Efficient fragment coupling approaches toward large oxacalix[n]arenes (n = 6, 8)

Article abstract of DOI:10.1021/ol900116h

The first rational, stepwise synthesis of enlarged oxacalix[n]arenes (n > 4) is described. Variously substituted oxacalix[3]arene[3]pyrimidines were prepared rather selectively by a straightforward [3 + 3] fragment coupling approach after a thorough searc

Full text of DOI:10.1021/ol900116h

ORGANIC
LETTERS
2009
Vol. 11, No. 8
1681-1684
Efficient Fragment Coupling Approaches
toward Large Oxacalix[n]arenes (n ) 6, 8)
Wim Van Rossom, Margriet Ovaere,† Luc Van Meervelt,† Wim Dehaen,* and
Wouter Maes
Molecular Design and Synthesis, Department of Chemistry, Katholieke UniVersiteit
LeuVen, Celestijnenlaan 200F, 3001 LeuVen, Belgium
wim.dehaen@chem.kuleuVen.be
Received January 19, 2009
ABSTRACT
The first rational, stepwise synthesis of enlarged oxacalix[n]arenes (n > 4) is described. Variously substituted oxacalix[3]arene[3]pyrimidines
were prepared rather selectively by a straightforward [3 + 3] fragment coupling approach after a thorough search for the optimum nucleophilic
aromatic substitution conditions. Similar procedures also allowed facile synthesis of unsymmetrical oxacalix[4]- and oxacalix[8]arenes.
Heteracalixarenes, reassessed members of the calixarene
family in which the classical methylene bridges are replaced
by heteroatoms, are currently being studied intensively for
the high promise they hold within diverse domains in
supramolecular chemistry.1-5 As a result of the difference
in bridging units, heteracalixarenes inherently possess distinct
physical and chemical properties, e.g., macrocycle and cavity
size, conformational behavior, and molecular recognition
ability. The lack of synthetic availability and versatility has
severely hampered a detailed analysis of their supramolecular
properties in the past, but nowadays, straightforward proce-
(6) Some examples: (a) Chambers, R. D.; Hoskin, P. R.; Kenwright,
A. R.; Khalil, A.; Richmond, P.; Sandford, G.; Yufit, D. S.; Howard, J. A. K.
Org. Biomol. Chem. 2003, 1, 2137. (b) Li, X.; Upton, T. G.; Gibb, C. L. D.;
Gibb, B. C. J. Am. Chem. Soc. 2003, 125, 650. (c) Wang, M.; Yang, H.
J. Am. Chem. Soc. 2004, 126, 15412. (d) Katz, J. L.; Feldman, M. B.; Conry,
R. R. Org. Lett. 2005, 7, 91. (e) Hao, E.; Fronczek, F. R.; Vicente, M. G. H.
J. Org. Chem. 2006, 71, 1233. (f) Yang, F.; Yan, L.; Ma, K.; Yang, L.; Li,
J.; Chen, L.; You, J. Eur. J. Org. Chem. 2006, 1109. (g) Katz, J. L.; Geller,
B. J.; Conry, R. R. Org. Lett. 2006, 8, 2755. (h) Maes, W.; Van Rossom,
W.; Van Hecke, K.; Van Meervelt, L.; Dehaen, W. Org. Lett. 2006, 8,
4161. (i) Konishi, H.; Tanaka, K.; Teshima, Y.; Mita, T.; Morikawa, O.;
Kobayashi, K. Tetrahedron Lett. 2006, 47, 4041. (j) Konishi, H.; Mita, T.;
Morikawa, O.; Kobayashi, K. Tetrahedron Lett. 2007, 48, 3029. (k) Jiao,
L.; Hao, E.; Fronczek, F. R.; Smith, K. M.; Vicente, M. G. H. Tetrahedron
2007, 63, 4011. (l) Yang, H.-B.; Wang, D.-X.; Wang, Q.-Q.; Wang, M.-X.
