Competition of substituents for ortho direction of metalation of veratric acid Nguyet Trang Thanh Chau a, b , Thi Huu Nguyen a , Anne-Sophie Castanet a , Kim Phi Phung Nguyen b , Jacques Mortier a, * a Universite´ du Maine and CNRS, Unite´ de Chimie Organique Mole´culaire and Macromole ´culaire (UMR 6011), Faculte ´ des Sciences, Avenue Olivier Messiaen, 72085 Le Mans Cedex 9, France b Universite´ de Ho Chi Minh Ville, E ´ cole des Sciences Naturelles, Laboratoire de Chimie Organique, 227 Nguyen van Cu, Arrondissement 5, Ho Chi Minh Ville, Viet Nam article info Article history: Received 15 July 2008 Received in revised form 26 August 2008 Accepted 27 August 2008 Available online 4 September 2008 Keywords: ortho-Lithiation Organolithiums Benzoic acids abstract LTMP (5 equiv) metalates randomly veratric acid (1). Under external quench conditions, the thermody- namically more stable lithium 2-lithio-3,4-dimethoxybenzoate (2) reacts with a variety of electrophiles to give versatile building units that are not easily accessible by conventional means. Under in situ quench conditions (LTMP/TMSCl), a reversal of regioselectivity is observed and 6-trimethylsilyl-3,4-dimethox- ybenzoic acid (10) is formed predominantly. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction It is well known that certain substituents containing hetero- atoms are able to promote the lithiation of an aromatic ring at the ortho position (ortho-lithiation) by hydrogen–metal exchange with an alkyllithium reagent. 1,2 The effect of the heteroatom has been explained in terms both of increased intrinsic acidity of the ortho proton and of coordination of the metalating agent with consequent enhancement of its ability to abstract the ortho proton. 2,3 The directed metalation group CO 2 H increases the discrimina- tion between ortho positions and favors metalation over nucleophilic addition reactions to the aromatic nucleus. 4 We have recently described its synthetic utility by demonstrating a series of regioselective reactions derived from the competition of halo- benzoic acids, 5 anisic acids, 6 and biphenyl carboxylic acids 7 with organolithiums and superbases. Herein we record details of our investigations on the metalation of veratric acid (1). As this article will demonstrate, the ‘in situ quench protocol’ provides a powerful alternative to the stepwise reaction. We describe methodological aspects related to the prepa- ration of contiguously 2-substituted-3,4-dimethoxybenzoic acids, which have found wide uses in many areas of pesticidal, pharma- ceutical, and materials chemistry as versatile intermediates. For instance, 3,4-dimethoxy-2-methylbenzoic acid is a key intermediate for the synthesis of HIV protease inhibitors, 8 for the preparation of analogs of quercetin 9 and gossypol. 10,11 2-Chloro-3,4-dimethoxy- benzoic acid is a core building unit for the synthesis of, inter alia, urea inhibitors of protein kinases such as the mitogen-activated protein kinases, 12 analogs of lamellarin, 13 and arylpiperazine-benzoylamide derivatives of pharmaceutical interest. 14 In the prior art, 2- substituted-3,4-dimethoxybenzoic acids were prepared by de- manding classical and poorly regioselective multisteps sequences in low overall yield. 15 ortho-(Methoxy)aryloxazolines react with organolithium or Grignard reagents to give 2-substituted de- rivatives resulting from the nucleophilic methoxy displacement, 16 whereas meta-(methoxy)aryloxazolines are deprotonated at the C-2 position by n-BuLi. 17 Nevertheless these transformations require laborious protection and deprotection steps to restore the carboxylic acid moiety. 2. Results and discussion General conditions were chosen on the basis of preliminary experiments with different bases (Scheme 1 and Table 1). Veratric acid (1) did not undergo any detectable metalation when LDA was used in excess (5 equiv) in THF at 0  C (entry 1). The reaction was sluggish even at 66  C (entry 2). 3,4-Dimethoxy-2-methyl- benzoic acid (5) was prepared in only 9% yield after addition of iodomethane at 40  C. So we turned to the more basic lithium 2,2,6,6-tetramethylpiperidide (LTMP). The pK a values for diiso- propylamine and tetramethylpiperidine in THF are, respectively, 35.7 and 37.3. 18 A yield of 44% was obtained with 2.2 equiv of the latter base (entry 3). * Corresponding author. Tel.: þ33 243 833 336; fax: þ33 243 833 902. E-mail address: jacques.mortier@univ-lemans.fr (J. Mortier). 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.2008.08.086 Tetrahedron 64 (2008) 10552–10557