Download PDF
Synlett 2010(1): 115-118  
DOI: 10.1055/s-0029-1218523
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Domino Multicomponent Michael-Michael-Aldol Reactions under Phase-Transfer Catalysis: Diastereoselective Synthesis of Pentasubstituted Cyclohexanes

Diana I. S. P. Resendea, Cristina G. Olivaa, Artur M. S. Silva*a, Filipe A. Almeida Pazb, José A. S. Cavaleiroa
a QOPNA, Departamento de Química, Universidade de Aveiro, 3810-193 Aveiro, Portugal
Fax: +351(234)370084; e-Mail: artur.silva@ua.pt;
b CICECO, Departamento de Química, Universidade de Aveiro, 3810-193 Aveiro, Portugal
Further Information

Publication History

Received 8 October 2009
Publication Date:
20 November 2009 (online)

    Permissions and Reprints All articles of this category

Abstract

A simple, efficient, and environmental friendly domino multicomponent reaction to construct new cyclohexane derivatives with five new stereocenters, one of them quaternary, under phase-transfer catalysis is reported. This novel one-pot reaction allows the transformation of very simple starting materials into pentasubstituted cyclohexane derivatives bearing hydroxy, nitro, and ketone moieties and involving the formation of three new C-C bonds. All compounds have been formed in a completely diastereoselective way and have been isolated in high yields.

Key words

domino reaction - multicomponent reaction - phase-transfer catalysis - diastereoselectivity

    References and Notes

  • 1 Enders D. Huttl MRM. Grondal C. Raabe G. Nature (London)  2006,  441:  861 
    CrossrefPubMedGoogle Scholar
  • 2 Ho TL. Carbocycle Construction in Terpene Synthesis   Wiley-VCH; Weinheim: 1988. 
    Google Scholar
  • For examples, see:
  • 3a Ramachary DB. Reddy YV. Prakash BV. Org. Biomol. Chem.  2008,  6:  719 
    Google Scholar
  • 3b Ishikawa H. Suzuki T. Hayashi Y. Angew. Chem. Int. Ed.  2009,  48:  1304 
    Google Scholar
  • For reviews of this concept, see:
  • 4a Tietze LF. Chem. Rev.  1996,  96:  115 
    Google Scholar
  • 4b Nicolaou KC. Montagnon T. Snyder SA. Chem. Commun.  2003,  551 
    Google Scholar
  • 4c Zhe J. Bienaymé H. Multicomponent Reactions   1st ed.:  Wiley-VCH; Weinheim: 2005. 
    Google Scholar
  • 4d Ramón DJ. Yus M. Angew. Chem. Int. Ed.  2005,  44:  1602 
    Google Scholar
  • 4e Nicolaou KC. Edmonds DJ. Bulger PG. Angew. Chem. Int. Ed.  2006,  45:  7134 
    Google Scholar
  • 4f Tietze LF. Brasche G. Gericke K. Domino Reactions in Organic Synthesis   Wiley-VCH; Weinheim: 2006. 
    Google Scholar
  • 4g Guo HC. Ma JA. Angew. Chem. Int. Ed.  2006,  45:  354 
    Google Scholar
  • 4h Enders D. Grondal C. Huttl MRM. Angew. Chem. Int. Ed.  2007,  46:  1570 
    Google Scholar
  • 4i Tejedor D. García-Tellado F. Chem. Soc. Rev.  2007,  36:  484 
    Google Scholar
  • 4j Guillena G. Ramón DJ. Yus M. Tetrahedron: Asymmetry  2007,  18:  693 
    Google Scholar
  • 4k Padwa A. Bur SK. Tetrahedron  2007,  63:  5341 
    Google Scholar
  • 4l Yua XH. Wang W. Org. Biomol. Chem.  2008,  6:  2037 
    Google Scholar
  • 5 Hashimoto T. Maruoka K. Chem. Rev.  2007,  107:  5656 
    CrossrefPubMedGoogle Scholar
  • 6 Trost BM. Science  1991,  254:  1471 
    Google Scholar
  • 7a Hong BC. Wu MF. Tseng HC. Liao JH. Org. Lett.  2006,  8:  2217 
    Google Scholar
  • 7b Enders D. Narine AA. Benninghaus TR. Raabe G. Synlett  2007,  1667 
    Google Scholar
  • 7c Sridharan V. Menendez JC. Org. Lett.  2008,  10:  4303 
    Google Scholar
  • 7d Cabrera S. Aleman J. Bolze P. Bertelsen S. Jørgensen KA. Angew. Chem. Int. Ed.  2008,  47:  121 
    Google Scholar
  • 7e Hong BC. Nimje RY. Sadani AA. Liao JH. Org. Lett.  2008,  10:  2345 
    Google Scholar
  • 8 Carlone A. Cabrera S. Marigo M. Jørgensen KA. Angew. Chem. Int. Ed.  2007,  46:  1101 
    CrossrefGoogle Scholar
  • 9a Hayashi Y. Okano T. Aratake S. Hazelard D. Angew. Chem. Int. Ed.  2007,  46:  4922 
    Google Scholar
  • 9b Penon O. Carlone A. Mazzanti A. Locatelli M. Sambri L. Bartoli G. Melchiorre P. Chem. Eur. J.  2008,  14:  4788 
    Google Scholar
  • 9c Tan B. Chua PJ. Li YX. Zhong GF. Org. Lett.  2008,  10:  2437 
    Google Scholar
  • 9d Enders D. Huttl MRM. Raabe G. Bats JW. Adv. Synth.Catal.  2008,  350:  267 
    Google Scholar
  • 9e Zhao GL. Dziedzic P. Ullah F. Eriksson L. Cordova A. Tetrahedron Lett.  2009,  50:  3458 
    Google Scholar
  • 10a Reyes E. Jiang H. Milelli A. Elsner P. Hazell RG. Jørgensen KA. Angew. Chem. Int. Ed.  2007,  46:  9202 
    Google Scholar
  • 10b Ruano JLG. Marcos V. Suanzes JA. Marzo L. Aleman J. Chem. Eur. J.  2009,  15:  6576 
    Google Scholar
  • 11a Quaternary Stereocenters. Challenges and Solutions for Organic Synthesis   Christoffers J. Baro A. Wiley-VCH; Weinheim: 2005. 
    Google Scholar
  • 11b Cozzi PG. Hilgraf R. Zimmermann N. Eur. J. Org. Chem.  2007,  5969 
    Google Scholar
  • 12a Synthesis of 1a,c,d: Pinto DCGA. Silva AMS. Levai A. Cavaleiro JAS. Patonay T. Elguero J. Eur. J. Org. Chem.  2000,  2593 
    Google Scholar
  • 12b Synthesis of 1b: Silva AMS. Pinto DCGA. Tavares HR. Cavaleiro JAS. Jimeno ML. Elguero J. Eur. J. Org. Chem.  1998,  2031 
    Google Scholar
  • 12c Synthesis of 1h: Santos CMM. Silva AMS. Cavaleiro JAS. Levai A. Patonay T. Eur. J. Org. Chem.  2007,  2877 
    Google Scholar
  • 17 Park DY. Gowrisankar S. Kim N. Tetrahedron Lett.  2006,  47:  6641 
    CrossrefGoogle Scholar
13

