Preparation of N-(p-tolyl)azacalix[n](2,6)pyridines constructed of various numbers of the recurring unit

Article abstract of DOI:10.1055/s-2004-837201

Synthetic routes for N-(p-tolyl)-substituted azacalix[n](2,6)pyridines via Cu- and Pd-catalyzed aryl amination reactions have been elaborated, and the macrocycles constructed of various numbers (n = 3-8, and 10) of a N-(p-tolyl)aminopyridine recurring uni

Full text of DOI:10.1055/s-2004-837201

LETTER
263
Preparation of N-(p-Tolyl)azacalix[n](2,6)pyridines Constructed of Various
Numbers of the Recurring Unit
N
-(
p
-Tolyl)azacali
u
x[
n
](2,6)pyri
t
dines aka Suzuki, Takanori Yanagi, Takaki Kanbara,* Takakazu Yamamoto*
Chemical Resources Laboratory, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama, 226-8503, Japan
Fax +81(45)9245976; E-mail: tkanbara@res.titech.ac.jp
Received 31 October 2004
lar structures of 1, 2 (n = 4), 4 (n = 6, cf. Scheme 1). The
complexation of 1 toward Cu(I) is also presented.
Abstract: Synthetic routes for N-(p-tolyl)-substituted aza-
calix[n](2,6)pyridines via Cu- and Pd-catalyzed aryl amination re-
actions have been elaborated, and the macrocycles constructed of
various numbers (n = 3–8, and 10) of a N-(p-tolyl)aminopyridine
recurring unit have been isolated. A cyclic trimer 1 was obtained in
good yield. Molecular structures of some macrocycles and a Cu(I)
complex of 1 were determined by X-ray crystallography.
The trimer 1 was prepared by the Cu-catalyzed aryl
amination3 of N,N-bis[2-(6-bromopyridy)]-p-toluidine4
(8) with 2,6-bis(p-tolylamino)pyridine5 (9);6 see the top
equation in Scheme 2. The reaction was carried out under
dilute conditions to minimize formation of linear oligo-
mers, and provided 1 in 73% yield.6 A similar reaction un-
der 10 times higher concentrated conditions afforded 1 in
a moderate yield (35%). On the other hand, the cyclization
reaction of 2,6-dibromopyridine with 9 shown by the mid-
dle equation in Scheme 2 provided even-numbered mac-
rocycles; a cyclic tetramer 2 was a main product (yield: 2,
24%, 4, 12%, 6, 1%, 7, trace).7 The Cu-catalyzed cycliza-
tion of 2-bromo-6-(p-tolylamino)pyridine8 (10, see bot-
tom equation in Scheme 2) also afforded 1 (44%).
Although other macrocycles (n = 4–8) were detected by
HPLC and FAB-mass spectroscopy, they could not be iso-
lated due to the coexistence of linear oligomers formed in
Key words: macrocycles, aminations, pyridines, copper, palladi-
um, complexes
Oligo-a-aminopyridines have recently attracted much
attention because they have multidentate coordination
sites with significant flexibility that afford unique oligo-
nuclear metal complexes.1 Cyclization of the oligomers
will change their coordination behavior and structural
feature of the complexes because of restricted flexibility
of the macrocycles. However, reported examples of such
macrocyclic ligands have been limited.2
We previously reported the preparation of N-methyl-sub- the reaction. When a Pd catalyst was used for the aryl
stituted azacalix[n](2,6)pyridines (n = 4 and 6) by the Pd- amination of 10,9 the produced macrocycles (n = 3–8)
catalyzed aryl amination of 2,6-dibromopyridine with were isolated in good total yields (yield: 1, 38%, 2, 31%,
2,6-bis(methylamino)pyridine.2a They acted as macrocy- 3, 6%, 4, 7%, 5, 2%, 6, trace).10
clic ligands and afforded a zinc complex. However, the
previous process was effective to provide only the macro-
cycles constructed of even-numbered recurring units. In
order to achieve selective metal ion inclusion, preparation
of such macrocycles constructed of various numbers of
the recurring unit is considered to be important. In parallel
with this, substitution of the bridging amino group in the
macrocycles will also be of interest. Introduction of bulky
substituents such as aromatic groups, instead of the meth-
yl group, at the bridging amino groups is expected to mod-
ify the cyclization reaction to give the macrocycles with
various ring sizes, which will exhibit interesting inclusion
behavior.
