Palladium-catalyzed C-H bond direct alkynylation of 5-membered heteroarenes: A well-defined synthetic route to azole derivatives containing two different alkynyl groups

Article abstract of DOI:10.1021/jo3008385

A widely applicable oxidative coupling of 5-membered heteroarenes and terminal alkynes that uses a combination of palladium and silver salts was developed. Under suitable conditions, imidazole and benzimidazole, which are sluggish under similar previously reported oxidative coupling conditions, as well as imidazo[1,5-a]pyridines, oxazole, benzoxazole, thiazole, and benzothiazole could be alkynylated. In addition, the bromine atom on the substrates was intact under the reaction conditions, and conventional Sonogashira coupling did not occur at all. With these reactivities in hand, a well-defined synthetic route to imidazo[1,5-a]pyridines and thiazole containing two different alkynyl groups was achieved in a simple manner. In addition, linear correlations were observed between the fluorescence wavelength and the Hammett substituent constants of aryl groups, not only on the C1- but also on the C3-alkynyl group of the obtained 1,3-bis(arylethynyl)imidazo [1,5-a]pyridines.

Full text of DOI:10.1021/jo3008385

Article
pubs.acs.org/joc
Palladium-Catalyzed C−H Bond Direct Alkynylation of 5-Membered
Heteroarenes: A Well-Defined Synthetic Route to Azole Derivatives
Containing Two Different Alkynyl Groups
Fumitoshi Shibahara,* Yoshimasa Dohke, and Toshiaki Murai*
Department of Chemistry, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193, Japan
S
* Supporting Information
ABSTRACT: A widely applicable oxidative coupling of 5-membered
heteroarenes and terminal alkynes that uses a combination of
palladium and silver salts was developed. Under suitable conditions,
imidazole and benzimidazole, which are sluggish under similar
previously reported oxidative coupling conditions, as well as
imidazo[1,5-a]pyridines, oxazole, benzoxazole, thiazole, and benzo-
thiazole could be alkynylated. In addition, the bromine atom on the
substrates was intact under the reaction conditions, and conventional
Sonogashira coupling did not occur at all. With these reactivities in
hand, a well-defined synthetic route to imidazo[1,5-a]pyridines and thiazole containing two different alkynyl groups was achieved
in a simple manner. In addition, linear correlations were observed between the fluorescence wavelength and the Hammett
substituent constants of aryl groups, not only on the C1- but also on the C3-alkynyl group of the obtained 1,3-bis-
(arylethynyl)imidazo [1,5-a]pyridines.
To obtain such bisalkynylated compounds, the direct C−H
coupling of monoalkynylated products and haloalkynes is a
promising approach (Scheme 1, middle),5 but commercially
available haloalkynes are still limited. The direct dehydrogen-
ative coupling (oxidative coupling) of terminal alkynes and
monoalkynylated (hetero)arenes is an alternative route to such
dialkynylated compounds (Scheme 1, lower).6 However, the
previously reported reaction systems have usually been suitable
only for highly acidic (low pKa) C−H bonds, such as those of
C2 in benzoxazole and oxadiazole.
INTRODUCTION
■
Ethynylene-bridged π-conjugated systems are widely found in
functional materials since the ethynylene moiety acts as a
π-conjugated spacer.1 Sonogashira coupling has been used to
introduce such alkynyl moieties to π-conjugated systems.2
However, it has been difficult to introduce two or more different
alkynyl groups to (hetero)arenes by conventional Sonogashira
coupling because of the low chemo- and regioselectivities of the
reaction of polyhalogenated (hetero)arenes, such as dihaloarenes
(Scheme 1, upper). For selective reactions, arenes bearing
We recently found that 1-arylethynylated 3-arylimidazo[1,5-
a]pyridines show linear correlations between the Hammett
substituent constants σ of aryl groups on the C1-alkynyl group
and the fluorescence wavelength (Figure 1).7,8 In contrast,
there is no noticeable correlation between the constants σ of a
directly bonded C3-aryl group and the fluorescent wavelength,
perhaps due to the formation of distorted π-conjugated systems
on the biaryl moieties as a result of steric hindrance. Our
subsequent interest in the electronic influence of the arylalkynyl
group on fluorescence prompted us to investigate the synthesis
of 1,3-bis(arylalkynyl)imidazo[1,5-a]pyridines. Initially, we
attempted the oxidative coupling of 1-(arylalkynyl)imidazo-
[1,5-a]pyridines and terminal alkynes under previously
reported conditions,6 but the reaction did not occur at all,
perhaps because of the relatively low acidity of the C−H bond
on C3 of the imidazo[1,5-a]pyridines. Therefore, we then
sought to identify conditions under which such C−H bonds
could participate in the reaction. We report herein a widely
Scheme 1. Approaches to Heteroarenes Containing Two
Different Alkynyl Groups by Coupling Reactions
bromine and iodine atoms have usually been used as substrates,
but a multistep synthesis is needed to obtain these substrates.3,4
Received: April 26, 2012
Published: May 21, 2012
© 2012 American Chemical Society
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Table 1. Optimization of the Oxidative Coupling of 1a and
a
2a
b
yields (%)
T
(min)
total reaction
time (h)
recovered alkyne
c
c
d
entry
X
3a
5a
as 4a (%)
1
2
3
4
5
2
−
30
40
20
90
20
20
20
20
20
3
3
3
1
3
1
1
1
1
1
11
15
52
80
18
11
30
77
32
46
41
26
−
0
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
ND
14
Figure 1. Correlation between the fluorescence wavelength and the
Hammett substituent constants σ of the substituents on the aryl group
on the C1 alkynyl group of 1-alkynylated 3-arylimidazo[1,5-a]-
pyridines.
