Synthesis of strained pyridine-containing cyclyne via reductive aromatization

Article abstract of DOI:10.1021/jo1006202

The Sonogashira-Hagihara coupling reactions of 2,6-diiodopyridine and cis-3,6-diethynyl-3,6-dimethoxycyclohexa-1,4-diene or cis-9,10-diethynyl-9,10- dimethoxy-9,10-dihydroanthracene gave macrocyclic compounds having alternating 2,6-diethynylpyridine and 3,6-dimethoxycyclohexa-1,4-diene segments. Transformation of the C₃-symmetric 2,6-diethynylpyridine-based cyclotrimer was efficiently achieved using tin-mediated reductive aromatization under mild conditions.

Full text of DOI:10.1021/jo1006202

pubs.acs.org/joc
cross-coupling reactions as a final step are not appli-
Synthesis of Strained Pyridine-Containing Cyclyne
via Reductive Aromatization
cable to the synthesis of constrained skeletons involving p-
phenyleneacetylene segments (Scheme 1, route 1). Therefore,
several synthetic approaches including bromination-
debromination,2 photochemical valence isomerization,3 laser-
induced or photochemical cycloreversion,4 reduction using
lithium naphthalenide,5 dehydration-oxidation,6 and re-
ductive elimination of diarylmetal species7 have been developed
to construct strained macrocycles composed of bent benzene
rings or bent acetylene moieties. However, almost all of these
transformations require harsh conditions. Meanwhile, Lewis
acid mediated reductive aromatization is a well-known method
for constructing benzene rings from cyclohexa-1,4-dienes under
mild conditions with high efficiency.8,9 Swager and co-worker
have achieved the elegant synthesis of poly(anthrylenebuta-
diynylene)s using same tin-mediated reductive aromatization
approach.10 Based on the results of previous studies, we focused
our attention on tin-mediated reductive aromatization to con-
struct strained π-conjugated macrocycles (Scheme 1, route 2).
Koji Miki, Michiyasu Fujita, Yuki Inoue, Yoshinori Senda,
Toshiyuki Kowada, and Kouichi Ohe*
Department of Energy and Hydrocarbon Chemistry,
Graduate School of Engineering, Kyoto University,
Nishikyo-ku, Kyoto, 615-8510, Japan
ohe@scl.kyoto-u.ac.jp
Received April 1, 2010
SCHEME 1. Synthetic Approaches To Construct Strained
Diethynylbenzene-Containing Macrocycles
The Sonogashira-Hagihara coupling reactions of 2,6-
diiodopyridine and cis-3,6-diethynyl-3,6-dimethoxycy-
clohexa-1,4-diene or cis-9,10-diethynyl-9,10-dimethoxy-
9,10-dihydroanthracene gave macrocyclic compounds
having alternating 2,6-diethynylpyridine and 3,6-di-
methoxycyclohexa-1,4-diene segments. Transformation
of the C3-symmetric 2,6-diethynylpyridine-based cyclo-
trimer was efficiently achieved using tin-mediated reduc-
tive aromatization under mild conditions.
Pyridine-containing π-conjugated systems have attracted
much attention because of their electron-deficient properties
and their coordinative character.11 The 2,6-diethynylpyridine
(5) Jasti, R.; Bhattacharjee, J.; Neaton, J. B.; Bertozzi, C. R. J. Am. Chem.
Soc. 2008, 130, 17646–7647.
(6) Takaba, H.; Omachi, H.; Yamamoto, Y.; Bouffard, J.; Itami, K.
Angew. Chem., Int. Ed. 2009, 48, 6112–6116.
(7) Yamago, S.; Watanabe, Y.; Iwamoto, T. Angew. Chem., Int. Ed. 2010,
49, 757–759.
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(b) Ried, W.; Schmit, H.-J.; Urschel, A. Chem. Ber. 1958, 91, 1280. (c) Ried,
W.; Donner, W.; Schlegelmilch, W. Chem. Ber. 1961, 94, 1051–1058.
(d) Clauss, G.; Ried, W. Chem. Ber. 1975, 108, 528–537. (e) Walborsky, H.
