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Synlett 2013; 24(18): 2375-2382
DOI: 10.1055/s-0033-1340043
letter
© Georg Thieme Verlag Stuttgart · New York

1,6-Conjugate Addition of Carbon Nucleophiles to (E)-2-Styrylchromones: Unexpected Synthesis of a Stereochemically Complex Pentasubstituted Spirocyclohexane

Eduarda M. P. Silva*
Department of Chemistry, QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal   Fax: +351(234)370714   Email: eduarda.silva@ua.pt   Email: artur.silva@ua.pt
,
Kinga Grenda
Department of Chemistry, QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal   Fax: +351(234)370714   Email: eduarda.silva@ua.pt   Email: artur.silva@ua.pt
,
Inês N. Cardoso
Department of Chemistry, QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal   Fax: +351(234)370714   Email: eduarda.silva@ua.pt   Email: artur.silva@ua.pt
,
Artur M. S. Silva*
Department of Chemistry, QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal   Fax: +351(234)370714   Email: eduarda.silva@ua.pt   Email: artur.silva@ua.pt
› Author Affiliations
Further Information

Publication History

Received: 26 July 2013

Accepted after revision: 30 September 2013

Publication Date:
16 October 2013 (online)

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Abstract

The regioselective 1,6-conjugate addition of ethyl malonate and malononitrile to (E)-2-styrylchromones is described. A synthesis of novel pentasubstituted spirocyclohexanes discovered during the course of these studies is also discussed. A novel domino multicomponent 1,6-/1,6-/1,4-conjugate addition reaction for the formation of these new spirocyclohexanes is proposed.

Key words

heterocycles - polycycles - nucleophilic additions - addition reactions - spiro compounds - domino reactions - multicomponent reactions
 

  • References and Notes

  • 1 Perlmutter P In Conjugate Addition Reactions in Organic Synthesis. Pergamon; Oxford: 1992
    Search in Google Scholar
  • 3 Nishimura T, Noishiki A, Hayashi T. Chem. Commun. 2012; 48: 973
    CrossrefPubMedSearch in Google Scholar
  • 4 Nishimura T, Yasuhara Y, Sawano T, Hayashi T. J. Am. Chem. Soc. 2010; 132: 7872
    CrossrefPubMedSearch in Google Scholar
  • 6 Brooks JL, Caruana PA, Frontier AJ. J. Am. Chem. Soc. 2011; 133: 12454
    CrossrefSearch in Google Scholar
  • 8 Murphy JJ, Quintard A, McArdle P, Alexakis A, Stephens JC. Angew. Chem. Int. Ed. 2011; 50: 5095
    CrossrefSearch in Google Scholar
  • 9 Bernardi L, López-Cantarero J, Niess B, Jørgensen KA. J. Am. Chem. Soc. 2007; 129: 5772
    CrossrefPubMedSearch in Google Scholar
  • 10 Sun H.-W, Liao Y.-H, Wu Z.-J, Wang H.-Y, Zhang X.-M, Yuan W.-C. Tetrahedron 2011; 67: 3991
    CrossrefSearch in Google Scholar
  • 11 Ballini R, Bosica G, Fiorini D. Tetrahedron Lett. 2001; 42: 8471
    CrossrefSearch in Google Scholar

      • For selected examples, see:
    • 13a Gomes A, Fernandes E, Silva AM. S, Santos CM. M, Pinto DC. G. A, Cavaleiro JA. S, Lima JL. F. C. Bioorg. Med. Chem. 2007; 15: 6027
      CrossrefSearch in Google Scholar
    • 13b Gomes A, Fernandes E, Silva AM. S, Pinto DC. G. A, Santos CM. M, Cavaleiro JA. S, Lima JL. F. C. Biochem. Pharmacol. 2009; 78: 171
      CrossrefSearch in Google Scholar
  • 14 Gomes A, Freitas M, Fernandes E, Lima JL. F. C. Mini-Rev. Med. Chem. 2010; 10: 1
    CrossrefPubMedSearch in Google Scholar