Me
Me
N
N
N
N
n – 2
N
N
1: n = 3
2: n = 4
3: n = 5
4: n = 6
5: n = 7
6: n = 8
7: n = 10
Me
Scheme 1
Formation of the macrocycles was confirmed by FAB-
mass and NMR spectroscopy. In the 1H NMR spectra of 1
and 2, sharp signals with aromatic AB2 and AB spin
patterns were observed at room temperature. They were
assigned to the aromatic protons in pyridine units and the
p-tolyl substituent, respectively. These signals were
broadened at –50 °C, suggesting conformational flexibil-
ity of the macrocycles in the solution at room temperature.
As for 4, a split of the aromatic AB2 pattern was observed
at –50 °C. Intramolecular hydrogen bonding interaction
between the pyridine units seems to bring about unequiv-
alency for the pyridine units at –50 °C.
This situation prompted us to expand the chemistry of
azacalix[n](2,6)pyridines to N-(p-tolyl)-substituted deriv-
atives, and we found that adoption of new cyclization con-
ditions gave the macrocycles with various numbers of the
recurring unit. Especially, a cyclic trimer 1 (n = 3) was
obtained in good yield. We here report the preparation of
the new macrocycles (n = 3–8, and 10, 1–7), and molecu-
SYNLETT 2005, No. 2, pp 0263–0266
0
1.
0
2.
2
0
0
5
Advanced online publication: 17.12.2004
DOI: 10.1055/s-2004-837201; Art ID: U30104ST
© Georg Thieme Verlag Stuttgart · New York

264
Y. Suzuki et al.
LETTER
Br
Br
N
N
Me
Me
CuI
N
1 (n = 3)
+
K2CO3
N
H
N
N
H
73%
8
9
Me
Me
Me
2 (n = 4)
4 (n = 6)
6 (n = 8)
24%
12%
1%
CuI
K2CO3
+
Br
N
Br
N
H
N
N
7 (n = 10) trace
H
9
1 (n = 3) a) 44%, b) 38%
a) Cul, K2CO3
or
b) Pd2(dba)3 + XANTPHOS/
Me
2 (n = 4)
3 (n = 5)
4 (n = 6)
5 (n = 7)
6 (n = 8)
31%
6%
7%
2%
trace
Br
N
N
H
NaOt-Bu
10
Scheme 2
The molecular structures of 1, 2 and 4 were determined by As described above, new heterocalixarenes constituted of
X-ray crystallography (Figure 1).11 Compound 1 adopts a various numbers of aminopyridine unit, N-(p-tolyl)aza-
triangular shape with approximate CS symmetry, and one calix[n](2,6)pyridines (n = 3–8, and 10), have been pre-
pyridine ring orients in a direction opposite to other two pared by the Cu- and Pd-catalyzed aryl amination
pyridine rings due to electrostatic repulsion between the reactions, and 1 (n = 3) was obtained in good yield. The
pyridine nitrogens (Npy’s). The crystal packing suggests reaction of 1 with CuI afforded a unique Cu(I) complex.
that the conformation of 1 is stabilized via intermolecular The larger macrocycles have many N-donor sites in the
hydrogen bonds between Npy’s and aromatic protons of cavity, which will allow the molecules to include other
the p-tolyl substituents. The ORTEP drawing of 2 metal ions and organic molecules. The macrocycles are
[Figure 1(b)] indicates that 2 adopts a saddle shape with thus expected to serve as host molecules and building
an 1,3-alternating conformation, and the two of the op- blocks for the construction of molecular architectures and
posed pyridine rings are in almost face-to-face arrange- coordination polymers.
ment with a twist angle of 28.3(4)° (C7–C6–C20–C19).
