Subscribe to RSS
Please copy the URL and add it into your RSS Feed Reader.
https://www.thieme-connect.de/rss/thieme/en/10.1055-s-00000083.xml
Synlett 2013; 24(18): 2375-2382
DOI: 10.1055/s-0033-1340043
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
Further Information
Publication History
Received: 26 July 2013
Accepted after revision: 30 September 2013
Publication Date:
16 October 2013 (online)
![](https://www.thieme-connect.de/media/synlett/201318/lookinside/thumbnails/10.1055-s-0033-1340043-1.jpg)
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.
-
References and Notes
- 1 Perlmutter P In Conjugate Addition Reactions in Organic Synthesis. Pergamon; Oxford: 1992
- 2a Silva EM. P, Silva AM. S. Synthesis 2012; 44: 3109
- 2b Csákÿ AG, Herrán G, Murcia MC. Chem. Soc. Rev. 2010; 39: 4080
- 2c Krause N, Thorand S. Inorg. Chim. Acta 1999; 296: 1
- 3 Nishimura T, Noishiki A, Hayashi T. Chem. Commun. 2012; 48: 973
- 4 Nishimura T, Yasuhara Y, Sawano T, Hayashi T. J. Am. Chem. Soc. 2010; 132: 7872
- 5a Roscales S, Salado IG, Csákÿ AG. Synlett 2011; 2234
- 5b Nishimura T, Makino H, Nagaosa M, Hayashi T. J. Am. Chem. Soc. 2010; 132: 12865
- 5c Herrán G, Csákÿ AG. Synlett 2009; 585
- 5d Nishimura T, Yasuhara Y, Hayashi T. Angew. Chem. Int. Ed. 2006; 45: 5164
- 5e Tseng N.-W, Mancuso J, Lautens M. J. Am. Chem. Soc. 2006; 128: 5338
- 5f Herrán G, Murcia C, Csákÿ AG. Org. Lett. 2005; 7: 5629
- 5g Hayashi T, Takahashi M, Takaya Y, Ogasawara M. J. Am. Chem. Soc. 2002; 124: 5052
- 6 Brooks JL, Caruana PA, Frontier AJ. J. Am. Chem. Soc. 2011; 133: 12454
- 7a Tissot M, Müller D, Belot S, Alexakis A. Org. Lett. 2010; 12: 2770
- 7b Wencel-Delord J, Alexakis A, Crévisy C, Mauduit M. Org. Lett. 2010; 12: 4335
- 7c Hartog T, Dijken DJ, Minnaard AJ, Feringa BL. Tetrahedron: Asymmetry 2010; 21: 1574
- 7d Hartog T, Harutyunyan SR, Font D, Minnaard AJ, Feringa BL. Angew. Chem. Int. Ed. 2008; 47: 398
- 7e Okada S, Arayama K, Murayama R, Ishizuka T, Hara K, Hirone N, Hata T, Urabe H. Angew. Chem. Int. Ed. 2008; 47: 6860
- 7f Hénon H, Mauduit M, Alexakis A. Angew. Chem. Int. Ed. 2008; 47: 9122
- 7g Yoshikai N, Yamashita T, Nakamura E. Chem. Asian J. 2006; 1: 322
- 7h Kusama H, Sawada T, Okita A, Shiozawa F, Iwasawa N. Org. Lett. 2006; 8: 1077
- 7i Fillion E, Wilsily A, Liao E-T. Tetrahedron: Asymmetry 2006; 17: 2957
- 7j Hayashi T, Yamamoto S, Tokunaga N. Angew. Chem. Int. Ed. 2005; 44: 4224
- 7k Fukuhara K, Urabe H. Tetrahedron Lett. 2005; 46: 603
- 7l Hayashi T, Tokunaga N, Inoue K. Org. Lett. 2004; 6: 305
- 7m Caro B, Le Poul P, Guen FR.-L, Sénéchal-Tocquer M.-C, Saillard J.-Y, Kahlal S, Ouahab L, Golhen S. Eur. J. Org. Chem. 2000; 577
- 7n Uerdingen M, Krause N. Tetrahedron 2000; 56: 2799
- 8 Murphy JJ, Quintard A, McArdle P, Alexakis A, Stephens JC. Angew. Chem. Int. Ed. 2011; 50: 5095
- 9 Bernardi L, López-Cantarero J, Niess B, Jørgensen KA. J. Am. Chem. Soc. 2007; 129: 5772
- 10 Sun H.-W, Liao Y.-H, Wu Z.-J, Wang H.-Y, Zhang X.-M, Yuan W.-C. Tetrahedron 2011; 67: 3991
- 11 Ballini R, Bosica G, Fiorini D. Tetrahedron Lett. 2001; 42: 8471
- 12a Gerwick WH, Lopez A, Van Dyune GD, Clardy J, Ortiz W, Baez A. Tetrahedron Lett. 1986; 27: 1979
- 12b Gerwick WH. J. Nat. Prod. 1989; 52: 252
- 12c Yoon JS, Lee MK, Sung SH, Kim YC. J. Nat. Prod. 2006; 69: 290
- 12d Yang L, Qiao L, Xie D, Yuan Y, Chen N, Dai J, Guo S. Phytochemistry 2012; 76: 92
- 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
- 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
- 14 Gomes A, Freitas M, Fernandes E, Lima JL. F. C. Mini-Rev. Med. Chem. 2010; 10: 1
- 15a Resende DI. S. P, Oliva CG, Silva AM. S, Paz FA. A, Cavaleiro JA. S. Synlett 2010; 115
- 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
- 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
- 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-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.
For reviews, see:
For selected examples, see:
For recent examples, see: