Synthesis, structure, and functionalization of homo heterocalix[2]arene[2] triazines: Versatile conformation and cavity structures regulated by the bridging elements

Article abstract of DOI:10.1021/jo100571c

Figure presented A number of homo[2] and homo[4] heterocalix[2]arene[2] triazines were synthesized through a general and good-yielding fragment coupling approach starting from cyanuric halides, aromatic and aliphatic diols, and diamines under very mild reaction conditions. While homo[2] tetraazacalix[2] arene[2]triazine gave a twisted and pinched 1,2-alternate conformer, almost all homo[2] heterocalix[2]arene[2]triazines adopted different partial cone conformations in the solid state. Homo[4] heterocalix[2]arene[2]triazines yielded more diverse conformational structures including partial cone, pinched partial cone, 1,2-alternate and twisted 1,2-alternate, depending on the nature of bridging moieties. On the basis of ¹H NMR spectra, homo[2] and homo[4] heterocalix[2]arene[2]triazines were fluxional macrocycles in solution, and they underwent rapid conformation interconversion at different temperatures. Efficient and straightforward nucleophilic aromatic substitution reaction and palladium-catalyzed cross-coupling reactions on chlorotriazine rings, and the nucleophilic alkylation reaction on the bridging nitrogen atoms led to the construction of various highly functionalized homo heterocalix[2]arene[2] triazine derivatives.

Full text of DOI:10.1021/jo100571c

pubs.acs.org/joc
Synthesis, Structure, and Functionalization of Homo
Heterocalix[2]arene[2]triazines: Versatile Conformation and Cavity
Structures Regulated by the Bridging Elements
Yin Chen,† De-Xian Wang,† Zhi-Tang Huang,† and Mei-Xiang Wang*,†,‡
†Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition
and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China, and ‡The Key
Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education),
Department of Chemistry, Tsinghua University, Beijing 100084, China
wangmx@mail.tsinghua.edu.cn; mxwang@iccas.ac.cn
Received March 26, 2010
A number of homo[2] and homo[4] heterocalix[2]arene[2]triazines were synthesized through a general
and good-yielding fragment coupling approach starting from cyanuric halides, aromatic and
aliphatic diols, and diamines under very mild reaction conditions. While homo[2] tetraazacalix-
[2]arene[2]triazine gave a twisted and pinched 1,2-alternate conformer, almost all homo[2] hetero-
calix[2]arene[2]triazines adopted different partial cone conformations in the solid state. Homo[4]
heterocalix[2]arene[2]triazines yielded more diverse conformational structures including partial
cone, pinched partial cone, 1,2-alternate and twisted 1,2-alternate, depending on the nature of bridg-
ing moieties. On the basis of 1H NMR spectra, homo[2] and homo[4] heterocalix[2]arene[2]triazines
were fluxional macrocycles in solution, and they underwent rapid conformation interconversion at
different temperatures. Efficient and straightforward nucleophilic aromatic substitution reaction
and palladium-catalyzed cross-coupling reactions on chlorotriazine rings, and the nucleophilic
alkylation reaction on the bridging nitrogen atoms led to the construction of various highly
functionalized homo heterocalix[2]arene[2]triazine derivatives.
Introduction
spherands,3 and cryptands4 promoted tremendous advances
in supramolecular science.1 One of the recent examples is
calixarenes.5 Following Gutsche’s pioneering work6 of synth-
esis and structural elucidation, calix[n]arenes have become
classic macrocyclic molecules because of their easy availabi-
lity, unique conformational and cavity structures, and power-
ful recognition properties.
One of the challenging tasks in supramolecular chemistry is
the design and synthesis of novel and functional macrocyclic
molecules. Historically, the emergence of crown ethers,2
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Published on Web 05/05/2010
DOI: 10.1021/jo100571c
r
2010 American Chemical Society

Chen et al.
JOCArticle
As a novel type of [1n]metacyclophanes, heterocalixaro-
matics or the heteroatom-bridged calix(hetero)arenes7-11
have recently been emerging as a unique type of macrocyclic
host molecules in supramolecular chemistry. Based on the
stepwise fragment coupling strategy8e,9d and one-pot macro-
cyclic condensation reaction approach,9j a number of dis-
symmetric and symmetric heterocalixaromatics have been
synthesized in good yields. Functionalized heterocalixaromatics
are also obtained conveniently either from starting materials
containing functional groups9g,h,11 or from postmacrocycliza-
tion functionalizations on aromatic rings8m,n,9d,f,i,o and bridging
heteroatoms.8h,n Owing to the bridging heteroatoms such as
nitrogen, oxygen, and sulfur that can adopt different electronic
configurations and form different degrees of conjugation with
their neighboring aromatic rings, heterocalixaromatics are able
to form fine-tunable conformation and cavity structures.8f
Furthermore, the various electronic effects of the heteroatoms
also regulate the electron density of aromatic rings, producing
the cavity of varied electronic features.9d,12 Heterocalixaro-
matics have been shown to act as versatile macrocyclic host
molecules to recognize metal cations,8g,l,13 halides,12 neutral
molecules,8f,i,14 including fullerenes.8e,j,k
Our continuous interest7a in exploring the supramolecular
chemistry of macrocyclic host molecules has led us to design
and construct novel and functional homo heterocalixaro-
matics.15 By the insertion of methylene units into the brid-
ging position of heterocalixaromatics, we envisioned that
homo heterocalixaromatics would give an enlarged cavity
and varied conformations other than 1,3-alternate. Remain-
ing the direct connectivity between heteroatoms and aro-
matic rings, the electronic features of the aromatic surfaces
of the homo heterocalixaromatic macrocycles might be
regulated by the bridging nitrogen and oxygen atoms. We
report herein a general and high-yield fragment coupling
method for the synthesis of nitrogen and oxygen bridged
homo calix[2]arene[2]triazines. Depending on the nature of
the bridging units, the macrocycles adopt indeed versatile
conformational structures and give varied cavity sizes. We
will also demonstrate that the homo heterocalix[2]arene-
[2]triazines prepared from cyanuric chloride are amenable
to facile functionalizations on triazine rings simply via
nucleophilic aromatic substitution reaction and palladium-
catalyzed cross-coupling reaction. Functionalization on the
bridging positions was accomplished through exclusive and
exhaustive N-allylation reaction of homo[4] tetraazacalix-
[2]arene[2]triazine.
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Results and Discussion
Synthesis. We initiated our study with the synthesis of
homo[2] diazadioxacalix[2]arene[2]triazine 3a.16 In the pre-
sence of diisopropylethylamine (DIPEA) as an acid scavenger,
a linear trimer 1a, which was prepared in a good yield from the
reaction of resorcinol with 2 equiv of cyanuric chloride,9d
underwent macrocyclic condensation reaction with 1,3-phenyl-
enedimethaneamine 2a in acetonitrile at room temperature to
give a hardly soluble white solid product 3a in 40% yield. To
increase its solubility and therefore to facilitate its characteriza-
tion, the chloro substituent on triazine ring was replaced by a
diethylamino group via nucleophilic aromatic substitution
reaction with diethylamine to afford homo[2] diazadioxacalix-
[2]arene[2]triazine product 4a in 78% yield (Scheme 1). With-
out the isolation of 3a, the product 4a was synthesized readily in
31% yield from the reaction between 1a and 2a in acetonitrile at
(12) Wang, D.-X.; Zheng, Q.-Y.; Wang, Q.-Q.; Wang, M.-X. Angew.
Chem., Int. Ed. 2008, 47, 7485.
(13) Gong, H.-Y.; Wang, D.-X.; Zheng, Q.-Y.; Wang, M.-X. Tetrahedron
2009, 65, 87.
(14) Gong, H.-Y.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. Sci. China
Ser. B: Chem. 2009, 52, 1646.
(15) A few examples of homocalixarenes, ethylene-bridged phenol deri-
€
vatives, are known. Ibach, S.; Prautzsch, V.; Vogtle, F. Acc. Chem. Res. 1999,
32, 729. To the best of our knowledge, however, no homo heterocalixaro-
matics have been reported.
