Preparation of ethynylpyridine macrocycles by oxidative coupling of an ethynylpyridine trimer with terminal acetylenes

Article abstract of DOI:10.1021/jo101921e

Macrocycles consisted of pyridine rings and acetylene bonds were prepared by Eglinton coupling from a tandem precursor bearing two terminal alkynyl groups. The composition of molecular size in the cyclized products changed by the reaction solvent. In pyridine, 9-meric and bigger macrocycles were obtained, while that of 6-mer was not. On the other hand, in pyridine/THF mixed solvent, the 6-mer was obtained as a major product.

Full text of DOI:10.1021/jo101921e

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recognition (Figure 1).2 The pyridine rings were linked with
Preparation of Ethynylpyridine Macrocycles by
Oxidative Coupling of an Ethynylpyridine Trimer
with Terminal Acetylenes
acetylene bonds to keep rigidity and proper distances for this
purpose. Incorporation of this module into the macrocyclic
structure was essential to obtain the binding strength to
monosaccharides.3 We next designed macrocyclic oligomers
such as 2 with increased symmetry and the number of bind-
ing sites to further improve the binding strength.4,5 For the
preparation of those macrocycles, the Sonogashira reaction was
attempted to link the pyridine rings with acetylene bonds.
However, acyclic polymers were obtained instead of expected
macrocycles, which incidentally gave us fruitful results, in which
the polymer recognizes saccharides within the helical structure.6
To achieve macrocyclic hosts, we made an alternative plan to
attempt oxidative homocoupling mediated by a copper salt7 for
the tandem acetylene 3 bearing three pyridine rings. Herein, we
report the synthesis of ethynylpyridine macrocycles by oxidative
homocoupling, depending on the solvents used.
Hajime Abe,* Hiroyuki Kurokawa, Yusuke Chida, and
Masahiko Inouye*
Graduate School of Pharmaceutical Sciences, University of
Toyama, Sugitani 2630, Toyama 930-0194, Japan
abeh@pha.u-toyama.ac.jp; inouye@pha.u-toyama.ac.jp
Received September 30, 2010
The precursor for macrocyclization, tandem trimeric 2,6-
pyridylene ethynylene compound 13, was prepared as shown
in Scheme 1. Aliphatic alkoxy groups at the 4-positions of the
pyridine rings were introduced to improve solubility. Commer-
cially available 2,6-dibromopyridine 4 was converted into 2,6-
dibromo-4-nitropyridine 5 in three steps,8 and it was allowed to
react with metal alkoxides to give 4-alkoxypyridines 6 and 8.
The tert-butoxy derivative 6was treated with CuI/NaI9 to afford
diiodide 7. The octyloxy derivative 8 was converted into
dissymmetric diyne 10 via 9 by subsequent Sonogashira cou-
plings with 3-methylbutyn-2-ol and (tert-butyldimethylsilyl)-
acetylene. Base-promoted liberation of acetone from 10
Macrocycles consisted of pyridine rings and acetylene
bonds were prepared by Eglinton coupling from a tandem
precursor bearing two terminal alkynyl groups. The
composition of molecular size in the cyclized products
changed by the reaction solvent. In pyridine, 9-meric and
bigger macrocycles were obtained, while that of 6-mer
was not. On the other hand, in pyridine/THF mixed
solvent, the 6-mer was obtained as a major product.
(4) For a review of acetylenic macrocyclic π-systems with host ability, see:
€
Hoger, S. In Acetylene Chemistry; Diederich, F., Stang, P. J., Tykwinski,
R. R., Eds.; Wiley-VCH: Weinheim, 2005; pp 427-452.
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macrocyclic π-systems, see: (a) Miki, K.; Fujita, M.; Inoue, Y.; Senda, Y.;
Kowada, T.; Ohe, K. J. Org. Chem. 2010, 75, 3537–3540. (b) Sonoda, M.;
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DOI: 10.1021/jo101921e
r
Published on Web 12/08/2010
J. Org. Chem. 2011, 76, 309–311 309
2010 American Chemical Society

