15), 49.3 (C-1), 61.2 (CO2CH2CH3), 78.2 (C-10), 107.2 (C-7), 108.2 (C-3), 110.1 (C-5), 134.5 (C-14), 138.4 (C-6), 139.5 (C-13), 160.3 (C-8), 162.7 (C-4), 163.5 (CO2Et), 176.0 (C-2), 198.8 (C-2); mp 217–219 °C.

Supplementary Materials

The following are available online at www.mdpi.com/1422-8599/2017/1/M928, Figure S1: 1H-NMR spectrum of compound 5, Figure S2: 13C-NMR spectrum of compound 5, Figure S3: HSQC spectrum of compound 5, Figure S4: HMBC spectrum of compound 5, Figure S5: 1H-NMR spectrum of compound 6, Figure S6: 13C-NMR spectrum of compound 6, Figure S7: HSQC spectrum of compound 6, Figure S8: HMBC spectrum of compound 6.
Supplementary File 1Supplementary File 2Supplementary File 3Supplementary File 4

Acknowledgments

We are grateful to Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) Grant 1140753.

Author Contributions

J.H-M. and R.A-M. conceived and designed the experiments; J.H-M performed the experiments; J.H-M and R.A-M analyzed the data; R.A-M contributed reagents/materials/analysis tools; R. A-M and J.H-M wrote the paper.

Conflicts of Interest

The authors declare no conflict of interest. The funding sponsors played no role in the design of the study; the collection, analysis, or interpretation of data, the writing of the manuscript; or the decision to publish the results.

