Template-directed synthesis of macrocyclic aminopyridines: Azacalix[n](2,6)pyridines (n = 3, 4)

Article abstract of DOI:10.1016/j.tetlet.2014.03.126

Template-induced synthetic routes for azacalix[n](2,6)pyridines (n = 3, 4) have been elaborated. The proton and nickel ion served as the efficient template for the cyclization reactions, and the presence of the templates preferentially afforded the cyclic

Full text of DOI:10.1016/j.tetlet.2014.03.126

Tetrahedron Letters 55 (2014) 3070–3072
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Template-directed synthesis of macrocyclic aminopyridines:
azacalix[n](2,6)pyridines (n = 3, 4)
⇑
Natsuko Uchida, Ruoxi Zhi, Junpei Kuwabara, Takaki Kanbara
Tsukuba Research Center for Interdisciplinary Materials Science (TIMS), Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai,
Tsukuba 305-8573, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Template-induced synthetic routes for azacalix[n](2,6)pyridines (n = 3, 4) have been elaborated. The pro-
ton and nickel ion served as the efficient template for the cyclization reactions, and the presence of the
templates preferentially afforded the cyclic trimers and tetramers in moderate to good yields, respec-
tively. The compatibility of the cyclic tetramer with nickel ion was also confirmed by X-ray
crystallography.
Received 15 February 2014
Revised 25 March 2014
Accepted 28 March 2014
Available online 4 April 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Azacalixarene
Macrocycle
Template-directed synthesis
Nickel
Synthesis and characterization of new macrocyclic compounds
have been a research focus in the fields of host–guest and supra-
molecular chemistry. Azacalix[n](2,6)pyridines and their homologs
are among the recently emerging new generation of macrocyclic
compounds because they exhibit specific molecular recognition
properties owing to their multiple Lewis base points and cavity
size.1 Their complexation properties have been utilized for detect-
ing guests such as Zn2+ ion (n = 4) and fullerenes (n = 4–10).2 The
structure of azacalix[3](2,6)pyridine is also of interest; synergistic
hydrogen-bonding ability of the three pyridine nitrogen atoms in
its cavity is appropriate for capturing a single proton and works
as an efficient organic superbase catalyst.3 Moreover, azaca-
lix[n](2,6)pyridines (n = 3, 4) exhibited unique delayed fluorescent
behaviors.4 However, for the synthesis of azacalix[n](2,6)pyridines
and their homologs, skillful syntheses including step-by-step C–N
coupling reactions and/or dilute conditions have generally been
adopted.1–3 A step-economical synthesis method that can produce
the macrocyclic compound having a desirable ring size is impor-
tant for practical applications. Alternatively, the template effect,
caused by ions or uncharged organic molecules, is a very useful
tool for the synthesis of macrocyclic compounds; the macrocyclic
ring size strongly depends on the size of the template.5 Therefore,
the template considerably increases the yield of the macrocyclic
product with the desired ring size. We thus envisioned that
azacalix[n](2,6)pyridines can be synthesized by template-directed
synthesis; the use of appropriate templates such as proton and
transition-metal ions induce the cyclization reactions. This
approach provides an efficient one-step synthesis of the cyclic
trimer and tetramer separately from the same starting material.
Herein, we report the template-directed synthesis of azaca-
lix[n](2,6)pyridines (n = 3, 4) (Figure 1).
The starting materials (1a–1c) were synthesized by the aro-
matic nucleophilic substitution reactions of 2,6-dibromopyridine
derivatives with aniline derivatives in high yields (see the Supple-
mentary data). First, the Ullmann reaction of each starting material
was conducted under the previously reported reaction conditions
for the step-wise synthesis.3b The reaction of 1a afforded the
corresponding monoprotonated macrocyclic trimer (2aHꢀBr) selec-
tively and in 80% yield; the cyclic trimer (2a) was obtained as an
inner monoprotonated form (2aHꢀBr) owing to its high basicity
(pKBH+ = 23.1 in acetonitrile).3a The other proton adducts,
2bꢁ2cHꢀBr, were also obtained in almost excellent yields (Table 1,
entries 2 and 3). Notably, only trace amounts of differently sized
macrocycles and linear oligomers were observed, as confirmed
by the matrix-assisted laser desorption/ionization time-of-flight
mass spectrometry (MALDI-TOF-MS); the undesired products
could be easily separated by column chromatography. The yields
of the azacalix[3](2,6)pyridines did not decrease even under high
concentration conditions (entries 5–7). The high yields of
2aꢁ2cHꢀBr could be attributed to the template effect of proton.
The Ullmann reaction produces hydrogen bromide as the
by-product, and the proton serves as the template. The captured
proton in the intermediate selectively afforded the cyclic trimer,
⇑
Corresponding author. Tel.: +81 29 853 5066; fax: +81 29 853 4490.
E-mail address: kanbara@ims.tsukuba.ac.jp (T. Kanbara).
http://dx.doi.org/10.1016/j.tetlet.2014.03.126
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

