A [2+3] fragment coupling approach to N,O-bridged calix[1]arene[4]pyridines and their complexation with C60

Article abstract of DOI:10.1016/j.tetlet.2009.10.047

Functionalized N,O-bridged calix[1]arene[4]pyridines, first examples of the odd-numbered heterocalixaromatics containing mixed heteroatom bridges and mixed aromatic units, have been synthesized from the Pd₂(dba)₃/dppp-catalyzed 2+3 m

Full text of DOI:10.1016/j.tetlet.2009.10.047

Tetrahedron Letters 50 (2009) 7209–7212
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A [2+3] fragment coupling approach to N,O-bridged calix[1]arene[4]pyridines
and their complexation with C60
a
a,b,
Jin-Cheng Wu a, De-Xian Wang a, , Zhi-Tang Huang , Mei-Xiang Wang
*
*
a Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100190, China
b The Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Functionalized N,O-bridged calix[1]arene[4]pyridines, first examples of the odd-numbered heterocalix-
aromatics containing mixed heteroatom bridges and mixed aromatic units, have been synthesized from
the Pd2(dba)3/dppp-catalyzed 2+3 macrocyclic fragment coupling reaction between readily available
staring materials. These novel macrocyclic compounds, which adopted distorted 1,3-alternate conforma-
tion in solid state, were powerful host molecules able to form 1:1 complex with fullerene C60 in solution,
Received 22 August 2009
Revised 3 October 2009
Accepted 9 October 2009
Available online 29 October 2009
giving binding constant up to 49,494 MÀ1
.
Ó 2009 Elsevier Ltd. All rights reserved.
As a new generation of macrocyclic host molecules, heterocalix-
aromatics have attracted a fast growing interest in recent years.1–5
Because of the different electronic nature of heteroatoms from car-
bon, the heteroatom-bridged calixaromatics exhibit interesting
structural and molecular recognition properties in contrast to con-
ventional calixarenes. Due to the intrinsic nature of nitrogen that
can adopt sp2 and/or sp3 electronic configurations to form different
degrees of conjugation with its adjacent aromatic rings, the confor-
mation and the cavity structures of the heterocalixaromatics are
fine-tuned by the bond lengths and bond angles of the bridging
heteroatoms. For example, by the formation of marginally different
conjugations between the bridging nitrogen atoms and their neigh-
boring pyridines, (NMe)4-bridged calix[4]pyridine has been found
to give cavities of different sizes to interact with the different guest
species.2d,e,l–o In addition, the various electronic effects of the het-
eroatoms also influence the electron density of aromatic rings,
yielding the cavity of varied electronic features. The azaca-
lix[n]pyridines (n = 5–10),2n for instance, are able to interact with
fullerenes C60 and C70 whereas the oxacalix[2]arene[2]triazines
employed. In this Letter, we report an efficient synthesis of N,O-
bridged calix[1]arene[4]pyridines, the first examples of odd-num-
bered calixaromatic species with two different heteroatom bridges
and two different aromatic components, from a 2+3 macrocyclic
fragment coupling reaction. The method allowed the installation
of the functional group on either upper rim position or on the
bridging nitrogen atom. All heterocalix[5]aromatics synthesized
showed excellent ability to bind fullerene C60
.
We initially examined the synthesis of (NMe)3(O)2-bridged
calix[1]arene[4]pyridine 3 by means of macrocyclic coupling reac-
tion between fragments 1a and 2. The fragment 1a was prepared
conveniently in a good yield from cheap and readily available
2,6-dibromopyridine and resorcinol (see Scheme S1, Supplemen-
tary data). In the presence of Pd2(dba)3 as a catalyst and dppp as
a ligand, the reaction of 1a with 2 produced desired 2+3 macrocy-
clic fragment coupling (NMe)3(O)2-bridged calix[1]arene[4]pyri-
dine 3 as the major product. In addition, a larger macrocyclic
homolog, (NMe)6(O)4-bridged calix[2]arene[8]pyridine 4, was also
isolated (Scheme 1). It is interesting to note that the total chemical
yield of 3 and 4 and the ratio of 3 over 4 were dependent upon the
base used. As summarized in Table 1, when Cs2CO3 was used as a
base, products 3 and 4 were obtained in 31% and 9%, respectively
(Table 1, entry 1). The use of NaOBut lead to the increase of 4 to
23% (Table 1, entry 2). NaH appeared as a base beneficial for the
selective formation of 3 (Table 1, entries 3 and 4). With NaH as
the base, chemical yield of 3 was further improved to 45% when
the reaction was executed in a high dilute solution (Table 1, entry
4) (see Supplementary data).