21
e
6
no reaction
21 trace
no reaction
f
7
74
g
8
−
39
49
h
9
54
50
14
applicable oxidative coupling of 5-membered heteroarenes and
terminal alkynes that uses a combination of palladium and silver
salts. This catalytic system allowed the reaction to proceed even
at C−H bonds with a large pKa, such as in an imidazole deriv-
ative, with good efficiency. Furthermore, the transformation
realized a well-defined synthetic route to imidazo[1,5-a]-
pyridines and thiazole containing two different alkynyl groups.
In addition, linear correlations were observed between the
fluorescence wavelength and the Hammett substituent con-
stants σ of aryl groups, not only on the C1- but also on the C3-
alkynyl group of the obtained 1,3-bis(arylethynyl)imidazo[1,5-a]-
pyridines.
i
10
trace
a
Reaction conditions: To a solution of alkyne 1a (X equiv),
imidazo[1,5-a]pyridine 2a (0.4 mmol), Pd(OAc)2 (2.5 mol %),
Ag2CO3 (1.5 equiv), and AcOH (1 equiv) in a mixture of DMF
(0.9 mL) and DMSO (0.1 mL) was added dropwise a solution of 1a
(2−X equiv) in DMF (1 mL) over the indicated time period (T) at
120 °C. Isolated yields. Based on imidazopyridine 2a. ND: not
determined. Based on alkyne 1a. The reaction was carried out in the
absence of Pd(OAc)2. In the absence of AcOH. 2a was recovered in
66% yield after the reaction. In the absence of Ag2CO3. In the
absence of DMSO. In DMSO.
b
c
d
e
f
g
h
i
under these conditions. The homocoupling of 1a was
suppressed when all of 1a was added dropwise over 30 min,
whereas the competitive homocoupling of imidazopyridine 2a
significantly took place to result in no improvement in the yield
of 3a (Table 1, entry 2). Meanwhile, those results implied
that competitive homocouplings may be controlled by the
concentration of the alkyne monomer 1a in the reaction
solution. In fact, we found that the initial amount and the rate
of addition of the alkyne strongly influenced the yield of the
cross-coupling product 3a, and the best yield (80%) of 3a was
achieved when half an equivalent of the alkyne 1a was used in
the reaction mixture as an initial amount and 1.5 equiv of 1a
was added dropwise over 20 min (Table 1, entry 4). The slower
addition of 1a was ineffective, and the yield of 3a decreased
(Table 1, entry 5). Each additive was essential for obtaining
satisfactory yields (Table 1, entries 6−10). In particular, the
catalytic activity significantly dropped in the absence of acetic
acid (Table 1, entry 7). Furthermore, no reaction occurred in
the absence of silver carbonate (Table 1, entry 8). The former
result suggests that the reaction may proceed via a concerted
metalation−deprotonation (CMD) pathway at the stage of the
palladation of imidazopyridine, which may allow it to react at
relatively low acidic C−H bonds.11
RESULTS AND DISCUSSION
■
The use of less-expensive metals such as copper, nickel, and
iron as a catalyst for C−H bond functionalization reactions of
aromatic compounds is attractive, but reported examples of
these reactions, particularly of the oxidative coupling of hetero-
arenes and terminal alkynes, with those metals have usually
occurred at highly acidic C−H bonds on the substrates.6 On
the other hand, palladium catalysts have often participated in
related direct C−H bond functionalization reactions at
nucleophilic C−H bonds that show a large pKa.8b,9 Thus, we
focused on palladium systems to develop the target oxidative
coupling at the C3 position of imidazopyridines. During our
initial survey of the reaction conditions, we found that a
combination of palladium and silver salts showed good catalytic
activity for the reaction of imidazopyridines and terminal
alkynes,10 while the reaction scarcely occurred under previously
reported Pd salt−tBuOLi−air6b and Pd salt−Cs2CO3−O2
systems.6c For example, the reaction of 4-trifluoromethylphe-
nylacetylene (1a, 2 equiv) and 1-(4-methoxyphenylethynyl)-
imidazo[1,5-a]pyridine (2a) with Pd(OAc)2 (2.5 mol %),
Ag2CO3 (1.5 equiv), and acetic acid (1 equiv) as an additive in
a mixture of DMF and DMSO (5%) gave the desired
bisalkynylated imidazopyridine 3a in 11% yield (Table 1,
entry 1). However, most of the alkyne 1a underwent a homo-
coupling reaction, and the dimer 4a was recovered in 77% yield
Although the conditions required further optimization for
each combination of the substrates, cross-coupling products
3b−g were obtained in moderate to good yields (Chart 1).
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Chart 1. Scope of Substrates
Figure 2. Correlation between fluorescence spectra and the Hammett
substituent constants σ of the substituents on the arylethynyl group on
C1 of bisalkynylated imidazo[1,5-a]pyridines.
Figure 3. Correlation between fluorescence spectra and the Hammett
substituent constants σ of the substituents on the arylethynyl group on
C3 of bisalkynylated imidazo[1,5-a]pyridines.
Next, the reaction of unsubstituted imidazo[1,5-a]pyridine (6),
which has two potentially reactive C−H bonds, was investigated.
The results are summarized in Table 2. The reaction of 6 with
a
Table 2. Oxidative Coupling of 6 and Terminal Alkynes
b
yields (%)
c
d
entry
R
7
4
In contrast, the cross-coupling reactions did not proceed well
with substrates bearing a dimethylamino group (1e and 2d)
and gave a complex mixture.
1
2
3
4
5
4-F3CC6H4
Ph
7a
7b
7c
7d
7f
60
63
78
67
53
4a
4b
4c
4d
4f
44
42
18
51
21
4-MeOC6H4
4-MeC6H4
1-cyclohexenyl
The UV/vis and fluorescence spectra of the resulting 1,3-
bis(arylethynyl)imidazo[1,5-a]pyridines were measured.12 The
results are summarized in Table S1 (Supporting Infomation).