J. Org. Chem. 2007, 72, 3757. (m) Hou, B.-Y.; Wang, D.-X.; Yang, H.-B.;
Zheng, Q.-Y.; Wang, M.-X. J. Org. Chem. 2007, 72, 5218. (n) Wang, Q.-
Q.; Wang, D.-X.; Zheng, Q.-Y.; Wang, M.-X. Org. Lett. 2007, 9, 2847. (o)
Hou, B.-Y.; Zheng, Q.-Y.; Wang, D.-X.; Wang, M.-X. Tetrahedron 2007,
63, 10801. (p) Van Rossom, W.; Maes, W.; Kishore, L.; Ovaere, M.; Van
Meervelt, L.; Dehaen, W. Org. Lett. 2008, 10, 585. (q) Wang, D.-X.; Zheng,
Q.-Y.; Wang, Q.-Q.; Wang, M.-X. Angew. Chem., Int. Ed. 2008, 47, 7485.
† Biomolecular Architecture, Department of Chemistry.
(1) Ko¨nig, B.; Fonseca, M. H. Eur. J. Inorg. Chem. 2000, 2303
(2) (a) Lhotak, P. Eur. J. Org. Chem. 2004, 1675. (b) Morohashi, N.;
Narumi, F.; Iki, N.; Hattori, T.; Miyano, S. Chem. ReV. 2006, 106, 5291
(3) (a) Tsue, H.; Ishibashi, K.; Tamura, R. In Heterocyclic Supramol-
ecules I; Matsumoto, K., Ed.; Topics in Heterocyclic Chemistry; Springer:
Heidelberg, 2008; Vol. 17, pp 73-96. (b) Vale, M.; Pink, M.; Rajca, S.;
Rajca, A. J. Org. Chem. 2008, 73, 27. (c) Zhang, E.-X.; Wang, D.-X.; Zheng,
.
.
Q.-Y.; Wang, M.-X. Org. Lett. 2008, 10, 2565
(4) Wang, M.-X. Chem. Commun. 2008, 4541
(5) A recent review on oxacalixarenes: Maes, W.; Dehaen, W. Chem.
Soc. ReV. 2008, 37, 2393
.
.
.
10.1021/ol900116h CCC: $40.75
Published on Web 03/19/2009
2009 American Chemical Society

dures toward novel heteracalixarenes (mostly S,2 N,3,4
O4,5 ) and postmacrocyclization functionalizations of the
heteracalixarene skeleton are frequently appearing in the
literature.
accessible starting from dichloropyrimidine precursors, a
more selective synthesis (allowing easier purification) of
these higher homologues is highly desirable if one wants to
develop their supramolecular chemistry to a further extent.
Since (nontemplated) synthetic approaches starting from
electrophilic and nucleophilic monomers are likely to afford
the oxacalix[4]arene predominantly, we opted for a fragment
coupling SNAr strategy toward expanded oxacalix[n]arenes.
A combination of triaryl building blocks carrying comple-
mentaryfunctionalityshouldallowustoobtainoxacalix[6]arenes
selectively, at least if fragmentation and recombination of
the building blocks affording the thermodynamic product
(oxacalix[4]arene) can be limited. Bis(pyrimidine) electro-
philic triaryl fragments could easily be synthesized on
reacting (res)orcinol (1a,b) with a slight excess (∼2.2 equiv)
of an appropiately substituted 4,6-dihalopyrimidine 2b-e.
Among several conditions studied for monosubstitution of
the dihalopyrimidine, best results were achieved in acetone
at rt with K2CO3 base and 18-crown-6 (18C6) (Scheme 2,
The synthetic chemistry involving oxacalixarenes has been
overlooked for many years but has now reached a more
mature state due to an increasing amount of effort in recent
years.4-6 Virtually all procedures toward oxacalix[n]arenes
reported to date focus on the preparation of oxacalix[4]arenes,
[14]metacyclophanes composed of four O-bridged aryl
moieties, either directly starting from monomeric precursors
orviaastepwiseapproach.Themajorityofoxacalix[4](het)arenes
have been synthesized by nucleophilic aromatic substitution
(SNAr) procedures involving a nucleophilic m-dihydroxy-
benzene component and an electrophilic 1,3-dihalogenated
(hetero)aromatic building block. Careful optimization of the
SNArreactionconditionshasoftenaffordedtheoxacalix[4]arene
rather selectively over other (larger) cyclooligomers and
noncyclic materials by thermodynamic control.5,6
Larger oxacalix[n](het)arenes (n ) 6-12, mostly 6) have
been reported as being formed in modest yield upon usage
of more “kinetic” SNAr conditions, and (chromatographic)
separation of these larger homologues is often not
trivial.6e,g-i,m,7,8 Hence, one of today’s main challenges
within the oxacalixarene field involves the selective synthesis
of such large oxacalix[n]arenes, preferably by straightforward
SNAr procedures, to enable them to develop from rare
examples into useful molecular probes for selective recogni-
tion studies. Herein, we present the first rational design of
“expanded” oxacalix[n]arenes (n ) 6, 8) via a fragment
coupling protocol. Unsymmetrically substituted oxacalix[6]-
and oxacalix[8]arenes were prepared in a selective way by
limiting thermodynamic equilibration to the cyclotetramer.