(16) There are two different types of homo heterocalixaromatics synthe-
sized in this study. Homo[2] and homo[4] heterocalixaromatics refer to
macrocycles having two methylene and four methylene units in bridging
positions, respectively. Based on cyclophane nomenclature, they are also
named, respectively, as [2.2.1.1]metacyclophanes and [2.2.2.2]metacyclo-
phanes.
(10) For a review of thiacalixarenes, see: Morohashi, N.; Narumi, F.; Iki,
N.; Hattori, T.; Miyano, S. Chem. Rev. 2006, 106, 5291.
(11) For a recent example of calixaromatics bridged by a mixture of
heteroatoms, see: Wu, J.-C.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X.
Tetrahedron Lett. 2009, 50, 7209. Other examples can be found in ref 9d.
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SCHEME 1. Synthesis of Homo Heterocalix[2]arene[2]triazines from Macrocyclic Condensation Reactions of 1,3-Phenylenedimethyl-
amine and 1,3-Phenylenedimethanol with Trimers 1 Derived from Resorcinol and 1,3-Phenylenediamines
room temperature followed by the treatment of the resulting
precipitate with diethylamine at 85 °C in dimethyl sulfoxide
(DMSO). It is very interesting to note that when the reaction of
1a with 2a was performed in acetone, the macrocyclic con-
densation reaction yielded N-prop-1-en-2-yl-substituted homo-
[2] diazaoxacalix[2]arene[2]triazines 5a and 5b in 31% and
14%, respectively. Under the identical conditions for the prepa-
ration of 5a and 5b, however, the homo[2] diazadioxacalix-
[2]arene[2]triazine 3a was not converted into its N-prop-1-en-2-
yl-substituted derivatives 5. It might suggest that the reaction of
bridging nitrogen atom(s) with acetone occurred prior to the
macrocyclization step.
Applying the same reaction conditions for the synthesis of
5a and 5b, the macrocyclic condensation reaction between 1b
and 2a gave homo[2] tetraazacalix[2]arene[2]triazine 3b,
which underwent nucleophilic aromatic substitution reac-
tion with diethylamine to afford product 4b in an overall
yield of 24%. N-Benzylated homo[2] tetraazacalix[2]arene-
[2]triazine 3c was prepared in 52% yield from the reaction of
linear trimer 1c with N,N0-(1,3-phenylenebis(methylene))bis-
(1-phenylmethaneamine) 2b (Scheme 1). It should be noted
that the reaction of linear trimer 1a-c with 1,3-phenylene-
dimethanol 2c under the identical conditions did not produce
the desired macrocyclic products, due to probably the low
nucleophilicity of aliphatic diol 2c.
with 2 equiv of cyanuric chloride 6a to produce the corre-
sponding linear trimers 7a and 7b in 84% and 94%, respec-
tively (Scheme 2). Oxygen-linked linear trimer 7c has been
prepared by Krische17 from 1,3-phenylenedimethanol 2c and
cyanuric chloride using lutidine as a base. Following the
literature method,17 we found it difficult to get pure product 7c.
Employing the conditions for the synthesis of 7a and 7b,
reaction between cyanuric chloride and 1,3-phenylenedi-
methanol 2c proceeded very sluggishly, probably due to
the low nucleophilicity of aliphatic diol. Interestingly, chan-
ging the solvent from THF to chloroform, the reaction
proceeded exothermically to afford pure 7c as white solid
in 34% yield. Starting with cyanuric fluoride 4b instead of
cyanuric chloride 4a, the reaction in THF afforded the
oxygen-linked linear trimer 7d in 55% yield. A much imp-
roved chemical yield (87%) of 7d was obtained when the
reaction was performed in diethyl ether at room temperature
(Scheme 2). Macrocyclic condensation reaction of the result-
ing linear trimers 7 proceeded effectively with dinucleophiles
2 in the presence of a base at ambient temperature to form
targeted homo[4] heterocalix[2]arene[2]triazines 8. Since the
parent homo[4] heterocalix[2]arene[2]triazines 7 were not
soluble in most of the organic solvents, they were trans-
formed into products 8 simply through the nucleophilic
displacement of chloro substituent on triazine ring by a
dialkylamine. For example, nitrogen-linked linear trimers
7a and 7b underwent macrocyclic condensation reaction
with diamines 2a and 2b, respectively, in acetone at room
temperature with the aid of DIPEA as an acid scavenger to
Encouraged by the facile synthesis of homo[2] heterocalix-
[2]arene[2]triazines 3-5 (Scheme 1), we then attempted the
synthesis of homo[4] heterocalix[2]arene[2]triazines16 that
contained four methylene units in the bridging positions
using the fragment coupling approach. In the presence of a
base such as DIPEA or K2CO3 in tetrahydrofuran (THF) or
acetonitrile at 0 °C, diamines 2a and 2b reacted efficiently
(17) Archer, E. A.; Caube, D. F., Jr.;Lynch, V.; Krische, M. J. Tetrahedron
2002, 58, 721.
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Chen et al.
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give intermediates 8a and 8b. Treatment of 8a with dimethyl-
amine in N,N-dimethylformamide (DMF) at 85 °C led to the
formation of homo[4] NH-bridged calix[2]arene[2]triazine
9a in an overall yield of 65%. Homo[4] NBn-bridged calix-
[2]arene[2]triazine 9b was obtained after intermediate 8b was
interacted with diethylamine in DMSO at 85 °C. The room
temperature reaction of oxygen-linked linear trimer 7c with
diamine 2a using DIPEA as a base and acetonitrile as the
solvent resulted in the formation of intermediate 8c which
underwent further reaction with diethylamine to afford
homo[4] diazadioxacalix[2]arene[2]triazine 9c in 32% yield.
Synthesis of homo[4] tetraoxacalix[2]arene[2]triazine from
the reaction between 7c and 1,3-phenylenedimethanol 2c met
with failure. Various reaction conditions such as using
different inorganic and organic base, different organic sol-
vent and reaction temperature yielded no desired product.
Either macrocyclic condensation reaction did not proceed or
the reaction gave a mixture of inseparable and insoluble
oligomers (see the Supporting Information). Fortunately, all
oxygen-linked homo[4] calix[2]arene[2]triazine product 9d
was isolated in 66% from the reaction of fluoro-substituted
trimer 7d with 1,3-phenylenedimethanol 2c in diethyl ether
utilizing triethylamine as a base, followed by the treatment
with di-n-propylamine in refluxing chloroform (Scheme 2).
The linear trimers 7 derived from 1,3-phenylenedimethanea-
mine 2a and 1,3-phenylenedimethanol 2c were also very useful
fragments for the construction of homo[2] heterocalix[2]arene-
[2]triazines. More importantly, they provided a complementary
approach to homo[2] heterocalix[2]arene[2]triazines 3 that can
not be accessed using the method described in Scheme 1. This
has been evidenced by the synthesis of homo[2] tetraoxacalix-
[2]arene[2]triazine 11a and homo[2] diazadioxacalix[2]arene-
[2]triazine 11b. As aforementioned, the reactions between 1,3-
phenylenedimethanol 2c and linear trimers 1a and 1b gave no
desired macrocyclic products at all owing probably to the
diminished nucleophilic activity of aliphatic diol (Scheme 1).
In stark contrast, the oxygen-linked linear trimer 7c underwent
macrocyclic condensation reaction with resorcinol 10a to
produce homo[2] tetraoxacalix[2]arene[2]triazine 11a in 54%
yield. Homo[2] diazadioxacalix[2]arene[2]triazine 11b was also
synthesized successfully in 48% yield from the reaction of 7c
with 1,3-phenylenediamine 10b (Scheme 3). It seems apparent
that the careful design of the reaction partners, viz. linear trimer
and dinucleophile, on the basis of their reactivity would enable
the construction of all nitrogen- and oxygen-bridged homo[2]
calix[2]arene[2]triazines.