The photophysical properties of the imidazo[1,5-a]pyridines
indicated that the arylethynyl groups clearly influence the
emission maxima λem, though the influence of those on the
absorption wavelength is unclear. In fact, the λem values of the
1,3-bis(arylethynyl)imidazo[1,5-a]pyridine derivatives still
show linear correlations with the Hammett substituent con-
stants σ of the substituents on the arylethynyl group on C1, as
shown in Figure 2.7 Gratifyingly, the arylethynyl groups on C3
also showed similar correlations, as we expected (Figure 3).
The dual linear correlations may make it possible to obtain
predictable photofunctional materials by careful selection of the
substituents.
a
Reaction conditions: To a solution of imidazo[1,5-a]pyridine (6)
(0.4 mmol), Pd(OAc)2 (2.5 mol %), Ag2CO3 (1.5 equiv), and AcOH
(1 equiv) in a mixture of DMF (0.9 mL) and DMSO (0.1 mL) was added
dropwise a solution of 1 (2 equiv) in DMF (1 mL) over 50 min at 120 °C.
b
c
d
Isolated yields. Based on imidazopyridine 2a. Based on alkyne 1.
arylacetylenes proceeded at C3 selectively to give the correspond-
ing alkynylated products 7 in good yields regardless of the
arylacetylenes (Table 2, entries 1−4). In this case, trace amounts
of the imidazopyridine dimers were observed by GC mass analysis,
whereas most of the remaining alkynes were recovered as their
dimers. In addition, the reaction also coupled 6 and enyne 1f in
53% yield (Table 2, entry 5).
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The scope of azoles was then investigated to probe the
generality of the present catalytic system. The results are
summarized in Chart 2. Prior to the investigations, we briefly
Chart 2. Oxidative Coupling of Phenylacetylene and
Azoles 8
Further investigations of oxidative C−C bond-forming
reactions and the application of bisalkynylated heteroarenes
as functional materials are underway in our group.
screened the catalyst as shown in Table S2 (Supporting
Information)13 and found that bi(4-nitropyridinyl)-Pd complex
10 was an efficient catalyst for the reaction even under low
catalyst loading conditions, although the reaction conditions
were not yet fully optimized. Under these conditions, the
reaction proceeded at C−H bonds with relatively large pKa
values, which are sluggish or inert under previously reported
conditions, such as N-benzylbenzimidazole (9d: pKa of related
N-methylbenzimidazole at C2: 32.5) and N-benzimidazole (9e:
pKa of N-methylimidazole at C2: 35.1), as well as benzoxazole
(9a: pKa at C2: 24.8), benzothiazole (9b: pKa at C2: 27.3), and
thiazole (9c: pKa at C2: 29.5).14
Notably, the reaction tolerates halogen substituents on
both substrates such as 4-bromophenylacetylene (1g), 1-
bromoimidazo[1,5-a]pyridine (11), and 4-bromothiazole (13)
to give the corresponding cross-coupling products 7g, 12, and
14 in good yields. The bromine atom remained intact under the
reaction conditions, and no conventional Sonogashira coupling
products were observed (eqs 1−3), although 5-bromothiazole
(16) was inert and the starting 16 was recovered quantitatively
(eq 4). The results probably indicated that reoxidation of the
reduced Pd catalyst by the Ag salt is much faster than the
oxidative addition of the halides under these conditions.
Regarding chemoselectivity, an alternative synthetic route to
the bisalkynylated compounds can also be achieved. For
example, the obtained monoalkynylated bromothiazole 14 was
readily alkynylated by conventional Sonogashira coupling
conditions to give the bisalkynylated 15 in 58% yield (eq 3,
lower).
EXPERIMENTAL SECTION
■
General Methods. The 1H NMR (400 MHz), 13C NMR (100 MHz),
and 19F NMR (376 MHz) spectra were recorded in CDCl3. Chemical
shifts of 1H and 13C were reported in δ values referred to tetra-
methylsilane and CDCl3 as an internal standard, respectively. The 19F
chemical shifts are expressed in δ value deshielded with respect to
CF3COOH as an external standard. The mass spectra (MS) and high
resolution mass spectra (HRMS) were obtained by ionizing samples
via electron ionization (EI) or fast atom bombardment (FAB) in
positive mode with magnetic sector analyzer. All reactions were carried
out in argon atmosphere.
Materials. Unless otherwise noted, reagents were commercially
available and were used without further purifications. Complex 1015
was prepared according to the literature. Silica gel 60N (Spherical,
Neutral, 40−50 mm) from Kanto Chemical Co., Inc. was used on flash
column chromatography.
Synthesis of 1-Alkynylimidazo[1,5-a]pyridines (2).
Selective Bromination of Imidazo[1,5-a]pyridine (6). To a
solution of imidazo[1,5-a]pyridine (6) (2.4 g, 3.1 mmol) in
CH2Cl2 was added NBS (3.6 g, 1 equiv) at −78 °C under Ar
atmosphere. The resulting mixture was stirred for 1.5 h at room
temperature. The reaction mixture was quenched with Na2S2O3
aq and extracted with CH2Cl2. The organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel (hexane/
EtOAc = 4:1 then 2:1) to give 1-bromoimidazo[1,5-a]pyridine
(11) (2.5 g, 60%), 3-bromoimidazo[1,5-a]pyridine (18) (0.92 g,
23%), and 1,3-dibromoimidazo[1,5-a]pyridine (19) (0.53 g,
17%).
CONCLUSION
■
In conclusion, a widely applicable direct oxidative coupling of
azole derivatives and terminal alkynes has been developed
through the use of a combination of Pd and Ag salts under the
finely tuned dropwise addition of terminal alkynes. This
catalytic system allowed us to easily access imidazo[1,5-a]-
pyridines and thiazole containing two different alkynyl groups.
