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Synlett 2009(17): 2789-2794  
DOI: 10.1055/s-0029-1217981
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

An Efficient Microwave-Promoted Route to (Z)-Stilbenes from trans-Cinnamic Acids: Synthesis of Combretastatin A-4 and Analogues

Marc-Antoine Bazina, Marie Jouannea, Hussein El-Kashefb, Sylvain Rault*a
a Centre d’Etudes et de Recherche sur le Médicament de Normandie (CERMN), UPRES EA-4258, FR CNRS INC3M, Université de Caen Basse-Normandie, U.F.R. des Sciences Pharmaceutiques, Boulevard Becquerel, 14032 Caen Cedex, France
Fax: +33(2)31931188; e-Mail: sylvain.rault@unicaen.fr;
b Chemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt
Further Information

Publication History

Received 18 June 2009
Publication Date:
25 September 2009 (online)

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Abstract

cis-Stilbenes were synthesized from trans-cinnamic acids, involving ethylenic-bond bromination and a subsequent one-pot microwave-promoted stereoselective debrominative decarboxylation-Suzuki cross-coupling strategy. This sequence represents a useful way to prepare a variety of combretastatin A-4 derivatives.

Key words

cis-stilbenes - cinnamic acids - combretastatin A-4 - debrominative decarboxylation - Suzuki-Miyaura cross-coupling ­reaction

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1

Current address: Université de Nantes, Nantes Atlantique Universités, IICiMed EA1155, UFR des Sciences Pharmaceutiques, Laboratoire de Chimie Thérapeutique, 1 Rue Gaston Veil, BP 53508, 44000 Nantes, France.

19

General Procedure for the One-Pot Synthesis of 5a-n
In a 10 mL microwave vial were introduced a magnetic stir bar, a anti-2,3-dibromo-3-arylpropanoic acid 2 (5.0 mmol, 1.00 equiv), and Et3N (1.05 equiv) in DMF (1 mL). The vial was sealed, and the suspension was then heated at 140 ˚C for 1 min. After CO2 removal were added a boronic acid 4 (1.20 equiv), K2CO3 (2.50 equiv) or NaOH (3.50 equiv), Pd(PPh3)4(0.05 equiv), and DME-H2O (2:1, 8 mL). The vial was sealed and purged with argon through the septum inlet. The suspension was then heated at 100 ˚C for 15 min. The resulting mixture was acidified with 1 N HCl. H2O and Et2O were added, and the aqueous layer was extracted with Et2O (3 × 30 mL). The combined organic layers were washed with H2O, dried over MgSO4, filtered, and evaporated. The crude product was then purified by silica gel chromatography (eluent: cyclohexane-EtOAc) to afford (Z)-stilbene 5 as a pure compound. Compound trans-5 was isolated too, to determine the Z/E ratio.
Selected Data Compound 5d: orange solid; yield 0.51 g (63%); mp 78 ˚C. IR (KBr): ν = 2931, 2831, 1581, 1510, 1487, 1454, 1330, 1235, 1129, 1024, 1006, 846 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 3.71 (s, 6 H, 2 × OMe), 3.85 (s, 3 H, OMe), 5.92 (s, 2 H, OCH2O), 6.42 (d, J = 11.7 Hz, 1 H, =CH), 6.48 (d, J = 11.7 Hz, 1 H, =CH), 6.51 (s, 2 H, Har), 6.73 (d, J = 8.8 Hz, 1 H, Har), 6.79-6.81 (m, 2 H, Har). ¹³C NMR (100 MHz, CDCl3): δ = 55.9 (2 C, 2 × OMe), 60.9 (OMe), 100.9, 105.9 (2 C), 108.1, 109.0, 122.9, 129.1, 129.4, 131.1, 132.5, 137.1, 146.6, 147.3, 152.9 (2 C). ESI-MS: m/z = 315 [M + H]+. HRMS (EI): m/z calcd for C18H18O5: 314.1154; found: 314.1165.
Compound 5m: yellow solid; yield 0.17 g (45%); mp 58 ˚C. IR (KBr): ν = 3417, 2956, 1605, 1511, 1465, 1274, 1241, 1175, 1029, 870 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 3.67 (s, 3 H, OMe), 3.79 (s, 3 H, OMe), 5.58 (s, 1 H, OH), 6.42 (part A of AB system, ³ J AB = 11.7 Hz, 1 H, =CH), 6.45 (part B of AB system, ³ J AB = 11.7 Hz, 1 H, =CH), 6.77-6.79 (m, 5 H, Har), 7.22 (d, J = 8.8 Hz, 1 H, Har). ¹³C NMR (100 MHz, CDCl3): δ = 55.2 (OMe), 55.7 (OMe), 111.1, 113.5, 114.1, 122.4, 126.1, 127.4, 128.3, 128.7, 130.1, 144.7, 146.0, 158.5. ESI-MS: m/z = 257 [M + H]+. HRMS (EI): m/z calcd for C16H16O3: 256.1099; found: 256.1109.