In previous work, we have reported that a mixture of
oxacalix[m]arene[m]pyrimidines (m ) 2-6) can be obtained
starting from orcinol (1a) and 4,6-dichloro-2-phenylpyrimi-
dine (2a) under nonequilibrating conditions (Scheme 1).6h
Scheme 2. Synthesis of Triaryl Precursors 8a-f/9a-c
Scheme 1. Synthesis of Oxacalix[m]arene[m]pyrimidines 3-7a
Table 1).6k A few substituent combinations were examined,
affording triaryl precursors 8a-c in high yield (90-96%).
Upon reaction of two different dichloropyrimidines with
orcinol, the unsymmetrical triaryl compound 8d was prepared
in 66% yield. This building block can be applied for the
construction of oxacalix[n]arenes with a completely asym-
metric substitution pattern.
The complementary linear precursors 9a-c could be
synthesized by dropwise addition of a dichloropyrimidine
2a-c to a large excess (10 equiv) of a (res)orcinol derivative
(DMF, K2CO3, 18C6, 90 °C, 12 + 12 h; 57-73%) (Scheme
2, Table 1).9 The need for a large excess of (res)orcinol can
(7) You and co-workers obtained an oxacalix[6]arene in 25% yield
through an Ullmann coupling protocol.6f
Chromatographic separation afforded pure oxacalix[8] (10%),
[10] (8%), [6] (8%), [12] (8%), and [4] (30%), respectively.
On the other hand, on optimizing the SNAr conditions,
oxacalix[4]arene 3a could be synthesized selectively in over
80% yield. Although large oxacalix[n]arenes are hence
(8) A totally different approach was reported by Gibb et al.6b They
demonstrated that functionalized oxacalix[8]arenes are accessible by removal
of the resorcinarene template from their cavitand structures.
(9) A considerable part of the excess of (res)orcinol (∼75%) can be
recovered on chromatographic purification.
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Org. Lett., Vol. 11, No. 8, 2009

Table 1. Scope of Synthesized Triaryl Building Blocks.
Table 2. Scope of Synthesized Oxacalix[4]hetarenes
electrophilic
component
nucleophilic
component
product
(yield %)
1b (R1 ) H)
1a (R1 ) Me)
1b (R1 ) H)
1a (R1 ) Me)
2b (R2 ) H, X ) Cl)
2c (R2 ) SMe, X ) Cl)
2d (R2 ) Me, X ) Cl)
2b (R2 ) H, X ) Cl)
2c (R2 ) SMe, X ) Cl)
2e (R2 ) SMe, X ) F)
2b (R2 ) H, X ) Cl)
2c (R2 ) SMe, X ) Cl)
2a (R2 ) Ph, X ) Cl)
8a (90)
8b (95)
8c (96)
8d (66)a
1a (R1 ) Me)
1b (R1 ) H)
1b (R1 ) H)
1a (R1 ) Me)
8f (84)
9a (73)
9b (57)
9c (58)
SNAr
triaryl diphenol
conditions
oxacalix[4]arene
a Concurrent formation of 8b (37%)/8e (R1 ) Me, R2 ) H, X ) Cl;
8c
8c
8c
1a
1a
1a
1b
1b
MeCN, K2CO3,
3b (R1 ) H, R2 ) Me,
14%).
70 °C, 12 + 5 ha
THF, K2CO3, 18C6,
reflux, 36 h
R3 ) Me; 29%)b
3b (R1 ) H, R2 ) Me,
R3 ) Me; 35%)
DMF, K2CO3, 18C6,
3b (R1 ) H, R2 ) Me,
150 °C, 2.5 h
R3 ) Me; 47%)b
be circumvented by a two-step procedure involving substitu-
tion with 3-methoxyphenol and subsequent deprotection with
boron tribromide (see Supporting Information).