1-Bromoimidazo[1,5-a]pyridine (11). Brownish solid: mp 79−
80 °C, Rf = 0.20 (hexane/AcOEt = 4:1); IR (KBr) 3136, 3076, 3033,
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1
2363, 1770, 1632, 1266, 1003, 736 cm−1; H NMR (CDCl3) δ 6.53
(dd, J = 7.1, 6.6 Hz, 1H), 6.70 (dd, J = 9.2, 6.6 Hz, 1H), 7.29 (d, J =
9.2 Hz, 1H), 7.81 (d, J = 7.1 Hz, 1H), 7.96 (s, 1H); 13C NMR
(CDCl3) δ 113.6, 117.5, 117.6, 119.8, 119.8, 122.3, 126.5; MS (EI) m/
z 196 (96, M+), 198 (100, M+ + 2); HRMS (EI) m/z calcd for
C7H5BrN2 (M+), 195.9636, found 195.9631.
122.6, 127.2, 132.3, 132.5, 149.9; MS (EI) m/z 261 (M+); HRMS (EI)
m/z calcd for C17H15N3 (M+), 261.1266, found 261.1269.
General Procedure for the Oxidative Coupling of 1-
Alkynylimidazo[1,5-a]pyridines and Terminal Alkynes (Table 1
and Chart 1). To a solution of 1-arylethynylimidazo[1,5-a]pyridines
(0.4 mmol), Pd(OAc)2 (2.5 mol %), Ag2CO3 (150 mol %), AcOH
(100 mol %), and terminal alkynes (X equiv) in a mixture of DMF
(0.6 mL) and DMSO (0.08 mL) was added dropwise a solution of
terminal alkynes (2−X equiv) in DMF (1.0 mL) over T min at 120 °C.
The resulting mixture was cooled at room temperature, filtered, and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel to give bisalkynylated imidazo[1,5-
a]pyridines 3.
3-Bromoimidazo[1,5-a]pyridine (18). Yellow solid: mp 30−
32 °C, Rf = 0.45 (hexane/AcOEt = 4:1); IR (KBr) 3445, 3087, 2360,
1928, 1776, 1739, 1632, 1505, 1396, 1261, 1026, 736 cm−1; H NMR
1
(CDCl3) δ 6.65 (dd, J = 7.8, 7.3 Hz, 1H), 6.75 (dd, J = 8.8, 7.3 Hz,
1H), 7.40 (d, J = 8.8 Hz, 1H), 7.43 (s, 1H), 7.85 (d, J = 7.3 Hz, 1H);
13C NMR (CDCl3) δ 107.9, 113.2, 118.0, 119.0, 120.5, 121.2, 132.5;
MS (EI) m/z 196 (96, M+), 198 (100, M+ + 2); HRMS (EI) m/z calcd
1-(4-Methoxyphenyl)ethynyl)-3-(4-trifluoromethylphenylethy-
nyl)imidazo[1,5-a]pyridine (3a). 80% yield (0.133 g), yellow solid:
mp 211−214 °C, Rf = 0.24 (hexane/AcOEt = 4:1); IR (KBr) 3445,
3069, 3001, 2934, 2834, 2360, 2342, 2204, 1605, 1499, 1321, 1244,
for C7H5BrN2 (M+), 195.9636, found 195.9638.
1,3-Dibromoimidazo[1,5-a]pyridine (19). Brownish solid: mp
129 °C, Rf = 0.55 (hexane/AcOEt = 4:1); IR (KBr) 2361, 1631, 1396,
1260, 1026, 955, 736 cm−1; 1H NMR (CDCl3) δ 6.71 (dd, J = 7.3, 6.3
Hz, 1H), 6.82 (dd, J = 9.3, 6.3 Hz, 1H), 7.35 (d, J = 9.3 Hz, 1H), 7.83
(d, J = 7.3 Hz, 1H); 13C NMR (CDCl3) δ 104.7, 106.3, 114.3, 117.4,
120.0, 121.6, 130.5; MS (EI) m/z 274 (51, M+), 276 (100, M+ + 2);
HRMS (EI) m/z calcd for C7H4Br2N2 (M+), 273.8741, found
273.8735.
General Procedure for Sonogashira Coupling of 1-
Bromoimidazo[1,5-a]pyridine. To a solution of 1-bromoimidazo-
[1,5-a]pyridine (11) in MeCN (0.25 M) was added PdCl2(NCPh)2
(10 mol %), t-Bu3PH·BPh4 (10 mol %), CuI (10 mol %), terminal
alkyne (2 equiv), and i-Pr2NEt (3 equiv) under Ar atmosphere. The
resulting mixture was stirred at 60 °C for 24 h. The resulting mixture
was cooled at room temperature and directly separated by flash
column chromatography on silica gel (hexane/EtOAc = 2:1 then 1:1)
to give 1-alkynylated imidazo[1,5-a]pyridine 2.
1-(4-Methoxyphenylethynyl)imidazo[1,5-a]pyridine (2a). On
3 mmol scale, 86% yield (0.64 g), yellow solid: mp 70−79 °C, Rf =
0.20 (hexane/AcOEt = 1:1); IR (KBr) 3389, 2836, 2202, 1631, 1604,
1504, 1244, 1049 cm−1; 1H NMR (CDCl3) δ 3.75 (s, 3H), 6.54 (dd, J
= 8.0, 7.1, Hz, 1H), 6.76 (dd, J = 7.1, 6.8 Hz, 1H), 6.82 (d, J = 8.3 Hz,
2H), 7.46 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.85 (d, J =
6.8, 1H), 7.99 (s, 1H); 13C NMR (CDCl3) δ 55.1, 81.1, 91.7, 113.4,
113.8, 114.5, 115.5, 118.2, 120.6, 122.6, 127.3, 132.6, 159.2 (some of
peaks are overlapped); MS (EI) m/z 248; HRMS (EI) m/z calcd for
C16H12N2O (M+), 248.0950, found 248.0953.
