The Synthesis of (Iodobenzyl)oxybenzaldehydes, Useful Intermediates for Biologically Active Targets

Author(s): Hedvig Bölcskei, Andrea Német-Hanzelik, István Greiner, Zsófia Dubrovay, Viktor Háda, György Keglevich.

Journal Name: Letters in Drug Design & Discovery

Volume 14 , Issue 2 , 2017

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Abstract:

The benzyloxy-benzyl moiety is a valuable building block in medicinal chemistry, e.g. in case of the voltage gated sodium channel blockers Safinamide and Ralfinamide. To prepare further derivatives a series of (iodobenzyl)oxybenzaldehydes (3a-3i) useful intermediates for the synthesis of biologically active compounds were synthesized in high yields by O-benzylation of 2-, 3- and 4- hydroxybenzaldehydes (2a-2c) with a variety of iodobenzylbromides (1a-1c). The title compounds were obtained in 77-100 % yield in 2-5 hours. Longer reaction time or addition of water favoured the formation of aldol-type by-products, mainly 4-hydroxy-4-{[(iodophenyl)methoxy]phenyl}butan-2-one derivatives (5a-5g), which contained the iodine group and the 4-hydroxy-butan-2-one moiety in various positions. In one case (3E-)-4-{3-[(2-iodophenyl)methoxy]phenyl}but-3-en-2-one (6c) with a double bond has been isolated. These side-reactions could be avoided by using acetonitrile as solvent. The structures of the new products were established by high resolution MS and NMR measurements, where 1H-1H, direct 1H-13C, long-range 1H-13C scalar spin-spin connectivities were established from 1D 1H, 13C, 2D gHSQCAD, zTOCSY and gHMBCAD NMR experiments.

Keywords: Alkylation, hydroxybenzaldehyde, iodobenzylbromide, (iodobenzyloxy)benzaldehydes, aldol reaction, aldol condensation.

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Article Details

VOLUME: 14
ISSUE: 2
Year: 2017
Page: [233 - 239]
Pages: 7
DOI: 10.2174/1570180813666160804142245

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