Intraannular Functionalization of Macrocyclic Polyethers Via Organolithium Intermediates

1,3-Xylyl crown ethers substituted at the 2-position with an acidic (COOH, OH, SO₂H) or reactive (CHO) functional group can be synthesized from a common starting material by a generally applicable method that does not require the protection of these groups. 2-Bromo-1,3-xylyl crown ethers 1 react at-78 °C with n-butyllithium to yield the corresponding 2-lithio-1,3-xylylcrown ethers 2 without extensive cleavage of the polyether ring. Subsequent reaction with electrophilic reagents (dimethyl disulfide, N,N-dimethylformamide, CO₂, or SO₂) yielded the corresponding macrocycles 3-6. Reaction of 2 with trimethyl borate, followed by hydrolysis and oxidation by hydrogen peroxide, provides an excellent alternative for the published synthesis of 2-hydroxy-1,3-xylyl crown ethers 8. The single-crystal X-ray structures of 2-bromo-1,3-xylyl-18-crown-5 (1b) and 2-sulfino-1,3-xylyl-18-crown-5 (6b) reveal a restricted flexibility of the macroring in these 18-membered macrocycles. In 6b, the macrocyclic cavity is filled by the SOH group, which is engaged in a bifurcated hydrogen bond with two ether oxygen atoms.