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42090-B1
Investigation of Arene-Heteroatom and Arene-Carbon Bond Formation by Aryllithiums

Donald Slocum, Western Kentucky University

As part of our program to introduce hydrocarbon solvents as exceptional media for the execution of ortho-metalations, we have studied several selected substrates with the intent of improving their respective metalation procedures. How better to demonstrate the efficiency of metalation in hydrocarbon solvents than to successfully tackle systems that present a problem. Recent studies in our laboratory have resulted in significant improvements in the metalation of several substrates. In each case a 1:1 ratio of alkyllithium reagent was utilized at concentrations ranging between 0.67 M and 2.0 M. These substrates and the conditions for their metalation are listed in Table I. For those where >95% of the ortho-lithio intermediate has been generated, atom-economy is deemed to have been achieved. 

Each of these procedures requires additional description and explanation. For the metalation of anisole, the catalytic system that produces 95-97% o-LiA is 0.1 equiv. of TMEDA. If the product o-LiA, a flocculent precipitate, is allowed to settle in the reaction flask, the supernate drawn off with a syringe and replaced with an equal volume of pure cyclohexane, a system which analyzes as 97-99% o-LiA is produced. Likewise, metalation of DMA at 60^oC utilizes just 0.15 equiv. of TMEDA to achieve the highest percent o-LiDMA. The initially generated 90-93% o-LiDMA system can be enriched in a fashion similar to that for o-LiA. For both systems use of a full equivalent of TMEDA results in lower yields of the desired ortho-lithio intermediate. Curiously, increments of   (-)-sparteine in cyclohexane is effective for the ortho-metalation of anisole at 25^oC, but the same system is ineffective for the metalation of DMA.  Many descriptions of the ortho-lithiation of each of these substrates have appeared in the literature, but none rival the efficiencies of metalation described here.

Metalation of DMBA and o-MA each exhibit a problem with contamination by a secondary site of metalation. For DMBA, lateral α-metalation needed to be excluded to cleanly afford the ortho-lithiated amine while for o-MA, ortho-lithiation was to be avoided to cleanly produce the α-product. In each case, examination of our “designer media” systems, fractional equiv. of TMEDA in hydrocarbon solvent and equiv. of THF in hydrocarbon solvent, failed to afford the sought selectivity. ⁷Li NMR suggested that MTBE at relatively low concentrations in cyclohexane deoligomerizes n–BuLi at least as effectively as THF. From this observation a successful, regiospecific ortho-metalation of DMBA was developed.

A somewhat similar approach led to the successful α-metalation of o-MA. This realization was most promising for our program in that, in addition to literature studies assessed in a recent review,  a computational study also concluded that regiospecific lithiation of o-MA could not be accomplished using alkyllithium reagents. The formulation for this successful metalation procedure for o-MA arose from the confluence of ideas and observations reflecting our original proposition that metalation reactions, in this case an α-metalation, can be significantly improved by being performed in designer hydrocarbon media.

The above described protocols for ortho-lithiations of anisole (A), dimethylaniline (DMA), dimethylbenzylamine (DMBA) and o-methylanisole (o-MA) in hydrocarborbon solvents have been extended to the dimethoxybenzenes (DMB's) the p-haloanisoles (p-XA's) and p-tetramethylphenylenediamine (p-TMPDA). In these instances, previously designed protocols or slight modifications thereof, were discovered which satisfied two of our stated criteria (1) that ether media were to be avoided or their complement minimized and (2) that higher, atom-economical procedures be developed that were at least equal to any recorded in the literature. In certain instances, e.g., those for p-BrA and p-IA, procedures were found that avoided the literature described use of phenyllithium. Matalations utilizing phenyllithium produce benzene, the generation of which is to be avoided in the present day.

TABLE 1. Efficient Metalation of Arenes in Hydrocarbon Solvents

By the minimumization or avoidance all together of the use of ethers for these metalations, the plagues normally associate with the use of ethers (hydroscopic nature, peroxides, reactivity with alkyllithiums) are avoided, thus rendering our developed protocols more environmentally acceptable and more sustainable.

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