Resorcinarenes as templates: A general strategy for the synthesis of large macrocycles

Article abstract of DOI:10.1021/ja029116g

The concept that resorcinarenes can be used as templates for the synthesis of large macrocycles is introduced. By way of example, previously inaccessible, aromatic crown ethers compounds are synthesized. Copyright

Full text of DOI:10.1021/ja029116g

Published on Web 12/24/2002
Resorcinarenes as Templates: A General Strategy for the Synthesis of Large
Macrocycles
Xuehe Li, Thomas G. Upton, Corinne L. D. Gibb, and Bruce C. Gibb*
Department of Chemistry, UniVersity of New Orleans, New Orleans, Louisiana 70148
Received October 28, 2002 ; E-mail: bgibb@uno.edu
Scheme 1a
The use of templation to affect the formation of one product,
from a reaction milieu that could potentially form many, is an
1
increasingly important aspect of supramolecular chemistry. The
2
synthesis of crown ethers is just one example of an important class
of compounds whose availability predominantly relies on (metal
ion) templation.3 However, for the synthesis of crown ethers
possessing more than approximately 24 atoms in their macrocyclic
chain, metal ion templation is less useful. As a result, large crown
ethers are usually synthesized in a stepwise manner. Although fine-
a
Key: (a) 4.4 equiv of the benzal bromide, excess K2CO3, or DBU,
DMA 60 °C, 3 d.
Scheme 2a
4
tuning can give reasonable overall yields for these approaches, by
and large the combination of a stepwise process, the slow rate of
the final cyclization step, as well as general purification difficulties,
5
usually results in poor yields. Here we demonstrate that resor-
cinarenes, macrocycles that are themselves no strangers to su-
6
pramolecular chemistry, can be used as covalent templates to
engender the efficient synthesis of large crown ethers. The approach
is a general one and should be applicable to the formation of other
families of macrocycles.
a
Key: (a) 4.4 equiv of the corresponding resorcinol, excess K CO , CuO,
2
3
pyridine, reflux, 7 d.
Large, fully aromatic crown ethers are rare. The only two
examples that have been reported5b are hexabenzo-18-crown-6 1
and heptabenzo-21-crown-7 2. Both were formed in low yield
2 4
was dissolved in 1:1 EtOH and H SO and the resulting solution
was refluxed for 7 days. Presumably, under the reversible condi-
tions, each acetal group that is cleaved has the chance to re-form
(
<0.1%) using multiple Ullmann ether reactions. Initial studies into
5b
the metal binding properties of these derivatives were negative;
however, the limited amount of material precluded a thorough
examination of their properties.
before a second acetal can be broken. Although AlCl
3
also proved
ineffective, the stronger Lewis acid BBr smoothly and rapidly
3
furnished the removal of the template. After hydrolysis of the crude
reaction mixture, the fully aromatic crown ether 9a was isolated in
8
7% yield (Scheme 3).12 This corresponds to a 50% yield starting
An alternative route to the synthesis of these types of compounds
begins with resorcinarenes such as 3. The stereoselective bridging
from resorcinol 3 and the bridging material (3,5-dibromobenzal
bromide). The 32-crown-8 derivative 9a has not been previously
7
of these compounds with benzal bromides yields a family of deep-
8
Scheme 3a
cavity cavitands of general structure 4 (Scheme 1). The overall
result of this process is to position the four new aromatic rings at
set distances from each other. In other words, they are preorganized
in a positional sense. This organization is apparent when the “upper”
rings of 5 are linked in eight-fold Ullmann ether reactions involving
resorcinol, 2-Me-resorcinol, or 5-Me- resorcinol (Scheme 2); the
9,10
respective products, 6a-c, are formed in 80-88% yield.
This
is a general process which can be expanded to include the synthesis
of cavitands 6d, 7, and 8. Thus, by treating 5 with 3,5-dihydroxy-
benzyl alcohol, hydroquinone, or 2,7-dihydroxy naphthalene, these
cavitands can be isolated in 60, 45, and 70% yields, respectively.11
Removal of the resorcinarene template was initially attempted
with dilute, aqueous HCl in THF. Only starting material was
recovered. Indeed, only starting material was recovered after 6a
a
Key: (a) (1) For 6a-c, 6 equiv of BBr3, CH2Cl2, room temperature, 1
h; then CH2Cl2/10% aqueous HCl, room temperature, 16 h. (2) For 6d, 8
equiv of BCl3 in SOCl2; then 10% aqueous HCl, room temperature, 3 h.
650
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J. AM. CHEM. SOC. 2003, 125, 650-651
10.1021/ja029116g CCC: $25.00 © 2003 American Chemical Society

