Single step synthesis of acetylene-substituted oxacalix[4]arenes

Article abstract of DOI:10.1021/ol5010627

Oxacalixarenes bearing acetylene groups are synthesized in a single step by nucleophilic aromatic substitution reactions of orcinol with various 1,5-diethynyl-2,4-difluorobenzenes. Thermodynamic equilibration of the cyclooligomer mixtures was accomplished

Full text of DOI:10.1021/ol5010627

Letter
pubs.acs.org/OrgLett
Single Step Synthesis of Acetylene-Substituted Oxacalix[4]arenes
Jay Wm. Wackerly,‡ Mengfei Zhang,† Stephen T. Nodder,† Stephen M. Carlin,† and Jeffrey L. Katz*,†
†Department of Chemistry, Colby College, 5754 Mayflower Hill, Waterville, Maine 04901, United States
‡Department of Chemistry, Central College, 812 University Street, Pella, Iowa 50219, United States
S
* Supporting Information
ABSTRACT: Oxacalixarenes bearing acetylene groups are
synthesized in a single step by nucleophilic aromatic
substitution reactions of orcinol with various 1,5-diethynyl-
2,4-difluorobenzenes. Thermodynamic equilibration of the
cyclooligomer mixtures was accomplished for arylethynyl
activating groups, leading to increased yields of the
corresponding oxacalix[4]arenes. A 1,3-alternate macrocycle
conformation is observed in the solid state, presenting a large
V-shaped π-surface.
Scheme 1. Substitution of Ethynylbenzenes 16
xacalixarenes remain a heavily investigated and compel-
O
ling platform for the design of molecular receptors.1
Since early publications on their synthesis via nucleophilic
aromatic substitution (SNAr) methods,2,3 researchers continue
to diversify the accessible oxacalixarene architectures through
modification of the nucleophilic and electrophilic aromatic
starting materials.4,5 The nucleophilic coupling partner,
typically a resorcinol, is the most extensively varied reactant;
oxacalixarenes have been constructed using dihydroxy-ben-
zenes, naphthalenes, tryptycenes, and biphenylenes, terpheny-
lenes, and related extended aromatic systems.4,5
Alterations of the electrophilic component in SNAr-based
oxacalixarene formation have so far proven more limited in
scope. Most commonly constructed using 2,4,6-trichloro-1,3,5-
triazine3a or 1,5-difluoro-2,4-dinitrobenzene,3b successful mac-
rocyclizations have also been reported using alternative
nitrogen heterocycles including pyridines, pyrazines, pyrimi-
dines, quinazolines, quinoxalines, and naphthyridines.4,5 Frame-
works composed of all-carbon arenes, however, continue to
depend on 1,5-difluoro-2,4-dinitrobenzene as the electrophile,
and this restricts the accessible functional group profiles of
oxacalixarenes bearing all-carbon aromatic rings.
Our laboratory recently reported that ethynyl groups are
sufficiently electron-withdrawing to activate fluorobenzenes for
nucleophilic aromatic substitution.6 In addition to simple 4-
fluoroethynylbenzenes, 1,5-diethynyl-2,4-difluorobenzenes 1
were effectively substituted by oxygen and aniline nucleophiles
with displacement of both fluorine atoms. Phenols were shown
to be competent nucleophiles for this process, with 1,5-
diethynyl-2,4-difluorobenzenes 1a and 1b reacting with p-cresol
at 60 °C to produce disubstitution products 2 in 89−93% yields
with negligible alkyne addition side reactions (Scheme 1).
Alkyne-substituted oxacalixarenes have not yet been reported in
the literature, although such systems are compelling scaffolds
for further expansion of the oxacalixarene functional group
profile, and for the electronic properties imparted by the
arylethynyl moieties. The efficiency of aryl ether formation
using 1,5-diethynyl-2,4-difluorobenzenes 1 prompted us to
investigate such systems as viable electrophiles for the single-
step construction of acetylene-substituted oxacalixarenes.
We initially attempted oxacalixarene formation by reacting
1,5-di(trimethylsilylethynyl)-2,4-difluorobenzene 1c with orci-
nol 3 using Cs2CO3 or CsF base in DMSO (120 °C, 18 h; see
Table 1). With Cs2CO3 base we observed the formation of a
complex mixture of side products resulting from degradation of
the pendant ethynyl groups, along with only small amounts of
oxacalix[4]arene 4a. A change to CsF base mitigated but did
not eliminate alkyne degradation. Using either Cs2CO3 or CsF,
it was evident that the TMS groups are rapidly removed in situ,
prior to aromatic substitution. Optimizing time and temper-
ature with CsF base (125 °C, 24 h) allowed us to raise the
isolated yield of oxacalix[4]arene 4a to 32%. Along with 4a,
oxacalix[6]arene 5a and oxacalix[8]arene 6a were also isolated
in 17% and 13% yield, respectively (Table 1, entry 1).
Extending the reaction time beyond 24 h or raising the
temperature of the reaction resulted only in increased alkyne
decomposition and lower isolated quantities of oxacalixarenes
4a−6a.
