Suzuki Cross-Coupling Reaction of Sterically Hindered Aryl Boronates with 3-Iodo-4-methoxybenzoic Acid Methylester H. Chaumeil, * S. Signorella ² and C. Le Drian Laboratoire de Synthe Áse Organique et de Chimie Microbienne, Universite  de Haute Alsace, CNRS UPRES-A 7015, 3 rue Alfred Werner, 68093 Mulhouse Cedex, France Received 20 May 2000; revised 10 July 2000; accepted 29 September 2000 Abstract ÐThe cross-coupling reaction of 3-iodo-4-methoxybenzoic acid methylester with sterically hindered arylboronic esters and especially 5,5-dimethyl-2-mesityl-1,3,2-dioxaborinane, is reported. The optimisation of the process in order to obtain biaryls in good yield by using anhydrous benzene at re¯ux and sodium phenoxide in the presence of 0.06 equiv. of Pd(PPh 3 ) 4 is described. q 2000 Elsevier Science Ltd. All rights reserved. Introduction A large number of precursors to drugs, polymers, liquid crystals as well as ligands for organo-metallic chemistry possess a biaryl structure. Therefore, numerous catalytic methods devoted to the preparation of biaryls by cross- coupling reactions have been developed over the last two decades. One of the most useful approaches, commonly referred as Suzuki coupling, 1 is based on Pd(0) catalysed cross-coupling reactions of various organoboron derivatives with aryl halides, tri¯ates or diazonium salts under basic conditions. The original procedure, using Pd(PPh 3 ) 4 and aqueous Na 2 CO 3 in benzene at re¯ux gives good yields with many substituted arylboronic acids. 1c In general, cross-coupling reactions of organobon derivatives with organic halides are believed to process through a catalytic cycle 1d,1f,1g,1j,1k,1l,2 related to the cycles proposed for the cross-couplings induced by other metals such as Mg, 3 Zn 4 and Sn. 5 However, a particularity of the Suzuki cross- coupling reaction is that it proceeds only in the presence of bases. 1a,2 One of the admitted possibilities is that the catalytic cycle includes a step in which the base is intro- duced in the coordination sphere of palladium since the formation of Ar-PdL 2 -OR from Ar-PdL 2 -X is known to accelerate the transmetalation step. 1b,2a,6 Another important feature of the Suzuki coupling reaction, in the usual conditions, must be emphasized. Arylboronic acids which are sterically hindered generally give low yields and hydrolytic deboronation of the C±B bond predomi- nates. 7 Furthermore, both electron-withdrawing and electron-attracting groups could, at least, in some cases, accelerate the protonolysis. 7b,8 One of the alternative is to replace the boronic acids by the corresponding esters. This allows the use of anhydrous conditions in which no protonolysis occurs, enabling the synthesis of hindered biaryls in good yields. 1e,7b,9 However, until now, no systematic investigation of the cross-coupling reaction of hindered arylboronic esters seems to have been published. Therefore, since in literature, ortho ± ortho 0 tetrasubstituted biaryls could not be prepared in acceptable yields, 7b,7d,8c we decided to focus our efforts on the Suzuki coupling of sterically hindered arylboronic esters 2 ± 8 with a substituted anisic acid derivative 1 (Scheme 1). The other retrosynthetic possibility: the coupling of an hindered aromatic halide with a boronic ester seemed less favourable. Among the various boronic esters, mostly cyclic, already used in literature for coupling reactions, we chose 1,2,3-dioxaborinanes, 10 since 2,2-dimethyl-1,3-propanediol is known to give easily crystallised acetals. Results and Discussion In a ®rst set of experiments, the coupling reaction of 1 with the unsubstituted boronic ester 2 and the two ortho-substi- tuted 5,5-dimethyl-2-aryl-1,3,2-dioxaborinanes 3 and 4 (Table 1, entries 1 to 3) was studied. The two latter reactions of 1 were conducted using conditions already reported in literature, 9 i.e. Pd(Ph 3 ) 4 as catalyst, Tl 2 CO 3 as base, benzene at re¯ux as solvent. It appeared that the cross-coupling reac- tion occurred in high yields and no trace of protonolysis could be observed. A prolonged reaction time was required Tetrahedron 56 (2000) 9655±9662 Pergamon TETRAHEDRON 0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved. PII: S0040-4020(00)00928-5 Keywords: Suzuki cross-coupling reaction; hindered arylboronic esters; biaryls. * Corresponding author. Fax: 133-389336860; e-mail: h.chaumeil@univ-mulhouse.fr ² Present address: Departamento de Quõ Âmica, Facultad de Ciencias Bioquõ Âmicas y Farmace Âuticas, UNR. Suipacha 531, 2000 Rosario, Argen- tina.