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

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.

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

References and Notes

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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.

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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 (C_Ar), 126.5 (C-2′′′,6′′′), 126.6 (C-α′), 127.4 (C_Ar), 127.8 (C_Ar), 127.9 (C_Ar), 128.1 (C-2′′,6′′), 128.2 (C_Ar), 128.4 (C_Ar), 128.5 (C_Ar), 128.6 (C_Ar), 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

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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) Å^³, colorless needles with crystal size of 0.20 × 0.08 × 0.06 mm^³. 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.

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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): d_{O ˙˙˙ O} = 2.6726 (19) Å and <(DHA) = 141.3˚.

17 Park DY. Gowrisankar S. Kim N. Tetrahedron Lett.  2006,  47:  6641