SCHEME 2. Fragment Coupling Approach for the Synthesis of
Homo Heterocalix[2]arene[2]triazines from 1,3-Phenylene-
dimethylamine and 1,3-Phenylenedimethanol with Trimers 1
Derived from Resorcinol and 1,3-Phenylenediamines
Structure. The structures of homo heterocalix[2]arene-
[2]triazines synthesized were elucidated on the basis of spectro-
scopic date and microanalysis. All products are crystalline and
many of them gave high-quality single crystals suitable for
X-ray diffraction analysis. The X-ray crystallographic data
(see Supporting Information) then allowed us to study the
molecular structures of homo heterocalix[2]arene[2]triazines in
the solid state.
It has been reported that heterocalix[4]aromatics7a,9d
adopt predominantly the 1,3-alternate conformation in the
solid state. Surprisingly, by the introduction of methylene
linkages into the bridging positions, the homo calix[2]arene-
[2]triazines gave various different conformational structures
other than 1,3-alternate. More interestingly and remarkably,
the conformational structures and the cavity sizes of the
macrocycles changed with the variations of both bridging
heteroatoms and methylene units and of their combinations.
For example, having two methylene groups inserted into the
bridging positions, homo[2] tetraoxacalix[2]arene[2]triazine
11a (Figure 1), homo[2] diazadioxacalix[2]arene[2]triazine 4a
SCHEME 3. Synthesis of Homo Heterocalix[2]arene[2]triazines from Macrocyclic Condensation Reactions of Resorcinol and
1,3-Phenylenediamine with Trimers 7 Derived from 1,3-Phenylenedimethylamine and 1,3-Phenylenedimethanol
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Chen et al.
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FIGURE 1. X-ray crystal structure of homo[2]tetraoxacalix[2]-
˚
arene[2]triazine 11a. Selected bond lengths (A): O(1)-C(5) 1.336,
O1-C3 1.413, O(2)-C(7) 1.320, O(2)-C(8) 1.457. Selected intera-
˚
tomic distances (A): C(6)-C(6A) 9.757, N(3)-N(3A) 5.696, C(4)-
FIGURE 3. X-ray crystal structure of homo[2]diazadioxacalix-
[2]arene[2]triazine 11b. Selected bond lengths (A): O(2)-C(12)
C(9) 4.577, C(6)-C(12), 6.702, C(6A)-C(12) 6.702.
˚
1.333, O(2)-C(13) 1.443, O(1)-C(1) 1.333, N(4)-C(3) 1.337, N(4)-
C(5) 1.425, N(5)-C(10) 1.347, N(5)-C(9) 1.409. Selected interatomic
˚
distances (A): N(8)-N(1) 4.307, C(14)-C(4) 5.391, C(11)-C(17)
6.138, C(11)-C(7) 7.062.
FIGURE 2. X-ray crystal structure of homo[2]diazadioxacalix-
[2]arene[2]triazine 4a. Ethyl substituents on N(9) and N(10) atoms
˚
were omitted for clarity. Selected bond lengths (A): O(1)-C(7)
1.385, O(1)-C(6) 1.390, N(4)-C(9) 1.343, N(4)-C(10) 1.451. Se-
˚
lected interatomic distances (A): N(5)-N(4) 4.981, C(8)-C(19)
5.222, N(1)-N(8) 4.900, C(8)-C(13) 7.132, C(13)-C(19) 6.272.
(Figure 2), and homo[2] tetraazacalix[2]arene[2]triazine 3c
(Figure S3, Supporting Information) adopted a partial cone
conformation with the benzene ring linked to methylenes
orientating to the same direction as two triazine rings. All
four bridging heteroatoms were found to locate almost on
the same plane. The cavity size, which was defined by the
upper rim distance between two triazine rings, varied, how-
FIGURE 4. X-ray crystal structure of homo[2]tetraazacalix-
[2]arene[2]triazine 4b. Only one of two discrete molecules in a unit
cell was shown. Ethyl substituents on N(11B) and N(12B) atoms
˚
were omitted for clarity. Selected bond lengths (A): N(1B)-C(7B)
1.444, N(5B)-C(10B) 1.356, N(5B)-C(11B) 1.412, N(11B)-C(9B)
˚
1.351. Selected interatomic distances (A): C(1B)-C(19B) 6.788,
C(9B)-C(13B) 6.788, C(1B)-C(13B) 10.989, N(4B)-N(7B) 4.259.
˚
˚
˚
ever, from 5.222 A of 4a to 9.755 A of 3c and to 10.419 A
of 11a. In the case of homo[2] diazadixoacalix[2]arene-
[2]triazines 11b (Figure 3, and Figure S4, Supporting
Information) and 5a (Figure S5, Supporting Information),
twisted partial cone conformations were observed. No pla-
narity was evidenced for four bridging heteroatoms in these
cases. Moreover, being different from the structures of 3c,
4a, and 11a, in both molecular structures 5a (Figure S5,
Supporting Information) and 11b (Figure 3 and Figure S4,
Supporting Information), it was the triazine rings that were
alternately orientated. Most noticeably, however, when two
oxygen bridges in 4a or in 11b units were changed into two
NH moieties, NH-bridged homo[2] tetraazacalix[2]arene-
[2]triazine 4b gave surprisingly a twisted and pinched 1,2-
alternate conformer (Figure 4 and Figure S6, Supporting
Information).
9a-d adopted even more diverse conformational structures
in the solid state. Partial cone, pinched partial cone, 1,2-
alternate, and twisted 1,2-alternate conformational struc-
tures were yielded depending on the heteroatoms and on the
substituents attaching at the nitrogen bridges. For example,
homo[4] tetraazacalix[2]arene[2]triazine 9a gave a typical
1,2-alternate conformation (Figure 5 and Figure S7, Sup-
porting Information). Two triazine rings and two benzene
rings in 9a were nearly perpendicular to the plane formed by
four bridging nitrogen atoms, with the dihedral angles being
80.7° and 75.46°, respectively. The upper rim and the lower
rim distances between proximal benzene and triazine rings
were 5.183 A (dC(1)-C(7)) and 4.587 A (dC(4)-N(5)), respec-
tively (see the caption in Figure 5). The replacement of four
NH bridges with oxygen atoms resulted in a slightly twis-
ted 1,2-alternate conformation of homo[4] tetraoxacalix[2]-
arene[2]triazine 9d (Figure S8, Supporting Information). The
dihedral angles of benzene and triazine rings to the plane
˚
˚
When another two methylene units were introduced into
the linking positions between heteroatoms and benzene
rings, the resulting homo[4] heterocalix[2]arene[2]triazines
3790 J. Org. Chem. Vol. 75, No. 11, 2010

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FIGURE 7. X-ray crystal structure of homo[4]tetraazacalix[2]-
arene[2]triazine 9b. Ethyl substituents on N(11) and N(11A) atoms
and benzyl substituents on N(4), N(5), N(4A), and N(5A) were
˚
omitted for clarity. Selected bond lengths (A): N(4)-C(3) 1.353,
˚
N(4)-C(11) 1.451. Selected interatomic distances (A): C(12)-C-
(12A) 7.287, C(2)-C(15) 7.076, C(15)-C(15A) 12.761, N(1)-C-
(2A) 4.802.
FIGURE 5. X-ray crystal structure of homo[4]tetraazacalix[2]arene-
[2]triazine 9a. DMSO molecule was omitted for clarity. Selected bond
˚
lengths (A): N(1)-C(6) 1.349, N(1)-C(5) 1.444, N(5)-C(6) 1.338.
˚
Selected interatomic distances (A): C(1)-C(7A) 5.183, C(4)-N(5A)
that two benzene rings were edge-to-edge orientated and they
located almost in the same plane. On the other hand, two
triazine rings, which were alternately orientated, were almost
perpendicular to the two benzene plane with the dihedral
angle being around 82°.
