Carbonyl Umpolung Reactivity of Enals: NHC-Catalyzed Synthesis of Aldol Products via Epoxide Ring Opening

Abstract

A novel one-pot N-heterocyclic carbene catalyzed synthesis of aldol products and their application to a facile and highly cis-selective synthesis of tetrahydropyran-4-ones is reported. The protocol involves carbonyl umpolung reactivity of enals in which the carbonyl carbon attacks nucleophilically on electrophilic terminal epoxides, regioselectively, to afford aldol adducts in good to excellent yields.

Key words

N-heterocyclic carbenes - umpolung - epoxides - aldols - enals - tetrahydropyran-4-ones

References and Notes

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11

General Procedure for the Synthesis of Aldol Products 4 A flame-dried round-bottom flask was charged with benzimidazolium salt 3a (0.3 mmol). α,β-unsaturated aldehyde 1 (1.0 mmol), epoxide 2 (1.5 mmol), and THF-
t-BuOH (10:1, 5 mL) under positive pressure of nitrogen followed by addition of DBU (0.3 mmol) with a syringe. The resulting yellow-orange solution was stirred for 15-18 h at r.t. (Table 2). After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chroma-tography on silica gel using hexane-EtOAc (10:1) as eluent to afford analytically pure 4.
Characterization Data of Representative Compounds 4 Compound 4c: IR (KBr): ν_max = 3439, 3021, 2929, 1676, 1627, 1608, 1585, 1453, 1347 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 3.09 (dd, 1 H, J = 17.3, 9.1 Hz, α′-H_a), 3.17 (dd, 1 H, J = 17.3, 3.5 Hz, α′-H_b), 3.69 (d, 1 H J = 2.9 Hz, OH), 5.20 (ddd, 1 H, J = 9.1, 3.5, 2.9 Hz, β′-H), 6.73 (d, 1 H, J = 16.5 Hz, α-H), 7.53-7.41 (m, 5 H_arom, Ph), 7.59 (d, 2 H_arom, J = 8.7 Hz, 4-O₂NC₆H₄), 7.65 (d, 1 H, J = 16.5 Hz, β-H), 8.27 (d, 2 H_arom, J = 8.7 Hz, 4-O₂NC₆H₄). ^¹³C NMR (100 MHz, CDCl₃-TMS): δ = 48.6, 69.5, 122.3, 126.5, 127.8, 128.5, 129.1, 129.9, 134.2, 141.3, 144.1, 147.9, 199.7. MS (EI): m/z = 297 [M⁺]. Anal. Calcd for C₁₇H₁₅NO₄: C, 68.68; H, 5.09; N, 4.71. Found: 68.96; H, 4.82; N, 4.50.
Compound 4f: IR (KBr): ν_max = 3421, 3011, 2921, 1665, 1626, 1603, 1587, 1451 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = δ 3.01 (dd, 1 H, J = 17.1, 8.5 Hz, α′-H_a), 3.09 (dd, 1 H, J = 17.1, 3.7 Hz, α′-H_b), 3.78 (s, 3 H, OMe), 3.49 (d, 1 H, J = 2.8 Hz, OH), 5.19 (ddd, 1 H, J = 8.5, 3.7, 2.8 Hz, β′-H), 6.76 (d, 1 H, J = 16.1 Hz, α-H), 7.31-7.01 (m, 4 H_arom, 3-MeOC₆H₄), 7.51-7.39 (m, 5 H_arom, Ph), 7.59 (d, 1 H, J = 16.1 Hz, β-H). ^¹³C NMR (100 MHz, CDCl₃-TMS): δ = 49.5, 56.3, 70.3, 111.9, 114.7, 119.5, 126.7, 127.5, 128.1, 129.4, 130.3, 136.9, 141.5, 144.3, 161.3, 200.4. MS (EI): m/z = 282 [M⁺]. Anal. Calcd for C₁₈H₁₈O₃: C, 76.57; H, 6.43. Found: C, 76.92; H, 6.33.
Compound 4i: IR (KBr): ν_max = 3441, 3027, 2920, 1679, 1618, 1606, 1584, 1458, 1349 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 3.09 (dd, 1 H, J = 17.5, 8.5 Hz, α′-Ha), 3.19 (dd, 1 H, J = 17.5, 3.8 Hz, α′-H_b), 3.49 (d, 1 H, J = 2.9 Hz, OH), 3.83 (s, 3 H, OMe), 5.21 (ddd, 1 H, J = 8.5, 3.8, 2.9 Hz, β′-H), 6.69 (d, 1 H, J = 16.5 Hz, α-H), 6.93 (d, 2 H_arom, J = 8.7 Hz, 4-MeOC₆H₄), 7.23 (d, 2 H_arom, J = 8.7 Hz, 4-MeOC₆H₄), 7.62 (d, 2 H_arom, J = 8.9 Hz, 4-O₂NC₆H₄), 7.71 (d, 1 H, J = 16.5 Hz, β-H), 8.21 (d, 2 H_arom, J = 8.9 Hz, 4-O₂NC₆H₄). ^¹³C NMR (100 MHz, CDCl₃-TMS): δ = 49.3, 60.1, 69.7, 115.2, 122.3, 126.9, 128.1, 129.3, 133.9, 142.3, 144.1, 148.4,159.8, 200.1. MS (EI): m/z = 327 [M⁺]. Anal. Calcd for C₁₈H₁₇NO₅: C, 66.05; H, 5.23; N, 4.28. Found: C, 65.69; H, 5.34; N, 4.51.
Compound 4o: IR (KBr): ν_max = 3431, 3028, 2930, 1681, 1623, 1608, 1585, 1456, 1351 cm-1. ^¹H NMR (400 MHz, CDCl₃): δ = 3.11 (dd, 1 H, J = 17.3, 9.2 Hz, α′-H_a), 3.17 (dd, 1 H, J = 17.3, 3.1 Hz, α′-H_b), 3.74 (d, 1 H, J = 3.0 Hz, OH), 5.43 (ddd, 1 H, J = 9.2, 3.1, 3.0 Hz, β′-H), 6.78 (d, 1 H, J = 16.5 Hz, α-H), 7.63 (d, 1 H, J = 16.5 Hz, β-H), 8.29-7.71 (m, 8 H_arom, 2 Ž 4-O₂NC₆H₄). ^¹³C NMR (100 MHz, CDCl₃-TMS): δ = 49.3, 69.5, 121.5, 122.3, 125.9, 127.9, 128.7, 142.4, 144.5, 146.2, 147.1, 147.9, 200.1. MS (EI): m/z = 342 [M⁺]. Anal. Calcd for C₁₇H₁₄N₂O₆: C, 59.65; H, 4.12; N, 8.18. Found: C, 59.90; H, 4.24; N, 7.91.