The p-tolyl substituents are also oriented in opposite
directions alternately. Compound 4 adopts a triangular
Acknowledgment
This work was partly supported by a Tokuyama Science Founda-
tion.
shape and each pyridine ring alternately inclines upward
and downward to the macrocyclic plane [Figure 1(c)] due
to the electrostatic repulsion between the Npy’s and
bridging amino groups in the cavity.
References
Pyridine-containing macrocycles form complexes with
Cu(I) ion, and the Cu(I) ion usually assumes a tetrahedral
geometry.12 The reaction of 1 with CuI also yielded a
Cu(I) complex 11,13 and the molecular structure of the
complex was determined by X-ray crystallography
(Figure 2).14 The ORTEP drawing of 11 shows that the
conformation of 1 is similar to that of free 1 and the Cu(I)
ion is coordinated to two of the Npy’s and to an iodo ligand
in a distorted trigonal-planar arrangement. The Cu–Npy
bond lengths [2.053(9)–2.063(6) Å] are somewhat longer
and the Npy–Cu–Npy bond angle [84.2(3)°] is smaller than
those observed for the three-coordinated Cu(I) complexes
with di-2-pyridylamine.15 The unbound Npy (N1) is found
at a distance of 2.42 Å from Cu(I). The 1H NMR spectrum
of 11 also supports that there are two magnetically un-
equivalent pyridine units (2:1) in CD3CN at room temper-
ature.13 The stiff conformation of 1 seems to be due to the
presence of the bulky p-tolyl substituent.
(1) (a) Kempe, R. Eur. J. Inorg. Chem. 2003, 791.
(b) Hasanov, H.; Tan, U.-K.; Wang, R.-R.; Lee, G. H.; Peng,
S.-M. Tetrahedron Lett. 2004, 45, 7765; and references
therein.
(2) (a) Miyazaki, Y.; Kanbara, T.; Yamamoto, T. Tetrahedron.
Lett. 2002, 43, 7945. (b) Wang, M.-X.; Zhang, X.-H.;
Zheng, Q.-Y. Angew. Chem. Int. Ed. 2004, 43, 838.
(3) (a) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003,
42, 5400. (b) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003,
2428. (c) Selby, T. D.; Blackstock, S. C. Org. Lett. 1999, 1,
2053; and references therein.
(4) Compound 8: A mixture of 2,6-dibromopyridine (3.53 g, 15
mmol) and p-toluidine (535 mg, 5 mmol) was dissolved in
toluene (50 mL). Sodium-t-butoxide (1.44 g, 15 mmol),
tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3] (230
mg, 0.25 mmol), and 9,9-dimethyl-4,5-bis(diphenylphos-
phino)xanthene (XANTPHOS) (290 mg, 0.50 mmol) were
added to the solution. The reaction mixture was stirred at 80
°C for 18 h under nitrogen. After cooling to r.t., the mixture
was quenched by the addition of an aq solution of EDTA-2K
(ca. 100 mL), and the product was extracted with CHCl3.
Synlett 2005, No. 2, 263–266 © Thieme Stuttgart · New York

LETTER
N-(p-Tolyl)azacalix[n](2,6)pyridines
265
Figure 2 X-ray crystal structure of 11 with thermal ellipsoids drawn
at the 50% probability level. Hydrogen atoms and a solvent molecule
are omitted for simplicity.
(6) Macrocycle 1 (n = 3): A mixture of 8 (105 mg, 0.25 mmol)
and 9 (72 mg, 0.25 mmol) was dissolved in nitrobenzene (50
mL). CuI (70 mg, 0.37 mmol) and anhyd K2CO3 (138 mg,
1.0 mmol) were added to the solution. The reaction mixture
was stirred at 190 °C for 6 d under nitrogen. After the
reaction, the solvent was removed by vacuum distillation.