      • For recent examples, see:
    • 15a Resende DI. S. P, Oliva CG, Silva AM. S, Paz FA. A, Cavaleiro JA. S. Synlett 2010; 115
      Thieme Connect
    • 15b Oliva CG, Silva AM. S, Resende DI. S. P, Paz FA. A, Cavaleiro JA. S. Eur. J. Org. Chem. 2010; 3449
    • 15c Lévai A, Silva AM. S, Santos CM. M, Cavaleiro JA. S, Jeko J. Aust. J. Chem. 2009; 62: 82
      CrossrefSearch in Google Scholar
    • 15d Santos CM. M, Silva AM. S, Cavaleiro AM. S, Lévai A, Patonay T. Eur. J. Org. Chem. 2007; 2877
    • 15e Lévai A, Silva AM. S, Cavaleiro JA. S, Patonay T, Silva VL. M. Eur. J. Org. Chem. 2001; 3213
  • 16 Silva EM. P, Silva AM. S, Cavaleiro JA. S. Synlett 2011; 2740
    Thieme Connect
  • 17 Chromones 7a–d; General ProcedureA solution of the appropriate (E)-2-styrylchromone 5a–d (0.122 mmol) in anhyd EtOH (1 mL) was added dropwise to a solution of NaOEt [Na (1.7 mg) in anhyd EtOH (0.13 mL)] and ethyl malonate (0.263 mmol) at 0 °C. The mixture was flushed with N2 and stirred vigorously at r.t. for the appropriate time. 0.1 M aq HCl (1.2 mL) was added and the organic phase was separated, extracted with Et2O, dried (Na2SO4), and concentrated under reduced pressure. The residue was dissolved in EtOAc and purified by preparative TLC [silica, hexane–EtOAc (7:3)].Diethyl [2-(4-Oxo-4H-chromen-2-yl)-1-phenylethyl]malonate (7a)Colorless oil; yield: 26.0 mg (52%). 1H NMR (300.13 MHz, CDCl3): δ = 8.09 (dd, J = 1.7, 8.0 Hz, 1 H, H-5), 7.62 (ddd, J = 1.7, 7.0, 8.6 Hz, 1 H, H-7), 7.38–7.31 (m, 2 H, H-6, H-8), 7.22–7.15 (m, 5 H, Ph), 5.93 (s, 1 H, H-3), 4.25 (dq, J = 1.0, 7.1 Hz, 2 H, CO2CH 2CH3), 3.99–3.94 (m, 1 H, H-β), 3.93 (q, J = 7.1 Hz, 2 H, CO2CH 2CH3), 3.80 [d, J = 10.4 Hz, 1 H, CH(CO2CH2CH3)2], 3.19 (dd, J = 4.3, 14.2 Hz, 1 H, H-α), 2.92 (dd, J = 10.4, 14.2 Hz, 1 H, H-α), 1.30 (t, J = 7.1 Hz, 3 H, CO2CH2CH 3), 0.97 (t, J = 7.1 Hz, 3 H, CO2CH2CH 3). 13C NMR (75.47 MHz, CDCl3): δ = 177.9 (C=O), 168.0 (CO2CH2CH3), 167.3 (CO2CH2CH3), 166.2 (C-2), 156.3 (C-9), 138.6 (C-1′), 133.5 (C-7), 128.6 (C-3′, C-5′), 127.9 (C-2′, C-6′), 127.6 (C-4′), 125.5 (C-5), 124.9 (C-6), 123.5 (C-10), 117.8 (C-8), 111.6 (C-3), 61.9 (CO2 CH2CH3), 61.5 (CO2 CH2CH3), 57.5 [CH(CO2CH2CH3)2], 43.3 (C-β), 38.9 (C-α), 14.1 (CO2CH2 CH3), 13.7 (CO2CH2 CH3). HRMS (ESI): m/z [M + H]+ calcd for C24H25O6 +: 409.16456; found: 409.16467.