Strained macrocyclic π-conjugated molecules containing
p-phenylene and p-phenyleneacetylene segments have re-
ceived considerable attention due to their attractive struc-
tural features in material chemistry as well as host-guest
chemistry.1 Because of their strained structures, the simple
(1) (a) Steinberg, B. D.; Scott, L. T. Angew. Chem., Int. Ed. 2009, 48,
5400–5402. (b) Kawase, T.; Kurata, H. Chem. Rev. 2006, 106, 5250–5273.
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cited therein.
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Chem. Commun. 2000, 83–84. (b) Ohkita, M.; Ando, K.; Suzuki, T.; Tsuji, T.
J. Org. Chem. 2000, 65, 4385–4390. (c) Ohkita, M.; Ando, K.; Tsuji, T. Chem.
Commun. 2001, 2570–2571.
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K. E.; Houk, K. N.; Li, Y. Science 1986, 245, 1088–1090. (b) Tobe, Y.; Fujii,
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Varghese, B. Eur. J. Org. Chem. 2003, 660–665. (b) Bandyopadhyay, A.;
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Wakabayashi, T.; Achiba, Y. Chem. Commun. 1999, 1625–1626. (g) Tobe,
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DOI: 10.1021/jo1006202
r
Published on Web 04/26/2010
J. Org. Chem. 2010, 75, 3537–3540 3537
2010 American Chemical Society

Miki et al.
JOCNote
TABLE 1. Synthesis of Pyridine-Containing Macrocycles 5 and 6
entry
[Pd]/[Cu] (mol%/mol%)
concn (M)
time (d)
products and isolated yieldsa (%)
1
2
3
4
5
6
2.5/10
2.5/10
2.5/10
2.5/10
0.6/2.5
2.5/10
0.01
0.02
0.04
0.01
0.02
0.02
1
1
1
2
3
1
5a
5a
5a
5a
5a
6a
7
5
3
9
10
7
5b
5b
5b
5b
5b
6b
10
9
8
13
11
9
aIsolated yields based on the repeating segment in the brace.
unit is an attractive building block for pyridine-containing
π-conjugated systems, such as strong fluorescence-emitting
cyclyne 112 (Φrel = 0.59) and poly(meta-ethynylpyridines)
that can selectively form helical structures with saccharides
(Figure 1).13 Despite these attractive features of diethynyl-
pyridine-containing π-conjugated compounds, synthesis of
the smaller and more strained cyclyne 2 has not been
reported so far because of the synthetic difficulties in cross-
coupling approaches. In this paper, we report the synthesis of
a strained pyridine-containing cyclyne using mild and effi-
cient tin-mediated reductive aromatization.
compounds 5a (n=0), 5b (n=1), and oligomers was obtained
(Table 1, entry 1). The macrocycles 5a and 5b were purified
using gel permeation chromatography (GPC) with CHCl3 as
the eluent. The lower the concentration of the reactants, the
higher the yields that were obtained (entries 1-3). In 0.01 M
conditions, extension of the reaction time improved yields
slightly because of full conversion of short oligomers (entry
4). The reaction with low catalytic loading gave the corre-
sponding products in 10% and 11% yields, respectively,
although a longer reaction time was necessary (entry 5).
The reaction of 3a with 4-ethoxyl-2,6-diiodopyridine (4b)
also gave the corresponding products 6a (n=1) and 6b (n=2)
in 7% and 9% yields, respectively (entry 6). The macrocyclic
structures of 5a, 6a, and 6b were determined by X-ray crystal
structure analyses of crystals grown from CH2Cl2/MeOH
(see the Supporting Information). Next, we tried the cou-
pling reaction of cis-9,10-diethynyl-9,10-dimethoxy-9,10-di-
hydroanthracene (3b) with 4-octyloxy-2,6-diiodopyridine (4a)
or 2,6-diiodopyridine (4c). The macrocycles 7a (n = 0), 7b
(n=1), 8b (n=1), and 8c (n=1) including 9,10-dihydroan-
thracene were obtained (Scheme 2).14 Compared with cyclo-
hexa-1,4-diene 3a, the coupling reaction of 3b proceeded
slowly. Therefore, a higher reaction temperature was re-
quired to obtain the corresponding macrocycles in better
yields. Next, we attempted the stepwise synthesis of 7b from
diiodide 9 and diyne 10 to improve the yield, but the yield of
macrocycle was comparable to that of the coupling between
3b and 4b (13% yield) (Scheme 2).