3.734, C(4)-C(4A) 6.457, C(4A)-C(7A) 5.365, N(1)-N(6A) 5.345,
N(5)-N(5A) 5.317.
In contrast to the 1,3-alternate conformation of almost all
heterocalixaromatics reported,7a the formation of diverse
conformational structures of homo heterocalix[2]arene-
[2]triazines in the solid state was intriguing. Conventional
calix[4]arenes adopt cone conformation mainly because of
intramolecular circular hydrogen-bond interactions.5,6 No
intramolecular hydrogen-bond interaction is present, how-
ever, between aromatic rings within heterocalixaromatics
and homo heterocalix[2]arene[2]triazines. The preference of
heterocalixaromatics to forming the 1,3-alternate conforma-
tion is most probably due to the dipole-dipole interactions
among aromatic rings. This is also in agreement with the
observation of the two bridging heteroatom-conjugated tri-
azine rings of heterocalix[2]arene[2]triazines tending to be
edge-to-edge aligned.9d The presence of methylene segments
as extra bridging units in addition to heteroatoms in homo
calix[2]arene[2]triazines most likely reduced the dipole-dipole
repulsion between the neighboring benzene and triazine rings,
leading therefore to conformations other than 1,3-alternate.
The formation of a variety of conformations also reflected the
subtle but important role played by the bridging elements such
as the nature of heteroatoms, the substituents on the nitrogen,
and the number of methylenes. In other words, the conforma-
tion and the cavity structures of homo calix[2]arene[2]triazines
were regulated by the combination of the heteroatoms and
methylene units. The careful selection of the bridging elements
would give macrocycles with tailor-made conformation and
cavity. Last, but not least, although homo calix[2]arene-
[2]triazine macrocycles adopted a range of diverse conforma-
tional structures, it should be pointed out that four bridging
heteroatoms in all cases formed conjugation with triazine rings.
This has been judged by the shorter bond length between the
heteroatom and its attaching carbon atom of the triazine ring
(see captions in Figures S1-S10, Supporting Information).
This conjugation pattern, which was similar to that of hetero-
calix[2]arene[2]triazines,9d enabled the tuning of the electron
density of triazine ring by the bridging heteroatoms, a unique
FIGURE 6. X-ray crystal structure of homo[4]diazadioxacalix-
[2]arene[2]triazine 9c. Ethyl substituents on N(9) and N(10) atoms
˚
were omitted for clarity. Selected bond lengths (A): O(1)-C(14)
1.347, O(1)-C(15) 1.441, N(4)-C(3) 1.335, N(4)-C(4) 1.446. Se-
˚
lected interatomic distances (A): C(2)-C(19) 5.450, C(13)-C(19)
5.708, N(1)-C(16) 4.263, N(8)-C(16) 4.684, C(5)-C(16) 7.133,
C(2)-C(13) 5.416, N(1)-N(8)4.953, O(1)-O(2) 5.007, N(4)-N(5)
4.989.
defined by four oxygen bridges were, respectively, 46.11° and
45.21°. The cavity of homo tetraoxacalix[2]arene[2]triazine
9d was larger than that of homo tetraazacalix[2]arene-
[2]triazine 9a, as the upper rim and the lower rim distances
˚
between benzene and triazine rings in proximity were 6.506 A
˚
(dC(1)-C(7)) and 3.332 A (dC(4)-N(5)), respectively (see caption
in Figure S8, Supporting Information). Interestingly, the
combination of two nitrogen atoms and two oxygen atoms as
the bridging elements gave rise to a typical partial cone
conformer of homo[4] diazadioxacalix[2]arene[2]triazine 9c
in the solid state (Figure 6 and Figure S9, Supporting Infor-
mation). One benzene ring and two almost face-to-face
paralleled triazine rings were nearly perpendicular to the
plane of heteroatom bridges, whereas the other benzene ring
tended to be coplanar with the plane of bridging hetero-
atoms. Very interestingly, introduction of four benzyl groups
onto the bridging nitrogen atoms of 9a led macrocycle 9b to
adopt a flattened partial cone conformation (Figure 7 and
Figure S10, Supporting Information). It was noteworthy
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Chen et al.
JOCArticle
feature very useful in molecular recognition, particularly in
Compared to the formation of dual conjugations of heteroatom
with its adjacent aromatic rings in heterocalixaromatics,7a,9d
heteroatoms, especially nitrogen, in homo heterocalix[2]arene-
[2]triazines formed stronger conjugation with only their neigh-
boring triazine rings in solution. This enhanced conjugation
effect probably resulted in the rigidification of the macrocycles,
leading to relatively slow interconversion of conformational
structures in solution. Bulky substituents on the bridging nitro-
gen atoms further inhibited the conformational mobility of the
macrocycle because of the steric effect.
Functionalization. Homo heterocalix[2]arene[2]triazines
synthesized from the fragment coupling approach starting
with cyanuric halides provided a unique platform for the
elaboration of functionalized macrocyclic host molecules. As
we have already shown in Schemes 1 and 2, the electrophi-
licity of chlorotriazine moiety in macrocycles 3 and 8 was
utilized to introduce a dialkylamino group in order to
improve the solubility of homo heterocalix[2]arene[2]tri-
azines in organic solvents. When an amine containing a
functional group is applied, the functionalized homo calix-
[2]arene[2]triazines are feasible. Scheme 4 depicts the effi-
cient synthesis of allyl-functionalized homo[2] tetraozacalix-
[2]arene[2]triazine using allylamine as a nucleophile. One of
the further examples of functionalizations illustrated in
Scheme 4 was the arylation on the upper rim position of
the triazine rings. The Suzuki coupling reaction18 of homo[2]
tetraoxacalix[2]arene[2]triazine 11a and homo[4] tetraaza-
calix[2]arene[2]triazine 8b with 4-chlorophenylboronic acid
furnished the corresponding diarylated products 13 and 15 in
85% and 82% yield, respectively. Further reaction of 13 with
bis(pinacolato)diboron under palladium catalysis19 afforded
boronate product 14.
anion-π complexation.12
A few interesting features of intermolecular interactions of
some homo calix[2]arene[2]triazines in the crystalline state
were worth addressing. For the homo heterocalix[2]arene[2]-
triazines containing NH-bridges such as 4a (Figure S2, Sup-
porting Information), 4b (Figure S6, Supporting Informa-
tion), 5a (Figure S5, Supporting Information), 9c (Figure S9,
Supporting Information), and 11b (Figure S4, Supporting
Information), one or two pairs of intermolecular hydrogen
bonds were formed to give dimeric structures. In the case of
1,2-alternate NH-bridged homo[4] calix[2]arene[2]triazine
9a (Figure S7, Supporting Information), however, each
bridging NH unit formed a hydrogen bond with one DMSO
solvent molecule through the formation of hydrogen bonds.
Each DMSO molecule, which was included in the cavity,
used its oxygen atom as a hydrogen-bond bridge to link
another macrocycle, yielding an infinite two-dimensional as-
sembly. While the NBn-bridged homo[2] tetraazacalix[2]arene-
[2]triazine molecules 3c assembled via mainly intermolecular
Ar-H Cl and C-H π interactions (Figure S3, Support-
3 3 3
3 3 3
ing Information), a two-dimensional assembly of NBn-bridged
homo[4] tetraazacalix[2]arene[2]triazine 9b was obtained from
different Ar-H π interactions (Figure S10, Supporting
3 3 3
Information). The oxygen-linked 1,2-alternate homo[4] calix-
[2]arene[2]triazine 9d was assembled into a one-dimensional
molecular wire because of the formation of four pairs of Ar-
H
Ntriazine interactions (Figure S8, Supporting Informa-
3 3 3
tion). A network of intermolecular halogen bond between
two chloro substituents and lone-pair electron-π interactions
between the chloro and triazine ring was most probably
responsible for the formation of one-dimensional molecular
assembly of homo[2] tetraoxacalix[2]arene[2]triazine 11a in the
solid state (Figure S1, Supporting Information).