Abe et al.
JOCNote
Now homocoupling macrocyclization of the precursor 13
was investigated. Common procedures known as Glaser and
Hay coupling in the presence of catalytic amount of copper
salt under air gave only a tarry complex mixture.10 It was
found that Eglinton procedure yields macrocyclic products
by mixing 13 with an excess amount of copper(II) acetate in a
pyridine solution under an argon atmosphere (Table 1, entry 1).7
Interestingly, the macrocyclic products mainly consisted of
9-mer 15 and 12-mer 16, while the smallest 6-mer 14 was
not detected. In ESI-MS analyses, trace signals of 15-meric
product were also observed. On the other hand, when 13 was
treated with copper(II) acetate in pyridine/THF mixed solvent,
the 6-mer 14 was obtained as a major product in a moderate yield
(entry 4). The use of copper(II) triflate instead of copper(II)
acetate gave no cyclized products (entry 5).
Because of electric dipole moment on pyridine rings, the
pyridine-acetylene-pyridine structure prefers transoid con-
formation to cisoid one in order to avoid electrostatic
replusion.6a,b Actually, DFT calculations for a model trimer
17 indicated that cisoid conformer 17-cis is less stable than
transoid conformer 17-trans (Figure 2). The ring size of 9-mer
15 and bigger macrocycles allows transoid conformation by
forming a zigzag crown structure (Figure S1, Supporting
Information). However, 6-mer 14 is too small to form a zigzag
structure and is expected to form a virtually plain structure
consisting of only the cisoid conformation, in which all of the
pyridinicnitrogen atomsdirecttothe inside ofthe macrocycle.
The reason for the solvent effect in the oxidative macrocycli-
zation is still obscured. The solubility of copper salts would be
different in pyridine vs pyridine/THF. Copper(II) ion turns
into copper(I) at the oxidative dimerization. If the copper(I)
species disturbed the aimed reaction, its precipitation may be
favorable.
Among the macrocyclic products, the bigger product showed
the bigger Rf value in normal-phase TLC, possibly due to
hydrophobicity caused by alkyl groups. Only 14 is solid, and
it showed lower solubility to MeOH and chloroform, probably
because of good packing of the plain molecules. In 1H NMR
analyses, aromatic signals for bigger macrocycles appeared
downfield (Table 2). This finding would be due to the con-
tribution of the transoid conformation as supported by DFT
calculation for models 17-trans and cis (Figure S2, Supporting
Information). For the precursor 13, the chemical shifts were
close to those of the 12-mer 16, suggesting that 13 is predomi-
nantly in transoid conformation in a CDCl3 solution.
FIGURE 1. Ethynylpyridine macrocycles. 1: macrocyclic host mole-
cule previously reported. 2: highly symmetrical macrocycles, which
could not be obtained by Sonogashira coupling. Bottom: diyne-
including macrocycles by oxidative homocoupling of 3.
gave 11. The diiodide 7 was assembled with 2 equiv of 11 by
Sonogashira reaction to yield 12, whose two silyl groups were
finally deprotected to obtain the tandem precursor 13.
SCHEME 1. Preparation of Tandem Precursor 13
310 J. Org. Chem. Vol. 76, No. 1, 2011