N. Uchida et al. / Tetrahedron Letters 55 (2014) 3070–3072
3071
Figure 1. One step synthesis of azacalix[n]pyridine derivatives (n = 3, 4) in the presence of proton and nickel(II) ion as a template.
Table 1
Synthesis of azacalix[3](2,6)pyridine derivatives in the presence of proton as
template
Table 3
a
Synthesis of azacalix[4](2,6)pyridine derivatives (3aꢁ3c) in the presence of nickel(II)
ion as a template
Entry
R1
R2
Product
MeCNpKBH+ of 2a–2c)3
Concn.
(M)
Yielda
(%)
Entry R1
R2
Product (cyclic
4mer)
Yielda (%)
Cyclic
(
Cyclic
3merb
1
2
3
4c
5
6
7
H-
Tolyl-
Tolyl-
Anisyl-
Tolyl-
Tolyl-
Tolyl-
Tolyl-
2aHꢀBr (23.1)
2bHꢀBr (28.1)
2cHꢀBr (29.5)
2aHꢀBr (23.1)
2aHꢀBr (23.1)
2aHꢀBr (23.1)
2aHꢀBr (23.1)
0.017
0.017
0.017
0.017
0.05
0.1
80
94
92
4mer
Pyrrolidino-
Pyrrolidino-
H-
H-
H-
H-
1
2
3
H-
Tolyl-
3a
3b
5
23
16
40
57
46
b
Pyrrolidino- Tolyl-
Pyrrolidino- Anisyl- 3c
—
80
92
88
a
Isolated yield.
1
b
The yield means monoprotonated azacalix[3](2,6)prydines (2aꢁ2cHꢀPF6).
a
Isolated yield.
b
c
The linear aminopyridine oligomers were obtained.
NaOtBu was used as a base.
the yield of 3a considerably increased than those in the presence
of other additives and no additive (entry 6). Other nickel(II)halides
also afforded 3a in almost same yields as NiCl2 (entries 9 and 10),
whereas bis(1,5-cyclooctadiene) nickel(0) and nickel(II) acetyl-
acetonato failed to produce 3a (entries 11 and 12). No template
effect of Ni(acac)2 might be caused by stronger bidentate coordina-
tion of the acetylacetonato ligands. The nickel-catalyzed arylamin-
ation of aryl halides with aryl amines has been reported;7 however,
NiCl2 did not exhibit any catalytic activity in this study (entry 7).
Thus, nickel(II) ion served as a template in the reaction mixture.
Stability constants of Ni2+ and Cu2+ complexes with 2,20-dipyridyl-
amine are much higher than the other metal ions such as Zn2+ and
Co2+,8 and there is an example on the thermal stability of the metal
complexes with 2,20-dipyridylamine increases in the order
Co < Cu < Ni:9 These facts would be associated with the template
effect of Ni2+ in the reaction conditions. In the BuchwaldꢁHartwig
reaction of 1a, a C–N bond-forming reaction, NiCl2 did not show
any template effect even under diluted conditions (see the Supple-
mentary data, entry 8). The added phosphine ligand for the Pd cat-
alyst may coordinate to a nickel center and inhibit the template
effect. Starting materials with electron-donating groups (1b and
1c) also afforded the desired tetramers, 3b and 3c in the presence
of NiCl2 (Table 3).
as predicted in the previous report.3 In contrast, the reaction with
sodium tert-butoxide instead of K2CO3 did not afford the corre-
sponding macrocyclic trimer; however, it did afford linear amino-
pyridine oligomers and other sizes of macrocyclic compounds,
indicating that a strong base inhibits the template effect of a pro-
ton (entry 4).
Alternatively, the effect of metal-salt addition was examined for
the template-directed synthesis of macrocyclic tetramer, azaca-
lix[4](2,6)pyridine (3a) (Table 2). Copper(II) bromide, zinc
diacetate hexahydrate, calcium carbonate, and magnesium bis-
tert-butoxide were selected as the candidates for the template,
because the van der Waals radius of the metal ions were expected
to fit the macrocyclic cavity of 3a.6 However, the additives did not
show a clear template effect (entries 2–5). In contrast, when nick-
el(II) chloride (NiCl2) was added to the reaction as the template,
Table 2
Synthesis of azacalix[n](2,6)pyridine derivatives (n = 3, 4) in the presence of
transition-metal ion as a template
Entry
Template
Yielda (%)
To explain the template effect of Ni2+ ion, the complexation of
3a with Ni2+ was confirmed by X-ray crystallography. A single crys-
tal of 3a with Ni2+ (3aꢀNi) was obtained by the crystallization from
a mixture of 3a and NiCl2 in dichloromethane/methanol. The
ORTEP drawing is shown in Figure 2. The structure of the 3aꢀNi
complex has a nickel ion in the cavity of 3a.10 The nickel center
has a slightly distorted octahedral geometry. The complex is a cat-
ion with Clꢁ as the counter anion; the nickel center is coordinated
to the four pyridyl nitrogen atoms of 3a, a chloride, and one meth-
anol molecule. The distance between the coordinating pyridyl
nitrogen atoms and the nickel center, Ni1, is in the range
2.047ꢁ2.087 Å (Table S2); these distances are similar to the aver-
age Ni–N distance of 2.073ꢁ2.100 Å in cis-bis(bipyridine)nickel(II)
dichloride.11 The crystal structure shows that the nickel center fits
the cavity of azacalix[4](2,6)pyridine framework with a reasonable
geometry and bond distances. These results are consistent with the
2aHꢀPF6
3a
1
2
3
4
5
6
7
8
9
—
80d
85d
83d
82d
88d
5
n.r.
32
5
0
Zn(COOCH3)2ꢀ6H2O
Trace
Trace
Trace
Trace
40
CuBr2
CaCO3
Mg(OtBu)2
NiCl2
b
NiCl2
NiCl2
NiBr2
NiI2
Ni(acac)2
Ni(cod)2
c
30
43
41
4
10
11
12
4
82
87
2
a
b
c
Isolated yield.
No CuBr catalyst.
Using Pd-catalyzed reaction (the details are shown in Supplementary data).
d
The yield of 2aHꢀBr.