  • 18 Chromones 8a–d; General ProcedureA few drops of piperidine (1.59 μL, 0.1 equiv) were added to a solution of the appropriate (E)-2-styrylchromone 5a–d (0.161 mmol) and malononitrile (0.177 mmol) in anhyd EtOH (1 mL), and the mixture was stirred and refluxed under N2. The resulting solution was concentrated to dryness, taken up in EtOAc, and purified by preparative TLC [silica, hexane–EtOAc (7:3)].[2-(4-Oxo-4H-chromen-2-yl)-1-phenylethyl]-malononitrile (8a)Yellow solid; yield: 26.8 mg (53%); mp 141.6–142.2 °C. 1H NMR (300.13 MHz, CDCl3): δ = 8.12 (dd, J = 1.6, 7.9 Hz, 1 H, H-5), 7.67 (ddd, J = 1.6, 7.1, 8.5 Hz, 1 H, H-7), 7.42–7.35 (m, 7 H, Ph, H-6, H-8), 6.15 (s, 1 H, H-3), 4.14 [d, J = 5.8 Hz, 1 H, β-CH(CN)2], 3.88–3.81 (m, 1 H, H-β), 3.44 (dd, J = 6.5, 14.7 Hz, 1 H, H-α), 3.32 (dd, J = 8.9, 14.7 Hz, 1 H, H-α). 13C NMR (75.47 MHz, CDCl3): δ = 177.7 (C=O), 163.4 (C-2), 156.2 (C-9), 134.8 (C-1′), 134.0 (C-7), 129.62 (C-4′), 129.56 (C-3′, C-5′), 127.6 (C-2′, C-6′), 125.8 (C-5), 125.5 (C-6), 123.5 (C-10), 117.7 (C-8), 112.2 (C-3), 111.2 (CN), 111.1 (CN), 44.0 (C-β), 36.9 (C-α), 29.5 [β-CH(CN)2]. HRMS (ESI): m/z [M + H]+ calcd for C20H15N2O2 +: 315.11280; found: 315.11331.
  • 19 [1-(4-Oxo-4H-chromen-2-yl)-2-phenylethyl]-malononitrile (9a)Yellow oil; yield: 11.5 mg (23%). 1H NMR (300.13 MHz, CDCl3): δ = 7.95 (d, J = 6.8 Hz, 1 H, H-5), 7.64 (dt, J = 1.6, 7.9 Hz, 1 H, H-7), 7.51–7.37 (m, 7 H, H-6, H-8, Ph), 5.55 (s, 1 H, H-3), 5.11 [d, J = 3.2 Hz, 1 H, α-CH(CN)2], 4.23–4.17 (m, 1 H, H-α), 3.72 (dd, J = 8.6, 16.0 Hz, 1 H, H-β), 3.57 (dd, J = 5.6, 16.0 Hz, 1 H, H-β). MS (ESI): m/z [M + H]+ calcd for C20H15N2O2 +: 315.11280; found: 315.1.
  • 20 Silva AM. S, Almeida LM. P. M, Cavaleiro JA. S, Levai A, Patonay T, Pinto DC. G. A. J. Heterocycl. Chem. 1998; 35: 217
    CrossrefSearch in Google Scholar