complex halides through anion-p
interactions.6
Whereas the nitrogen-,1,2 oxygen-1,3 and sulfur-bridged4 hete-
rocalixaromatics with an even number of aromatic rings are popu-
lar, heterocalixaromatics composed of different heteroatoms and,
particularly, of an odd number of varied aromatic rings are very
rare.2m,n We envisioned, however, the fragment coupling approach
we developed previously1a would enable the generation of numer-
ous heterocalixaromatics when the combinations of varied (het-
ero)aromatic dinucleophilic and dielectrophilic fragments are
The 2+3 macrocyclic cross coupling method was successfully
extended to the synthesis of functionalized N,O-bridged
calix[1]arene[4]pyridines 5 and 7 starting from 3,5-dihydroxyben-
zoic acid methyl ester 1b and 3,5-dihydroxybenzamide derivative
* Corresponding authors. Tel.: +86 10 62565610; fax: +86 10 62564723.
E-mail addresses: dxwang@iccas.ac.cn (D.-X. Wang), mxwang@iccas.ac.cn (M.-X.
Wang).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.047

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J.-C. Wu et al. / Tetrahedron Letters 50 (2009) 7209–7212
acetate by slow evaporation of the solvent, and their X-ray molec-
ular structures, which were depicted in Figures 1–3, allowed
unambiguous determination of the macrocyclic ring structure. In
the solid state, both 5 and 10 adopted distorted 1,3-alternate con-
formation. The benzene ring tended to be perpendicular to the
plane defined by three bridging nitrogen atoms. It is interesting
to note that while each bridging nitrogen atom tended to form
stronger conjugation with one of its adjacent aromatic rings, two
bridging oxygen atoms formed conjugation with their neighboring
pyridine rings rather than benzene ring. (NMe)6(O)4-bridged
calic[2]arene[8]pyridine 11 adopted a parallelogram structure
with a Ci symmetry, yielding a giant cavity. The four bridging oxy-
gen atoms located on the same plane, and the distances between
O(1) and O(2A) and between O(1) and O(2) are 17.636 Å and
4.745 Å, respectively, and angle \O(2)–O(1)–O(2A) is 72.86°. While
two methyl groups (C(6) and C(6A)) were orientated outward of
the cavity, the other two (C(22) and C(22A)) were positioned in-
ward. Two pent-4-enyl substituents on bridging nitrogen atoms,
which caused a larger R value (0.10) in structure refinement (Sup-
plementary data), were located on the each side of plane. It is
important to address that the solid-state conformational structures
may not remain in solution. As exemplified by NMR spectra, all
Br
N
O
O
N
Br
1a
Me
Me
N
N
N
N
N
H
H
Me
2
Me
Me
N
N
N
Pd2(dba)3 (20 mol%),
dppp (40 mol%), base
(5 equiv), 1,4-dioxane,
reflux
N
N
O
Me N
N
O
n
3, n = 1; 4, n = 2
Scheme 1. Synthesis of N,O-bridged calix[m]arene[n]pyridines 3 (m = 1, n = 4) and
4 (m = 2, n = 8).