FIGURE 1. Pyridine-containing cyclynes.
First, we tried to prepare cyclic precursors using the
Sonogashira-Hagihara coupling reaction to synthesize the
target cyclyne 2. When the coupling reaction of cis-3,6-
diethynyl-3,6-dimethoxycyclohexa-1,4-diene (3a) and 2,6-
diiodo-4-octyloxypyridine (4a) with catalytic amounts of
Pd(PPh3)4 and CuI in toluene/Et3N (v/v=4:1, 0.01 M) was
carried out, a mixture of pyridine-containing macrocyclic
Having obtained the cyclic precursors 5b-8b containing
2,6-diethynylpyridine moieties, we next attempted the re-
ductive aromatization.15 First, we carried out the reaction of
5b and 6b including cyclohexa-1,4-diene with an excess
amount of SnCl2, but we could not purify the corresponding
(12) Yamaguchi, Y.; Kobayashi, S.; Miyamura, S.; Okamoto, Y.;
Wakamiya, T.; Matsubara, Y.; Yoshida, Z.-i. Angew. Chem., Int. Ed. 2004,
43, 366–369.
(13) (a) Waki, M.; Abe, H.; Inouye, M. Chem.;Eur. J. 2006, 12, 7839–
7847. (b) Inouye, M.; Waki, M.; Abe, H. J. Am. Chem. Soc. 2004, 126, 2022–
2027. (c) Abe, H.; Murayama, D.; Kayamori, F.; Inouye, M. Macromolecules
2008, 41, 6903–6909. (d) Abe, H.; Machiguchi, H.; Matsumoto, S.; Inouye,
M. J. Org. Chem. 2008, 73, 4650–4661.
(14) Macrocycle 8a (R=H, n=0) was detected by LRMS as well as
HRMS, but other spectral data could not be measured because of low
solubility in any organic solvents after evaporation. The macrocyclic struc-
ture of 8c was determined by X-ray crystal structure analysis. See the
Supporting Information.
(15) The reductive aromatization of 5a, 6a, and 7a (n=0) did not proceed
to give the corresponding cyclynes at all.
3538 J. Org. Chem. Vol. 75, No. 10, 2010

Miki et al.
JOCNote
SCHEME 2. Synthesis of Pyridine-Containing Macrocycles
7 and 8
FIGURE 2. Energy-minimized structure of anthracene-containing
cyclyne (B3LYP/6-31G(d)). Selected angles: —C1-C2-C3 =
168.0ꢀ; —C2-C3-C4 = 171.4ꢀ; —C3-C4-C5 = 174.3ꢀ; —C4-
C5-C6=173.5ꢀ; —C5-C6-C7=171.7ꢀ; —C6-C7-C8=169.2ꢀ;
—C9-C10-C11 = 167.2ꢀ; —C10-C11-C12 = 169.8ꢀ; —C11-
C12-C13=177.5ꢀ.
FIGURE 3. UV-vis absorption and fluorescence spectra of 11
(solid line) and 12 (broken line) in CHCl3 solution (1.0 ꢀ 10-5 M).
SCHEME 3. Reductive Aromatization of 7b
TABLE 2. Optical Properties of 11 and 12a
UV-vis λmax (nm) ε (L mol-1 cm-1
)
PL λmax (nm)b Φabs
c
3
3
11
12
441, 446, 474
439, 467
3.2 ꢀ 104
489, 523
475, 507
0.47
0.59
1.5 ꢀ 104
a1.0 ꢀ 10-6 M CHCl3 solution were measured. bThe excitation
wavelength was 439 nm in both cases. cDetermined by using an
integrating sphere.
cyclyne from the messy reaction mixtures.16 In contrast, the
reductive aromatization of 7b proceeded smoothly to give
the corresponding cyclyne 11 in excellent yield (Scheme 3).17
To clarify the structural features of the cyclyne, we performed a
DFT calculation on the core structure of 11 (Figure 2).18
Interestingly, two anthracene rings are twisted against
the plane including the core cyclyne skeleton, while the
bis(dipyridylethynyl)anthracene unit forms a π-conjugated
planar structure. This might be caused by the steric repulsion
of three anthracene rings. The angles shown in Figure 2
indicate that both the anthracene rings and the alkynes in the
nanoring structure are distorted.