Before combination of both triaryl fragments was pursued,
the ideal macrocyclization conditions were investigated using
8b
(X ) Cl)
8f
1,4-dioxane, K2CO3,
3c (R1 ) Me, R2 )
18C6, reflux, 3 + 3 ha SMe, R3 ) H; 55%)
1,4-dioxane, K2CO3,
3c (R1 ) Me, R2 )
(X ) F)
18C6, reflux, 3 + 3 ha SMe, R3 ) H; 76%)
a Time of simultaneous addition + extra time. b NMR yield.
a
[3
+
1] coupling strategy toward ABAC
oxacalix[4]arenes.6j,k,o Oxacalix[4]arene synthesis is an ideal
test case in the search for the requested kinetic SNAr
conditions, both from an economic (only one of the triaryls
is consumed) and a practical (the reaction outcome can easily
be monitored by ESI-MS and 1H NMR analysis of the crude
reaction mixture10) point of view. More thermodynamic
conditions will induce scrambling, and hence, three different
oxacalix[4]arenes will be obtained,6j whereas more kinetic
conditions will afford the ABAC cyclotetramer predomi-
nantly. A thorough search for the optimum, most kinetic
conditions (solvent, base, temp, reaction time, high dilution)
was conducted, and the most illustrative examples are
summarized in Table 2. The fragment coupling reaction of
triaryl 8c and orcinol in acetonitrile with K2CO3 base at 70
°C under high dilution conditions afforded 29% of the desired
ABAC product 3b.11 Similar reactions in THF and DMF
(for a short reaction time to limit equilibration) also afforded
3b in 35% and 47% yield, respectively. All three approaches
induced significant scrambling, and separation of the ABAC
calixarene from both symmetrical oxacalix[4]arenes was
difficult. An encouraging breakthrough was achieved on
performing the reaction in 1,4-dioxane at reflux with K2CO3
base using high dilution techniques (simultaneous dropwise
addition over 3 h and 3 additional h).12 Under these
conditions, scrambling could greatly be reduced and
oxacalix[4]arene 3c could be isolated in 55% yield. A longer
reaction time resulted in a decreased yield (12 + 72 h; 17%
3b). As observed before for the synthesis of
oxacalix[2]arene[2]pyrimidines,6h the change of a dichloro-
pyrimidine electrophilic (8b) building block for a difluoro
analogue (8f) resulted in a noticeable improvement (∼20%)
of the selectivity, affording 3c in 76% yield. More reactive
starting compounds and, hence, a short reaction time seem
to be highly benefical for the reaction outcome.
When the optimized SNAr procedure was applied to the
[3 + 3] coupling, pure oxacalix[6]arenes 4b and 4c were
isolated in 37% and 49% yield, respectively (Table 3). Again,
the bis(fluoropyrimidine) precursor 8f could beneficially be
used to afford 4d in an excellent 70% yield. During the
purification of 4d, oxacalix[12]arene analogue 7d (see
Supporting Information) could also be isolated in 9% yield.
Under nonoptimized conditions (e.g., in MeCN or THF), the
desired oxacalix[6]arenes were obtained in rather low yields
after cumbersome purification from considerable amounts
of calix[4]arenes. Reaction in DMF at 70 °C (K2CO3, 18C6,
12 + 12 h) resulted in a mixture of oxacalix[n]arenes (n )
4-12), whereas a similar reaction at 120 °C for 3 h afforded
only the thermodynamically favored oxacalix[4]arenes.