C O MMU N I C A T I O N S
reported. Hence, a precise measure of the efficiency of this
templation protocol cannot be determined. Nevertheless, this
approach is obviously a highly efficient route to previously
inaccessible molecules. Exposing 6b-6c, 7, and 8 to conditions
similar to those used in the synthesis of 9a gave the corresponding
Acknowledgment. This work was supported by the National
Science Foundation (CHE-0111133) and The Petroleum Research
Fund administered by the American Chemical Society.
Supporting Information Available: Detailed experimental pro-
cedures and characterization data for compounds 6d, 7-15, and 8
3
2-crown-8 ethers 9b and 9c, 36-crown-8 10, and 40-crown-8 11
in 85-95% yield. This approach did not lead to the clean cleavage
of the resorcinol moiety of 6d. However, a combination of BCl
and SOCl proved effective, producing highly functionalized 9d
in 71% yield.13
(PDF). This material is available free of charge via the Internet at http://
pubs.acs.org.
3
2
References
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(
1
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3) For examples of template effects and the formation of crown ethers, see:
(
(
a) Pedersen, C. J. J. Am. Chem. Soc. 1967, 89, 7017-7036. (b) Greene,
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979, 22, 2067-2070. (d) Habata, Y.; Fujishiro, F.; Akabori, S. J. Chem.
This strategy can be expanded to allow for the synthesis of lower
symmetry crown ethers. Crown 13 is one such example. It is derived
from precursor 12, itself formed from 5 by a two-stage Ullmann
ether process.14
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Gibson, M. D.; Delaviz, Y.; Lee, S.-H.; Liu, S.; Wang, L.; Nagvekar, D.;
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2, 2663-2704. (b) Cram, D. J.; Cram, J. M. Container Molecules and
Their Guests; Royal Society of Chemistry: Cambridge, 1994.
1
(
7) All resorcinarenes and cavitands discussed here are phenethyl footed (R
)
2 2
CH CH Ph).
(
8) (a) Xi, H.; Gibb, C. L. D.; Stevens, E. D.; Gibb, B. C. Chem. Commun.
1
1
998, 1743-1744. (b) Xi, H.; Gibb, C. L. D.; Gibb, B. C. J. Org. Chem.
999, 64, 9286-9288. (c) Green, J. O.; Baird, J.-H.; Gibb, B. C. Org.
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(
9) Gibb, C. L. D.; Stevens, E. D.; Gibb, B. C. J. Am. Chem. Soc. 2001, 123,
5
849-5850.
(
(
10) Laugherey, Z.; Gibb, C. L. D.; Gibb, B. C. Chem.-Eur. J., in press.
11) The reaction between 5 and 3,5-dihydroxybenzyl alcohol required more
concentrated conditions than those used in the synthesis of 6a-c. As a
result, the amount of polymer increased at the expense of 6d. We have
also tried bridging with 3,5-dihydroxy benzoic acid and 3,5-dihydroxy
benzaldehyde. The former gave no reaction, and the latter gave a very
small amount of partially bridged intermediates.
The series of macrocycles reported here are all crown ethers.
However, this approach should also be applicable to other macro-
cycles. Furthermore, as resorcinarenes15 and cavitands16 with up
(
3
12) The slightly weaker Lewis acid BCl gave lower yields.
to seven resorcinol rings are now known, this methodology may
be extended to the synthesis of even larger macrocycles. In theory,
the only limitation to using resorcinarenes as templates is that the
second bridging step, for example, 5 f 6a, should not involve acidic
or Lewis acid conditions, or else the acetal bridges will be cleaved.
In summary, we have demonstrated that resorcinarenes can be
used as efficient templates for the synthesis of a variety of
functionalized, aromatic crown ethers.
3 2
(13) Using a combination of BBr and SOCl resulted in the formation of an
inseparable mixture of macrocycles arising from Br/Cl exchange.
(
14) Gibb, C. L. D.; Li, X.; Gibb, B. C. Proc. Natl. Acad. Sci. U.S.A. 2002,
9
9, 4857-4862.
(15) (a) Konishi, H.; Ohata, K.; Morikawa, O.; Kobayashi, K. Chem. Commun.
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