Odd-numbered oxacalix[ n ]arenes (n = 5, 7): Synthesis and solid-state structures

Article abstract of DOI:10.1021/ol1026969

The critical synthetic access to odd-numbered calix[n]arenes has evidently resulted in less attention for these macrocycles, although specific molecular recognition phenomena have been observed for some of them. A straightforward fragment coupling approac

Full text of DOI:10.1021/ol1026969

ORGANIC
LETTERS
2011
Vol. 13, No. 1
126-129
Odd-Numbered Oxacalix[n]arenes
(n ) 5, 7): Synthesis and Solid-State
Structures
Wim Van Rossom, Koen Robeyns,† Magriet 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 November 7, 2010
ABSTRACT
The critical synthetic access to odd-numbered calix[n]arenes has evidently resulted in less attention for these macrocycles, although specific
molecular recognition phenomena have been observed for some of them. A straightforward fragment coupling approach has been designed,
applying kinetically controlled nucleophilic aromatic substitution reaction conditions, affording odd-numbered oxacalix[n]arenes (n ) 5, 7)
selectively in high yields. The solid-state conformational behavior and the oxacalix[n]arene cavity size were explored by single-crystal X-ray
diffraction studies.
Heteracalixarenes,1-7 emerging members of the [1n]meta-
cyclophane family in which the classical methylene bridges
are replaced by heteroatoms, currently rejuvenate conven-
tional calixarene chemistry. The conformational behavior,
size, and structure of the cavity of this novel generation of
cyclooligomers may be fine-tuned by the bond lengths and
bond angles of the bridging heteroatoms, enhancing their
molecular recognition ability. Nowadays, straightforward
protocols toward heteracalixarenes (mostly S-,2 N-,3,4 and
O-bridged5,6) and postmacrocyclization functionalizations of
these macrocycles are frequently appearing in the literature.
All procedures toward O-bridged heteracalixarenes7 re-
ported to date focus on the preparation of oxacalix[n]arenes,
wherein n is an even number between 4 and 12, either
directly starting from monomeric precursors or by means of
a stepwise approach. The vast majority of oxacalix[n]-
(het)arenes have been synthesized by nucleophilic aromatic
substitution (SNAr) reactions involving a nucleophilic m-
dihydroxybenzene component and an electrophilic 1,3-
dihalogenated (hetero)aromatic building block. Careful op-
timization of the SNAr reaction conditions has usually
afforded the oxacalix[4]arene predominantly over other
cyclooligomers and noncyclic materials by thermodynamic
control.5,6 Recently, more kinetic conditions have been de-
veloped affording larger oxacalix[n]arenes (n ) 6, 8) or
poly(m-phenylene oxides) selectively in good yields.6r,u
† Biomolecular Architecture, Department of Chemistry, KU Leuven.
‡ Current address: Institute for Materials Research (IMO), Research
Group Organic and (Bio)Polymer Chemistry, Hasselt University, Agoralaan
- Building D, 3590 Diepenbeek, Belgium.
(1) Ko¨nig, B.; Fonseca, M. H. Eur. J. Inorg. Chem. 2000, 2303
(2) Thiacalixarene reviews: (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) Azacalixarene review: Tsue, H.; Ishibashi, K.; Tamura, R. In
Heterocyclic Supramolecules I; Matsumoto, K., Ed.; Topics in Heterocyclic
Chemistry; Springer: Heidelberg, Germany, 2008; Vol. 17, pp 73-96.