We measured the UV-vis and fluorescence spectra of 11
and the reference compound 12 (Figure 3 and Table 2). The
UV-vis absorption spectrum of 11 is almost the same
spectrum as 12 with a slightly bathochromic shift.19 This
shows that the absorption bands of 11 are attributed to the
bis(dipyridylethynyl)anthracene unit. The bathochromic
(16) Bertozzi et al. also mentioned that the reductive aromatization of
cyclohexadiene moieties to synthesize cycloparaphenylenes led to a complex
mixture. See ref 5.
(17) The reductive aromatization of 8b also gave the corresponding
cyclyne, but the cyclyne gradually decomposed under the reaction condi-
tions. See the Supporting Information.
(18) Visualized by Molekel. (a) Flukiger, P.; Luthi, H. P.; Portmann, S.;
Weber, J. MOLEKEL 4.3, Swiss Center for Scientific Computing, Manno,
Switzerland, 2000-2002. (b) Portmann, S.; Luthi, H. P. Chimia 2000, 54,
766–770.
(19) The time-dependent (TD) calculation of the model cyclyne shown in
Figure 2 indicates that the UV-vis absorption spectrum of 11 is reasonable.
The results of calculation are summarized in the Supporting Information.
J. Org. Chem. Vol. 75, No. 10, 2010 3539

Miki et al.
JOCNote
shift of the fluorescence spectra of cyclyne 11 would be
caused by extension of the π-conjugated structure. The
absolute quantum yield of 11, which was similar to that of
1, indicates that the strained structure does not affect the
quantum efficiency.
In summary, we have demonstrated an efficient tin-
mediated reductive aromatization to construct a strained
diethynylpyridine-containing π-conjugated cyclyne. The re-
sulting cyclyne 11 emitted strong fluorescence around 500 nm
with a good fluorescence quantum yield. Although the efficien-
cies of macrocyclization using cross-coupling reactions should
be improved, the present results support the belief that the
reductive aromatization is a potential method to construct
strained π-conjugated systems. By using this efficient transfor-
mation, the syntheses of cycloparaphenyleneacetylenes as well
as heteroaromatic ring-containing cyclynes are currently being
investigated in our laboratory.
7b (n=1): pale yellow solid (48 mg, 0.098 mmol, 12%); mp >250
ꢀC; IR (KBr) 3435, 2292, 2233 (CtC), 1582, 1551, 1261, 1095,
802, 763 cm-1; 1H NMR (300 MHz, CDCl3, 25 ꢀC) δ 0.90 (t, J=
6.8 Hz, 3H), 1.25 (m, 10H), 1.31 (m, 2H), 2.88 (s, 6H), 3.62 (t, J=
6.3 Hz, 2H), 6.56 (s, 2H), 7.42 (dd, J=3.6, 5.9 Hz, 4H), 7.89 (dd,
J=3.6, 5.9 Hz, 4H); 13C NMR (75 MHz, CDCl3, 25 ꢀC) δ 14.1,
22.6, 25.8, 28.5, 29.1, 29.2, 31.8, 51.2, 68.0, 71.8, 85.4, 90.5,
114.3, 128.2, 129.2, 134.7, 143.6, 164.4; HRMS (FAB) calcd for
C99H100N3O9 (M þ Hþ) 1474.7460, found 1474.7440.
