New stabilising groups for lateral lithiation of ortho-cresol derivatives and a new route to 2-substituted chromans James A. Wilkinson * , Eun-Ang Raiber, Sylvie Ducki Centre for Molecular Drug Design, Biosciences Research Institute, Cockcroft Building, University of Salford, Salford M5 4WT, UK article info Article history: Received 30 January 2008 Received in revised form 4 April 2008 Accepted 24 April 2008 Available online 29 April 2008 Keywords: Lateral lithiation Alkylation ortho-Cresol Chromans abstract 2-(2-Methoxyethoxy)-toluene and 2-(2-dimethylaminoethoxy)-toluene have been lithiated using sec- BuLi under a variety of conditions and the laterally lithiated species trapped with electrophiles, including but-1-ene oxide, leading to a new synthesis of 2-ethylchroman. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction Lateral lithiation is an important methodology in organic syn- thesis. 1 Lateral lithiation of benzenoid aromatics requires a stabil- ising group capable of either delocalising negative charge or stabilising an organolithium by coordination. 2 Oxygen-based sta- bilising groups placed in the ortho-position have been used for a number of lateral lithiations but are problematic in the case of simple ortho-cresol derivatives. The methoxy group requires superbase conditions to effect deprotonation and the methoxy- methyl group gives exclusive ortho-lithiation (Scheme 1). 3 In a previous work on diarylmethane derivatives we have used the methoxyethoxy group in efficient lateral lithiations. 4 This led us to investigate the use of the same group as a potentially more efficient stabiliser for lateral lithiation of ortho-cresol derivatives. We have recently reported lateral lithiation reactions of ortho- cresol derivatives using both the methoxyethoxy and dimethyl- aminoethoxy stabilising groups. 5 Here, we report in full the results of these investigations. 2. Results and discussion Starting materials 2 and 3 were easily prepared by alkylation of ortho-cresol 1 using sodium hydride in DMF (Scheme 2). The results of alkylations of 2 are shown in Table 1 . Optimum conditions for alkylation of 2 involved generating the lithio species at 30  C for 2 h using 1.3 equiv of sec-BuLi before quenching (entry 2). Generating the lithio species at 78  C for 2 h led to isolation of starting material only, while stirring for a 4 h period before quenching or warming to 20  C led to lower conversions. Our assumption was that the organolithium was slowly quenched by solvent, which would explain the large amounts of starting R = Me OR OR Li OR Li R = CH 2 OMe Scheme 1. 2 X=OMe, 98% 3 X=NMe 2 , 81% OCH 2 CH 2 X 1 OH NaH, DMF HalCH 2 CH 2 X Scheme 2. * Corresponding author. Tel.: þ44 161 295 4046; fax: þ44 161 295 5111. E-mail address: j.a.wilkinson@salford.ac.uk (J.A. Wilkinson). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2008.04.093 Tetrahedron 64 (2008) 6329–6333