10.1021/ol1026969  2011 American Chemical Society
Published on Web 12/03/2010

Calix[n]arenes with an odd number of aromatic units (n
) 5, 7) are much less prominent as they are less readily
obtained. As a consequence they have been considerably less
studied, notwithstanding their specific host-guest properties
imposed by the particular diameter and shape of the
macrocycles.8 Odd-numbered (homo)heteracalixarenes are
also rare.9,10 A few azacalix[n]arenes (n ) 5, 7) and N,O-
bridged calix[n]arenes have recently been prepared by
stepwise strategies.9b-e To the best of our knowledge,
however, no odd-numbered oxacalixarenes were reported
until now. Of particular concern for the synthesis of enlarged
oxacalix[n]arenes (n > 4) is the high thermodynamic stability,
and hence preferential formation, of the cyclotetramer, which
introduces the necessity of more kinetically controlled
fragment coupling protocols.5
In earlier work our group optimized one-pot SNAr proce-
dures toward oxacalix[2]arene[2]pyrimidines starting from
dihalopyrimidine precursors and resorcinol derivatives,6f and
straightforward fragment coupling pathways ([3 + 3] and
[3 + 5] SNAr reactions) toward enlarged oxacalix[n]arenes
(n ) 6, 8).6r Upon simultaneous addition of the multiaryl
building blocks under more kinetically controlled reaction
conditions (K2CO3, 18-crown-6, 1,4-dioxane, high dilution,
reflux), scrambling of the fragments was prevented to a large
extent and the enlarged macrocycles were favored (over 70%
yield).6r By a similar stepwise approach it should be possible
to synthesize odd-numbered oxacalix[m]arene[n]pyrimidines,
the “missing links” in the oxacalixarene series, and inves-
tigations toward their synthesis and conformational behavior
were hence initialized.
(4) Recent additions to the azacalixarene field: (a) Vale, M.; Pink, M.;
Rajca, S.; Rajca, A. J. Org. Chem. 2008, 73, 27. (b) Touil, M.; Lachkar,
M.; Siri, O. Tetrahedron Lett. 2008, 49, 7250. (c) Tsue, H.; Ishibashi, K.;
Tokita, S.; Takahashi, H.; Matsui, K.; Tamura, R. Chem.sEur. J. 2008,
14, 6125. (d) Lawson, K. V.; Barton, A. C.; Spence, J. D. Org. Lett. 2009,
11, 895. (e) Xue, M.; Chen, C.-F. Org. Lett. 2009, 11, 5294. (f) Yao, B.;
Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. Chem. Commun. 2009, 2899.
(g) Yao, B.; Wang, D.-X.; Gong, H.-Y.; Huang, Z.-T.; Wang, M.-X. J.
Org. Chem. 2009, 74, 5361. (h) Clayden, J.; Rowbottom, S. J. M.; Ebenezer,
W. J.; Hutchings, M. G. Org. Biomol. Chem. 2009, 7, 4871. (i) Zhang,
E.-X.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. J. Org. Chem. 2009, 74,
8595. (j) Wang, L.-X.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. J. Org.
Chem. 2010, 75, 741. (k) Katz, J. L.; Tschaen, B. A. Org. Lett. 2010, 12,
4300.
First of all, a [2 + 3] fragment coupling approach toward
oxacalix[5]arenes was envisaged (Scheme 1). For this
(5) Oxacalixarene reviews: (a) Maes, W.; Dehaen, W. Chem. Soc. ReV.
2008, 37, 2393. (b) Wang, M.-X. Chem. Commun. 2008, 4541 (this review
also covers azacalixarenes from the same group)
Scheme 1. Synthesis of Oxacalix[3]arene[2]pyrimidines 5a-e
(6) Recent additions to the oxacalixarene field: (a) Wang, M.; Yang, H.
J. Am. Chem. Soc. 2004, 126, 15412. (b) Katz, J. L.; Feldman, M. B.; Conry,
R. R. Org. Lett. 2005, 7, 91. (c) Hao, E.; Fronczek, F. R.; Vicente, M. G. H.
J. Org. Chem. 2006, 71, 1233. (d) Yang, F.; Yan, L.; Ma, K.; Yang, L.; Li,
J.; Chen, L.; You, J. Eur. J. Org. Chem. 2006, 1109. (e) Katz, J. L.; Geller,
B. J.; Conry, R. R. Org. Lett. 2006, 8, 2755. (f) Maes, W.; Van Rossom,
W.; Van Hecke, K.; Van Meervelt, L.; Dehaen, W. Org. Lett. 2006, 8,
4161. (g) Csokai, V.; Kulik, B.; Bitter, I. Supramol. Chem. 2006, 18, 111.