16

General Procedure for the Diastereoselective Synthsis of Tetrahydropyran-4-ones 5
A mixture of aldol adduct 4 (0.2 mmol) and BF₃˙OEt₂ (0.2 mmol) in CH₂Cl₂ (5 mL) was stirred at 0 ˚C for 30-40 min (Table 3). After completion of the reaction (monitored by TLC), the mixture was diluted with EtOAc (30 mL), washed with sat. aq NaHSO₃ solution (2 × 30 mL) and then with brine (1 × 30 mL). The organic phase was separated and dried over anhyd MgSO₄. The solvent was removed under reduced pressure to give the crude product 5, which was purified by flash column chromatography on silica gel using hexane-EtOAc (20:1) as eluent to afford an analytically pure sample of 5.
Characterization Data of the Representative Compounds 5 Compound 5c: IR (KBr): ν_max = 3051, 2950, 1718, 1605, 1585, 1456, 1346 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.93-2.51 (m, 4 H, 2 × CH₂), 4.93 (dd, 1 H, J = 11.0, 4.1 Hz, H-2), 5.01 (dd, 1 H, J = 12.3, 2.6 Hz, H-6), 7.61 (d, 2 H_arom, J = 8.8 Hz, 4-O₂NC₆H₄), 7.67 (d, 2 H_arom, J = 8.7 Hz, 4-ClC₆H₄), 7.88 (d, 2 H_arom, J = 8.7 Hz, 4-ClC₆H₄), 8.29 (d, 2 H_arom, J = 8.8 Hz, 4-O₂NC₆H₄). ^¹³C NMR (100 MHz, CDCl₃-TMS): δ = 49.3, 50.1, 78.1, 79.3, 122.9, 128.1, 129.5, 130.2, 134.7, 136.4, 145.9, 148.2, 205.2. MS (EI):
m/z = 331, 333 [M⁺, M⁺ + 2]. Anal. Calcd for C₁₇H₁₄ClNO₄: C, 61.55.; H, 4.25; N, 4.22. Found: C, 61.19; H, 4.51; N, 4.01.
Compound 5f: IR (KBr): ν_max = 3055, 2957, 1725, 1605, 1587, 1449, 1352 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.88-2.73 (m, 4 H, CH₂), 5.03 (dd, 2 H, J = 12.1, 3.3 Hz, H-2, H-6), 8.31-7.51 (m, 8 H_arom, 2 × 4-O₂NC₆H₄). ^¹³C NMR (100 MHz, CDCl₃-TMS): δ = 49.8, 50.3, 78.1, 79.5, 122.2, 123.8, 128.5, 129.2, 142.8, 143.9, 147.6, 148.5, 205.2. MS (EI): m/z = 342 [M+]. Anal. Calcd for C₁₇H₁₄N₂O₆: C, 59.65; H, 4.12; N, 8.18. Found: C, 59.92; H, 3.89; N, 7.91.