Table 1
Synthesis of N,O-bridged calix[m]arene[n]pyridines 3 and 4
R
Entry
Base
Time (h)
3a (%)
4a (%)
2
1
2
Cs2CO3
NaOBut
NaH
8
5
30
25
31
34
40
45
9
23
15
11
Br
N
O
O
N
Br
3
1b, R = CO2Me; 1c, R = CO(Allyl)Me
4b
NaH
a
Isolated chemical yield.
Reaction was carried out in a high dilute solution (see Supplementary data).
Me
Me
b
N
N
N
Pd2(dba)3 (20 mol%),
dppp (40 mol%),
Cs2CO3 or NaH,
N
N
1,4-dioxane, reflux
1c, respectively (Scheme S1, Supplementary data). Thus, the anal-
ogous Pd2(dba)3/dppp-catalyzed cross coupling reaction between
1b and 2 using Cs2CO3 gave 28% yield of (NMe)3(O)2-bridged
calix[1]arene[4]pyridine 5, a macrocycle with ester functionality
on the upper rim of benzene ring. Fragment 1c underwent efficient
macrocyclic cross coupling reaction with diamine 2 using NaH
O
Me N
N
O
n
R
5, n = 1, 6, n = 2; R = CO2Me
7, n = 1, 8, n = 2; R = CON(Allyl)Me
as
a base to furnish amido-substituted (NMe)3(O)2-bridged
calix[1]arene[4]pyridine 7 in 30% yield. In both cases, the larger
macrocyclic ring homologs 6 and 8 were also obtained, respec-
tively, in the yield of 18% and 5% (Scheme 2).
Scheme 2. Synthesis of functionalized N,O-bridged calix[1]arene[4]pyridines 5 and
7.
Encouraged by the efficient formation of (NMe)3(O)2-bridged
calix[1]arene[4]pyridines that have a functional group on the
upper rim, we then attempted the synthesis of the bridging nitro-
gen atom-functionalized heterocalixaromatics, a type of function-
alized heterocalixaromatics that has remained largely unexplored
till now.7 As a demonstration, we chose N-alkenyl as a functional
group because of its versatility in chemical transformations. The
preparation of N-pent-4-enyl substituted diamine fragment 9
was carried out from N-alkylation of bis(6-bromopyridin-2-yl)a-
mine followed by nucleophilic substitution reaction with methyl-
amine in an autoclave (Scheme S2, Supplementary data). The
macrocyclic cross coupling reaction between 1a and 9 afforded de-
sired bridging nitrogen functionalized calix[1]arene[4]pyridine
product 10 in 38% yield along with calix[2]arene[8]pyridine homo-
log 11 in 14% yield. Changing base from NaH to NaOBut lead to a
slight improvement of the chemical yield of products, with 10
and 11 being isolated in 39% and 17%, respectively (Scheme 3).
The structure of all N,O-bridged calix[1]arene[4]pyridines syn-
thesized was established on the basis of their spectroscopic data
and microanalysis (see Supplementary data). The single crystals
of 5, 10, and 11 grew in a mixture of dichloromethane and ethyl
(CH2)3CH=CH2
N
NHMe
N
MeHN
N
1a
9
H2C=HC(H2C)3
Me
N
N
N
Pd2(dba)3 (20 mol%),
dppp (40 mol%),
NaOBut (5 equiv)
1,4-dioxane, reflux
N
N
Me N
O
N
O
n
10, n = 1; 11, n = 2
Scheme 3. Synthesis of bridging N-functionalized N,O-bridged calix[1]arene[4]pyr-
idine 10.

J.-C. Wu et al. / Tetrahedron Letters 50 (2009) 7209–7212
7211
a
1000
800
[C60]
600
400
200
0
F
exp
l
350
400
450
500
Wavelength/nm
Figure 4. Emission spectra (kex = 321 nm) of
3
(3.2 Â 10À5 mol dmÀ3
)
in the
presence of C60 in toluene at 25 °C. The concentrations of C60 for curves a-l (from
top to bottom) are 0, 1.20, 2.40, 3.60, 4.80, 6.00, 7.20, 8.40, 9.60, 10.80, 12.00, 15.60
(Â10À6 mol dmÀ3). Insets: The up inset is the variation of fluorescence intensity F0/
Fcal of 3 with increasing C60 concentration. The down inset is the Job plot for 3–C60
complex in toluene solution ([3] + [C60] = 2.4 Â 10À5mol dmÀ3).
