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

Eduarda M. P. Silva; Kinga Grenda; Inês N. Cardoso; Artur M. S. Silva

doi:10.1055/s-0033-1340043

Synlett, Inhaltsverzeichnis

Synlett 2013; 24(18): 2375-2382
DOI: 10.1055/s-0033-1340043

letter

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

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Abstract

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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

Volltext

Referenzen

References and Notes
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15a Resende DI. S. P, Oliva CG, Silva AM. S, Paz FA. A, Cavaleiro JA. S. Synlett 2010; 115
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16 Silva EM. P, Silva AM. S, Cavaleiro JA. S. Synlett 2011; 2740
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
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-6_B), 2.69 (d, J = 16.6 Hz, 1 H, H-9′), 2.01 (dd, J = 12.4, 14.4 Hz, 1 H, H-6_A). 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-6_B), 2.59 (dd, J = 4.0, 14.0 Hz, 1 H, H-6_A). 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-5_A), 2.95 (dd, J = 3.6, 14.0 Hz, 1 H, H-1_B′), 2.91 (dd, J = 6.5, 14.2 Hz, 1 H, H-5_A′), 2.77 (dd, J = 10.5, 14.0 Hz, 1 H, H-1_B). 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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