1
1126, 1065 cm−1; H NMR (CDCl3) δ 3.81 (s, 3H), 6.82 (t, J = 6.8
Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 6.98 (dd, J = 8.3, 6.8 Hz, 1H), 7.49
(d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H),
7.69 (d, J = 8.3 Hz, 1H), 8.20 (d, J = 6.8 Hz, 1H); 13C NMR (CDCl3)
δ 55.3, 80.0, 80.4, 92.2, 94.4, 114.0, 114.9, 115.2, 116.5, 118.7, 121.4,
122.3, 123.1, 123.8 (q, J = 271.8 Hz), 125.4, 125.5 (q, J = 4.1 Hz),
130.5 (q, J = 33.0 Hz), 131.6, 132.9, 133.4, 159.6; 19F NMR (CDCl3)
δ −63.2; MS (EI) m/z 416 (M+); HRMS (EI) m/z calcd for
C25H15F3N2O (M+), 416.1136, found 416.1123.
1-(4-Methoxyphenylethynyl)-3-(phenylethynyl)imidazo[1,5-
a]pyridine (3b). 68% yield (0.095 g), orange solid: mp 181−183 °C,
Rf = 0.22 (hexane/AcOEt = 4:1); IR (KBr) 3451, 2925, 2853, 2204,
1
1603, 1500, 1248 cm−1; H NMR (CDCl3) δ 3.80 (s, 3H), 6.78 (dd,
J = 7.1, 6.3 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 6.94 (dd, J = 8.8, 6.3 Hz,
1H), 7.35−7.37 (m, 3H), 7.50 (d, J = 8.8 Hz, 2H), 7.57−7.60 (m,
2H), 7.66 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 7.1 Hz, 1H); 13C NMR
(CDCl3) δ 55.3, 77.6, 80.7, 92.0, 95.7, 113.9, 114.5, 115.3, 115.9,
118.5, 121.7, 121.9, 122.1, 123,1, 128.5, 129.1, 131.6, 132.9, 133.1,
159.5; MS (EI) m/z 348 (M+); HRMS (EI) m/z calcd for C24H16N2O
(M+), 348.1263, found 348.1258.
3-(Phenylethynyl)-1-(4-trifluoromethylphenylethynyl)-
imidazo[1,5-a]pyridine (3c). 42% yield (0.065 g), yellow solid: mp
196−199 °C, Rf = 0.32 (hexane/AcOEt = 4:1); IR (KBr) 3451, 3049,
1
2924, 2854, 2204, 1613, 1322, 1065 cm−1; H NMR (CDCl3) δ 6.85
(dd, J = 7.0, 6.6 Hz, 1H), 7.04 (dd, J = 9.0, 6.6 Hz, 1H), 7.38−7.39 (m,
3H), 7.58−7.62 (m, 3H), 7.65 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 9.0 Hz,
2H), 8.23 (d, J = 7.0 Hz, 1H); 13C NMR (CDCl3) δ 77.3, 84.9, 91.0,
95.9, 114.7, 114.8, 118.3 121.5, 122.7, 122.8, 123.4, 124.0 (q, J = 270.9
Hz), 125.3 (q, J = 4.1 Hz), 127.1, 128.6, 129.3, 129.5 (q, J = 32.1 Hz),
131.4, 131.7, 133.9; 19F NMR (CDCl3) δ −63.1; MS (EI) m/z 386
(M+); HRMS (EI) m/z calcd for C24H13F3N2 (M+), 386.1031, found
386.1031.
1-(4-Trifluoromethylphenylethynyl)imidazo[1,5-a]pyridine
(2b). On 3 mmol scale, quantitative yield (0.86 g), yellow solid: mp
127−129 °C, Rf = 0.28 (hexane/AcOEt = 1:1); IR (KBr) 3437, 3129,
1
3068, 2204, 1611, 1322, 1105, 1066 cm−1; H NMR (CDCl3) δ 6.68
(dd, J = 7.1, 6.3 Hz, 1H), 6.92 (dd, J = 7.8, 7.1 Hz, 1H), 7.58 (d, J =
8.3 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 6.3 Hz, 1H), 7.95
(d, J = 7.8 Hz, 1H), 8.10 (s, 1H); 13C NMR (CDCl3) δ 85.4, 90.9,
113.6, 113.8, 118.1, 121.5, 122.8, 123.9 (q, J = 271.8 Hz), 125.1 (q, J =
3.3 Hz), 127.3, 127.8 (Ar), 129.2 (q, J = 32.2 Hz), 131.2, 133.; 19F
NMR (CDCl3) −63.0; MS (EI) m/z 286 (M+); HRMS (EI) m/z calcd
for C16H9F3N2 (M+), 286.0718, found 286.0727.
