Efficient synthesis of a variety of new functionalized oxacalixarenes by Ullmann coupling reactions

Article abstract of DOI:10.1002/ejoc.200500879

We have developed an efficient method to synthesize a new type of oxacalix[4]arenes containing nitrogen functional groups in a single step, through N,N-dimethylglycine-promoted Ullmann coupling reactions starting from aryl dibromides in yields of up to 37%. With a aryl difluoride as substrate, a large, fully aromatic crown ether 8 could be obtained in 25 % yield. Further functionalization of the nitrogen functional groups in the cores of these oxacalixarenes may offer new opportunities for constructing desirable molecular architectures and a range of nitrogen-based multidentate ligands. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500879

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200500879
Efficient Synthesis of a Variety of New Functionalized Oxacalixarenes by
Ullmann Coupling Reactions
Fei Yang,[a] Liwei Yan,[a] Kuoyan Ma,[a] Li Yang,[a] Jihong Li,[a] Lijuan Chen,[b] and
Jinsong You*[a,b]
Keywords: N ligands/ Ullmann coupling reactions/ Oxacalixarenes/ Cyclization
We have developed an efficient method to synthesize a new
type of oxacalix[4]arenes containing nitrogen functional
in 25% yield. Further functionalization of the nitrogen func-
tional groups in the cores of these oxacalixarenes may offer
groups in a single step, through N,N-dimethylglycine-pro- new opportunities for constructing desirable molecular archi-
moted Ullmann coupling reactions starting from aryl dibro-
mides in yields of up to 37%. With a aryl difluoride as sub-
strate, a large, fully aromatic crown ether 8 could be obtained
tectures and a range of nitrogen-based multidentate ligands.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
lixarenes incorporating bridging carbon atoms, here we
wish to report facile methods to synthesize oxacalixarenes
containing nitrogen functional groups, in which nitro
groups can be converted into various other functional
groups (e.g., amino groups). Further functionalization of
the nitrogen groups in the new cyclophanes may offer new
opportunities for constructing desirable molecular architec-
tures. In addition, the presence of nitrogen functional
groups at the core of a cyclophane is synthetically relevant
for catalysis, since nitrogen serves as a versatile binding site
for a variety of metal complexes.[11] Bidentate and tridentate
nitrogen ligands, for example, are important for many cata-
lytic transformations.[12]
Introduction
Calixarenes, [1n]metacyclophanes incorporating bridging
carbon atoms, have attracted considerable research interest
from supramolecular chemists for decades.[1] Surprisingly,
heterocalixarenes are far less prevalent, although modula-
tion of the calixarene skeleton by linking the aromatic rings
with atoms other than carbon has the potential to impart
new physical and chemical properties in this class of com-
pounds. Very recently, investigations into sulfur-,[2] nitro-
gen-,[3] silicon-, and germanium[4]-bridged calixarenes have
increased significantly because of the rapid development of
synthetic methodologies, especially in the catalytic field.
Oxygen-bridged calixarenes (named oxacalixarenes), how-
ever, are almost absent from the chemical literature. The
formation of an oxacalix[4]arene was first reported in
1966[5] and was followed by several manuscripts from 1974
to 1976,[6] all of which utilized nucleophilic aromatic substi-
tution (SNAr) to form the macrocycles. Only a few reports
describing the synthesis of new oxacalixarenes have ap-
peared over the past 29 years, however.[7,8]
Results and Discussion
We initially tried to synthesize the new functionalized oxa-
calixarenes through direct SNAr reactions between phenols
and 1,3-difluoro-2-nitrobenzene or 3,5-dibromo-4-nitro-
toluene as starting materials without any Cu catalyst, but
all attempts failed, giving either very low yields or none of
the desired product. We therefore chose the Ullmann reac-
tion to construct those new functionalized oxacalixarenes
bearing nitrogen functional groups in the cyclophane core.