(h) Konishi, H.; Tanaka, K.; Teshima, Y.; Mita, T.; Morikawa, O.;
Kobayashi, K. Tetrahedron Lett. 2006, 47, 4041. (i) Wang, Q.-Q.; Wang,
D.-X.; Zheng, Q.-Y.; Wang, M.-X. Org. Lett. 2007, 9, 2847. (j) Zhang, C.;
Chen, C.-F. J. Org. Chem. 2007, 72, 3880. (k) Van Rossom, W.; Maes,
W.; Kishore, L.; Ovaere, M.; Van Meervelt, L.; Dehaen, W. Org. Lett. 2008,
10, 585. (l) Wang, D.-X.; Zheng, Q.-Y.; Wang, Q.-Q.; Wang, M.-X. Angew.
Chem., Int. Ed. 2008, 47, 7485. (m) Ferrini, S.; Fusi, S.; Giorgi, G.;
Ponticelli, F. Eur. J. Org. Chem. 2008, 5407. (n) Konishi, H.; Mita, T.;
Yasukawa, Y.; Morikawa, O.; Kobayashi, K. Tetrahedron Lett. 2008, 49,
6831. (o) Hou, B.-Y.; Zheng, Q.-Y.; Wang, D.-X.; Huang, Z.-T.; Wang,
M.-X. Chem. Commun. 2008, 4541. (p) Capici, C.; Garozzo, D.; Gattuso,
G.; Messina, A.; Notti, A.; Parisi, M. F.; Pisagatti, I.; Pappalardo, S.
ARKIVOC 2009, Viii, 199. (q) Li, M.; Ma, M.-L.; Li, X.-Y.; Wen, K.
Tetrahedron 2009, 65, 4639. (r) Van Rossom, W.; Ovaere, M.; Van
Meervelt, L.; Dehaen, W.; Maes, W. Org. Lett. 2009, 11, 1681. (s) Wu, L.;
Jiao, L.; Lu, Q.; Hao, E.; Zhou, Y. Spectrochim. Acta, Part A 2009, 73,
353. (t) Ma, M.-L.; Li, X.-Y.; Wen, K. J. Am. Chem. Soc. 2009, 131, 8338.
(u) Wackerly, J. W.; Meyer, J. M.; Crannell, W. C.; King, S. B.; Katz,
J. L. Macromolecules 2009, 42, 8181. (v) Van Rossom, W.; Kundra´t, O.;
Ngo, T. H.; Lhota´k, P.; Dehaen, W.; Maes, W. Tetrahedron Lett. 2010, 51,
2423. (w) Wang, Q.-Q.; Wang, D.-X.; Yang, H.-B.; Huang, Z.-T.; Wang,
M.-X. Chem.sEur. J. 2010, 16, 7265. (x) Hu, S.-Z.; Chen, C.-F. Chem.
Commun. 2010, 46, 4199. (y) Van Rossom, W.; Kishore, L.; Robeyns, K.;
Van Meervelt, L.; Dehaen, W.; Maes, W. Eur. J. Org. Chem. 2010, 4122.
(7) We prefer the term heteracalixarenes to distinguish this class of
heteroatom-bridged macrocycles from heterocalixarenes, the heterocyclic
analogues of classical C-bridged calixarenes, e.g., calixpyrroles.
(8) Examples of odd-numbered (classical) calixarenes and their su-
pramolecular applications: (a) Atwood, J. L.; Barbour, L. J.; Heaven, M. W.;
Raston, C. L. Chem. Commun. 2003, 2270. (b) Martino, M.; Neri, P. Mini-
ReV. Org. Chem. 2004, 1, 219. (c) Garozzo, D.; Gattuso, G.; Notti, A.;
Pappalardo, A.; Pappalardo, S.; Parisi, M. F.; Perez, M.; Pisagatti, I. Angew.
