Scope and Limitations of Lithium-Ethylenediamine-THF-Mediated Cleavage at the α-Position of Aromatics: Deprotection of Aryl Methyl Ethers and Benzyl Ethers under Mild Conditions

Abstract

The scope and limitation of lithium-ethylenediamine-THF-mediated reductive bond cleavage at the a-position of aromatics were examined. Very mild conditions such as lithium metal (5 equiv) and ethylenediamine (7 equiv) in oxygen-free THF were quite effective for the demethylation of aromatic ethers even at as low as -10 °C. Allyl benzyl ethers were also deprotected under these conditions with very little change of the allylic alcohol moiety. Through this study, 2,6-dimethylbenzyl (m-xylylmethyl, MXM) group was developed as an alternative of benzyl group, which is readily cleavable under the above mentioned reductive conditions. An accompanying side reaction so far often observed in a dissolving metal-assisted reductive deconjugation of aromatics, the Birch reduction, 1,2 was the cleavage of C-O bonds in aromatic ethers. 3,4 In 1957, Wender reported that such ethereal bond cleavage, the demethylation of anisole to phenol, also occurred under Benkeser conditions, by applying lithium metal in ethylenediamine at as high as 90-100 °C. 5 Later, Meyer found that the demethylation reaction proceeded at very low temperature in THF solution. 6 When we, by chance, came across this phenomenon, we became interested in it in as much as we had previously found that the demethylation of 1a proceeded under similar conditions (Scheme 1).We first re-examined the reaction conditions, especially an optimal equivalence of both lithium metal and ethylenediamine, by using a simplified substrate 2a in Scheme 2. The results are shown in Table 1. The formation of a by-product 3 due to the over-reduction was confirmed by a far excess of the reagents (entry 1). The yield of the desired product reached a plateau (over 70%) between 5 equivalents to 3.5 equivalents of lithium (entries 2-7). The theoretically required 2 equivalents of lithium (entry 8) were not enough, as it was obviously seen that the reaction turned very slow. In regard to the relative equivalence of ethylenediamine to lithium [4 (entry 2) to 0.6 (entry 7)], an apparent maximum was observed at the equivalence between one and two (entries 3-6). To ensure the consistent progress of the reaction, the use of 5 equivalents of lithium and 7 equivalents of ethylenediamine (entry 3) was concluded, and the lowering of the reaction temperature to -10 °C was effective to suppress the overreduction (entry 9). Scheme 2 Lithium-ethylenediamine mediated reductive demethylation. Table 1 Equivalence of Lithium and Ethylenediamine in Demethylation Reaction Entry Li (equiv) Ethylenediamine (equiv) Time (h) Recovery Products 2a (%) 2b (%) 3 (%)