3-(4-Methoxyphenylethynyl)-1-(phenylethynyl)imidazo[1,5-a]-
pyridine (3d). 58% yield (0.081 g), yellow solid: mp 182−184 °C,
Rf = 0.20 (hexane/AcOEt = 4:1); IR (KBr) 3458, 2930, 2838, 2360,
1
2341, 2201, 1603, 1513, 1294, 1250 cm−1; H NMR (CDCl3) δ 3.83
1-(Phenylethynyl)imidazo[1,5-a]pyridine (2c). On 2 mmol
scale, 80% yield (0.35 g), yellow solid: mp 89−91 °C, Rf = 0.18
(hexane/AcOEt = 1:1); IR (KBr) 3124, 2202, 1597, 1487, 1335, 1239,
(s, 3H), 6.79 (dd, J = 7.0, 6.6 Hz, 1H), 6.90 (d, J = 8.7 Hz, 2H), 6.97
(dd, J = 9.0, 6.6 Hz, 1H), 7.33 (m, 3H), 7.54 (d, J = 8.7 Hz, 2H), 7.56
(d, J = 8.1 Hz, 2H), 7.69 (d, J = 9.0 Hz, 1H), 8.19 (d, J = 7.0 Hz, 1H);
13C NMR (CDCl3) δ 55.3, 76.3, 82.3, 92.1, 95.8, 113.7, 114.2, 114.4,
1
1047 cm−1; H NMR (CDCl3) δ 6.63 (dd, J = 6.8, 6.6 Hz, 1H), 6.85
(dd, J = 9.0, 6.6 Hz, 1H), 7.32 (m, 3H), 7.56 (dd, J = 6.8 Hz, 2H), 7.64
(d, J = 9.0 Hz, 1H), 7.91 (d, J = 6.8 Hz, 1H), 8.05 (s, 1H); 13C NMR
(CDCl3) δ 82.7, 92.1, 113.7, 114.5, 118.4, 121.0, 122.7, 123.5, 127.5,
127.7, 127.8, 128.3, 131.3; MS (EI) m/z 218 (M+); HRMS (EI) m/z
calcd for C15H10N2 (M+), 218.0844, found 218.0836.
1-(4-N,N-Dimethylphenylethynyl)imidazo[1,5-a]pyridine
(2d). On 1 mmol scale, quantitative yield (0.26 g), orange solid: mp
175−181 °C, Rf = 0.18 (hexane/AcOEt = 1:1); IR (KBr) 3466, 3114,
3036, 2919, 2359, 2199, 1603, 1515, 1358, 1048 cm−1; 1H NMR
(CDCl3) δ 2.92 (s, 6H), 6.54 (dd, J = 6.8, 6.6, Hz, 1H), 6.60 (d, J = 8.8
Hz, 2H), 6.74 (dd, J = 8.8, 6.6 Hz, 1H), 7.39 (d, J = 8.8 Hz, 2H), 7.57
(d, J = 8.8 Hz, 1H), 7.83 (d, J = 6.8 Hz, 1H), 7.98 (s, 1H); 13C NMR
(CDCl3) δ 40.2, 80.2, 92.9, 110.4, 111.8, 113.5, 115.3, 118.6, 120.2,
115.3, 118.4, 122.0, 123.2, 123.3, 128.0, 128.3, 128.3, 131.3, 131.4,
133.3, 160.3; MS (EI) m/z 348 (M+); HRMS (EI) m/z calcd for
C24H16N2O (M+), 348.1263, found 348.1281.
1-(Phenylethynyl)-3-(4-trifluoromethylphenylethynyl)-
imidazo[1,5-a]pyridine (3e). 45% yield (0.070 g), Yellow solid: mp
187−191 °C, Rf = 0.35 (hexane/AcOEt = 4:1); IR (KBr) 3454, 3044,
2361, 2206, 1611, 1514, 1323, 1126, 1065 cm−1; 1H NMR (CDCl3) δ
6.86 (dd, J = 7.0, 6.6 Hz, 1H), 7.03 (dd, J = 9.0, 6.6 Hz, 1H), 7.29−
7.37 (m, 3H), 7.57 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H), 7.69
(d, J = 8.3 Hz, 2H), 7.73 (d, J = 9.0 Hz, 1H), 8.22 (d, J = 7.0 Hz, 1H);
13C NMR (CDCl3) δ 79.9, 81.9, 92.3, 94.4, 114.9, 116.2, 118.7, 121.6,
122.6, 123.1, 123.2, 123.8 (q, J = 272.0 Hz), 122.5, 122.5 (q, J = 3.9 Hz),
128.2, 128.4, 130.6 (q, J = 33.0 Hz), 131.4, 131.7, 133.7; 19F NMR
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(CDCl3) δ −63.2; MS (EI) m/z 386 (M+); HRMS (EI) m/z calcd for
126.5, 127.2, 129.2, 129.3 (q, J = 31.9 Hz), 131.4, 134.7; 19F NMR
(CDCl3) δ −63.0; MS (FAB) m/z 571 (M + H+); HRMS (FAB) m/z
calcd for C32H17F6N4 (M + H+), 571.1357, found 571.1344.
C24H13F3N2 (M+), 386.1031, found 386.1033.
1-(Phenylethynyl)-3-(p-tolylethynyl)imidazo[1,5-a]pyridine
(3f). 58% (0.077 g), Yellow solid: mp 173−175 °C, Rf = 0.35 (hexane/
AcOEt = 4:1); IR (KBr) 3448, 3048, 2915, 2360, 2205, 1751, 1628,
1,1′-Bis(phenylethynyl)-3,3′-biimidazo[1,5-a]pyridinyl (5c).
20% yield (0.017 g), yellow solid: mp 226−227 °C, Rf = 0.33
(hexane/AcOEt = 4:1); IR (KBr) 3465, 3103, 3077, 2359, 2341, 2203,
1
1512, 1309, 1246, 746 cm−1; H NMR (CDCl3) δ 2.29 (s, 3H), 6.81
1
1627, 1510, 1488, 1329, 1242, 749 cm−1; H NMR (CDCl3) δ 6.88
(dd, J = 6.8, 6.6 Hz, 1H), 6.99 (dd, J = 8.8, 6.6 Hz, 1H), 7.10 (d, J =
7.8 Hz, 2H), 7.32−7.38 (m, 3H), 7.51 (d, J = 7.8 Hz, 2H), 7.58 (d, J =
7.3 Hz, 2H), 7.71 (d, J = 8.8 Hz, 1H), 8.21 (d, J = 6.8 Hz, 1H); 13C
NMR (CDCl3) δ 21.6, 76.8, 82.2, 92.1, 96.0, 114.4, 115.4, 118.4,
118.5, 122.1, 122.5, 123.1, 123.3, 128.0, 128.2, 129.2, 131.3, 131.5,
133.4, 139.5; MS (FAB) m/z 333 (M + H+); HRMS (FAB) m/z calcd
for C24H17N2 (M + H+), 333.1393, found 333.1378.