  • 21 (2R*,2′S*,3′R*,4′S*,5′S*)-4′-Nitro-2'-(4-oxo-4H-chromen-2-yl)-3′,5′-diphenylspiro[chromene-2,1′-cyclohexan]-4(3H)-one (10a) and (2R*,2′S*,3′R*,4′S*,5′R*)-4′-Nitro-2'-(4-oxo-4H-chromen-2-yl)-3′,5′-diphenylspiro[chromene-2,1′-cyclohexan]-4(3H)-one (11a)TBAB (22.0 mg, 0.068 mmol), Cs2CO3 (55.0 mg, 0.169 mmol), and MeNO2 (4.66 μL, 0.086 mmol) were added to a stirred solution of chromone 5a (40.0 mg, 0.161 mmol) in MeCN (1 mL), and the mixture was stirred at r.t. for 6 d. The reaction was then quenched with H2O (10 mL), and the mixture was extracted with CH2Cl2 (3  × 5 mL). The organic extracts were combined, dried (MgSO4), and concentrated under reduced pressure to give an oil that was purified by preparative TLC [silica, hexane–EtOAc (7:3)] to give 10a and 11a. The yield shown for compound 12a was obtained when the reaction was left for 2 days under the described conditions.10a: Yellow solid; yield: 15.3 mg (17%); mp 190 °C (dec.). 1H NMR (300.13 MHz, CDCl3): δ = 8.01 (dd, J = 1.6, 8.1 Hz, 1 H, H-5′′), 7.74 (dd, J = 1.6, 7.6 Hz, 1 H, H-6′), 7.64–7.56 (m, 2 H, H-4′, H-7′′), 7.36 (dd, J = 0.7, 8.3 Hz, 1 H, H-3′), 7.34–7.23 (m, 6 H, Ph-m, H-6′′, H-8′′), 7.21–7.08 (m, 6 H, Ph-o,p), 7.01 (dt, J = 0.7, 7.6 Hz, 1 H, H-5′), 6.36 (br s, 1 H, H-3′′), 5.04 (t, J = 12.4 Hz, 1 H, H-4), 4.47 (br t, J = 12.4 Hz, 1 H, H-3), 3.79 (dt, J = 3.6, 12.4 Hz, 1 H, H-5), 3.25 (d, J = 12.4 Hz, 1 H, H-2), 3.04 (d, J = 16.6 Hz, 1 H, H-9′), 2.72 (dd, J = 3.6, 14.4 Hz, 1 H, H-6B), 2.69 (d, J = 16.6 Hz, 1 H, H-9′), 2.01 (dd, J = 12.4, 14.4 Hz, 1 H, H-6A). 13C NMR (75.47 MHz, CDCl3): δ = 189.7 (C-8′), 177.2 (C-4′′), 163.2 (C-2’’), 157.9 (C-2′), 155.8 (C-9′′), 137.3 (C-1 of 5-Ph), 136.9 (C-4′), 135.2 (C-1 of 3-Ph), 133.8 (C-7′′), 129.14 and 129.09 (C-3,5 of 3- and 5-Ph), 128.6 and 128.4 (C-4 of 3- and 5-Ph), 127.1 (C-2,6 of 3- and 5-Ph), 126.8 (C-6′), 125.6 (C-5′′), 125.4 (C-6′′), 123.4 (C-10′′), 122.1 (C-5′), 120.1 (C-7′), 118.2 (C-3′), 117.6 (C-8′′), 114.4 (C-3′′), 95.7 (C-4), 79.4 (C-1), 55.1 (C-2), 46.2 (C-3), 45.8 (C-9′), 43.0 (C-5), 38.7 (C-6).HRMS (ESI): m/z [M + H]+ calcd for C35H28NO6 +: 558.19111; found: 558.19001.11a: White solid; yield: 2.7 mg (3%); mp 182.2–182.7 °C. 1H NMR (300.13 MHz, CDCl3): δ = 8.02 (dd, J = 1.7, 8.0 Hz, 1 H, H-5′′), 7.77 (dd, J = 1.7, 7.5 Hz, 1 H, H-6′), 7.61 (ddd, J = 1.7, 7.5, 8.4 Hz, 1 H, H-7′′), 7.51 (ddd, J = 1.7, 7.5, 8.5 Hz, 1 H, H-4′), 7.40 (d, J = 8.4 Hz, 1 H, H-8′′), 7.34–7.12 (m, 12 H, 3,5-Ph, H-6′′, H-3′), 6.98 (dt, J = 0.8, 7.5 Hz, 1 H, H-5′), 6.41 (s, 1 H, H-3′′), 5.20 (t, J = 4.0 Hz, 1 H, H-4), 4.35 (dd, J = 4.0, 12.9 Hz, 1 H, H-3), 4.28 (d, J = 12.9 Hz, 1 H, H-2), 3.72 (dt, J = 4.0, 14.0 Hz, 1 H, H-5), 3.11 (d, J = 16.6 Hz, 1 H, H-9′), 2.93 (d, J = 16.6 Hz, 1 H, H-9′), 2.90 (t, J = 14.0 Hz, 1 H, H-6B), 2.59 (dd, J = 4.0, 14.0 Hz, 1 H, H-6A). 