The remaining mixture was washed with an aq solution of
EDTA-2K (ca. 100 mL) and extracted with CHCl3. The
organic fraction was concentrated, and the crude product
was purified by column chromatography on aminopro-
pylated silica gel (100 mg, 73% yield). FAB-MS: m/z = 547
[M + H]+. 1H NMR (400 MHz, CDCl3): d = 7.32 (d, J = 8.4
Hz, 6 H), 7.27 (d, J = 8.4 Hz, 6 H), 7.16 (t, J = 8.2 Hz, 3 H),
6.06 (d, J = 8.0 Hz, 6 H), 2.41 (s, 9 H). 13C NMR (100 MHz,
CDCl3): d = 154.6, 146.8, 137.4, 137.0, 130.7, 129.1, 106.9,
21.2.
(7) Preparation of macrocycles 2, 4, 6, and 7 was carried out in
analogy with ref.6 using 2,6-dibromopyridine and 9 (yield: 2,
24%; 4, 12%; 6, 1%; 7, trace).
Macrocycle 2 (n = 4): FAB-MS: m/z = 729 [M + H]+, 365 [M
+ 2 H]2+. 1H NMR (400 MHz, CDCl3): d = 7.26 (t, J = 7.8
Hz, 4 H), 7.13 (d, J = 8.3 Hz, 8 H), 7.05 (d, J = 8.1 Hz, 8 H),
6.48 (d, J = 7.8 Hz, 8 H), 2.30 (s, 12 H). 13C NMR (100
MHz, CDCl3): d = 157.8, 142.2, 138.1, 134.2, 129.6, 126.3,
111.1, 21.0.
Figure 1 X-ray crystal structures of (a) 1, (b) 2, and (c) 4 with ther-
mal ellipsoids drawn at the 50% probability level. Hydrogen atoms
and solvent molecules are omitted for simplicity.
Macrocycle 4 (n = 6): FAB-MS: m/z 1093 [M + H]+, 547 [M
+ 2 H]2+. 1H NMR (400 MHz, CDCl3, 50 °C): d = 7.26 (t,
J = 8.0 Hz, 6 H), 6.96 (d, J = 8.3 Hz, 12 H), 6.91 (d, J = 8.5
Hz, 12 H), 6.40 (d, J = 7.8 Hz, 12 H), 2.32 (s, 18 H). 13
C
The crude product was purified by column chromatography
on silica gel (1.62 g, 78% yield). FAB-MS: m/z = 420 [M +
H]+. 1H NMR (400 MHz, CDCl3): d = 7.36 (t, J = 7.8 Hz, 2
H), 7.20 (d, J = 8.0 Hz, 2 H), 7.08 (d, J = 8.4 Hz, 2 H), 7.07
(d, J = 7.3 Hz, 2 H), 6.91 (d, J = 8.0 Hz, 2 H), 2.38 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 157.4, 141.0, 139.5, 136.9,
130.8, 128.1, 122.9, 122.0, 114.9, 21.5.
NMR (100 MHz, CDCl3): d = 155.9, 142.3, 137.8, 134.4,
129.4, 128.2, 109.2, 21.1.
Macrocycle 6 (n = 8): FAB-MS: m/z = 1457 [M + H]+, 729
[M + 2 H]2+. 1H NMR (400 MHz, CDCl3): d = 7.03 (d,
J = 8.1 Hz, 16 H), 6.98 (t, J = 8.2 Hz, 8 H), 6.88 (d, J = 7.8
Hz, 16 H), 6.28 (d, J = 7.8 Hz, 16 H), 2.32 (s, 24 H).
Macrocycle 7 (n = 10): FAB-MS: m/z = 1821 [M + H]+, 911
[M + 2 H]2+. 1H NMR (400 MHz, CDCl3, 50 °C): d = 7.00–
6.90 (m, 30 H), 6.85 (d, J = 8.1 Hz, 20 H), 6.31 (d, J = 8.1
Hz, 20 H), 2.29 (s, 30 H).