Figure 1. X-ray structure of 5 with 50% probability. Selected bond lengths: N(1)–
C(14) 1.380 Å, N(1)–C(26) 1.432 Å, N(3)–C(19) 1.405 Å, N(3)–C(27) 1.415 Å, N(5)–
C(7) 1.372 Å, N(5)–C(28) 1.429 Å, O(3)–C(5) 1.370 Å, O(3)–C(15) 1.394 Å, O(4)–
C(16) 1.394 Å, and O(4)–C(31) 1.374 Å.
N,O-Bridged calix[1]arene[4]pyridine compounds appeared as
powerful host molecules able to interact with fullerene C60
.
Fluorescence titration and the Job’s plot experiments (Fig. 4 and
Supplementary data) showed that all N,O-bridged calix[1]
arene[4]pyridines synthesized formed a 1:1 complex with fuller-
ene guest C60. Based on fluorescence titration data, association con-
stants Ka(1:1) were calculated,2d,8 which ranged from 35,113 106
(5), 40,963 757 (3), 44,342 1479 (7), to 49,494 1581 MÀ1
(10). The presence of an electron-withdrawing ester group on the
upper rim decreased the electron density of the benzene ring, lead-
ing to the weakest binding toward C60
.
In summary, we have synthesized, functionalized N,O-bridged
calix[1]arene[4]pyridine compounds, first examples of the odd-
numbered calixaromatics with mixed heteroatom bridges and
mixed aromatic components, using macrocyclic fragment coupling
protocol from readily available starting materials. These novel
macrocycles, which adopted distorted 1,3-alternate conformation
in the solid state formed 1:1 complex with fullerene C60 in toluene,
giving a binding constant (Ka(1:1)) up to 49,494 MÀ1. The heteroca-
lix[5]aromatics functionalized with an ester, amide, and alkene
moiety on the upper rim position and on the bridging nitrogen
would provide a unique platform for the construction of high level
molecular architectures in supramolecular chemistry.
Figure 2. X-ray structure of 10 with 50% probability. Selected bond lengths: N(2)–
C(11) 1.404 Å, N(2)–C(12) 1.398 Å, N(4)–C(16) 1.424 Å, N(4)–C(17) 1.392 Å, N(6)–
C(21) 1.423 Å, N(6)–C(22) 1.394 Å, O(1)–C(5) 1.389 Å, O(1)–C(7) 1.379 Å, O(2)–C(1)
1.391 Å, and O(2)–C(26) 1.373 Å.
Acknowledgments
We thank the National Natural Science Foundation of China,
Ministry of Science and Technology, the Chinese Academy of Sci-
ences for financial support.
Supplementary data
Supplementary data (experimental details, full characterization
of products, 1H and 13C NMR of the products, fluorescence titration
results, X-ray molecular structure of 5, 10 and 11 (CIFs)) associated
with this article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.10.047.
Figure 3. X-ray structure of 11 with 50% probability. Selected bond lengths: N(2)–
C(5) 1.407 Å, N(2)–C(7) 1.406 Å, N(4)–C(11) 1.427 Å, N(4)–C(17) 1.389 Å, N(6)–
C(21) 1.419 Å, N(6)–C(23) 1.384 Å, O(1)–C(27) 1.383 Å, O(1)–C(28) 1.399 Å, O(2)–
C(30) 1.398 Å, and O(2)–C(4A) 1.381 Å.
N,O-bridged calix[1]arene[4]pyridine derivatives displayed only
one set of proton and carbon signals, respectively, in their 1H and
13C NMR spectra, indicating that these macrocycles are very flux-
ional, and the interconversions between different conformational
structures take place rapidly on the NMR time scale.
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