(dd, J = 6.8, 6.6, Hz, 2H), 7.06 (dd, J = 8.8, 6.8 Hz, 2H), 7.35 (m, 6H),
7.63 (d, J = 6.8 Hz, 4H), 7.78 (d, J = 8.8 Hz, 2H), 9.94 (d, J = 6.6 Hz,
2H); 13C NMR (CDCl3) δ 82.6, 92.8, 114.2, 114.5, 117.8, 122.5,
123.3, 126.3, 128.1, 128.4, 129.1, 131.5, 134.1; MS (FAB) m/z 435
(M + H+); HRMS (FAB) m/z calcd for C30H19N4 (M + H+), 435.1610,
found 435.1630.
3-(4-Methoxyphenylethynyl)-1-(4-trifluoromethylphenylethy-
nyl)imidazo[1,5-a]pyridine (3g). 66% yield (0.110 g), yellow solid:
mp 230−233 °C, Rf = 0.23 (hexane/AcOEt = 4:1); IR (KBr) 3445,
2924, 2854, 2204, 1606, 1517, 1322, 1118, 1064 cm−1; 1H NMR
(CDCl3) δ 3.83 (s, 3H), 6.82 (dd, J = 7.0, 6.7 Hz, 1H), 6.90 (d, J = 8.8
Hz, 2H), 7.01 (dd, J = 9.0, 6.7 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.58
(d, J = 8.3 Hz, 2H), 7.64 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 9.0 Hz, 1H),
8.21 (d, J = 7.0 Hz, 1H); 13C NMR (CDCl3) δ 55.4, 76.1, 85.0, 91.0,
96.0, 113.5, 114.2, 114.2, 114.6, 118.3, 122.6, 123.1, 123.4, 124.0 (q, J
= 271.8 Hz), 125.3 (q, J = 4.1 Hz), 127.2, 129.5 (q, J = 32.5 Hz),
131.4, 133.4, 133.8, 160.4; 19F NMR (CDCl3) δ −63.1; MS (EI) m/z
416 (M+); HRMS (EI) m/z calcd for C25H15F3N2O (M+), 416.1136,
found 416.1134.
3-(4-N,N-Dimetylethynyl)-1-(4-trifluoromethylphenylethynyl)-
imidazo[1,5-a]pyridine (3h). 8% yield (0.014 g), yellow solid: mp
238−242 °C, Rf = 0.18 (hexane/AcOEt = 4:1); IR (KBr) 3455, 2925,
2359, 2341, 2198, 1606, 1532, 1321, 1118, 1064 cm−1; 1H NMR
(CDCl3) δ 3.00 (s, 6H), 6.66 (d, J = 8.8 Hz, 2H), 6.89 (dd, J = 6.8, 6.4
Hz, 1H), 6.99 (dd, J = 8.8, 6.4 Hz, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.58
(d, J = 8.3 Hz, 2H), 7.64 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 8.8 Hz, 1H),
8.20 (d, J = 6.8 Hz, 1H); 13C NMR (CDCl3) δ 40.1, 75.4, 85.3, 90.9,
97.5, 107.8, 111.7, 114.2, 114.3, 118.3, 122.4, 123.5, 123.8, 124.0 (q,
J = 271.8 Hz), 125.2 (q, J = 4.1 Hz), 127.3, 129.4 (q, J = 32.2 Hz),
131.3, 133.1, 133.7, 150.7; 19F NMR (CDCl3) δ −63.1; MS (EI) m/z
429 (M+); HRMS (EI) m/z calcd for C26H18F3N3 (M+), 429.1453,
found 429.1454.
1-(4-N,N-Dimetylphenylethynyl)-3-(4-trifluoromethylphenyl-
ethynyl)imidazo[1,5-a]pyridine (3i). 7% yield (0.012 g), yellow
solid: mp 231−235 °C, Rf = 0.33 (hexane/AcOEt = 4:1); IR (KBr)
3437, 2924, 2201, 1606, 1532, 1321, 1231, 1166 cm−1; 1H NMR
(CDCl3) δ 2.98 (s, 6H), 6.66 (d, J = 8.5 Hz, 2H), 6.82 (dd, J = 6.8, 6.3
Hz, 1H), 6.97 (dd, J = 8.8, 6.3 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.62
(d, J = 8.3 Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H), 7.71 (d, J = 8.8 Hz, 1H),
8.19 (d, J = 7.3 Hz, 1H); 13C NMR (CDCl3) δ 40.2, 79.6, 80.2, 93.4,
94.4, 109.8, 111.8, 114.8, 117.2, 118.9, 121.2, 121.9, 123.0, 123.8 (q,
J = 271.8 Hz), 125.5 (q, J = 3.7 Hz), 125.7, 130.5 (q, J = 33.0 Hz),
131.6, 132.7, 133.1, 150.1; 19F NMR (CDCl3) δ −63.2; MS (EI) m/z
429 (M+); HRMS (EI) m/z calcd for C26H18F3N3 (M+), 429.1453,
found 429.1445.
1,1′-Bis(4-methoxyphenylethynyl)-3,3′-biimidazo[1,5-a]-
pyridinyl (5a). 14% yield (0.014 g), brownish solid: mp 257−264 °C,
Rf = 0.3 (hexane/AcOEt = 4:1); IR (KBr) 3436, 3113, 2924, 2853,
2202, 1605, 1499, 1250, 827 cm−1; 1H NMR (CDCl3) δ 3.83 (s, 6H),
6.85 (dd, J = 6.8, 6.6, Hz, 2H), 6.90 (d, J = 8.8 Hz, 4H), 7.03 (dd, J =
9.0, 6.6 Hz, 2H), 7.56 (d, J = 8.8 Hz, 4H), 7.75 (d, J = 9.0 Hz, 2H),
9.92 (d, J = 6.8 Hz, 2H); 13C NMR (CDCl3) δ 55.3, 81.1, 92.6, 114.0,
114.4, 115.4, 117.9, 122.2, 126.3, 129.0, 129.9, 133.0, 133.8, 159.5; MS
(EI) m/z 494 (M+); HRMS (EI) m/z calcd for C32H22N4O2 (M+),
494.1743, found 494.1744.