(5) Preparation of compound 9 was carried out in analogy with
ref.4 using 2,6-diaminopyridine and 4-bromotoluene (58%
yield). FAB-MS: m/z = 290 [M + H]+. 1H NMR (400 MHz,
CDCl3): d = 7.30 (t, J = 8.1 Hz, 1 H), 7.21 (d, J = 8.3 Hz, 4
H), 7.12 (d, J = 8.3 Hz, 4 H), 6.25 (s, 2 H), 6.24 (d, J = 7.8
Hz, 2 H), 2.33 (s, 6 H). 13C NMR (100 MHz, CDCl3): d =
155.5, 139.2, 138.0, 132.2, 129.7, 121.0, 98.1, 20.8.
(8) Preparation of compound 10 was carried out in analogy with
ref.4 using 2,6-dibromopyridine and p-toluidine (58% yield).
FAB-MS: m/z = 263 [M + H]+. 1H NMR (400 MHz, acetone-
d6): d = 8.30 (s, 1 H), 7.48 (d, J = 8.4 Hz, 2 H), 7.40 (dd,
Synlett 2005, No. 2, 263–266 © Thieme Stuttgart · New York

266
Y. Suzuki et al.
LETTER
Crystallographic data for 4•2CHCl3: C74H62N12Cl6,
M = 1332.10, triclinic, P1bar, a = 13.283 (8), b = 14.980
(7), c = 19.459 (13) Å, a = 70.21 (3), b = 81.90 (3)°,
g = 67.21 (3)°, V = 3358.8 (34) Å3, Z = 2, Dcalcd = 1.317 g
cm–3, m(MoKa) = 3.09 cm–1, T = 113 K, F(000) = 1384,
49428 reflections measured, 14202 unique, 8401 observed
[I > 2s(I)], 829 variables, R1 = 0.132, Rw = 0.171, GOF =
1.058.16
J = 8.3, 8.3 Hz, 1 H), 7.11 (d, J = 8.1 Hz, 2 H), 6.86 (dd,
J = 7.5, 0.6 Hz, 1 H), 6.77 (dd, J = 8.3, 0.7 Hz, 1 H), 2.27 (s,
3 H). 13C NMR (100 MHz, CDCl3): d = 156.7, 140.2, 139.6,
136.6, 133.9, 129.9, 121.8, 117.6, 105.3, 20.8.
(9) (a) Hartwig, J. F. Angew. Chem. Int. Ed. 1998, 37, 2046.
(b) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002,
219, 131.
(10) Compound 10 (658 mg, 2.5 mmol) was dissolved in toluene
(500 mL). NaOt-Bu (360 mg, 3.75 mmol), Pd2(dba)3 (92 mg,
0.1 mmol), and XANTPHOS (115 mg, 0.2 mmol) were
added to the solution. The reaction mixture was stirred at
80 °C for 5 d under nitrogen. Purification of the product was
carried out in analogy with ref.6 (yield: 1, 38%; 2, 31%; 3,
6%; 4, 7%; 5, 2%; 6, trace).
(12) (a) Tanaka, R.; Yano, T.; Nishioka, T.; Nakajo, K.;
Breedlve, B. K.; Kimura, K.; Kinoshita, I.; Isobe, K. Chem.
Commun. 2002, 1686. (b) Kinoshita, I.; Hamazawa, A.;
Nishioka, T.; Adachi, H.; Suzuki, H.; Miyazaki, Y.;
Tsuboyama, A.; Okada, S.; Hoshino, M. Chem. Phys. Lett.
