Methylene-Bridged Glycoluril Dimers: Synthetic Methods

Methylene-bridged glycoluril dimers are the fundamental building blocks of cucurbituril (CB[6]),
its homologues (CB[n]), and its derivatives. This paper describes three complementary methods
for the synthesis of C- and S-shaped methylene-bridged glycoluril dimers (29−34 and 37−44). For
this purpose, we prepared glycoluril derivatives (1a−d) bearing diverse functionalities on their
convex face. These glycoluril derivatives were alkylated under basic conditions (DMSO, t-BuOK)
with 1,2-bis(halomethyl)aromatics 6−15 to yield 4a−d and 16−24, which contain a single aromatic
o-xylylene ring and potentially nucleophilic ureidyl NH groups. Glycoluril derivatives bearing
potentially electrophilic cyclic ether groups (5a−f) and 25−28 were prepared by various methods
including condensation reactions in refluxing TFA containing paraformaldehyde. The condensation
reactions of 4a−d and 16−24 with paraformaldehyde under anhydrous acidic conditions (PTSA,
ClCH2CH2Cl, reflux) give, in most cases, the C-shaped and S-shaped methylene-bridged glycoluril
in good to excellent yields. In many cases, the C-shaped compound is formed preferentially with
high diastereoselectivity. Cyclic ethers 5a,d−f and 25−26 undergo highly diastereoselective
dimerization reactions to yield methylene-bridged glycoluril dimers with the formal extrusion of
formaldehyde. Last, it is possible to perform selective heterodimerization reactions using both cyclic
ethers and glycoluril derivatives bearing ureidyl NH groups. These reactions deliver the desired
C- and S-shaped heterodimers with low to moderate diastereoselectivities. This heterodimerization
route is the method of choice in cases where the homodimerization reactions fail. The formation of
side products (±)-35b and (±)-35d helps clarify the electronic requirements for a successful CB[n]
synthesis. The X-ray structures of 30C, 38C, and 38S allow for a discussion of the structural features
of this class of compounds.