LETTER 2285 Single-Step Preparation of a 4-(Dimethylamino)pyridine Analogue Bearing a Sulfoxide as New Chiral Inducer. Preliminary Evaluation as Nucleophilic Catalyst Single-Step Preparation of a 4-(Dimethylamino)pyridine Analogue Thomas Poisson, a Maël Penhoat, a Cyril Papamicaël, a Georges Dupas, a Vincent Dalla, b Francis Marsais, a Vincent Levacher* a a Laboratoire de Chimie Organique Fine et Hétérocyclique, UMR 6014, IRCOF, CNRS, Université et INSA de Rouen, B.P. 08, 76131 Mont-Saint-Aignan Cédex, France b Laboratoire de chimie, URCOM, Faculté des Sciences et Techniques de l’Université du Havre, 76620 Le Havre, France Fax +33(2)35522962; E-mail: vincent.levacher@insa-rouen.fr Received 10 June 2005 SYNLETT 2005, No. 15, pp 2285–228819.09.2005 Advanced online publication: 29.07.2005 DOI: 10.1055/s-2005-872256; Art ID: D16605ST © Georg Thieme Verlag Stuttgart · New York Abstract: A one-step synthesis of a new chiral DMAP-1a equiva- lent is reported by bromine–magnesium exchange reaction of the 3- bromo-4-(dimethylamino)pyridine (2). The chiral sulfoxide ap- pendage is introduced by trapping the resulting Grignard intermedi- ate with (1R,2S,5R)-(–)-(S)-menthyl p-toluenesulfinate affording (S)-1a in 60% yield and high optical purity. A preliminary evalua- tion of 1a as nucleophilic catalyst has demonstrated promising se- lectivity (s = 4.5) during acylative kinetic resolution of various alcohols. Key words: chiral DMAP, sulfoxide, kinetic resolution, alcohol Chiral 4-(dimethylamino)pyridine (DMAP) analogues have received considerable attention in recent years. A number of these chiral DMAP have already demonstrated to be highly effective chiral nucleophilic catalysts in a wide range of synthetically useful catalytic processes. 1 These include, as the main illustrative examples, acylative kinetic resolution of secondary alcohols and amines, C- arylations of silyl ketene acetals and additions of 2-cyano- pyrrole to ketenes. In spite of the high potential exhibited by these chiral DMAP reagents, they have not yet gained full popularity due to the multi-step sequences and resolu- tion techniques such as semi-preparative HPLC or crystal- lization required during their preparation (Figure 1). The lack of straightforward and general existing methods for the preparation of these attractive synthetic tools stim- ulated us to develop an approach for the easy access of an array of new chiral DMAP derivatives, in which the chiral appendages would be installed in a single-step operation. Our strategy capitalizes on the expected versatility of the readily available 3-bromo-4-(dimethylamino)pyridine (2) 2 which, by means of various conventional chemical transformations should provide access to the desired structural and chiral diversities. In this communication, we assess the potential of the above working hypothesis by reporting the straightforward preparation, based on a bromine–metal exchange, of a new chiral DMAP equiva- lent 1a bearing a sulfoxide group (Figure 2, a). We also comment on the preliminary investigation of its potential during acylative kinetic resolution of various alcohols. By analogy with previous observations reported by Vedejs, 1d it was anticipated that the proximity of the dimethylamino group would prevent the free rotation of the chiral sulfox- ide inducer. A molecular modeling 3 study of DMAP ana- logue 1a revealed that the most stable conformation would place the lone pair of the sulfoxide and the pyridine ring in a coplanar arrangement (Figure 2, b). This confor- mational constraint is expected to be the main driving force in the stereodifferentiation of both faces of the pyri- dine ring. Initial attempts to install the chiral sulfoxide by bromine– lithium exchange reaction turned out to be rather disap- pointing. Treatment of 3-bromo-4-(dimethylamino)pyri- dine (2) 2 with n-BuLi (1.2 equiv, –70 °C, THF) followed by deuteriolysis, furnished DMAP 1b with modest deute- rium incorporation (40%). In addition, a substantial amount of unidentified by-products was observed making rather difficult the purification of the crude product (Table 1, entry 1). The situation was even worse when t- BuLi was used, affording only traces of the desired deu- terated DMAP 1b along with a myriad of by-products (Table 1, entry 2). Speculating that the formation of these by-products took place because of the low stability of the Figure 1 Chiral DMAP analogues previously reported. N R 2 N Fe R' R' R' R' N N H H OH G. C. Fu (ref. 1a) K. Fuji (ref. 1b) N NR 2 Ar A. C. Spivey (ref. 1e) E. Vedejs (ref. 1d) N NMe 2 OAc H CAr 3 R' Downloaded by: Thorsten Bach, Universite Rouen B.U. Sciences. Copyrighted material.