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Synthesis 2001(11): 1681-1685
DOI: 10.1055/s-2001-16759
PAPER
© Georg Thieme Verlag Stuttgart · New York

A Practical One-Pot Synthesis of 5-Aryl-2-furaldehydes

Michael S. McClure, Frank Roschangar*, Stephen J. Hodson, Alan Millar, Martin H. Osterhout
GlaxoSmithKline, Chemical Development - Synthetic Chemistry, Five Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709, USA
Fax: +1(919)3158735; e-Mail: fr83278@gsk.com;
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Publication History

Received 25 April 2001
Publication Date:
28 September 2004 (online)

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Abstract

A useful one-pot synthesis of 5-aryl-2-furaldehydes via palladium-mediated Suzuki coupling of aryl halides with in situ generated 5-(diethoxymethyl)-2-furylboronic acid is described. The procedure has general applicability, delivers high yields, and is amenable to scale-up.

Key words

furylboronic acids - Suzuki cross-coupling - Pd/C - 5-aryl-2-furaldehydes

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14

Although initial investigations indicated 2-(2-furyl)-1,3-dioxolane to be superior to 2-(diethoxymethyl)furan (4) for boronic acid generation, it has limited availability, and the resulting in situ generated boronic acid is less reactive in the Suzuki coupling. Therefore, our studies were focused on acetal 4.

15

5-Formyl-2-furylboronic acid (2a), available from Frontier Scientific, costs ca. $26,000/mol, while 2-(diethoxymethyl)furan (4) retails at Aldrich for ca. $1,000/mol ($340/kg for bulk quantities).

18

Column: Phenomenex Luna C18(2) 50 mm × 2.0 mm 3 micron. Mobile phase: A = 0.05 % (v/v) TFA in H2O, B = 0.05 % (v/v) TFA in MeCN. Gradient Profile: 0% to 95% B over 8 min. UV detection at λ = 280 nm. 1.0 mL/min flowrate with injection volume of 1.0 µL.

22

Typical degradation products observed upon prolonged standing were 2-(diethoxymethyl)furan (4) and the putative ”dimer" 6 (LC-MS) as shown in the Figure below:

Figure

30

The only type of Pd/C employed for this and all other experiments described herein was 10 wt% (dry basis)palladium on activated carbon, 50% water wet, Degussa type E101NE/W; it was used as purchased from Aldrich.

31

It is conceivable that EtOH enhances solubilization of the reaction components. We determined that omission of EtOH or use of EtOH-DME ratios less than 1:2 resulted in competitive degradation of 5-(diethoxymethyl)-2-furylboronic acid (2b) to 2-(diethoxymethyl)furan (4), thereby preventing complete conversion.