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

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.

aldehydes - lithiation - protection groups - steric hindrance - regioselectivity

References

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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.

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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.

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Other desilylating agents should easily overcome this disadvantage.

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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.