References

  1. Broja, T.; Fuchs, P.J.W.; Zeitler, K. Domino reactions, more than just a game. Nat. Chem. 2015, 7, 950–951. [Google Scholar] [CrossRef] [PubMed]
  2. Tietze, L.F. Domino reactions in organic synthesis. Chem. Rev. 1996, 96, 115–136. [Google Scholar] [CrossRef] [PubMed]
  3. Armstrong, R.W.; Combs, A.P.; Tempest, P.A.; Brown, S.D.; Keating, S.A. Multiple-component condensation strategies for combinatorial library synthesis. Acc. Chem. Res. 1996, 29, 123–131. [Google Scholar] [CrossRef]
  4. Nicolaou, K.C.; Edmonds, D.J.; Bulger, P.G. Cascade reactions in total synthesis. Angew. Chem. Int. Ed. 2006, 45, 7134–7186. [Google Scholar] [CrossRef] [PubMed]
  5. Tietze, L.F.; Rackelmann, N. The domino-Knoevenagel-hetero Diels-Alder reaction and related transformations. In Multicomponent reactions; Zhu, J., Bienaymé, H., Eds.; Wiley-VCH: Weinheim, Germany, 2005; Chapter 5; pp. 121–168. [Google Scholar]
  6. Tietze, L.F.; Steinmetz, A. Stereoselective solid-phase synthesis of cyclopentane and cyclohexane derivatives by two-component domino reactions: Generation of combinatorial libraries. Angew. Chem. Int. Ed. 1996, 35, 651–652. [Google Scholar] [CrossRef]
  7. Tietze, L.F.; Rischer, M. The tandem Sakurai–carbonyl–Ene reaction: A new and highly stereoselective sequential transformation and its use for the synthesis of steroid derivatives. Angew. Chem. Int. Ed. 1992, 31, 1221–1222. [Google Scholar] [CrossRef]
  8. Marko, I.E.; Dumeunier, R.; Leclercq, C.; Leroy, B.; Plancher, J.M.; Mekhalfia, A.; Bayston, D. Tandem Ene-Reaction/Intramolecular Sakurai Cyclisation (IMSC): A Novel Access to Polysubstituted Tetrahydropyrans and γ-Butyrolactones Using a Unique Allylation Strategy. Synthesis 2002, 7, 958–972. [Google Scholar] [CrossRef]
  9. Marko, I.E.; Leroy, B. Concise and stereocontrolled synthesis of polysubstituted tetrahydropyrans. Tetrahedron Lett. 2000, 41, 7225–7230. [Google Scholar] [CrossRef]
  10. Marko, I.E.; Plancher, J.M. Novel tandem “ene-ISMS” methodology. Efficient and versatile assembly of a pseudomonic acid C analogue. Tetrahedron Lett. 1999, 40, 5259–5262. [Google Scholar] [CrossRef]
  11. Bodwell, G.J.; Hawco, K.M.; da Silva, R.P. Electron deficient dienes 3: Rapid access to 2-hydroxybenzophenones via inverse electron demand Diels-Alder-driven domino reactions of a chromone-fused electron deficient diene with enamines. Synlett 2003, 179–182. [Google Scholar] [CrossRef]
  12. Bodwell, G.J.; Pi, Z. Electron deficient dienes I. Normal and inverse electron demand Diels-Alder reaction of the same carbon skeleton. Tetrahedron Lett. 1997, 38, 309–312. [Google Scholar] [CrossRef]
  13. Conyers, R.C.; Mazzone, J.R.; Siegler, M.A.; Posner, G.H. Highly regiocontrolled and stereocontrolled syntheses of polysubstituted aminocyclohexanes: mild inverse-electron-demand Diels–Alder cycloadditions of electrophilic 2-pyridones. Tetrahedron Lett. 2016, 57, 3344–3348. [Google Scholar] [CrossRef]
  14. Dang, A.T.; Miller, D.O.; Dawe, L.N.; Bodwell, G.J. Electron-deficient dienes. 5. An inverse-electron-demand Diels-Alder approach to 2-substituted 4-methoxyxanthones and 3,4-dimethoxyxanthones. Org. Lett. 2008, 10, 233–236. [Google Scholar] [CrossRef] [PubMed]
  15. Heredia-Moya, J.; Krohn, K.; Flörke, U.; Pessoa-Mahana, H.; Weiss-López, B.; Estévez-Braun, A.; Araya-Maturana, R. Domino inverse electron demand diels-alder reactions of chromones with ethyl vinyl ether. Heterocycles 2007, 71, 1327–1345. [Google Scholar] [CrossRef]
  16. Araya-Maturana, R.; Gavín-Sazatornil, J.A.; Heredia-Moya, J.; Pessoa-Mahana, H.; Weiss-López, B. Long-range correlations (nJC,H n > 3) in the HMBC spectra of 3-(4-oxo-4H-chromen-3-yl)-acrylic acid ethyl esters. J. Braz. Chem. Soc. 2005, 16, 657–661. [Google Scholar] [CrossRef]
  17. Boger, D.L.; Mullican, M.D. Inverse electron demand Diels-Alder reactions of 3-carbomethoxy-2-pyrones. Controlled introduction of oxygenated aromatics: Benzene, phenol, catechol, resorcinol, pyrogallol annulation. Tetrahedron Lett. 1983, 24, 4939–4942. [Google Scholar] [CrossRef]
Scheme 1. Alternative domino reactions of chromone derivatives with ethyl vinyl ether in toluene.
Scheme 1. Alternative domino reactions of chromone derivatives with ethyl vinyl ether in toluene.
Molbank 2017 m928 sch001
Scheme 2. Domino reaction of chromone 1 with N-vinylpyrrolidinone.
Scheme 2. Domino reaction of chromone 1 with N-vinylpyrrolidinone.
Molbank 2017 m928 sch002
Table 1. Selected H,H coupling constants of tetracycles 36 a.
Table 1. Selected H,H coupling constants of tetracycles 36 a.
JH,H3456
10-11β108.610.38.3
10-11α3.42.83.82.4
11α-11β13.813.713.914.2
11β-16β3.1---2.9---
11α-16α---3.7------
15-16β3.17.85.69.6
15-16α8.12.49.85.6
16α-16β1313.313.313.5
a values in Hz.
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