TETRAHEDRON LETTERS Tetrahedron Letters 44 (2003) 4961–4963 Pergamon o -Formylation of electron-rich phenols with dichloromethyl methyl ether and TiCl 4 Oscar Garcı ´a, a Ernesto Nicola ´s a, * and Fernando Albericio a,b, * a Departament of Organic Chemistry, University of Barcelona, E -08028 Barcelona, Spain b Barcelona Biomedical Research Institute, Barcelona Science Park, University of Barcelona, Josep Samitier 1, E -08028 Barcelona, Spain Received 6 April 2003; revised 10 May 2003; accepted 11 May 2003 Abstract—o -Formylation of electron-rich phenols is accomplished with dichloromethyl methyl ether and TiCl 4 . The reaction gives excellent yields, good regioselectivity, and does not leading to diformylation. © 2003 Elsevier Science Ltd. All rights reserved. 1. Introduction In solid-phase chemistry, 1 the lability of most of the acid-labile handles can be fine-tuned by the introduc- tion of electron-donating substituents into a phenyl ring. 2 The way that these building blocks are function- alized is usually through an aldehyde function, which can undergo reduction or aminative reduction to afford the corresponding alcohol or amine functions. The handles are bifunctional spacer molecules and so a phenol function can serve as an anchor to the solid support. Furthermore, formyl-substituted phenols bear- ing electron-donating substituents are important com- pounds and/or interesting intermediates in other fields of organic chemistry. 3 A number of methods have been described in the literature for the formylation of phe- nols, but most of these give only low yields, leading to diformylation, and/or lack regioselectivity. In one of our current programmes, we became inter- ested in preparing 2-formyl-3,5-dimethoxyphenol (1) from 3,5-dimethoxyphenol, 2-formyl-3,5,6-trimethyl- phenol (2) from 2,3,5-trimethylphenol, and 2-formyl- 3,4,5-trimethoxyphenol (3) from 3,4,5-trimethoxyphe- nol. The formyl derivatives are useful in their own right as direct handle precursors (e.g. 1 is the precursor of the o -backbond amide linker (BAL) handle 4 ) or inter- mediates for benzopyran- or benzofuran-based handles. The application of one of the most common formyla- tion methods, the Vilsmeier–Haack reaction (DMF, POCl 3 ), and the Duff reaction (hexamethylenetetramine in strong acid medium) in attempts to obtain 2 did not afford the desired product with good purity or regio- selectivity. This result was consistent with one of our earlier findings, when Vilsmeier–Haack conditions were applied to 3,5-dimethoxyphenol gave a mixture of the 2- and 4-formyl derivatives together with a small amount of the 2,4-diformyl derivative. 5 Moreover, the Vilsmeier–Haack reaction employs harsh conditions and the outcome strongly depends on the stirring con- ditions, with efficient mechanical stirring giving the best results. Given the problems outlined above, it was decided to investigate formylation with dichloromethyl methyl ether in the presence of titanium(IV) chloride—a method first described by Gross et al. 6 and further developed by Cresp et al. 7 An assessment of this reac- tion when applied to polysubstituted aromatic rings is presented. Keywords : benzofuran; benzopyran; handle; linker; protecting group; solid phase. * Corresponding authors: Tel.: +34-93-402-9057; fax: +34-93-339- 7878 (E.N.); Tel.: +34-93-403-7088; fax: +34-93-403-7126 (F.A.); e-mail: nicolas@qo.ub.es; albericio@pcb.ub.es 0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0040-4039(03)01168-7