hosts, with receptor sites preorganized to be complimentary
to the respective guest, such as those developed by Davis et
al. based on cholic acids.5 Even though these show strong
binding and good selectivity, they often require convoluted
and time-consuming syntheses that do not lend themselves
to easy modification.4
binding due to the concomitant perturbation in the ICT
(internal charge transfer) character of the chromophore.
We are interested in anion recognition2 and have previ-
ously employed both anthracene and naphthalimide mol-
ecules functionalized with thiourea binding units as lumi-
nescent sensors for anions, such as acetate, phosphate, and
fluorides, as well as dicarboxylate anions. In this letter, we
extend this approach and provide, to the best of our
knowledge, the first examples of polynorbornane frameworks
preorganized for anion recognition. The cleft-like polynor-
bornane frameworks are known for their inherent high degree
of structural order and, as such, compliment Davis’ cholic
acid design, yet their synthesis is highly amenable to
modification for both size and shape.5 Appending receptor
motifs to these frameworks allows them to be oriented in a
specific and predetermined topographical relationship, a
feature previously exploited when attaching peptide and
intercalator moieties.6 These frameworks are readily syn-
thesized by the cycloaddition reactions between functional-
ized cyclobutene epoxides, which ring open under thermal
treatment to form carbonyl ylides,7 and suitable norbornene
partners.8 The methodology is robust, and a range of
functionalities are tolerated.6,7,9 We envisaged that a receptor
combining the structural integrity of the [n]polynorbornane
framework together with proven anionophores, such as ureas,
thioureas, and carbamides, would yield a new family of
conformationally preorganized anion hosts.10
Figure 1. The [3]polynorbornane anion receptors employed within
the current study.
The synthesis of 1 and 2 was accomplished in six steps
commencing with the Diels-Alder cycloaddition of cyclo-
pentadiene with maleic anhydride to afford endo-norborn-
5-ene-2,3-dicarboxylic anhydride, 3, which, following heating
in neat 1,2-diaminoethane and treatment with di-tert-butyl
dicarbonate, gave the crystalline adduct 4 in good yield
(Scheme 1). The Mitsudo reaction11 of 4 provided the
Scheme 1. Synthesis of Cyclobutene Epoxide 6
Herein we detail the synthesis of the thiourea functional-
ized receptors 1 and 2 and report the preliminary anion
binding assays of these hosts. For 1 and 2, we choose the
aromatic derived 4-trifluoromethylphenyl and 4-nitrophenyl
thioureas as anion receptors, as these electron-withdrawing
groups would be expected to increase the acidity of the
thiourea protons and hence enhance their anion binding
ability through hydrogen bonding. Furthermore, 2 would be
expected to display significant color changes upon anion
(5) (a) Davis, A. P.; Joos, J. B. Coord. Chem. ReV. 2003, 240, 143. (b)
Ayling, A. J.; Perez-Payan, M. N.; Davis, A. P. J. Am. Chem. Soc. 2001,
123, 12716. (c) Davis, A. P.; Perry, J. J.; Wareham, R. S. Tetrahedron
Lett. 1998, 39, 45.
(6) (a) Warrener, R.; Butler, D.; Russell, R. Synlett 1998, 566. (b)
Warrener, R.; Margetic, D.; Amarasekara, A.; Butler, D. Org. Lett. 1999,
1, 199.
(7) (a) Pfeffer, F. M.; Russell, R. A. Org. Biomol. Chem 2003, 1, 1845.
(b) Pfeffer, F. M.; Russell, R. A. J. Chem. Soc., Perkin. Trans. 1 2002, 1,
2680. (c) Foley, P. J. Ph.D. Thesis, Centre for Molecular Architecture,
University of Central Queensland, 2001.
cyclobutene diester 5, which gave 6 in moderate yield (45%)
following a modified Weitz-Scheffer epoxidation.7b,12 Slow
evaporation of CH2Cl2/EtOAc solutions of 6 yielded crystals
suitable for a single-crystal X-ray structure determination,
which clearly shows (Figure 2) the cyclobutene ring and the
fused epoxide flanked by two methyl ester groups. This
arrangement is crucial as it predisposes 6 in such a way that
(8) (a) Seitz, G.; Gerninghaus, C. H. Pharmazie 1994, 49, 10. (b) Lin,
W. J.; Benson, R. E. J. Am. Chem. Soc. 1965, 87, 3657.
(9) Warrener, R. N.; Schultz, A. C.; Butler, D. N.; Wang, S. D.;
Mahagevan, I. B.; Russell, R. A. Chem. Commun. 1997, 11, 1023.
(10) Four factors were considered when designing these receptors. (i)
Anion size: as most anions of interest are not comparable in size to the
large [n]polynorbornane framework, hence, only [3]polynorbornanes were
employed in this study. (ii) Recognition unit: we chose to use substituted
aromatic thioureas as these may be readily tuned to enhance binding affinity.
(iii) Symmetry: to facilitate spectroscopic analysis, a highly symmetric
framework based on endo-norborn-5-ene-2,3-anhydride 3 was chosen. (iv)
Rigidity: to maximize the anion-receptor interaction without compromising
preorganization, a flexible ethyl spacer was placed between the rigid [3]-
polynorbornane backbone and the thiourea receptor units.
(11) (a) Mitsudo, T.; Kokuryo, K.; Shinsugi, T.; Nakagawa, Y.; Takeg-
ami, Y. J. Org. Chem. 1979, 44, 4492. (b) Mitsudo, T.; Naruse, H.; Kondo,
T.; Ozaki, Y.; Watanabe, Y. Angew. Chem., Int. Ed. Engl. 1994, 33, 580.
(12) (a) March J. AdVanced Organic Chemistry. Reactions Mechanisms
and Structures, 4th ed.; Wiley: New York, 1992; pp 826-829. (b) Clark,
C.; Hermans, P.; Meth-Cohn, O.; Moore, C.; Taljaard, H. C.; VanVuuren,
V. J. Chem. Soc., Chem Commun. 1986, 1378. (c) Meth-Cohn, O.; Moore,
C.; Taljaard, H. C. J. Chem. Soc., Perkin Trans. 1 1988, 2663. (d) Sharpless,
B. K.; Rossiter, B. E.; Hill, G. J. Org. Chem. 1983, 48, 3607.
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