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Synlett 2010(2): 240-246  
DOI: 10.1055/s-0029-1218563
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Lal Dhar S. Yadav*a, Santosh Singha, Vijai K. Raia,b
a Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
Fax: +91(532)2460533; e-Mail: ldsyadav@hotmail.com;
b School of Chemistry, College of Science, Shri Mata Vaishno Devi University, Katra, Jammu 182 320, India
Further Information

Publication History

Received 28 October 2009
Publication Date:
11 December 2009 (online)

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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

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): νmax = 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′-Ha), 3.17 (dd, 1 H, J = 17.3, 3.5 Hz, α′-Hb), 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 Harom, Ph), 7.59 (d, 2 Harom, J = 8.7 Hz, 4-O2NC6H4), 7.65 (d, 1 H, J = 16.5 Hz, β-H), 8.27 (d, 2 Harom, 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): νmax = 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′-Ha), 3.09 (dd, 1 H, J = 17.1, 3.7 Hz, α′-Hb), 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 Harom, 3-MeOC6H4), 7.51-7.39 (m, 5 Harom, 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): νmax = 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′-Hb), 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 Harom, J = 8.7 Hz, 4-MeOC6H4), 7.23 (d, 2 Harom, J = 8.7 Hz, 4-MeOC6H4), 7.62 (d, 2 Harom, J = 8.9 Hz, 4-O2NC6H4), 7.71 (d, 1 H, J = 16.5 Hz, β-H), 8.21 (d, 2 Harom, 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): νmax = 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′-Ha), 3.17 (dd, 1 H, J = 17.3, 3.1 Hz, α′-Hb), 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 Harom, 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): νmax = 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 Harom, J = 8.8 Hz, 4-O2NC6H4), 7.67 (d, 2 Harom, J = 8.7 Hz, 4-ClC6H4), 7.88 (d, 2 Harom, J = 8.7 Hz, 4-ClC6H4), 8.29 (d, 2 Harom, 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): νmax = 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 Harom, 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.