General Procedure for the Syntheses of 1e-g An aqueous solution of NaOH (60%, 25 mL) was slowly added to a methanolic solution (30 mL) of appropiate acetophenone (5.0 mmol). After cooling the solution to r.t., cinnamaldehyde (792 mg, 6.0 mmol) was added. The mixture was stirred at r.t. for 20 h, and then it was poured into H2O (100 mL), ice (100 g), and HCl (pH adjusted to ca. 2). The solid obtained was removed by filtration, dissolved in CHCl3 (50 mL), and washed with an aq solution of NaHCO3 (5%, 30 mL). The organic layer was collected, dried over anhyd Na2SO4, and the solution evaporated to dryness. The residue was purified by silica gel column chromatography using CH2Cl2 as eluent. Finally, the isolated compounds were recrystallized from EtOH. Selected Data for 1g
Yellow solid (1.13 g, 84% yield); 143-144 ˚C. ¹H NMR (300.13 MHz, CDCl3, 20 ˚C): δ = 7.04-7.01 (m, 2 H, H-4, H-5), 7.05 (d, ³ J trans  = 15.0 Hz, 1 H, H-2), 7.41-7.30 (m, 3 H, H-3′′,5′′, H-4′′), 7.52-7.44 (m, 4 H, H-2′′,6′′, H-3′,5′), 7.65-7.57 (m, 1 H, H-3), 7.92 (AA′BB ′, ³ J AB = 8.6, Hz, 4 J AA ′ = 2.2 Hz, 5 J AB ′ = 1.9 Hz, 2 H, H-2′,6′) ppm. ¹³C NMR (125.77 MHz, CDCl3, 20 ˚C): δ = 124.8 (C-2), 126.7 (C-5), 127.4 (C-2′′,6′′), 128.9 (C-3′,5′, C-3′′,5′′), 129.4 (C-4′′), 129.8 (C-2′,6′), 136.0 (C-1′′), 136.5 (C-1′), 139.1 (C-4′), 142.4 (C-4), 145.4 (C-3), 189.1 (C-1) ppm. Anal. Calcd: C, 75.98; H, 4.88. Found: C, 75.92; H, 4.86.