Ullmann ether formation reactions, in which aryl bromides
or iodides react with phenols under basic conditions in the
presence of copper salt catalysts, have been the focus of a
number of recent studies because they provide very direct
access to diaryl ethers.[13] They have traditionally been car-
ried out under rather harsh conditions, usually at high tem-
perature in pyridine as solvent. The yields are low to mod-
erate, and reactions between electron-rich aryl halides and
electron-deficient phenols typically do not work well. Clas-
sical Ullmann conditions are no longer state of the art, but
In recent years much attention has been devoted to the
synthesis and study of the properties of functionalized ca-
lixarenes, because of their potential utility as selective ion-
ophores for various cations or anions, as supramolecular
hosts for neutral guest molecules, and as non-viral DNA
vectors.[9,10] Inspired by these versatile functionalized ca-
[a] Key Laboratory of Green Chemistry and Technology of Minis-
try of Education, College of Chemistry, Sichuan University,
29 Wangjiang Road, Chengdu 610064, PR China
Fax: +86-28-85412203
E-mail: yjs19680401@yahoo.com.cn
[b] State Key Laboratory of Biotherapy, West China Hospital,
West China Medical School, Sichuan University,
Chengdu 610041, PR China
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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F. Yang, L. Yan, K. Ma, L. Yang, J. Li, L. Chen, J. You
SHORT COMMUNICATION
in recent years there has been great progress in Cu-catalyzed ramethylheptane-3,5-dione (TMHD), or phosphane-type li-
C–X bond formation under far less harsh conditions. Our gands in catalytic amounts to accelerate or enhance
initial investigations for the synthesis of the new oxacalix[4]- Ullmann reactions, allowing them to take place under more
arene 3 involved a classic Ullmann ether reaction between moderate conditions.[13,15] We were pleased to find that CuI/
3,5-dibromo-4-nitrotoluene and resorcinol in the presence N,N-dimethylglycine was an efficient catalytic system for
of simple copper salts without any extra ligand (Scheme 1). the Ullmann coupling reaction between 2,6-dibromo-4-ni-
For this model reaction, we tried to optimize reaction con- trotoluene (1) and resorcinol (2) under highly dilute condi-
ditions through the use of a variety of solvents (e.g., DMF, tions, and the yield of oxacalix[4]arene 3 was improved dra-
DMSO, pyridine, and N-methyl-2-pyrrolidine) (Table 1, En- matically. As summarized in Table 1, the results demon-
tries 1–4), bases (e.g., K2CO3, Na2CO3, NaHCO3, KOH, strated that the choice of copper salts appeared to be highly
NaH, and Cs2CO3), copper salts (e.g., CuO, CuI, CuCN, critical for this reaction (Table 1, Entries 7, 10 –14). We also
CuBr/dimethyl sulfide, and CuCl), concentrations, and tem- examined N-methylglycine and -proline as additives for the
peratures (100–140 °C). We found that CuO/K2CO3/pyri- reaction, but the yields were low due to poor conversion
dine was the best choice of reaction system. Use of stoichio- (Entries 8–9). The best result was obtained with Cs2CO3 as
metric quantities of CuO could afford a 3% product yield a base in the presence of a catalyst system generated in situ
at reflux for 1 day under highly dilute conditions (Table 1, from N,N-dimethylglycine (40 mol%) and CuI (20 mol%)
Entry 1), whilst none of the desired product was observed in dioxane at reflux, which gave a 37% yield (Table 1, En-
via the direct SNAr reaction between resorcinol and 3,5- try 7). It may be noted that our methodology also worked
dibromo-4-nitrotoluene in the absence of CuO and ligand well for a coupling between 2,7-dihydroxynaphthalene (4)
(Table 1, Entry 2). Unfortunately, all attempts to improve and 1,3-dibromo-2-nitrobenzene (5) to form the oxacalix[4]-
the yield of 3 failed.
arene 6 in a moderate yield (21%), whereas the classic
Ullmann ether reaction in the absence of extra N,N-dimeth-
ylglycine gave only a 1% yield of 6.
Scheme 1. Synthesis of oxacalix[4]arene 3.
