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)


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.

 
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  • 17 Chromones 7a–d; General ProcedureA solution of the appropriate (E)-2-styrylchromone 5ad (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 5ad (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.
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  • 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.
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