14

General Procedure for the Synthesis of 2a-g
To a stirred 0.2 M solution of the appropriate 1,5-diaryl-penta-2,4-dien-1-ones 1 (0.085 mmol) in MeCN (0.43 mL) was added TBAB (9.2 mg, 0.028 mmol), Cs2CO3 (27.7 mg, 0.085), and MeNO2 (2.3 µL, 0.043 mmol). The mixture was stirred at r.t. for 20 h, quenched with H2O (5 mL), and extracted with CH2Cl2 (3 × 5 mL). The combined organic extracts were dried over MgSO4. Evaporation of the solvent under reduced pressure afforded an oil, which was purified by column chromatography (hexane-EtOAc = 9:1 as eluent) and crystallized (hexane-EtOAc) to afford the desired products 2a-g as single diastereomers.
Selected Data for ( E , E ,1 R *,2 S *,3 S *,4 S *,5 S *)-2-Benzoyl-1-hydroxy-4-nitro-1-phenyl-3,5-distyrylcyclohexane (2a) White solid (17.7 mg, 79% yield; Figure  [³] ); 227-229 ˚C. ¹H NMR (500.13 MHz, CDCl3, 20 ˚C): δ = 2.00 (ddd, J = 14.4, 12.2, 2.6 Hz, 1 H, H-6B), 2.20 (dd, J = 14.4, 4.1 Hz, 1 H, H-6A), 3.72-3.84 (m, 2 H, H-3, H-5), 4.14 (d, J = 11.6 Hz, 1 H, H-2), 4.64 (t, J = 11.1 Hz, 1 H, H-4), 5.34 (d, J = 2.6 Hz, 1 H, OH), 5.71 (dd, J = 15.7, 9.8 Hz, 1 H, H-α′), 6.03 (dd, J = 15.7, 8.8 Hz, 1 H, H-α′′), 6.36 (d, J = 15.7 Hz, 1 H, H-β′), 6.56 (d, J = 15.7 Hz, 1 H, H-β′′), 6.85-6.87 (m, 2 H, H-2′′′,6′′′), 7.10-7.11 (m, 4 H, H-3′,5′, H-3′′′,5′′′), 7.20-7.31 (m, 9 H, H-2′′′′,6′′′′, H-3′′,5′′, H-3′′′′,5′′′′, H-4′, H-4′′′, H-4′′′′), 7.42 (t, J = 8.3 Hz, 1 H, H-4′′), 7.45 (dd, J = 8.3, 1.0 Hz, 2 H, H-2′,6′), 7.56 (dd, J = 8.3, 1.2 Hz, 2 H, H-2′′,6′′) ppm. ¹³C NMR (125.77 MHz, CDCl3, 20 ˚C): δ = 40.9 (C-5), 44.0 (C-6), 45.6 (C-3), 53.2 (C-2), 74.3 (C-1), 94.1 (C-4), 123.9 (C-α′′), 124.5 (C-2′,6′), 126.4 (CAr), 126.5 (C-2′′′,6′′′), 126.6 (C-α′), 127.4 (CAr), 127.8 (CAr), 127.9 (CAr), 128.1 (C-2′′,6′′), 128.2 (CAr), 128.4 (CAr), 128.5 (CAr), 128.6 (CAr), 133.5 (C-β′′), 133.6 (C-4′′), 135.5 (C-β′), 135.8 (C-1′′′), 136.4 (C-1′′′′), 137.8 (C-1′′), 144.7 (C-1′), 205.0 (C=O) ppm. HRMS (ESI+): m/z calcd for [C35H31NO4 + Na]+: 552.2145; found: 552.2147. Anal. Calcd: C, 79.37; H, 5.90; N, 2.64. Found: C, 78.97; H, 5.91; N, 2.73.

Figure 3

15

Crystal Data
C35H31NO4, M = 529.61, monoclinic, space group P21/n, Z = 4, a = 5.6904 (2) Å, b = 15.8717 (5) Å, c = 31.4292 (9) Å, β = 91.793 (2)˚, V = 2837.18 (16) ų, colorless needles with crystal size of 0.20 × 0.08 × 0.06 mm³. Of a total of 34281 reflections collected, 7584 were independent (R int = 0.0843). Final R1 = 0.0588 [I > 2σ(I)] and wR2 = 0.1497 (all data). CCDC-743412 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data request/cif.

16

Nonhydrogen atoms are represented as thermal ellipsoids drawn at the 50% probability level and hydrogen atoms as small spheres with arbitrary radii. For simplicity only one position of the disordered phenyl group is represented. Hydrogen-bonding geometry details of the intramolecular O-H˙˙˙O interaction (dashed green line): dO ˙˙˙ O = 2.6726 (19) Å and <(DHA) = 141.3˚.