Abe et al.
JOCNote
TABLE 1. Macrocyclic Products and Solvent Effect of Eglinton
Coupling of 13
TABLE 2. 1H NMR Chemical Shifts for Aromatic Protons of Macro-
cycles 14-16 and Substrate 13a
δ (ppm)
compd
Ha
Hb
Hc
13, precursor
14, 6-mer
15, 9-mer
7.19
7.08
7.14
7.20
7.14
7.02
7.06
7.11
6.99
6.98
7.00
7.02
16, 12-mer
aConditions: 500 MHz, CDCl3, 23 °C.
product/%a
Oxidative Coupling of 13 in Pyridine/THF. Preparation of
6-mer 14. A mixture of Cu(OAc)2 (1.1 g, 6.25 mmol), pyridine
(120 mL), and THF (200 mL) was bubbled with argon for 1 h,
and then acetylene precursor 13 (160 mg, 0.25 mmol) was added
to the resulting suspension. After being stirred for 12 h at room
temperature, the resulting mixture was diluted with H2O (200 mL)
and AcOEt (200 mL) and extracted with ether repeatedly. The
combined ether layer was washed with 5% hydrochloric acid,
water, aqueous NaHCO3, and brine subsequently and concentrated
with a rotary evaporator. The resulting residue was subjected to
silica gel column chromatography (eluent: CHCl3/MeOH=50:1
to 10:1) to yield 6-mer 14 (64 mg, 39%) as a pale brown solid.
9-Mer 15 (11 mg, 6%) and 12-mer 16 (6 mg, 4%) were also
isolated as pale brown oils. 14: mp 240 °C dec; 1H NMR (CDCl3,
500 MHz) δ 0.89 (t, J = 7.0 Hz, 12 H), 1.25-1.38 (m, 32 H),
1.42-1.45 (m, 8 H), 1.51 (s, 18 H), 1.77-1.81 (m, 8 H), 4.01 (t,
J = 6.5 Hz, 8 H), 6.98 (s, 4 H), 7.02 (s, 4 H), 7.08 (s, 4 H);
13C NMR (CDCl3, 125 MHz) δ 14.1, 22.6, 25.8, 28.8, 29.17,
29.22, 31.8, 68.5, 72.8, 80.4, 87.0, 87.4, 114.0, 114.2, 119.5, 143.3,
143.9, 144.2, 165.1; IR (KBr) 2928, 2856, 2227, 2153, 1576, 1545
cm-1; ESI-HRMS m/z calcd for C86H98N6NaO6 (M þ Naþ)
1333.7446, found 1333.7373. 15: 1H NMR (CDCl3, 500 MHz) δ
0.89 (t, J=7.3 Hz, 18 H), 1.25-1.38 (m, 48 H), 1.42-1.45 (m, 12 H),
1.49 (s, 27 H), 1.77-1.81 (m, 12 H), 4.01 (t, J=6.8 Hz, 12 H),
7.00 (d, J=2.5 Hz, 6 H), 7.06 (d, J=2.5 Hz, 6 H), 7.14 (s, 6 H);
13C NMR (CDCl3, 125 MHz) δ 14.1, 22.6, 25.8, 28.7, 29.1, 29.2,
31.7, 68.7, 73.0, 80.7, 81.1, 87.1, 87.5, 114.0, 114.7, 119.6, 143.1,
143.7, 144.2, 163.2, 165.3; IR (neat) 2925, 2855, 2227, 2154,
1579, 1544 cm-1; ESI-HRMS m/z calcd for C129H146DN9NaO9
(M þ Hþ) 1990.1252, found 1990.1255. 16: 1H NMR (CDCl3,
500 MHz) δ 0.89 (t, J = 7.0 Hz, 24 H), 1.25-1.38 (m, 64 H),
1.42-1.45 (m, 16 H), 1.50 (s, 36 H), 1.78-1.82 (m, 16 H), 4.02
(t, J=6.5 Hz, 16 H), 7.02 (d, J=2.3 Hz, 8 H), 7.11 (d, J=2.3 Hz,
8 H), 7.20 (s, 8 H); 13C NMR (CDCl3, 125 MHz) δ 14.1, 22.6,
25.8, 28.7, 29.16, 29.20, 31.8, 68.7, 73.0, 81.2, 87.1, 87.5, 115.0,
120.0, 143.1, 143.6, 144.2, 163.3, 165.3; IR (neat) 2925, 2855,
14, 6-mer
(n = 1)
15, 9-mer
(n = 2)
16, 12-mer
(n = 3)
entry
solvent
pyridine
pyridine/THF(1:1)
pyridine/THF(1:2)
pyridine/THF(2:5)
pyridine/THF(2:5)b
1
2
3
4
5
nd
13
24
39
nd
9
nd
nd
6
8
nd
nd
4
nd
nd
aIsolated yield. nd = not detected. bCu(OTf)2 was used instead of
Cu(OAc)2. Reaction time was 48 h, and 51% of 13 was recovered.
FIGURE 2. DFT-predicted relative stability of cisoid and transoid
conformers of trimeric precursor model 17. Conditions: geometry
optimization at the B3LYP/6-31 level; single-point energies at the
B3LYP/6-311þG(2d,p) level. Arrows indicate local dipole mo-
ments on pyridine rings.
The pyridine-containing macrocycles obtained here have
potential as a host molecule to accommodate polar guest
molecules such as saccharides by multiple hydrogen bonds. In
particular, the macrocyclic structures may suit to the size
recognition. tert-Butyl groups can be removed by acid cleavage
and subsequently brought to further functionalization to confer
additional properties. We are now investigating their host
abilities and improvement of the macrocycles.
Experimental Section
2224, 2153, 1579, 1544 cm-1; ESI-HRMS m/z calcd for C172
-
General Methods. H and 13C NMR spectra were recorded
1
H
194D2N12NaO12 (M þ Hþ) 2646.5058, found 2646.5071.
Acknowledgment. This study was supported by Mitsubishi
Chemical Corporation Fund.
at 500 and 125 MHz, respectively, using tetramethylsilane (TMS)
as an internal reference. Melting points were not corrected. THF
was freshly distilled from sodium benzophenone ketyl before use.
Pyridine was also distilled from CaH2 before use. The tandem
precursor 13 was prepared by the procedure following our
previous study2 (see the Supporting Information).
Supporting Information Available: Experimental proce-
dures, Figures S1 and S2, details of theoretical analyses, and
copies of NMR spectra for compounds 6, 7, and 9-16. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(10) For examples of the attempted reagents, Cu(OAc)2/TMEDA/THF/
air; CuI/2,2-bipyridyl/I2/K2CO3/benzene.
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