The main advantage of oxacalix[m]arene[m]pyrimidines
compared to their counterparts prepared from other (het-
ero)aromatic electrophilic building blocks is the ease and
broad scope of modification of the oxacalixarene substitution
pattern. Functionalization can be achieved via the use of
(easily accessible) substituted pyrimidine building blocks or
by unique postmacrocyclization modifications. It has been
shown that oxacalix[2]arene[2]pyrimidines can easily be
functionalized by Liebeskind-Srogl or SNAr procedures.6p
These functionalizations can now be extended to oxa-
calix[6]arenes, and depending on the number of thiomethyl
groups, mono-, di-, and trifunctionalized oxacalixarenes can
be prepared. As a proof-of-principle, a postmacrocyclization
functionalization strategy was performed on 4d. The meth-
ylsulfanyl moieties were first oxidized to methylsulfonyl
groups (affording 4e in 83% yield), after which SNAr with
(10) Due to the distinct chemical shift for some intra-annular protons
of oxacalix[4]arenes, e.g., the strongly shielded 5-pyrimidinyl signals.6h
(11) Alternatively, ABAC oxacalix[4]arenes were obtained via combina-
tion of orcinol with a mixture of dichloropyrimidines (43%).6h
(12) Too strong dilution has to be avoided; no (or very slow) reaction
has been observed under such conditions.
Org. Lett., Vol. 11, No. 8, 2009
1683

4-tert-butylphenol (at 70 °C in 1,4-dioxane) afforded
oxacalix[6]arene 4f (R1 ) Me, R2 ) R4 ) 4-tBuPhO, R3 )
H; 57%).13
Scheme 3. Synthesis of Oxacalix[4]arene[4]pyrimidine 5b
Table 3. Scope of Synthesized Oxacalix[6]hetarenes
triaryls
oxacalix[6]arenea
8c and 9b 4b (R1 ) H, R2 ) Me, R3 ) H, R4 ) SMe; 37%)
8b and 9a 4c (R1 ) Me, R2 ) SMe, R3 ) H, R4 ) H; 49%)
8f and 9b
4d (R1 ) Me, R2 ) SMe, R3 ) H, R4 ) SMe; 70%)
a General SNAr conditions: 1,4-dioxane, K2CO3, 18C6, reflux, 3 + 3 h.
A logical extension to oxacalix[8]arenes involves combi-
nation of a penta- and triaryl building block. Since the
synthesis of the bis(pyrimidine) fragments 8a-f proceeded
smoothly, tris(pyrimidine) pentaaryl precursor 10 was pre-
pared by a similar strategy (triaryl 9a and pyrimidine 2e in
acetone at rt, 95% yield) (Scheme 3).14 A difluoro fragment
was again preferred for formation of the oxacalix[8]arene
due to its beneficial effect on the reaction yield. Under the
previously optimized conditions, pentaaryl moiety 10 and
triaryl 9c were combined to afford 5b in an exceptional 77%
yield (Scheme 3).
Diffraction-quality crystals of an oxacalix[8]arene were
obtained by vapor diffusion of pentane in a CHCl3 solution
of 5a.15,16 This example represents the first X-ray structure
reported in literature of an enlarged oxacalix[n]arene (n *
4) (more details in Supporting Information).17,18
In summary, we have established conditions that allow
the synthesis of variously functionalized large oxacalix-
Figure 1. Single-crystal X-ray structure for oxacalix[8]arene 5a.
[n]arenes (n ) 6, 8) with unprecedentedly high selectivity
by convenient stepwise SNAr strategies, enabling further
supramolecular research on these attractive macrocycles.
(13) The failure of the SNAr functionalization in DMF at 90 °C (the
conditions optimized for the oxacalix[4]arene) and the reduced yield seem
to reflect the lower stability of larger oxacalix[n]arenes.
(14) For the opposite combination, the conditions (DMF, 90 °C) required
to prepare the pentaaryl are likely to induce scrambling.
(15) Full synthetic details for this compound can be found in ref 6h.
(16) Crystallographic data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre as suppl. publ.
no. CCDC-718550. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
+44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
(17) Katz reported the structure of an oxacalix[6]- and an oxacalix[8]arene
at the Calix 2007 conference (College Park, MD).
(18) The structures of two ortho-linked [16]oxacyclophanes were very
recently reported: Ma, M.; Wang, H.; Li, X.; Liu, L.; Jin, H.; Wen, K.
Tetrahedron 2009, 65, 300.
Acknowledgment. The authors thank the FWO for
financial support and a postdoctoral fellowship to W.M. and
the KU Leuven and the Ministerie voor Wetenschapsbeleid
for continuing financial support.
Supporting Information Available: Experimental pro-
cedures and data, and 1H and 13C NMR spectra for all novel
building blocks and oxacalix[n]arenes. X-ray structure for
5a in CIF format. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL900116H
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Org. Lett., Vol. 11, No. 8, 2009