Synthesis of Annulated and Spirocyclic Butenolide Derivatives by Condensation of Malonates with Cyclic α-Hydroxy β-Dicarbonyl Compounds

Abstract

Cyclocondensation of alicyclic and heterocyclic α-hydroxy β-dicarbonyl compounds with dimethyl malonate gives bicyclic butenolide derivatives. The reaction sequence is catalyzed by 4-(N,N-dimethylamino)pyridine and consists of two processes: Knoevenagel condensation followed by transesterification. Depending on the chemical nature of the β-dicarbonyl moiety (oxoester, diketone or α-acetyl lactone or lactam), products with either annulated or spirocyclic constitution are obtained.

Keywords

annulation - heterocycles - Knoevenagel reaction - lactones - spiro compounds

• References and Notes


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• 11 7a-Ethyl 3-Methyl 2-Oxo-2,4,5,6,7,7a-hexahydrobenzofuran-3,7a-dicarboxylate (7b); Typical Procedure: A mixture of α-hydroxy ketone 6b (0.60 g, 3.2 mmol), CH₂(CO₂Me)₂ (1.28 g, 9.69 mmol), and DMAP (20 mg, 0.16 mmol) in toluene (10 mL) was stirred and heated to reflux in a Dean–Stark trap for 28 h until conversion was complete (monitored by GC). After cooling to ambient temperature, MTBE (10 mL) was added and the mixture was washed with hydrochloric acid (1 M, 3 mL). The organic layer was dried over Na₂SO₄, filtered, and the solvent was removed under reduced pressure. The crude product was purified by chromatography (SiO₂; hexane–EtOAc, 4:1; R_f  = 0.18) to give the title compound 7b (0.77 g, 2.89 mmol, 89%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃): δ = 1.26 (t, J = 7.1 Hz, 3 H), 1.42 (qt, J = 13.3, 4.1 Hz, 1 H), 1.46 (td, J = 13.4, 4.4 Hz, 1 H), 1.71 (qt, J = 13.9, 3.7 Hz, 1 H), 1.86–1.93 (m, 1 H), 2.10–2.14 (m, 1 H), 2.32 (td, J = 13.5, 5.8 Hz, 1 H), 2.85–2.89 (m, 1 H), 3.66–3.71 (m, 1 H), 3.88 (s, 3 H), 4.19–4.25 (m, 2 H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ = 13.89 (CH₃), 21.86 (CH₂), 27.05 (CH₂), 27.47 (CH₂), 36.99 (CH₂), 52.24 (CH₃), 62.80 (CH₂), 85.38 (C), 116.89 (C), 161.46 (C), 166.26 (C), 167.06 (C), 178.06 (C). HRMS (ESI, +): m/z [M + Na⁺] calcd for C₁₃H₁₆NaO₆ (268.26): 291.0839; found: 291.0837.
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• 13 The reason for the selectivity switch from annulated to spirocyclic product remains unclear. Actually, one might assume that the prolonged reaction times and elevated temperatures clearly indicate that all products are formed under thermodynamic control. This seems to be evident for the formation of annulated product 7h, with the six-membered ring, which is approximately 36 kJ·mol^–1 more stable then the corresponding spirocycle, as DFT calculations indicated.¹⁵ Nevertheless, for starting material 6i, with a seven-membered ring, the annulated product is thermodynamically also slightly more stable than spirocycle 8a, although this effect is less pronounced (20 kJ·mol^–1). The latter case is therefore clearly a result of kinetic control. We were, however, unable to detect or identify any reaction intermediates that could shed light on this selectivity switch.
• 14 CCDC-1031225 (7h) and 1031226 (8a) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk, or by emailing [e-mail], or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: [phone].
• 15 The electronic structure calculations were performed within density functional theory (DFT) using the B3LYP functional for exchange and correlation and a 6-311G (d) basis set. Throughout the study the Gaussian 09 program package was used: Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA. Jr, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam MJ, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ. Gaussian 09, Revision D.01. Gaussian, Inc; Wallingford CT: 2009