One of the unique and distinguishable features of hetero-
calixaromatics from conventional calixarenes is the reacti-
vity of bridging moieties.8h,n Facile reactions on the bridg-
ing positions of NH-linked homo calix[2]arene[2]triazines
would generate novel heterocalixaromatics with functional
groups specifically installed on the bridging elements. As a
demonstration, we prepared exhaustive N-allylated homo[4]
tetraazacalix[2]arene[2]triazine 16 in 64% yield from alky-
lation reaction of 9a with allyl bromide in the presence
of NaH (Scheme 5). Both allyl and boronate are versa-
tile functional groups amenable to further chemical mani-
pulations.
Although in the solid state homo calix[2]arene[2]triazines
existed in certain conformations with different conjugation
systems being observed, these macrocycles might not be able to
retain these stable conformational structures in the solution. As
evidenced by the 1H and 13C NMR spectra (see the Supporting
Information), most of them were fluxional at certain tempera-
tures and the rates of interconversion of various conforma-
tional structures might be very rapid relative to the NMR time
scale. For instance, all homo[2] heterocalix[2]arene[2]triazines
1
including 4, 5, and 11 gave only one set of the H and 13C
signals at ambient temperature in the 1H and 13C NMR
spectra, respectively. While home[4] tetraoxacalix[2]arene[2]-
triazine 9d showed nicely a single set of signals at room
temperature, homo[4] tetraazacalix[2]arene[2]triazine 9a and
diazadioxacalix[2]arene[2]triazine 9c gave descent NMR spec-
tra at an elevated temperature (around 380 K). Only with the
N-benzyl-substituted homo[2] tetraazacalix[2]arene[2]triazine
3c and homo[4] tetraazacalix[2]arene[2]triazine9b were no very
Conclusion
In summary, we have devised a novel type of macrocyclic
molecules, namely, homo heterocalixaromatics. Through a
general and good-yielding fragment coupling approach, a
number of homo[2] and homo[4] aza- and oxa-calix[2]arene-
[2]triazines were synthesized under very mild conditions from
simple and readily available starting materials. All hetero-
atoms formed strong conjugation with triazine rings. The
combination of methylene, heteroatom such as nitrogen and
oxygen, and substituent as the bridging units enabled the
generation of tunable diverse conformational structures of
homo heterocalix[2]arene[2]triazines in the solid state. Homo
heterocalix[2]arene[2]triazines were fluxional macrocycles in
1
well resolved H NMR spectra observed at 385 K. It was
interesting to address that the flexibility of macrocycles de-
creased with the increase of methylene linkages and with the
increase of the NH bridges. The presence of a benzyl substi-
tuent on the bridging nitrogen atom greatly decreased the
conformational mobility of the macrocycle. The influence of
the bridging elements on the flexibility of conformational
structures was most probably attributable to the conjugation
effect of the bridging heteroatoms with triazine rings and the
steric effect of the substituent on the bridging nitrogen atoms.
(18) Janietz, D.; Bauer, M. Synthesis 1993, 33.
(19) Ishiyama, T.; Ishida, K.; Miyaura, N. Tetrahedron 2001, 57, 9813.
3792 J. Org. Chem. Vol. 75, No. 11, 2010

Chen et al.
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SCHEME 4. Functionalizations of Homo Heterocalix[2]arene[2]triazines
SCHEME 5. Synthesis of N-Functionalized Homo[4]
tetraazacalix[2]arene[2]triazine 16
Experimental Section
Synthesis of 3c. To a solution of DIPEA (1.22 g, 9.6 mmol) in
acetone (200 mL) at room temperature were added dropwise
both solutions of 1c (2.33 g, 4 mmol) in acetone (75 mL) and 2b
(1.26 g, 4 mmol) in acetone (75 mL) at nearly the same rate
during 5 h. The resulting mixture was allowed to stir for another
20 h. After removal of the solvent, the residue was mixed with
silica gel (6 g) and subjected to silica gel chromatography with
dichloromethane as an eluent. Product 3c (1.71 g, 52%) was
obtained as a white powder. 3c: mp 237-238 °C; MS (MALDI-
TOF) m/z 827.2 [M þ Hþ] (100), 829.2 (73), 849.2 [M þ Naþ]
(54), 851.2 (40); 1H NMR (300 MHz, o-C6H4Cl2, 340 K) δ
7.10-6.70 (m, 24H), 6.55 (d, J=7.4 Hz, 2H), 6.33 (br s, 2H), 4.75
(br, s, 8H), 4.14 (br, s, 4H); 13C NMR (75 MHz, CDCl3, TMS) δ
169.7, 165.4, 165.3, 142.4, 137.6, 137.4, 137.4, 128.6, 128.5,
128.3, 128.2, 128.0, 127.9, 127.6, 127.4, 124.7, 122.7, 53.2,
51.5, 50.4; IR (KBr) ν 3027, 1596, 1561 cm-1. Anal. Calcd for
C48H40Cl2N10: C, 69.64; H, 4.87; N, 16.92. Found: C, 69.69; H,
4.88; N, 16.67.
solution, and they underwent rapid conformation intercon-
version at different temperatures depending on the nature of
the bridging elements. Efficient and straightforward chemical
manipulations on triazine rings and the bridging NH units led
to functionalized homo heterocalix[2]arene[2]triazine deriva-
tives. The easy availability, versatile conformational and
cavity structures, and amenability to functionalization would
render homo calix[2]arene[2]triazines useful macrocyclic host
molecules in supramolecular science.
Synthesis of 4a. To a solution of DIPEA (3.1 g, 24 mmol) in
acetonitrile (300 mL) at room temperature were added dropwise
solutions of 1a (4.04 g, 10 mmol) in acetonitrile (100 mL) and 2a
(1.4 g, 10 mmol) in acetonitrile (100 mL) at nearly the same rate
during 5 h. The resulting mixture was allowed to stir for another
12 h, and the white precipitate was formed gradually. Filtration
gave 1.88 g of crude product as the white solid. The crude
J. Org. Chem. Vol. 75, No. 11, 2010 3793

Chen et al.
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product (0.93 g) was mixed with diethylamine (0.36 g, 5 mmol)
and DIPEA (0.64 g, 5 mmol) in DMSO (50 mL), and then the
mixture was allowed to stire at 85 °C for 12 h. Water (150 mL)
was added, and the mixture was extracted with chloroform (3 ꢀ
50 mL). After drying with anhydrous Na2SO4 and removal of
the solvent, the residue was chromatographed on a silica gel
column eluting with a mixture of petroleum ether and acetone
(4:1) to afford product 4a as a white powder (0.84 g, 31% overall
yield based on 1a). 4a: mp 271 °C; MS (MALDI-TOF) m/z 543.4
[M þ Hþ] (100); 1H NMR (300 MHz, CDCl3, TMS) δ 8.07 (t, J=
12.5 Hz, 2H, NH), 7.45 (t, J=8.2 Hz, 1H), 7.05-7.17 (m, 5H),
6.89 (s, 1H), 6.68 (s, 1H), 4.13 (d, J=5.7 Hz, 4H), 3.51 (q, J=6.3
Hz, 4H), 1.1 (t, J=6.8 Hz, 6H); 13C NMR (75 MHz, CDCl3,
TMS) δ 170.2, 166.7, 165.5, 152.7, 140.2, 128.1, 128.0, 127.3,
125.2, 119.8, 115.1, 43.9, 40.5, 13.2; IR (KBr) ν 3263, 1602, 1551
cm-1. Anal. Calcd for C28H34N10O2: C, 61.98; H, 6.32; N, 25.81.
Found: C, 61.75; H, 6.31; N, 25.68.
1506 cm-1. Anal. Calcd for C26H22N8O2Cl2: C, 56.84; H, 4.04;
N, 20.40. Found: C, 56.66; H, 4.14; N, 20.46.