2003, 371, 451. (c) Vedernikov, A. N.; Pink, M.; Caulton,
K. G. Inorg. Chem. 2004, 43, 4300.
(13) Cu(I) complex 11: An MeCN solution (1 mL) of CuI (19 mg,
0.1 mmol) was added to an MeCN solution (1 mL) of 1 (54
mg, 0.1 mmol). The mixture was allowed to stir at r.t. for 30
min. An addition of Et2O (about 1 mL) afforded a yellow
precipitate. The precipitate was filtered and washed with
Et2O (21 mg, 56% yield). A single crystal was obtained by
slow diffusion of hexane into a CH2Cl2 solution of the
product. 1H NMR (400 MHz, CD3CN): d = 7.60–7.20 (m, 15
H), 6.52 (d, J = 8.3 Hz, 2 H), 6.00 (d, J = 8.4 Hz, 4 H), 2.49
(s, 6 H), 2.39 (s, 3 H).
(14) Crystallographic data for 11•CH2Cl2: C37H32CuCl2IN6,
M = 822.06, triclinic, P1bar, a = 10.253 (5), b = 11.726 (7),
c = 16.545 (9) Å, a = 82.68 (3), b = 74.12 (3)°, g = 66.16
(2)°, V = 1749.5 (17) Å3, Z = 2, Dcalcd = 1.560 g cm–3,
m(MoKa) = 16.95 cm–1, T = 113 K, F(000) = 824, 25354
reflections measured, 7399 unique, 4688 observed [I >
2s(I)], 456 variables, R1 = 0.072, Rw = 0.086, GOF =
0.881.16
Macrocycle 3 (n = 5): FAB-MS: m/z = 911 [M + H]+. 1H
NMR (400 MHz, CDCl3): d = 7.16 (t, J = 8.0 Hz, 5 H), 7.01
(d, J = 9.0 Hz, 10 H), 6.98 (d, J = 8.8 Hz, 10 H), 6.38 (d,
J = 7.8 Hz, 10 H), 2.31 (s, 15 H). 13C NMR (100 MHz,
CDCl3): d = 156.3, 142.1, 137.7, 134.2, 129.4, 127.3, 110.5,
21.1.
Macrocycle 5 (n = 7): FAB-MS: m/z = 1275 [M + H]+. 1H
NMR (400 MHz, CDCl3): d = 7.07 (t, J = 8.1 Hz, 7 H), 6.96
(d, J = 8.1 Hz, 14 H), 6.89 (d, J = 8.3 Hz, 14 H), 6.41 (d,
J = 8.1 Hz, 14 H), 2.30 (s, 21 H). 13C NMR (100 MHz,
CDCl3): d = 155.6, 141.6, 137.5, 134.0, 129.1, 127.5, 108.8,
20.8.
(11) Crystallographic data for 1: C36H30N6, M = 546.67, mono-
clinic, P21/a, a = 11.225 (7), b = 21.541 (13), c = 12.989 (9)
Å, b = 113.747 (8)°, V = 2874.8 (32) Å3, Z = 4,
Dcalcd = 1.263 g cm–3, m(MoKa) = 0.77 cm–1, T = 113 K,
F(000) = 1152, 42080 reflections measured, 6688 unique,
3778 observed [I > 3s(I)], 379 variables, R1 = 0.037,
Rw = 0.048, GOF = 0.929.
Crystallographic data for 2: C48H40N8, M = 728.90, triclinic,
P1bar, a = 11.111 (9), b = 12.354 (7), c = 14.633 (9) Å,
a = 71.37 (3), b = 89.86 (4)°, g = 82.48 (4)°, V = 1885.4 (22)
Å3, Z = 2, Dcalcd = 1.284 g cm–3, m(MoKa) = 0.78 cm–1,
T = 113 K, F(000) = 768, 28672 reflections measured, 8100
unique, 5582 observed [I > 1s(I)], 505 variables, R1 = 0.090,
Rw = 0.131, GOF = 0.930.
(15) Thompson, J. S.; Whitney, J. F. Inorg. Chem. 1984, 23,
2813.
(16) Crystallographic data for the structural analysis have been
deposited with the Cambridge Crystallographic Data Centre;
publication numbers CCDC 253651 (1), 241558 (2), 241559
(4), and 253652 (11).
Synlett 2005, No. 2, 263–266 © Thieme Stuttgart · New York