Chem., Int. Ed. 2005, 44, 4892. (d) Makha, M.; McKinnon, J. J.; Sobolev,
A. N.; Spackman, M. A.; Raston, C. L. Chem.sEur. J. 2007, 13, 3907. (e)
Dalgarno, S. J.; Tian, J.; Warren, J. E.; Clark, T. E.; Makha, M.; Raston,
C. L.; Atwood, J. L. Chem. Commun. 2007, 4848. (f) Gargiulli, C.; Gattuso,
G.; Liotta, C.; Notti, A.; Parisi, M. F.; Pisagatti, I.; Pappalardo, S. J. Org.
Chem. 2009, 74, 4350. (g) Gattuso, G.; Notti, A.; Parisi, M. F.; Pisagatti,
I.; Amato, M. E.; Pappalardo, A.; Pappalardo, S. Chem.sEur. J. 2010, 16,
2381.
purpose an electrophilic triaryl building block 1a (R1 ) Me,
R2 ) Ph) was prepared, combining orcinol (5-methyl-1,3-
dihydroxybenzene, 2a) and a slight excess (2.05 equiv) of
4,6-difluoro-2-phenylpyrimidine (3a) in acetone with K2CO3
base and 18-crown-6 (85% yield).6r The use of difluoropy-
rimidines over their dichloro analogues was preferred as a
noticeable improvement of the selectivity was observed
before for the synthesis of oxacalix[2]arene[2]pyrimidines.6f,r
3,3′-Oxydiphenol (4) was selected as the nucleophilic diaryl
Org. Lett., Vol. 13, No. 1, 2011
127

precursor and could be synthesized by combining 3-meth-
oxyphenol and 3-bromoanisol in a Cu-assisted coupling
reaction and subsequent cleavage of the methyl groups with
HBr in acetic acid.11 Coupling of the two complementary
fragments 1a and 4 under the previously optimized SNAr
conditions afforded the first oxacalix[3]arene[2]pyrimidine
5a (Scheme 1). After purification by column chromatogra-
phy, 5a was isolated in an acceptable yield of 57% (Table
1).Inaddition,16%ofthelargeroxacalix[6]arene[4]pyrimidine
6a was obtained.12
diaryl building block 4 was now first reacted with an
electrophilic 4,6-difluoropyrimidine (2.05 equiv) affording
bispyrimidine tetraaryl fragments 7 (7a: R2 ) Ph, 95%, and
7b: R2 ) SMe, 82%; Scheme 1). Upon reaction of tetraaryl
precursor 7a and orcinol (2a), an improved 68% yield was
achieved for cyclopentamer 5a, with an additional 14% of
cyclodecamer 6a. By combining 7a with resorcinol (2b) or
5-tert-butyl-1,3-dihydroxybenzene (2c), the respective cy-
clopentamers 5c (74%) and 5d (75%) were also prepared in
high yields. Coupling tetraaryl derivative 7b with resorcinol
afforded bis(methylsulfanyl)oxacalix[5]arene 5e in 50%
yield, whereas combination with orcinol gave a slightly
higher yield (64% 5b).
An alternative electrophilic diaryl compound, 6,6′-oxy-
bis(4-fluoro-2-methylsulfanylpyrimidine) (8), was obtained
as a side product during fluorination of 4,6-dichloro-2-
methylsulfanylpyrimidine. Simultaneous addition of 8 and
nucleophilic triaryl building block 96r (R1 ) SMe; see
Scheme 2) under kinetic [3 + 2] fragment coupling condi-
Table 1. Scope of Synthesized Oxacalix[n]arenes (n ) 5, 7)
SNAr
R1
R2
calix[5] (%)
calix[10] (%)
[2 + 3]
[2 + 3]
[1 + 4]
[1 + 4]
[1 + 4]
[1 + 4]
[1 + 4]
Me
Me
Me
Me
H
Ph
SMe
Ph
SMe
Ph
Ph
5a (57)
5b (41)
5a (68)
5b (64)
5c (74)
5d (75)
5e (50)
6a (16)
6b (17)
6a (14)
6b (9)
6c (13)
6da
t-Bu
H
SMe
6ea
Scheme 2. Synthesis of Oxacalix[4]arene[3]pyrimidines 12a,b
SNAr
R1
R2
calix[7] (%)
calix[14] (%)
[2 + 5]
[2 + 5]
[3 + 4]
H
SMe
SMe
SMe
Ph
Ph
12a (73)
12b (59)
12b (66)
13a (8)
13b (14)
13b (11)
a Could not be isolated in pure form.