Synthesis of 9a. To a solution of DIPEA (3.1 g, 24 mmol) in
acetone (300 mL) were added at room temperature dropwise
solutions of 7a (4.3 g, 10 mmol) in acetone (100 mL) and 2a
(1.37 g, 10 mmol) in acetone (100 mL) at nearly the same rate
during 5 h. The mixture was reacted for another 20 h, and a
white precipitate was formed. After filtration, the crude product
(4.19 g) was collected as a white solid. A mixture of crude
product (1.0 g) and aqueous dimethylamine (30%, 1.5 mL) in
DMF (50 mL) was allowed to stir at 85 °C for 12 h. After being
cooled to room temperature, the product 9a (0.86 g, 65% overall
yield based on 7a), which was complexed with 1 equiv of DMF,
was precipitated. 9a: mp 265-266 °C; MS (ESI) m/z 513.2 [M þ
Hþ] (100); 1H NMR (300 MHz, DMSO, TMS, 370 K) δ 7.28 (s,
2H), 7.15 (t, J=7.1 Hz, 2H), 7.05 (d, J=7.1 Hz, 4H), 6.55 (br, s,
4NH), 4.40 (br, s, 8H), 2.94 (s, 12H); 13C NMR (75 MHz,
CF3CO2D, TMS) δ 165.8, 165.3, 141.0, 127.1, 126.2, 125.1, 43.1,
35.4; IR (KBr) ν 3379, 1550, 1511 cm-1. Anal. Calcd for
Synthesis of 4b. To a solution of DIPEA (3.1 g, 24 mmol) in
acetone (300 mL) at room temperature were added dropwise
solutions of 1b (4.06 g, 10 mmol) in acetone (100 mL) and 2a
(1.4 g, 10 mmol) in acetone (100 mL) at nearly the same rate
during 5 h. The resulting mixture was allowed to stir for another
20 h, and the white precipitate was formed gradually. Filtration
gave 2.64 g of crude product as the white solid. The crude
product (0.94 g) was mixed with diethylamine (0.36 g) and
DIPEA (0.64 g) in DMSO (50 mL), and then the mixture was
kept stirring at 85 °C for 12 h. Water (150 mL) was added, and
the mixture was extracted with chloroform (3 ꢀ 50 mL). After
drying with anhydrous Na2SO4 and removal of the solvent, the
residue was chromatographed on a silica gel column eluting with
a mixture of petroleum ether and acetone (5:1) to afford product
4b as a white powder (0.84 g, 24% overall yield based on 1b). 3b
was also synthesized in 19% overall yield from 7a and 11b.
Product 4b (recrystallized from chloroform and n-hexane). 4b:
mp 232-233 °C; MS (MALDI-TOF) m/z 541.0 [M þ Hþ] (100);
1H NMR (300 MHz, CDCl3, TMS) δ 9.28 (s, 1H), 7.21-7.31 (m,
3H), 7.08 (m, 3H), 6.70 (s, 2NH), 6.48 (q, J=2.2 Hz, 2H), 5.28 (t,
J=6.6 Hz, 2NH), 4.70 (d, J=6.6 Hz, 4H), 3.50 (q, J=7.1 Hz,
8H), 1.09 (br, s, 12H); 13C NMR (75 MHz, CDCl3, TMS) δ
165.4, 163.6, 163.4, 140.1, 138.7, 127.4, 126.9, 123.5, 119.8,
112.2, 111.1, 42.1, 39.8, 12.1; IR (KBr) ν 3259, 3113, 1590,
C26H32N12 2DMSO: C, 53.87; H, 6.63; N,25.13. Found: C,
3
53.72; H, 6.67; N, 25.04.
Synthesis of 9b. To a solution of DIPEA (2.1 g, 16.8 mmol) in
acetone (200 mL) were added at room temperature dropwise
solutions of 7b (4.30 g, 7 mmol) in acetone (75 mL) and 2b (2.10 g,
7 mmol) in acetone (75mL) at nearly the same rateduring5 h. The
mixture was reacted for another 12 h, and a white precipitate was
formed. After filtration, the crude product (3.7 g) was collected as
a white solid. The crude product (1.3 g), diethylamine (0.36 g,
5 mmol), and DIPEA (0.64 g, 5 mmol) were mixed in DMSO
(50 mL). The reaction mixture was stirred at 85 °C for 12 h. Water
(150 mL) was added, and the product was extracted with chloro-
form (3 ꢀ 50 mL). After drying with anhydrous Na2SO4 and the
removal of the solvent, the residue was chromatographed on a
silica gel column eluted with a mixture of petroleum ether and
dichloromethane (1:1) to afford pure product 9b (1.14 g, 50%
overall yieldbasedon7b) asa whitesolid. 9b:mp218-219°C;MS
(MALDI-TOF) m/z 929.6 [M þ Hþ] (100); 1H NMR (300 MHz,
o-C6H4Cl2, 385K) δ 6.77-7.05 (m, 28H), 3.6-6.0 (m, 16H), 3.28
(s, 8H), 0.86 (s,12H); 13C NMR (75 MHz, CDCl3, TMS) δ 166.4,
165.1, 139.6-140.0, 122.8-130.9, 49.6, 48.5-48.6, 41.7-42.2,
13.7-14.2; IR (KBr) ν 2927, 1537, 1492 cm-1. Anal. Calcd for
C58H64N12: C, 74.97; H, 6.94; N, 18.09. Found: C, 74.78; H, 6.82;
N, 17.95.
1543, 1508 cm-1. Anal. Calcd. for C30H38N10O2 CHCl3: C,
3
52.77; H, 5.65; N, 25.47. Found: C, 53.22; H, 5.69; N, 25.66.
Synthesis of 5a and 5b. To a solution of DIPEA (0.75 g,
6 mmol) in acetone (200 mL) at room temperature were added
dropwise solutions of 1a (1.01 g, 2.5 mmol) in acetone (75 mL)
and 2a (0.35 g, 2.5 mmol) in acetone (75 mL) at nearly the same
rate during 3 h. The resulting mixture was allowed to stir for
another 5 h. After removal of the solvent, the residue was mixed
with silica gel (3 g) and subjected to silica gel chromatography
with a mixture of petroleum ether and acetone (4:1) as eluent.
