Jared R. Mitchell and Dr. Matt A. Peterson, Chemistry and Biochemistry
Organolithium reagents have long been known as useful reagents for carbon-carbon bond formation in synthetic organic chemistry. Although a variety of techniques have been developed for their generation, one of the most frequently used methods involves treating either an alkyl or aryl halide (R-X, X = halogen) with a commercially available organolithium such as nbutyllithium (nBuLi). When these reactions are carried out at low temperature in inert solvents, the lithium atom of nBuLi and the halogen atom of the alkyl or aryl halide are exchanged, hence this process is referred to as a lithium-halogen exchange reaction (Figure 1).
Lithium-halogen exchange reactions have traditionally been performed in ethereal solvents such as diethyl ether or tetrahydrofuran at dry ice temperatures (-78 ‘C). These conditions lead to clean conversion to the desired organolithium reagent in most cases. However the method suffers from the fact that the ethereal solvents used for generating the organolithium can act as Lewis acids and play significant (often undesired) roles in the outcome of subsequent reactions in which the organolithiums are employed. For example, diethyl ether and tetrahydrofuran have been shown to greatly influence the stereoselectivity of certain carbon-carbon bond forming reactions, particularly those in which formation of an intramolecular chelate ring is involved. The presence of ethereal solvents in these reactions tends to decrease the strength of the chelate ring and, as a result, decrease the selectivity of the reaction.
In recent years significant effort has been expended in examining non-traditional (i.e. nonethereal) solvents for lithium-halogen exchange reactions. As part of research directed towards the synthesis of a new bipyridine ligand, we were required to generate an aryllithium (2-bromo-6-lithopyridine)in a non-ethereal solvent. Use of ethereal solvents yielded mixtures of the desired monolithiopyridine and the undesired dilithiopyridine (Figure 2, 1 and 2 respectively). After examining several solvents, it was found that in dichloromethane at -78 C the lithium-halogen exchange reaction provided exclusively aryllithium 1 in high yield. Formation of the dilithiopyridine 2 did not occur even after adding two molar equivalents of nBuLi. A thorough review of the literature reveals that aryllithium 1 has not previously been generated in dichloromethane. Since use of dichloromethane as solvent for lithium-halogen exchange constitutes a novel contribution to organolithium chemistry and since others might benefit from a highly efficient method for generating 2-bromo-6-lithiopyridine in non-ethereal solvent, we decided to examine this reaction in greater detail. The goal of my project was to generate aryllithium in dichloromethane and react this aryllithium with various electrophiles (Table 1). This was done in order to determine the scope and limitations of our new method for generating 1 in dichloromethane. All of the compounds shown in Table I were purified by column chromatography and characterized by 1 H and 13 C nuclear magnetic resonance spectroscopy. Product yields were excellent (70-100%). Thus this method represents a useful tool for generating 2-bromo-6-lithiopyridine in non-ethereal solvents.