Combination of diaryl compound 4 with bispyrimidine
triaryl precursor 1b (R1 ) Me, R2 ) SMe) under the same
[2 + 3] fragment coupling conditions afforded oxacalix[5]arene
5b in 41% yield, together with 17% of oxacalix[10]arene
6b (Scheme 1, Table 1). The use of a 2-methylsulfanylpy-
rimidine building block implements the possibility to perform
substitution reactions, either by Liebeskind-Srogl or, after
oxidation, SNAr reactions. Such postmacrocyclization func-
tionalization options are rather specific for oxacalix[m]are-
ne[n]pyrimidines and highly interesting toward the prepa-
ration of a broad range of potential host molecules.6k
When attempting to improve the oxacalix[5]arene yield,
a [4 + 1] fragment coupling strategy was also examined
(Scheme 1). To obtain the appropriate linear precursors,
(9) Examples of odd-numbered heteracalixarenes (N-/S-/N,O-bridged):
(a) Nakabayashi, S.; Fukushima, E.; Baba, R.; Katano, N.; Sugihara, Y.;
Nakayama, J. Electrochem. Commun. 1999, 1, 550. (b) Liu, S.-Q.; Wang,
D.-X.; Zheng, Q.-Y.; Wang, M.-X. Chem. Commun. 2007, 3856. (c) Tsue,
H.; Matsui, K.; Ishibashi, K.; Takahashi, H.; Tokita, S.; Ono, K.; Tamura,
R. J. Org. Chem. 2008, 73, 7748. (d) Zhang, E.-X.; Wang, D.-X.; Zheng,
Q.-Y.; Wang, M.-X. Org. Lett. 2008, 10, 2565. (e) Wu, J. C.; Wang, D.-
X.; Huang, Z.-T.; Wang, M.-X. Tetrahedron Lett. 2009, 50, 7209.
(10) Examples of odd-numbered homoheteracalixarenes: (a) Shokova,
E. A.; Kovalev, V. V. Russ. J. Org. Chem. 2004, 40, 607. (b) Ashram, M.
J. Inclusion Phenom. Macrocyclic Chem. 2006, 54, 253. (c) Thomas, J.;
Maes, W.; Robeyns, K.; Ovaere, M.; Van Meervelt, L.; Smet, M.; Dehaen,
W. Org. Lett. 2009, 11, 3040. (d) Kaewtong, C.; Pulpoka, B. J. Inclusion
Phenom. Macrocyclic Chem. 2009, 65, 129. (e) Chen, Y.; Wang, D.-X.;
Huang, Z.-T.; Wang, M.-X. J. Org. Chem. 2010, 75, 3786.
tions afforded pentaoxacalix[2]arene[3]pyrimidine 10 in 18%
yield (see the structure in the Supporting Information). The
rather low yield is most probably the result of the labile
bispyrimidine oxygen bridge, which can be envisaged to
cleave and promote scrambling more rapidly.
To expand the scope of odd-numbered oxacalix[n]arenes
and study their molecular recognition features on a later
stage, calix[7]arene macrocycles were also prepared. To this
extent a [5 + 2] fragment coupling strategy applying the
(11) Yang, F.; Zhao, J.; Li, Y.; Zhang, S.; Shao, Y.; Shao, H.; Ma, T.;
Gong, C. Eur. Polym. J. 2009, 45, 2053.