Both products 5a (0.18 g, 14%) and 5b (0.37 g, 31%) were
obtained as a white powder. 5a: mp >300 °C; MS (MALDI-
TOF) m/z 509.2 [M þ Hþ] (100), 511.2 (61); 1H NMR (300 MHz,
CDCl3, TMS) δ 8.12 (m, 2NH) 7.41 (t, J=8.0 Hz, 1H), 6.9-7.2
(m, 7H), 5.11 (s, 1H), 4.93 (s, 1H), 4.63 (br s, 2H), 4.39 (d, J=6.0
Hz, 1H), 2.04 (s, 3H); 13C NMR (75 MHz, CDCl3, TMS) δ
171.6, 170.7, 170.4, 167.2, 165.1, 152.1, 152.0, 145.4, 138.0,
137.4, 128.9, 128.7, 125.2, 120.5, 119.8, 115.0, 113.2, 54.0,
45.4, 20.9; IR (KBr) ν 3260, 3126, 1568, 1507 cm-1. Anal. Calcd
for C23H18N8O2Cl2: C, 54.24; H, 3.56; N, 22.00. Found: C, 54.28
H, 3.64; N, 21.88. 5b: mp > 300 °C; MS (MALDI-TOF) m/z
549.2 [M þ Hþ] (100), 551.2 (71); 1H NMR (300 MHz, CDCl3,
TMS) δ 7.37 (t, J = 8.1 Hz, 1H), 7.14 (t, J = 8.1 Hz, 1H),
7.01-7.06 (m, 5H), 6.87 (s, 1H), 5.17 (s, 2H), 5.02 (s, 2H), 4.65
(br s, 4H), 2.08 (s, 6H); 13C NMR (100 MHz, CDCl3, TMS) δ
171.4, 170.3, 165.2, 152.2, 145.7, 137.1, 128.9, 128.4, 126.5,
125.4, 120.0, 114.9, 113.3, 54.3, 20.8; IR (KBr) ν 1559, 1541,
Synthesis of 9c. To a solution of DIPEA (3.1 g, 24 mmol) in
acetonitrile (300 mL) were added at room temperature dropwise
solutions of 7c (4.3 g, 10 mmol) in acetonitrile (100 mL) and 2a
(1.38 g, 10 mmol) in acetonitrile (100 mL) at nearly the same rate
during 5 h. A white precipitate was formed, and the mixture
was reacted for another 12 h. After filtration, the crude product
(3.01 g) was collected as white solid. The crude product (0.96 g),
diethylamine (0.36 g, 5 mmol), and DIPEA (0.64 g, 5 mmol)
were mixed in DMSO (50 mL). The reaction mixture was stirred
at 85 °C for 12 h. Water (150 mL) was added, and the product
was extracted with chloroform (3 ꢀ 50 mL). After drying with
anhydrous Na2SO4 and the removal of the solvent, the residue
was chromatographed on a silica gel column eluted with a
mixture of petroleum ether, dichloromethane, and acetone
(4:8:1) to afford pure product 9c (0.58 g, 32% overall yield
based on 7c) as a white solid. 9c: mp 260-262 °C; MS (MALDI-
TOF) m/z 571.1 [M þ Hþ] (100), 572.2 (53); 1H NMR (300 MHz,
DMSO-d6, 380K, TMS) δ 7.37 (s, 1H), 7.07-7.27(m, 7H) 6.92
(s, 2NH), 5.32 (s, 4H), 4.42 (d, J=6.2 Hz, 4H), 3.43 (q, J=6.7 Hz,
8H), 1.02 (t, J=6.7 Hz, 12H); 13C NMR (75 MHz, CF3CO2D,
TMS, 380 K) δ 157.5, 156.7, 154.4, 139.6, 137.3, 133,3, 132.9,
131.9, 131.4, 130.2, 73.6, 49.2, 49.0, 46.9, 14.5, 14.3; IR (KBr) ν
3256, 3117, 1618, 1590, 1556 cm-1. Anal. Calcd for C30H38-
N10O2: C, 63.14; H, 6.71; N, 24.54. Found: C, 63.04; H, 6.72;
N, 24.52.
3794 J. Org. Chem. Vol. 75, No. 11, 2010

Chen et al.
JOCArticle
137.8 (br), 135.3 (br), 129.5, 129.1, 126.6, 126.1, 125.7, 120.4,
Synthesis of 9d. To a solution of triethylamine (2.1 g,
21 mmol) in dry diethyl ether (300 mL) were added at room
temperature dropwise solutions of 7d (3.70 g, 10 mmol) in dry
ether (200 mL) and 2c (1.39 g, 10 mmol) in dry ether (200 mL) at
nearly the same rate during 10 h. The mixture was reacted for
another 12 h. After filtration, the crude product (4.8 g) was
collected as a white solid. The crude product (0.47 g) was
refluxed with dipropylamine (0.51 g, 5 mmol) in chloroform
(50 mL) for 2 h. Water (50 mL) was added, chloroform was
separated, and the aqueous layer was extracted with an addi-
tional 50 mL of chloroform. After drying with anhydrous
Na2SO4 and the removal of the solvent, the residue was chro-
matographed on a silica gel column eluted with a mixture of
petroleum ether and dichloromethane (2:1) to afford pure
product 9d (0.42 g, 66% overall yield based on 7d) as a white
solid. 9d: mp 205 °C; MS (MALDI-TOF) m/z 629.1 [M þ Hþ]
(100), 630.1 (30); 1H NMR (300 MHz, CDCl3, TMS) δ 7.73 (s,
2H), 7.30 (m, 6H), 5.40 (s, 4H), 3.43 (t, J=7.7 Hz, 8H), 1.58 (m,
J=7.5 Hz,8H), 0.87 (t, J=7.4 Hz,12H); 13C NMR (75 MHz,
CDCl3, TMS) δ 171.4, 166.9, 137.1, 128.4, 128.1, 127.8, 68.0,
49.1, 20.9, 11.4; IR (KBr) ν 1583, 1533 cm-1. Anal. Calcd for
C34H44N8O4: C, 64.95; H, 7.05; N, 17.82. Found: C, 64.58; H,
7.15; N, 17.44.
115.8, 68.0 (br), 43.0; IR (KBr) ν 3264, 3138, 3021, 1622, 1578
cm-1. Anal. Calcd for C26H24N8O6 CH3CN: C, 60.75; H, 4.92;
N, 22.77. Found: C, 60.30; H, 5.03; N, 23.02.
3
Synthesis of 13. Under argon protection, 11a (0.13 g, 0.3
mmol), p-chlorobenzoboric acid (0.10 g, 0.65 mmol), and Pd-
(PPh3)4 (17 mg, 5% mol) were mixed in dry toluene (30 mL). An
aqueous solution of Na2CO3 (1 M, 2 mL) was added, and the
resulting mixture was allowed to stir at 80 °C for 4 h. Water (50
mL) was then added, and product was extracted with dichloro-
methane (3 ꢀ 50 mL). After drying with anhydrous Na2SO4 and
the removal of the solvent, the residue was chromatographed on
a silica gel column eluted with a mixture of petroleum ether and
dichloromethane (1:1) to afford pure product 13 (0.14 g, 85%)
as a white powder. 13: mp >300 °C; MS (MALDI-TOF) m/z
623.4 [M þ Hþ] (100), 625.4 (70) [M þ Naþ] (645.4); 1H NMR
(300 MHz, CDCl3, TMS) δ 8.39 (d, J=8.6 Hz, 4H), 7.41 (d, J=
8.6 Hz, 4H), 7.53 (t, J=7.2 Hz, 1H), 7.27 (t, J=7.3 Hz, 1H),
7.24-7.30 (m, 4H), 6.89 (s, 1H), 6.66 (s, 1H); 13C NMR (75
MHz, CDCl3, TMS) δ 175.5, 172.5, 172.4, 152.5, 139.6, 136.6,
133.1, 130.5, 129.3, 129.1, 128.9, 126.5, 125.3, 120.5; IR (KBr) ν
1566, 1522 cm-1. Anal. Calcd for C32H20Cl2N6O4: C, 61.65; H,
3.23; N, 13.48. Found: C, 61.26; H, 3.25; N, 13.37.
Synthesis of 14. Under protection of argon, Pd2(dba) 3 (9 mg,
5% mol), a solution of PCy3 in toluene (20%, 50 mg), and newly
distilled 1,4-dioxane (5 mL) were mixed for 20 min. A mixture of
reactant 13 (125 mg, 0.2 mmol), bis(pinacolato)diboron (130 mg,
0.5 mmol), and KOAc (100 mg, 1 mmol) was added followed by
the addition of newly distilled 1,4-dioxane (20 mL). The resulting
mixture was allowed to stir at 80 °C for 10 h. After removal of
solvent, water (30 mL) was added, and the mixture was extracted
with dichloromethane (2 ꢀ 25 mL). After drying with anhydrous
Na2SO4 and removal of the solvent, the residue was chromato-
graphed on a silica gel column eluted with a mixture of petroleum
ether and ethyl acetate (5:1) to afford pure product 14 (98 mg,
78%) as a white powder. 14: mp >300 °C; MS (MALDI-TOF)
m/z 807.5 [M þ Hþ] (12), 829.5 [M þ Naþ] (100), 830.5 (52), 845.4
[M þ Kþ] (37); 1H NMR (300 MHz, CDCl3, TMS) δ 8.53 (d, J=
7.7 Hz, 4H), 7.96 (d, J=7.7 Hz, 4H), 7.60 (t, J=7.2 Hz, 1H), 7.37
(d, J=7.7 Hz, 1H), 7.24-7.30(m, 4H), 7.01(s, 1H), 6.76 (s, 1H),
5.34 (s, 4H), 1.38 (s, 24H) ; 13C NMR (75 MHz, CDCl3, TMS) δ
176.5, 172.2, 172.4, 152.8, 136.8, 136.3, 134.9, 129.2, 129.0, 128.2,
126.5, 125.4, 120.5, 115.5, 84.2, 69.2, 24.9; IR (KBr) ν 2978, 1564,
1525, 1471 cm-1. Anal. Calcd for C44H44B2N6O8: C, 65.53; H,
5.50; N, 10.42. Found: C, 65.52; H, 5.48; N, 10.48.
