DOI: 10.1002/chem.200601488 Palladium-Catalyzed Suzuki–Miyaura Reaction Involving a Secondary sp 3 Carbon:Studies of Stereochemistry and Scope of the Reaction Nuria Rodr,guez, Carmen Ram,rez de Arellano, Gregorio Asensio,* and Mercedes Medio-Sim1n [a] Introduction Palladium-catalyzed cross-coupling between organic electro- philes and organometalliccompoundshas developed to become a usefulmethodology forthe formation of C C bonds. [1, 2, 3] Combinationsof aryl halidesor pseudohalides with differentorganometalliccompoundsto provide new C sp 2 C sp 2 bondshave been extensively reported. [4] In con- trast, reactions between alkyl halides and organometallics to form C sp 3 C sp 2 or C sp 3 C sp 3 bonds are much less usual [5] and remain a challenging problem in organic synthesis. In gener- al, oxidative addition to C sp 3 X bonds is slow [6] and the b- elimination process becomes an important competitive side reaction. Functionalized primary halo alkyl compounds lack- ing b hydrogens are therefore suitable substrates for cross- coupling reactionsinvolving sp 3 -hybridized carbonssince the undesiredb-hydride elimination cannot take place, while the presence of functional groups allows for synthetic applications, and in this context a few examples of Suzuki– Miyaura cross-coupling reaction using functionalized halo compounds are known. Reactions involving primary a-halo carbonylshave been reported by Suzukiand Miyaura, [7] Gooßen et al., [8] and Deng et al. [9] In this context, we recent- ly reported [10] the first example of this type of reaction with primary a-halo sulfoxides. A complementary approach con- sistsof the cross-coupling of an aryl halide (electrophile) and a palladium enolate (nucleophile bearing the function) generated in situ with base. This procedure has been devel- oped by Buchwald et al. [11] and Hartwig et al., [12] while ni- triles [13] and activated sulfones [14] have also been reported as suitable substrates for this kind of reaction. Despite ongoing work in the development of suitable methodologies in the field of palladium-catalyzed cross-coupling reactions with functionalized alkylsand the potentialsynthetic utility of the described procedures, cross-coupling reactions involving functionalized secondary halides—and also the stereochemi- cal course ofthe cross-coupling when a reaction involve a stereogeniccenter—remain unexplored. Although secon- dary halides are uncommon substrates [5a, 15] in transition- metal cross-coupling reactions, several examples of reactions of unfunctionalized secondary alkyls have been reported re- cently. [5a, 15] Metals other than palladium (Ni, Fe, Co) have been used with these substrates, and radical mechanisms seem to be involved. [5a, 15] With regard to studies of the ste- reochemical courses of palladium-catalyzed reactions at ste- reogenic carbons, examples are scarce, being practically re- duced to the pioneering reportsby Stille et al. [16] on the Abstract: Palladium-catalyzedC C bond formation involving secondary sp 3 -hybridized carbon is described. These reactionsoccur with secondary 1-bromoethyl arylsulfoxides and differ- ent arylboronic acids, to produce the correspondingarylated sulfoxidesin moderate to high yields and with com- plete stereospecificity.Despite the presence ofb hydrogensin the sub- strate,the competitive b-hydride elimi- nation is not a significant side reaction when coordinating solvents are used. The reported cross-coupling involves secondaryC sp 3 C sp 2 bond formation: this is the first time that a mechanistic study hasbeen carried outwith such substrates. The reaction proceeds with inversion of configuration atthe ste- reogenic C sp 3 carbon.The high stereo- specificity of the coupling and the mildness of the reaction conditions allow for the preservation of the opti- cal purities of reagentsand products and the preparation of useful chiral tar- gets. Keywords:bromo sulfoxide · cross- coupling · palladium · stereochemistry · sulfur [a]N. Rodr>guez, Dr. C. Ram>rez de Arellano, Prof. Dr. G. Asensio, Dr. M. Medio-Sim?n Departamento de Qu>mica OrgBnica, Universidad de Valencia Avda. V>cent AndrEs EstellEs s/n, 46100-Burjassot-Valencia (Spain) Fax: (+ 34) 963-544-939 E-mail : gregorio.asensio@uv.es Chem. Eur. J. 2007, 13, 4223 – 4229 J 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4223 FULL PAPER