(12) Chromatographic purification of the oxacalix[5]arene from the
oxacalix[10]arene congener is often not trivial.
128
Org. Lett., Vol. 13, No. 1, 2011

versions than calix[4]arenes. To elucidate the solid-state
structure of some of the novel oxacalix[5]arenes, X-ray
diffraction studies were undertaken.13 Vapor diffusion of
pentane into a CHCl3 solution of 5b resulted in suitable single
crystals (Figure 1). A distorted 1,3-alternate conformation,
which is dominant for oxacalix[4]arenes,5,6 can still be
recognized in the structure but the alternation is disrupted
at the stage of the oxybisphenol part: ring B breaks the
alternation order, whereas ring A adopts an almost parallel
(twisted) position in respect to the orcinol ring. X-ray
diffraction analysis of single crystals of 5c showed a very
similar “interrupted alternating” conformation (see the Sup-
porting Information), whereas for oxacalix[5]arene 10 the
alternation is disrupted at ring D of the bispyrimidine part
(Figure 1).
Inthesamewaythesolid-stateconformationofoxacalix[10]-
arene 6b was analyzed, showing a stretched rectangular
conformation (more details in the Supporting Information).
A diffraction-quality single crystal of oxacalix[7]arene 12b
was also obtained (Figure 1, more details in the Supporting
Information).13,14
Figure 1. Single-crystal X-ray structures for oxacalix[5]arenes 5b
(top) and 10 (middle) and oxacalix[7]arene 12b (bottom).
In summary, the first odd-numbered oxacalix[n]arenes (n
) 5, 7) have been synthesized through efficient fragment
coupling approaches by using easily obtainable building
blocks. Straightforward access to these provisionally under-
investigated macrocycles provides a springboard for further
supramolecular research based on these novel cyclooligo-
mers.
same kinetic SNAr conditions was performed (Scheme 2),
joining oxybisphenol (4) and trispyrimidine pentaaryl precur-
sor 11a (R1 ) H, R2 ) SMe).6r An encouragingly high yield
of 73% was obtained for oxacalix[4]arene[3]pyrimidine 12a
in combination with 8% of oxacalix[8]arene[6]pyrimidine
13a (Table 1). Such an enormous oxacalix[14]arene mac-
rocycle has never been reported before (or at least not isolated
in pure form and adequately characterized).5,6 Upon com-
bination of diaryl building block 4 and pentaaryl fragment
11b (R1 ) SMe, R2 ) Ph) a somewhat lower yield (59%)
was obtained for oxacalix[7]arene 12b. As an alternative
procedure, with the previous success in mind, a [4 + 3] coupling
approach was also pursued (Scheme 2). Bispyrimidine tetraaryl
precursor 7a (R2 ) Ph) and nucleophilic triaryl derivative 9
(R1 ) SMe) were combined to obtain oxacalix[7]arene 12b in
66% yield (11% [14] 13b, Table 1).
Acknowledgment. We 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-
1
cedures and data, H and 13C NMR spectra for all novel
building blocks and oxacalix[n]arenes, and X-ray structures
for 5b, 5c, 6b, and 12b in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
Because of the wider dimension of their annulus,
calix[5]arenes are more prone to conformational intercon-
OL1026969
(13) The only single-crystal X-ray structures of enlarged oxacalix[n]are-
nes ([6]/[8]) have been reported in refs 6r and 6w although Katz reported
similar structures at the Calix 2007 conference (Maryland, VS). The
structures of two ortho-linked [16]oxacyclophanes were also recently
reported: Ma, M.; Wang, H.; Li, X.; Liu, L.; Jin, H.; Wen, K. Tetrahedron
2009, 65, 300.
(14) Crystallographic data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre; deposition no.
CCDC-798286 up to 798289. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre, 12 Union Rd., Cambridge
CB2 1EZ, UK, by fax: +44(0)-1223-336033, or by e-mail: deposit@ccdc.
cam.ac.uk.
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