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Synlett 2007(7): 1037-1042  
DOI: 10.1055/s-2007-973896
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Functionalized Spiroheterocycles by Sequential Multicomponent Reaction/Metal-Catalyzed Carbocylizations from Simple β-Ketoesters and Amides

Hadjira Habib-Zahmania, Jacques Viala*b, Salih Hacinia, Jean Rodriguez*b
a Laboratoire de Synthèse Organique, Institut de Chimie, Université d’Oran-Es-Sénia, BP-1524, 31000 Oran, Algérie
b Faculté des Sciences et Techniques, Université Paul Cézanne (Aix-Marseille III), UMR CNRS 6178 SYMBIO, Boîte 531, 13397 Marseille Cedex 20, France
Fax: +33(4)91289187; e-Mail: jean.rodriguez@univ-cezanne.fr;
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Publication History

Received 12 February 2007
Publication Date:
13 April 2007 (online)

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Abstract

A new strategy from simple cyclic β-ketoesters or amides involving a selective three-component reaction and a ring-closing metathesis or a palladium-catalyzed carbocyclization in a sequential fashion to access spiroheterocycles is reported. This ­expedient two-step sequence generates compounds of significant molecular complexity and high synthetic and biological relevance from simple and readily available starting materials.

Key words

multicomponent reactions - ring-closing metathesis - Heck reaction - spiroheterocycles - 1,3-dicarbonyl compounds

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General Procedure for MCRs: To a solution of ketoester or ketoamide 1 (1 mmol) and DBU (3 mmol) in appropriate solvent (4 mL, Table 1) was added the corresponding aldehyde 2 (1.1 mmol) and halide 3 (2 mmol). The resulting solution was stirred for the indicated time and at the indicated temperature (Table 1). After completion of the reaction and evaporation of most of the solvent under reduced pressure, 1 N solution of HCl (30 mL) was added to the oily residue. Extraction with Et2O (3 × 40 mL) followed by successive washing with distilled H2O (2 × 20 mL) and brine (20 mL) gave, after drying (MgSO4) and evaporation of the solvent, the crude compounds which were purified by flash chromatography on silica gel.
Physical Data for Compound 4b: yellow oil; R f [Et2O-PE (50:50)] 0.79. IR (liquid film): 2942, 1740, 1678, 1588, 1472, 1208, 1133, 927 cm-1. MS: m/z (%) = 305 (100) [M + H+], 264 (13), 247 (36), 219 (12), 206 (8). 1H NMR (300.13 MHz, CDCl3): δ = 7.50 (d, J = 1.5 Hz, 1 H), 7.35 (s, 1 H), 6.72 (d, J = 3.5 Hz, 1 H), 6.53 (dd, J = 1.5, 3.5 Hz, 1 H), 5.65-5.92 (m, 2 H), 5.13-5.32 (m, 4 H), 4.63 (dd, J = 1.0, 5.6 Hz, 2 H), 3.71 (d, J = 11.2 Hz, 1 H), 3.15 (d, J = 11.2 Hz, 1 H), 2.84 (dd, J = 7.1, 13.8 Hz, 1 H), 2.58 (dd, J = 7.6, 13.8 Hz, 1 H). 13C NMR (75.47 MHz, CDCl3): δ = 197.3, 168.9, 151.6, 144.7, 131.3, 132.0, 128.2, 118.8, 115.9, 120.1, 112.9, 115.5, 66.6, 60.4, 38.6, 32.7.

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General Procedure for RCMs: To a 6 × 10-3 M solution of spiroheterocyclic precursors 4a-e in anhyd CH2Cl2, under an atmosphere of argon, Grubbs’ catalyst 5b was introduced in several portions of 2% every 2 h. The mixture was stirred at reflux and completion of reaction was checked by TLC. The mixture was filtered through a pad of silica gel and celite and the crude material was purified by flash chromatography on silica gel.
Physical Data for Compound 6c: yellow solid; mp 104-106 °C. IR (liquid film): 2960, 1708, 1620, 1460, 1201, 1030 cm-1. MS: m/z (%) = 290 (100) [M + H+], 233 (17), 190 (5). 1H NMR (300.13 MHz, CDCl3): δ = 7.53 (d, J = 1.7 Hz, 1 H), 7.32 (s, 1 H), 6.67 (d, J = 3.3 Hz, 1 H), 6.49 (dd, J = 1.7, 3.3 Hz, 1 H), 5.75-5.85 (m, 2 H), 3.90-4.18 (m, 2 H), 3.81 (d, J = 11.7 Hz, 1 H), 3.03 (s, 3 H), 3.00 (d, J = 11.7 Hz, 1 H), 2.89-2.98 (m, 1 H), 2.26-2.35 (m, 1 H). 13C NMR (75.47 MHz, CDCl3): δ = 198.6, 170.2, 151.8, 144.4, 127.7, 125.8, 128.4, 112.8, 115.5, 115.0, 60.4, 49.8, 38.9, 35.1, 31.9.

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General Procedure for Heck Reaction: To a 4 × 10-2 M solution of spiroheterocyclic precursors 4f and 4g in anhyd MeCN, under an atmosphere of argon, palladium acetate (4 equiv) and PPh3 (8 equiv) were added, followed by Et3N (1.2 equiv). The mixture was stirred at reflux and the completion of reaction was checked by TLC. The mixture was filtered through a pad of celite and the crude material was purified by flash chromatography on silica gel.
Physical Data for Compound 7b: yellow powder; mp 169-171 °C. IR (liquid film): 2926, 1719, 1626, 1444, 1337, 1256, 940 cm-1. MS: m/z (%) = 326 (100) [M + H+], 295 (3), 255 (3), 201 (3), 164 (16). 1H NMR (300.13 MHz, CDCl3): δ = 7.34-7.64 (m, 6 H), 5.41 (d, J = 0.9, 16.6 Hz, 2 H), 5.02 (d, J = 9.3 Hz, 1 H), 4.72 (dd, J = 1.1, 15.1 Hz, 2 H), 4.04 (dd, J = 0.9, 11.3 Hz, 1 H), 3.57 (d, J = 15.3 Hz, 1 H), 3.07 (d, J = 11.2 Hz, 1 H), 3.03 (s, 3 H), 2.98 (d, J = 14.4 Hz, 1 H), 2.56 (d, J = 14.4 Hz, 1 H). 13C NMR (75.47 MHz, CDCl3): δ = 200.9, 169.0, 143.5, 141.8, 135.0, 130.5, 129.6, 129.5, 129.2, 128.8, 115.3, 112.8, 61.4, 54.2, 39.4, 37.1, 31.1.