Reductive Aromatization of 7b. To a solution of 7b (14 mg,
9.0 μmol) in CH2Cl2 (8 mL, bubbling of N2 for 30 min before
use) was added a solution of SnCl2 2H2O (0.60 g, 2.7 mmol,
3
100 equiv) in aqueous HCl solution (18 mL, 1 N, bubbling of N2
for 30 min before use) at room temperature in dark. After the
reaction mixture was stirred at room temperature for 60 h in the
dark, the color changed from pale yellow to red. The solution
was separated, and the aqueous layer was extracted with CH2Cl2
(10 mL ꢀ 2). The combined organic solution was washed with
saturated NaHCO3 (10 mL) and brine (10 mL) and dried over
MgSO4. The organic solvent was removed under reduced pres-
sure, and the crude product was subjected to GPC with CHCl3
as an eluent to give cyclyne 11 (10 mg, 7.8 μmol, 89%) as a redish
brown solid: mp >250 ꢀC; IR (KBr) 2923, 2852, 2187 (CtC),
1581, 1540, 1434, 1261, 1156, 1027 cm-1; 1H NMR (300 MHz,
CDCl3, 25 ꢀC) δ 0.93 (m, 3H), 1.33 (m, 10H), 1.90 (m, 2H), 4.17
(t, J=6.6 Hz, 2H), 7.26 (s, 2H), 7.52 (dd, J=3.5, 6.6 Hz, 4H),
8.85 (dd, J=3.5, 6.6 Hz, 4H); 13C NMR (75 MHz, CDCl3, 25 ꢀC)
δ 14.1, 22.7, 25.9, 28.9, 29.2, 29.4, 29.7, 31.8, 68.7, 89.0, 103.9,
110.7, 118.5, 127.2, 127.4, 132.8, 145.4, 166.1; HRMS calcd for
C93H82N3O3 (M þ Hþ) 1288.6356, found 1288.6375.
Experimental Section
The General Procedure for the Synthesis of Macrocycles 5-8
Exemplified by Macrocycle 7. A solution of diyne 3b (0.24 g,
0.83 mmol) and 4a (0.38 g, 0.83 mmol) in toluene/Et3N (v/v=
4:1, 80 mL, 0.01 M) was degassed. To this solution were added
CuI (16 mg, 0.084 mmol) and Pd(PPh3)4 (24 mg, 0.020 mmol) at
room temperature. After being stirred for 48 h at 60 ꢀC, the
reaction mixture was washed with saturated NH4Cl aque-
ous solution. The aqueous solution was extracted with CHCl3
(20 mL ꢀ 2), and the combined organic solution was dried over
MgSO4. The organic solvents were removed under reduced
pressure, and the residue was subjected to short column chro-
matography on SiO2 with hexane/AcOEt (v/v=1:1) to remove
polymeric compounds. The organic solvents were removed
under reduced pressure, and the residue was subjected to GPC
with CHCl3 as an eluent to give macrocycles 7. Macrocycle 7a
(n=0): pale yellow solid (20 mg, 0.040 mmol, 5%); mp >250 ꢀC;
IR (KBr) 2925, 2854, 2235 (CtC), 1585, 1552, 1224, 1113, 1068,
Acknowledgment. This work is supported by a Grant-in-
Aid for Young Scientists (B) (No. 08103906) from the
Ministry of Education, Culture, Sports, Science, and Tech-
nology of Japan. We acknowledge Dr. Tetsuaki Fujihara in
Kyoto University for helpful discussions of X-ray crystal
analysis, and Ms. Keiko Kuwata in Kyoto University for
measurement of FAB spectra. K.M. thanks the Kinki In-
vention Center for financial support.
1
761 cm-1; H NMR (300 MHz, CDCl3, 25 ꢀC) δ 0.92 (t, J=
6.9 Hz, 3H), 1.32 (m, 10H), 1.79 (m, 2H), 2.71 (s, 6H), 3.97 (t, J=
6.6 Hz, 2H), 6.96 (s, 2H), 7.38 (dd, J=3.3, 5.8 Hz, 4H), 7.79 (dd,
J=3.3, 5.8 Hz, 4H); 13C NMR (75 MHz, CDCl3, 25 ꢀC) δ 14.0,
22.7, 25.8, 28.8, 29.2, 29.2, 31.8, 50.5, 68.4, 71.2, 84.5, 91.0,
113.2, 128.2, 129.5, 134.4, 143.8, 164.7; HRMS (FAB) calcd for
C66H67N2O6 (M þ Hþ) 983.4999, found 983.4992. Macrocycle
Supporting Information Available: Experimental details,
spectroscopic data, and X-ray crystallographic data. This ma-
terial is available free of charge via the Internet at http://pubs.
acs.org.
3540 J. Org. Chem. Vol. 75, No. 10, 2010