Synthesis 2004(12): 2062-2065  
DOI: 10.1055/s-2004-829154
PSP
© Georg Thieme Verlag Stuttgart · New York

Simple, Short and Efficient Procedure for the Preparation of Hydroxyl- and Hydroxymethyl-Substituted 2,6-Dichlorobenzaldehydes

Thomas von Hirschheydt*, Edgar Voss
Roche Diagnostics GmbH, Nonnenwaldstr. 2, 82372 Penzberg, Germany
Fax: +49(8856)604445; e-Mail: [email protected];
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Publikationsverlauf

Received 23 December 2003
Publikationsdatum:
13. Juli 2004 (online)

Abstract

Hydroxyl- and hydroxymethyl-substituted 2,6-dichlorobenzaldehydes 1-4 have been obtained by lithiation of the corresponding TIPS-protected dichlorophenols or dichlorobenzylic alcohols followed by reaction with DMF and subsequent deprotection of the hydroxy group. Yields are high and formation of regioisomers is not observed.

    References

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1

Examples from the patent literature, especially in the field of kinase inhibitors, are legion by now. In addition, the Derwent World Drug Index is a (commercial) source of information for marketed and development drugs. It contains well over 100 examples of compounds with 2,6-dichlorophenyl substitution.

9

We have found that the lithiation of 3,5-dichloroanisole in THF at -78 °C and subsequent reaction with DMF leads to a 2:1 mixture of 2,4-dichloro-6-methoxybenzaldehyde and 2,6-dichloro-4-methoxybenzaldehyde, which had to be separated by tedious column chromatography.

12

Other desilylating agents should easily overcome this disadvantage.

13

The bulk of the TIPS group hinders the rotation of the phenolic C-O bond and causes a symmetry breakdown on 1H NMR timescale. Therefore a spin system of higher order was observed.