The high yields observed for many oxacalix[4]arene
formations are often attributed to thermodynamic equilibration
of the initially formed linear and cyclooligomeric mixture to the
thermodynamically preferred oxacalix[4]arene.4b The modest
isolated yield of oxacalixarene 4a, along with appreciable
quantities of higher cyclooligomers, appeared to result from a
Received: April 11, 2014
Published: May 15, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
Table 1. Formation of Ethynyl-Substituted Oxacalixarenes
Scheme 2. Synthesis of Oxacalix[4]arenes 4d and 4e
4−6
a
yield (%)
temp
(°C)
entry
1
time
products
4
5
6
1
2
3
1c
1b
1b
125
130
160
24 h
4 d
4a−6a (R = H)
4b−6b (R = Ph)
32
43
54
17
22
9
13
10
<5
b
4 d
4b−6b (R = Ph)
groups were found to be resistant to decomposition at high
temperature, and optimal isolated yields of 4d were obtained at
160 °C over 2 d (66% yield). The 4-trifluoromethyl(phenyl-
ethynyl) groups were more sensitive to degradation, and the
highest yields of 4e were obtained at slightly lower temper-
atures (150 °C, 2 d, 49% yield) in order to minimize
decomposition under the strongly anionic conditions.
a
b
Isolated yield unless otherwise noted. Measured by 1H NMR
integration.
kinetic ring formation without significant macrocycle equilibra-
tion. Reversible C−O bond formation with only alkyne
activating groups was not effective at 125 °C, and the use of
higher temperatures for that system was precluded due to the
sensitivity of the ethynyl groups.
X-ray quality crystals of 4b were obtained by vapor diffusion
of hexanes into CH2Cl2 (Figure 1). As is common with
We next investigated the use of 1,5-di(phenylethynyl)-2,4-
difluorobenzene 1b, an electrophile bearing phenylethynyl
groups that are more resistant to anionic side reactions in
alkyne-activated SNAr reactions than the in situ revealed ethynyl
groups using 1c.6 Reaction of 1b with orcinol 3 (CsF, DMSO,
125 °C, 24 h) provided a mixture of oxacalixarene cyclo-
oligomers similar to that seen using 1c, but without appreciable
alkyne decomposition or side reactions. Extending the reaction
time and temperature to 130 °C for 4 d furnished a separable
mixture of oxacalixarenes more strongly favoring oxacalix[4]-
arene 4b (43%) but still containing oxacalix[6]arene 5b (22%),
oxacalix[8]arene 6b, 10%, as well as smaller quantities of higher
cyclooligomers (Table 1, entry 2). Although electrophile 1b
reacts completely with phenol and alcohol nucleophiles at
relatively mild temperatures (see Scheme 1),6 equilibration of
aryloxy substituents on the diethynylbenzene electrophile was
found to be remarkably sluggish. Higher temperatures and
extended reaction times using 1b promoted slow but continued
equilibration of cyclooligomers to oxacalix[4]arene 4b along
with only minor alkyne decomposition, and our optimized yield
of 4b (54%) was obtained after 4 days at 160 °C (Table 1,
entry 3).
With an optimized procedure for oxacalix[4]arene 4b, we
turned to investigating modifications to the arylethynyl
substituents on electrophiles 1. Difluorides 1d and 1e bearing
3-pyridyl and 4-trifluoromethylphenyl groups, respectively,
were accessed via Sonogashira coupling of 1,5-dibromo-2,4-
difluorobenzene7 with the appropriately functionalized acety-
lene. Both 1d and 1e condense effectively with orcinol 3 to
furnish tetraethynyloxacalix[4]arenes 4d and 4e (Scheme 2).
The added electron-withdrawing capacity of the arylethynyl
groups on 1d and 1e also served to modestly increase the rate
of equilibration over that observed for 1b. The 3-pyridylethynyl
Figure 1. Solid state structure of oxacalix[4]arene 4b, two views.
Atoms modeled at partial occupancy have been depicted in single
positions for clarity.
oxacalixarenes derived from alternative electrophiles, macro-
cycle 4b adopts a distorted 1,3-alternate conformation in the
solid state. The nucleophile-derived rings are nearly eclipsed,
with a 4.3° angle between ring planes. The electron-
withdrawing capacity of the phenylethynyl groups is evident
from inspection of the C−O bond lengths. As seen in
oxacalix[4]arene structures bearing 2,4-dinitrobenzenes,3a,4b
bond lengths from the bridging oxygen atoms to the
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oxacalixarenes, permitting the synthesis of the first examples
of acetylene-substituted oxacalixarenes. Investigations to further
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data for com-
pounds 1c−e, 4−6, and X-ray crystallographic data for
compound 4b (CIF format). This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jlkatz@colby.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by the National Science Foundation
(CHE-1147787, CHE-1062944), the Camille and Henry
Dreyfus Foundation, and Colby College.
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