3072
N. Uchida et al. / Tetrahedron Letters 55 (2014) 3070–3072
template-directed synthesis of azacalix[n](2,6)pyridines (n = 3, 4)
with improved overall yields than the step-by-step methodologies
reported previously.
Acknowledgments
This research was supported by the Sasagawa Scientific
Research Grant from the Japan Science Society. The authors are
grateful to the Chemical Analysis Center of University of Tsukuba
for the measurements of X-ray analysis, Mass spectrometry, and
elemental analysis.
Supplementary data
Supplementary data (general experimental information, exper-
imental detail, characterization data) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2014.03.126.
References and notes
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Figure 2. ORTEP drawing of 3aꢀNi with thermal ellipsoids shown at the 30%
probability level. Hydrogen atoms except for the proton of the methanol (H1), the
four tolyl groups, a Cl anion, a solvated methanol molecule, and a NiCl2(CH3OH)4
molecule are omitted for clarity. (a) Top view of 3aꢀNi and (b) side view of 3aꢀNi.
fact that a Ni2+ ion serves as the template for preferentially afford-
ing azacalix[4](2,6)pyridines.
In summary, we demonstrated the one-step synthesis of
azacalix[4](2,6)pyridines and azacalix[3](2,6)pyridines from
the same starting material separately using Ni2+ and a proton
as the templates, respectively. This is the first example of the
11. Fontaine, F. G. Acta Crystallogr., Sect. E 2001, 57, m270.