13C NMR (75.47 MHz, CDCl3): δ = 190.1 (C-8′), 177.3 (C-4′′), 164.8 (C-2’’), 157.9 (C-2′), 155.9 (C-9′′), 137.0 (C-1 of 5-Ph), 136.7 (C-4′), 135.6 (C-1 of 3-Ph), 133.8 (C-7′′), 129.2 and 129.1 (C-3,5 of 3- and 5-Ph), 128.5 and 128.3 (C-4 of 3- and 5-Ph), 127.4 and 127.1 (C-2,6 of 3- and 5-Ph), 126.8 (C-6′), 125.6 (C-5′′), 125.4 (C-6′′), 123.6 (C-10′′), 122.0 (C-5′), 120.2 (C-7′), 117.9 (C-3′), 117.8 (C-8′′), 114.2 (C-3′′), 93.3 (C-4), 80.4 (C-1), 48.1 (C-2), 46.4 (C-9′), 44.3 (C-3), 40.3 (C-5), 30.9 (C-6). HRMS (ESI): m/z [M + H]+ calcd for C35H28NO6 +: 558.19111; found: 558.19000.2,2′-[(2R*,3S*,4R*)-3-Nitro-2,4-diphenylpentane-1,5-diyl]bis(4H-chromen-4-one) (12a)Colorless oil; yield: 3.1 mg (3%). 1H NMR (300.13 MHz, CDCl3): δ = 8.17 (dd, J = 1.6, 7.6 Hz, 1 H, H-5′), 8.04 (dd, J = 1.6, 7.9 Hz, 1 H, H-5′′), 7.67–7.57 (m, 2 H, H-7′, H-7′′), 7.40 (td, J = 0.9, 7.6 Hz, 1 H, H-6′), 7.34–7.27 (m, 5 H, H-6′′, H-8′′, 4-Ph-m,p), 7.19–7.15 (m, 2 H, H-8′, 2-Ph-p), 7.10 (t, J = 7.8 Hz, 2 H, 2-Ph-m), 7.03–7.00 (m, 2 H, 4-Ph-o), 6.93 (dd, J = 1.4, 7.8 Hz, 2 H, 2-Ph-o), 6.29 (s, 1 H, H-3′′), 5.72 (s, 1 H, H-3′), 5.25 (dd, J = 3.2, 10.5 Hz, 1 H, H-3), 3.70 (dt, J = 3.6, 10.5 Hz, 1 H, H-2), 3.62–3.56 (m, 1 H, H-4), 3.30 (dd, J = 9.4, 14.2 Hz, 1 H, H-5A), 2.95 (dd, J = 3.6, 14.0 Hz, 1 H, H-1B′), 2.91 (dd, J = 6.5, 14.2 Hz, 1 H, H-5A′), 2.77 (dd, J = 10.5, 14.0 Hz, 1 H, H-1B). 13C NMR (75.47 MHz, CDCl3): δ = 177.8 (C-4′), 177.6 (C-4′′), 164.9 (C-2′), 164.8 (C-2′′), 156.2 (C-9′), 156.0 (C-9′′), 136.6 (2-Ph), 135.7 (4-Ph), 133.6 (C-7′, C-7′′), 129.4 (2-Ph-m), 128.8 (4-Ph-m), 128.7 (4-Ph-p), 128.4 (2-Ph-p), 128.1 (4-Ph-o), 128.0 (2-Ph-o), 125.7 (C-5′), 125.5 (C-5′′), 125.3 (C-6′), 125.1 (C-6′′), 123.5 (C-10′′), 123.3 (C-10′), 117.8 (C-8′), 117.7 (C-8′′), 112.5 (C-3′′), 111.9 (C-3′), 92.5 (C-3), 44.6 (C-2), 43.5 (C-4), 38.6 (C-1), 37.6 (C-5). HRMS (ESI): m/z [M + H]+ calcd for C35H28NO6 +: 558.19111 [M + H]+; found: 558.19035.