Recent work with a copper() triflate catalyst in Buch-
wald’s group has made it possible to carry out Ullmann
ether reactions in good yields under milder conditions with
Large fully aromatic crown ethers are rare. The only two
a wider variety of substrates.[14] Unfortunately, use of this examples to have been reported, both in 1977, are hexa-
methodology still did not work well for the synthesis of the benzo-18-crown-6 and heptabenzo-21-crown-7, both ob-
oxacalix[4]arene 3, giving only a 4.5% yield (Table 1, En- tained in low yields (Ͻ0.1%) by use of multiple Ullmann
try 5). Recently, a number of groups have reported using ether reactions.[16] Over the past 28 years only two manu-
pyridine-type ligands, nitrogen-type ligands, 2,2,6,6-tet- scripts, by Gibb and co-workers in 2003 and 2001, describ-
Table 1. Ullmann coupling reactions between 3,5-dibromo-4-nitrotoluene (1) and resorcinol (2) to afford the oxacalix[4]arene 3 under
highly dilute conditions.[a]
Run
Temp. [°C]
Base
Solvent
Copper salt[b,c]
Ligand
Yield [%][d]
1
2
3
4
5
6
7
8
100
100
140
140
100
100
100
100
100
100
100
100
100
100
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
pyridine
pyridine
DMF
CuO
–
CuO
CuO
CuOTf
CuI
CuI
CuI
CuI
CuI
CuOTf
CuBr
CuCl
CuCN
–
–
–
–
–
–
3
none
1.5
1
4.5
none
37
4
N-methyl-2-pyrrolidine
pyridine
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
N,N-dimethylglycine
N-methylglycine
-proline
N,N-dimethylglycine
N,N-dimethylglycine
N,N-dimethylglycine
N,N-dimethylglycine
N,N-dimethylglycine
9
5
10
11
12
13
14
11
15
18
18
7
dioxane
[a] Reaction conditions: 3.39 mmol of resorcinol, 3.39 mmol of 3,5-dibromo-4-nitrotoluene, copper salt, 0.4 mmol of extra ligand, and
6.78 mmol of base in 220 mL of solvent were heated at 100–140 °C under nitrogen for 1 day. [b] 1.0 equiv. of copper salt in the absence
of extra ligand (Entries 1–6). [c] 0.2 mmol of copper salt in the presence of extra ligand (Entries 7–14). [d] Isolated yields.
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Eur. J. Org. Chem. 2006, 1109–1112

New Functionalized Oxacalixarenes by Ullmann Coupling Reactions
SHORT COMMUNICATION
Scheme 2. Synthesis of the large fully aromatic crown ether 8 under highly dilute conditions.
ing the synthesis of large macrocycles through Ullmann have also synthesize the fully aromatic crown ether 8 from
ether reactions with resorcinarenes as templates have ap- the aryl difluoride. The nitro groups in the oxacalixarene
peared.[8c,8d] Our initial synthetic strategy to make the large could be smoothly converted into amino groups in high
oxacalix[6]arene 8 focused on the utilization of the CuI/ yield through hydrogenation. The diamine functionality can
N,N-dimethylglycine catalytic system, but this approach be readily functionalized for various nitrogen-based multi-
failed when we started from aryl dibromides (e.g., 1,3-di- dentate ligands that may potentially find applications in
bromo-2-nitrobenzene or 3,5-dibromo-4-nitrotoluene). Very many metal-catalyzed transformations. Moreover, facile
interestingly though, the fully aromatic crown ether 8 could functionalization of the diamines into amides and peptide-
be obtained by use of an aryl difluoride instead of an aryl based moieties offers opportunities to design new hosts for
dibromide. In the absence of N,N-dimethylglycine as addi- molecular recognition studies.
tive, coupling between 1,3-difluoro-2-nitrobenzene (7) and
resorcinol 2 promoted by the CuI/K2CO3/pyridine system
Experimental Section
afforded the [3 + 3] product 8, in a 25% yield, rather than
the [2 + 2] cyclophane 9 (Scheme 2), although the yield was
not improved significantly when the extra ligand was em-
ployed. In addition, we did not observe any formation of
large fully aromatic crown ethers with use of other dihy-
General Ullmann Ether Reactions: A mixture of the dihydroxy aro-
matic derivative (resorcinol or 2,7-dihydroxynaphthalene,
3.39 mmol), the aryl dibromide (3,5-dibromo-4-nitrotoluene or 1,3-
dibromo-2-nitrobenzene, 3.39 mmol), the copper salt (0.2 mmol or
droxy aromatic derivatives (e.g., 2,7-dihydroxynaphthalene, 1 equiv.), N,N-dimethylglycine (0.4 mmol), and Cs2CO3
(6.78 mmol) in 220 mL of solvent (dioxane or pyridine) was heated
at 100–140 °C under nitrogen for 1 day. The solvent was concen-
trated under vacuum to give a brown solid, which could be purified
by chromatography on silica gel with CHCl3 as eluent to afford a
white solid.
hydroquinone, and 1,5-dihydroxynaphthalene).
