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Synlett 2007(14): 2179-2184  
DOI: 10.1055/s-2007-985572
LETTER
© Georg Thieme Verlag Stuttgart · New York

Carboxylate-Directed Kumada Coupling of an Acetaldehyde Synthon with 2-Bromobenzoates Used towards the Synthesis of Isochromanes

Ioannis N. Houpis*, Jean-Pierre Van Hoeck, Ulf Tilstam
Chemical Product Research and Development, Lilly Research Laboratories, rue Granbonpre 11, 1348 Mont-st-Guibert, Belgium
Fax: +32(14)605755; e-Mail: yhoupis@prdbe.jnj.com; e-Mail: ulf.tilstam@cmcsol.com;
Further Information

Publication History

Received 25 April 2007
Publication Date:
13 August 2007 (online)

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Abstract

This letter describes the Kumada coupling of bromo­benzoic acid derivatives with the acetaldehyde enolate synthon (1,3-dioxolan-2-ylmethyl)magnesium bromide. The lithium carbo­xylate salt shows the highest reactivity in the coupling reaction while addition of t-BuOLi affords optimal selectivity. During this work, we have observed a strong directing effect of the sodium ­carboxylate function which can be useful in differentiating electronically similar diaryl bromides.

Key words

directed Kumada coupling - carboxylate-directed Pd cross-coupling - isochromane synthesis

    References and Notes

  • 1a

    Current address: Johnson and Johnson Pharmaceutical Research and Development, Chemical Development, Turnhoutseweg 30, 2340, Beerse, Belgium.

  • 1b

    Current address: CMC Solutions, Overhemstraat 3, 3320 Hoegarden, Belgium.

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6

An extensive screening protocol was conducted. Some examples of the catalysts that were evaluated include: Cl2Ni(PPh3)2, Cl2Ni(dppp), Cl2Ni(dppe) [dppe: 1,2-bis(diphenylphosphino)ethane], Ni(acac)2, Ni(acac)2-Imes+Cl- (Imes: 1,3-dimesitylimidazol-2-ylidene), Ni/C, in THF, Bu2O, toluene, NMP, at 60-80 °C.

7

The catalysts screened include: Pd(PPh)4, Pd(OAc)2-P(cy)3, Pd(OAc)2-Pt-Bu3, PdCl2-dppf [1,1-bis(diphenylphos-phino)ferrocene], Pd2(dba)3-P(tol)3, Pd2(dba)3-P(furyl)3.

9

Solvent screens with NMP, DMSO, toluene, trifluoro-toluene, MTBE, gave no reaction under these reaction conditions.

10

Attempts to convert 8 into the corresponding Zn, boronic acid or trifluoroborate derivatives, to evaluate its coupling under Pd catalysis, were not successful.

11

Variations on the ratio of 4:9 from 80:20 to 92:8 were observed, reaction time varied between five hours and 24 hours, while the conversion varied more than 20%.

13

The product 4 can be isolated in ca 98% purity in 92% yield by crystallization from EtOAc-heptane. The styrene derivative 9 can be thus completely removed.