Synthesis of 11a. To a solution of DIPEA (1.5 g, 12 mmol) in
acetone (300 mL) were added at room temperature dropwise
solutions of 7c (2.1 g, 5 mmol) in acetone (100 mL) and 10a
(0.55 g, 5 mmol) in acetone (100 mL) at nearly the same rate
during 5 h. The mixture was reacted for another 5 h. After
removal of solvent, the residue was chromatographed on a silica
gel column eluted with a mixture of petroleum ether and acetone
(4:1) to afford pure product 11a (1.26 g, 54%) as a white solid.
11a: mp >300 °C; MS (MALDI-TOF) m/z 492.8 [M þ Naþ]
(100), 494.8 (64); 1H NMR (300 MHz, CDCl3, TMS) δ 7.61 (t,
J=8.3 Hz, 1H), 7.23-7.28(m, 3H), 7.21 (d, J=2.2 Hz, 2H), 6.87
(t, J=2.2 Hz,1H), 6.62(s, 1H), 5.28 (s, 1H); 13C NMR (75 MHz,
CDCl3, TMS) δ 173.9, 172.1, 171.9, 152.1, 135.5, 129.6, 129.5,
126.6, 125.0, 120.7, 115.0, 70.0; IR (KBr) ν 1551 cm-1. Anal.
Calcd for C20H12Cl2N6O4: C, 50.97; H, 2.57; N, 17.83. Found:
C, 50.79; H, 2.61; N, 17.48.
Synthesis of 11b. To a solution of DIPEA (1.5 g, 12 mmol) in
acetone (200 mL) were added at room temperature dropwise
solutions of 7c (2.1 g, 5 mmol) in acetone (75 mL) and 10b
(0.54 g, 5 mmol) in acetone (75 mL) at nearly the same rate
during 5 h. The mixture was reacted for another 12 h. After
removal of solvent, the residue was chromatographed on a silica
gel column eluted with a mixture of petroleum ether and acetone
(4:1) to afford pure product 11b (1.14 g, 49%) as white solid. 11b:
mp >300 °C; MS (MALDI-TOF) m/z 469.3 [M þ Hþ] (83),
471.3 (77), 491.2 [M þ Naþ] (100), 493.2 (84), 507.2 [M þ Kþ]
(84); 1H NMR (300 MHz, CDCl3, TMS) δ 10.73 (s, 2H, NH),
8.61 (s, 1H), 7.56 (s, 1H), 7.38-7.34 (m, 4H), 7.05(q, J=1.5 Hz,
2H), 5.46 (s, 4H); 13C NMR (75 MHz, CDCl3, TMS) δ 170.5,
169.7, 165.3, 137.9, 136.6, 129.1, 128.7, 127.1, 126.3, 119.4,
116.3, 67.8; IR (KBr) ν 3287, 1576, 1551 cm-1. Anal. Calcd
for C20H14Cl2N8O2: C, 51.19; H, 3.01; N, 23.88. Found: C,
50.98; H, 2.97; N, 23.52.
Synthesis of 15. Following the same procedure for the pre-
paration of 13, the reaction of 8b (0.65 g, 0.75 mmol) for 12 h
afforded product 15 (0.6 g, 82%). 15: mp 176-178 °C; MS
(MALDI-TOF) m/z 1009.6 [M þ Hþ] (100), 1007.6 (41), 1010.6
(62); 1H NMR (300 MHz, o-C6H4Cl2, 385 K) δ 8.5-7.6 (m, 4H),
6.6-7.3 (m, 32H), 6.0-5.0 (m, 8H), 4.0-3.6 (m, 8H); 13C NMR
(75 MHz, CDCl3, TMS) δ 169.11, 166.2 (br), 137-139 (br),
124-130 (br), 48 (br); IR (KBr) ν 3028, 2920, 1586, 1538 cm-1
.
Anal. Calcd for C62H52Cl2N10: C, 73.87; H, 5.20; N, 13.89.
Found: C, 73.85; H, 5.30; N, 13.87.
Synthesis of 16. A mixture of 9a 2DMSO (purified from the
3
Synthesis of 12. A mixture of 11a (68 mg, 0.15 mmol),
allylamine (20 mg, 0.35 mmol), and DIPEA (0.12 g, 0.95 mmol)
in acetonitrile (20 mL) was refluxed for 4 h, and white precipi-
tates were generated. The solvent was concentrated to around
5 mL, and the white solid product 12 (56 mg, 85%) was obtained
through filtration. 12: mp >300 °C; MS (MALDI-TOF) m/z
513.3 [M þ Hþ] (9), 535.2 [M þ Naþ] (100), 536.2 (52), 551.2
[M þ Kþ] (57), 552.2 (28); 1H NMR (300 MHz, DMSO-d6,
TMS) δ 8.25 (q, J =5.6 Hz, 2NH), 7.53 (t, J= 8.2 Hz, 1H),
7.15-7.26 (m, 5H), 7.03 (s, 1H), 6.82 (s, 1H), 5.85 (m, 2H),
5.06-5.17 (m, 8H), 3.92 (d, J=4.6 Hz, 1H); 13C NMR (75 MHz,
DMSO-d6, TMS) δ 172.0 (br), 171.5 (br), 168.9 (br), 152.9 (br),
recrystallization from DMSO) (121 mg, 0.2 mmol), NaH (40
mg), and DMF (8 mL) was allowed to stir at 80 °C for 0.2 h.
3-Bromopropene (100 mg, 0.83 mmol) was added, and the
resulting mixture was reacted at 80 °C for another 1 h. After
removal of DMF under vacuum, water (20 mL) was added very
slowly, and the mixture was extracted with dichloromethane
(2 ꢀ 30 mL). After drying with anhydrous Na2SO4 and removal
of the solvent, the residue was chromatographed on a silica gel
column eluted with a mixture of n-pentane and ethyl acetate
(5:1) to afford pure product 16 (89 mg, 64%) as pale yellow oil.
16: MS (MALDI-TOF) m/z 673.4 [M þ Hþ] (100), 674.4 (40);
1H NMR (300 MHz, DMSO-d6, TMS, 385K) δ 7.19-7.05
J. Org. Chem. Vol. 75, No. 11, 2010 3795

Chen et al.
JOCArticle
(br m, 8H), 5.72 (br, s, 6H), 4.96 (br, s, 11H), 3.97 (br, s, 11H),
2.94 (br, s, 12H); 13C NMR (75 MHz, CDCl3) δ 165.9 (br), 165.5
(br), 139.6 (br), 134.9 (br), 127.3 (br), 125.9 (br), 124.3 (br), 115.9
(br), 49.5-47.1 (br), 35.8 (br); IR (KBr) ν 3264, 3138, 3021,
1622, 1578 cm-1; ESI (M þ Hþ) calcd for C38H48N12 þ Hþ
673.4198, found 673.4196 .
for financial support. We are also grateful to Xiang Hao and
Tong-Lin Liang for their help with X-ray diffraction analysis.
Supporting Information Available: Experimental proce-
dures and analytical and spectral characterization data for
1
compounds 7; copies of H and 13C NMR spectra of 4, 5, 9,
and 11-16; X-ray crystallographic data and molecular struc-
tures of homo heterocalix[2]arene[2]triazines (CIF). This mate-
rial is available free of charge via the Internet at http://pubs.
acs.org.
Acknowledgment. We thank the National Natural Science
Foundation of China (20772125, 20875094), Ministry of Science
and Technology (2007CB808055), Chinese Academy of Sciences,
3796 J. Org. Chem. Vol. 75, No. 11, 2010