In addition, we also tried to hydrogenate the NO2 groups
of aromatic crown ethers so that these oxacalixarenes might
easily be further modified. We examined a range of solvents,
such as CHCl3, CH2Cl2, MeOH, MeOH/CHCl3, and DMF,
and found that DMF was the best choice. In the presence
of 10% of Pd/C (5%), the oxacalix[4]arene 3 could be
smoothly converted in a 90% yield into the aromatic crown
ether 10, containing amino groups (Scheme 3).
1
Oxacalix[4]arene 3: H NMR (400 MHz, CDCl3, 25 °C): δ = 2.33
(s, 6 H), 5.28 (t, J = 2.4 Hz, 2 H), 6.85 (m, 8 H), 7.28 (t, J = 6.6 Hz,
2 H) ppm. 13C NMR (100.62 MHz, CDCl3, 25 °C): δ = 156.4,
150.2, 143.4, 127.9, 123.0, 110.3, 109.9, 106.1, 24.1 ppm. HRMS
(FAB): calcd. for [C26H18N2O8Na] ([M + Na]+) 509.0961; found
509.0970. C26H18N2O8(486.1): C 64.20, H 3.73, N 5.76; found C
64.10, H 3.81, N 5.61.
1
Oxacalix[4]arene 6: H NMR (400 MHz, CDCl3, 25 °C): δ = 6.51
(d, J = 2.5 Hz, 4 H), 7.26 (m, 8 H), 7.71 (d, J = 8.8 Hz, 2 H), 7.77
(d, J = 9.0 Hz, 4 H) ppm. 13C NMR (100.62 MHz, CDCl3, 25 °C):
δ = 153.4, 149.9, 135.0, 134.2, 129.4, 126.4,124.1, 115.5, 114.8,
107.4 ppm. HRMS (FAB): calcd. for [C32H18N2O8Na] ([M +
Na]+) 581.0961; found 581.0970. C32H18N2O8 (558.1): C 68.82, H
3.25, N 5.02; found C 68.70; H 3.40; N 4.93.
Scheme 3. Synthesis of the aromatic crown ether 10 with amino
Synthesis of the Large Fully Aromatic Crown Ether 8: A mixture of
resorcinol (3.14 mmol), 1,3-difluoro-2-nitrobenzene (3.14 mmol),
CuI (6.28 mmol), and K2CO3 (6.28 mmol) in pyridine (250 mL)
was heated at reflux for 1 day. The solid was filtered off and the
filtrate was concentrated under vacuum to give a brown solid,
which could be purified by chromatography on silica gel with
CHCl3/hexanes 8:2 as eluent to afford a white solid.
groups.
Conclusions
We have developed an efficient method to synthesize a
new type of oxacalix[4]arene containing nitrogen functional
groups in a single step through N,N-dimethylglycine-pro-
Oxacalix[6]arene 8: 0.18 g, 25%. 1H NMR (400 MHz, CDCl3,
25 °C): δ = 6.51 (t, J = 2.0 Hz, 3 H), 6.67 (d, J = 8.5 Hz, 6 H), 7.06
moted Ullmann coupling reactions of aryl dibromides. We (2×d, J = 1.9, 2.0 Hz, 6 H), 7.30 (t, J = 8.6 Hz, 2 H), 7.44 (t, J =
Eur. J. Org. Chem. 2006, 1109–1112
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1111

F. Yang, L. Yan, K. Ma, L. Yang, J. Li, L. Chen, J. You
SHORT COMMUNICATION
8.8 Hz, 4 H) ppm. 13C NMR (100.62 MHz, CDCl3, 25 °C): δ =
156.3, 148.9, 134.0, 127.5, 125.8, 111.1, 109.8, 106.1 ppm. HRMS
(FAB): calcd. for [C36H21N3O12Na] ([M + Na]+) 710.1023; found
710.1029. C36H21N3O12 (687.1): C 62.89, H 3.08, N 6.11; found C
62.77; H 3.19, N 6.03.
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Acknowledgments
This work was supported by grants from the Outstanding Young
Scientist Award of Sichuan Province, the Setup Foundation of
Sichuan University, and the Foundation for Returnees of the Chi-
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Received: November 8, 2005
Published Online: January 12, 2006
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