The stereospecific cross-coupling of enantioenriched non-benzylic secondary alkyl boron compounds has been achieved. The high selectivity toward product formation over an undesired β-H elimination pathway is achieved via an intramolecular coordination of an ancillary carbonyl to the metal center in the diorganopalladium intermediate.

Cross-coupling reactions, and in particular the Suzuki-Miyaura reaction, 1 are among the most important reactions in modern organic synthesis. Although there are many effective protocols for the cross-coupling of secondary alkyl halides with arylmetallics, 2 the complementary crosscoupling of secondary (and potentially enantiomerically enriched) organometallics with aryl halides is a notable and significant unsolved problem. 3 There have been at least two isolated examples of secondary boronic acids being cross-coupled. In the earliest example, cyclopentylboronic acid was cross-coupled in good yield with an aryl chloride (eq 1). 3e The second partners sec-butylboronic acid with an aryl bromide generating a mixture of the desired sec-butylarene along with the undesired isomerized n-butylated derivative (eq 2). 3f However, neither study was there development toward identifying a general solution to the challenge of cross-coupling secondary organometallics.The difficulty in this transformation derives from two key steps of the mechanistic cycle: the transmetalation step, which is more difficult for secondary alkyl groups than other organic moieties, 3d and the reductive elimination process, which competes with facile β-hydride elimination. To address the former issue we have employed organotrifluoroborates, 4 which have a demonstrated ability to undergo transmetalation with limited interference from competitive protodeboronation. 5 To overcome the second obstacle and find suitable conditions for the cross-coupling of challenging aryl chlorides to secondary alkyltrifluoroborates, we used parallel micro-scale experimentation. During the course of our investigations, a similar approach with more highly reactive aryl bromide electrophiles was reported by van den Hoogenband et al. 6 Spencer_dreher@merck.com, gmolandr@sas.upenn.edu. The electron rich and sterically hindered 2-chloroanisole 1 and the heterocyclic 3-chloropyridine 2 were chosen as electrophilic models, while potassium cyclopentyltrifluoroborate 3 was selected as the nucleophilic partner (Scheme 1). In attempting to develop conditions that would perform well simultaneously for these two electrophilic substrates, we hoped that a common solution might evolve for a wide range of coupling partners. NIH Public AccessThe parallel experimentation used in this study was accomplished using a 96-well-plate reactor with 1 mL reaction vials [10 μmol of substrate per reaction, 100 μL of solvent, 10 mol % of Pd(OAc) 2 , and 20 mol % of ligand]. For each substrate, 12 ligands were employed that have been shown in the literature to be effective in oxidative addition with aryl chlorides, in conjunction with 3 solvents [toluene, THF, cyclopentyl methyl ether (CPME)] and Cs 2 CO 3 base, conditions previously shown to be useful for primary alkyltrifluoroborate coupling. 7 From these experiments, the combination of n-butyldiadamantylphosphine (n-BuPAd 2 , Catacxium A) with Cs 2 CO 3 in toluene was by far the most reactive combination for both substrates.The generality of th...

Parallel microscale experimentation was used to develop general conditions for the Suzuki-Miyaura cross-coupling of diversely functionalized primary alkyltrifluoroborates with a variety of aryl chlorides. These conditions were found to be amenable to coupling with aryl bromides, iodides, and triflates as well. The conditions that were previously identified through similar techniques to promote the cross-coupling of secondary alkyltrifluoroborates with aryl chlorides were not optimal for the primary alkyltrifluoroborates, thus demonstrating the value of parallel experimentation to develop novel, substrate specific results.