Scheme 1
functionalized derivatives10 and (2) the poor solubility of 2
formally extruded in this reaction with the formation of the
methylene bridges. The C2h-17 diastereomer was not present
in the reaction mixture.13 This observation was surprising,
in water. We envisioned that both of these deficiencies could
be alleviated if the extremely harsh conditions (H2SO4, 135-
145 °C) used in the synthesis of 2 could be adapted to allow
the use of glycoluril derivatives that incorporate hydrophilic
functional groups. This paper describes our investigation of
the synthesis, X-ray crystallographic characterization, and
acid-catalyzed isomerization of nonmacrocyclic methylene-
bridged glycoluril dimers.
Scheme 2
As a first step toward the preparation of functionalized
congeners of 2, it was necessary to devise methods to prepare
the methylene-bridged glycoluril dimer substructure of 2 (in
bold). Scheme 1 shows starting materials 3-611 and the
synthesis of 7-16. We chose 10 as our model substrate to
develop conditions for the preparation of the methylene-
bridged glycoluril dimer substructure for two reasons: (1)
its ethyl ester groups could be readily transformed to water
solubilizing carboxylate (13) or amidoamine (14) substituents
in high-yielding reactions, and (2) the bridging xylylene ring
protected two of the glycoluril nitrogen atoms that reduced
the complexity of the reaction to the formation of dimers.
After much experimentation, it was discovered that heating
10 under acidic conditions (PTSA) in refluxing dichloro-
ethane for 24 h resulted in the formation of C2V-17 in 92%
yield (Scheme 2).12 Two equivalents of formaldehyde was
especially since the relative stereochemistry of 17 was
determined by the formation of the first covalent bond
between the two equivalents of 10. This stereochemical
assignment was based on the observation of two doublets
(6.01 and 4.58 ppm) for the diastereotopic methylene protons
of the central eight membered ring.
The X-ray crystal structure of C-shaped C2V-17, obtained
as the benzene solvate (Figure 1a), confirmed the stereo-
chemical assignment. There were several interesting aspects
of the structure of C2V-17. First, C2V-17 was facially am-
phiphilic since all four ethyl ester groups are displayed on a
single face of the molecule. Second, C2V-17 crystallized in a
conformation where the two phenyl walls defined a hydro-
phobic cleft. Third, the distance between the centers of the
substituted phenyl rings measured 7.4 Å; this distance is
suitable for the complexation of an aromatic ring.3,14
Scheme 2 presents the results of several dimerization
reactions that were performed. Compounds 13-15 were
(6) (a) Mock, W. L. Top. Curr. Chem. 1995, 175, 1-24. (b) Mock, W.
L.; Shih, N.-Y. J. Org. Chem. 1983, 48, 3618-3619. (c) Mock, W. L.;
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3620. (d) Mock, W. L.; Shih, N.-Y. J. Org. Chem. 1986, 51, 4440-4446.
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Chem. Soc. 1995, 117, 85-88. (b) Kang, J.; Hilmersson, G.; Santamar´ıa,
J.; Rebek, J. Jr. J. Am. Chem. Soc. 1998, 120, 3650-3656. (c) Diederich,
F.; Jonas, U.; Gramlich, V.; Herrmann, A.; Ringsdorf, H.; Thilgen, C. HelV.
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(13) After 24 h all of the successful reactions shown in Scheme 2 lead
to the exclusive formation of the C2V-diastereomer.
(14) (a) Diederich, F. Angew. Chem., Int. Ed. Engl. 1988, 27, 362-386.
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Org. Lett., Vol. 2, No. 6, 2000