General Procedure for the Oxidative Coupling of Unsub-
stituted Imidazo[1,5-a]pyridine and Terminal Alkynes (6)
(Table 2). To a solution of imidazo[1,5-a]pyridine (6) (0.5 mmol),
Pd(OAc)2 (2.5 mol %), Ag2CO3 (150 mol %), and AcOH (100 mol %)
in a mixture of DMF (1.0 mL) and DMSO (0.010 mL) was added
dropwise a solution of terminal alkyne (2 equiv) in the DMF (1.0 mL)
over 50 min at 120 °C. The resulting mixture was cooled at room
temperature, filtered, and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel to give 3-
alkynylated imidazo[1,5-a]pyridines 7.
3-(4-Trifluoromethylphenylethynyl)imidazo[1,5-a]pyridine
(7a). 60% yield (0.086 g), colorless solid: mp 115−118 °C, Rf = 0.15
(hexane/AcOEt = 4:1); IR (KBr) 3446, 3068, 2359, 2199, 1611, 1501,
1
1321, 1114, 1067, 736 cm−1; H NMR (CDCl3) δ 6.77 (dd, J = 7.1,
6.6 Hz, 1H), 6.88 (dd, J = 8.8, 6.6 Hz, 1H), 7.52 (s, 1H), 7.52(d, J =
8.8 Hz, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.69 (d, J = 8.3 Hz, 2H), 8.20
(d, J = 7.1 Hz, 1H); 13C NMR (CDCl3) δ 80.6, 94.4, 114.0, 118.6,
120.8, 121.8, 121.9, 122.7, 123.8 (q, J = 271.8 Hz), 125.4 (q, J = 3.9 Hz),
125.9, 130.3 (q, J = 32.8 Hz), 131.5, 131.5; 19F NMR (CDCl3) δ −63.2;
MS (EI) m/z 286 (M+); HRMS (EI) m/z calcd for C16H9F3N2 (M+),
286.0718, found 286.0719.
3-(Phenylethynyl)imidazo[1,5-a]pyridine (7b). 63% yield
(0.069 g), orange solid: mp 99−102 °C, Rf = 0.18 (hexane/AcOEt =
4:1); IR (KBr) 3457, 3107, 3086, 2929, 2214, 1920, 1786, 1631, 1497,
1
1348, 1246, 1049, 766 cm−1; H NMR (CDCl3) δ 6.72 (dd, J = 7.3,
6.8 Hz, 1H), 6.82 (dd, J = 9.3, 6.8 Hz, 1H), 7.34−7.37 (m, 3H), 7.48
(d, J = 6.8 Hz, 2H), 7.58−7.60 (m, 2H), 8.18 (d, J = 7.8 Hz, 1H); 13C
NMR (CDCl3) δ 78.1, 95.6, 113.6, 118.3, 120.3, 121.1, 121.9, 122.5,
128.3, 128.7, 131.0, 131.3, 131.4; MS (EI) m/z 218 (M+); HRMS (EI)
m/z calcd for C15H10N2 (M+), 218.0844, found 218.0837.
3-(4-Methoxyphenylethynyl)imidazo[1,5-a]pyridine (7c).
78% yield (0.097 g), brownish solid: mp 107−110 °C, Rf = 0.30
(hexane/AcOEt = 4:1); IR (KBr) 3447, 3094, 2844, 2543, 2359, 2203,
1884, 1604, 1519, 1254, 1024, 830 cm−1; 1H NMR (CDCl3) δ 3.80 (s,
3H) 6.67 (dd, J = 7.1, 6.8 Hz, 1H), 6.78 (dd, J = 7.8, 7.1 Hz, 1H), 6.87
(d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 7.50 (s, 1H), 7.51 (d, J =
7.8 Hz, 1H), 8.14 (d, J = 6.8 Hz, 1H); 13C NMR (CDCl3) δ 55.3, 76.8,
95.6, 113.4, 114.0, 114.1, 118.3, 120.1, 121.0, 122.6, 122.7, 130.9,
133.1, 160.1; MS (EI) m/z 248 (M+); HRMS (EI) m/z calcd for
C16H12N2O (M+), 248.0950, found 248.0949.
3-(p-Tolylethynyl)imidazo[1,5-a]pyridine (7d). 67% yield
(0.078 g), orange solid: mp 105−110 °C, Rf = 0.18 (hexane/AcOEt
= 4:1); IR (KBr) 3444, 2916, 2198, 1631, 1519, 1502, 1353, 1248, 807
cm−1; 1H NMR (CDCl3) δ 2.32 (s, 3H) 6.65 (dd, J = 6.6, 5.6 Hz, 1H),
6.76 (dd, J = 7.3, 6.6 Hz, 1H), 7.13 (d, J = 7.8 Hz, 2H), 7.41−7.47 (m,
4H), 8.11 (d, J = 5.9 Hz, 1H); 13C NMR (CDCl3) δ 21.5, 77.5, 95.8,
113.5, 118.3, 118.9, 120.2, 121.1, 122.5, 129.1, 130.9, 131.3, 131.3,
139.1; MS (EI) m/z 232 (M+); HRMS (EI) m/z calcd for C16H12N2
(M+), 232.1000, found 232.1008.
3-(Cyclohex-1-en-1-ylethynyl)imidazo[1,5-a]pyridine (7f).
53% yield (0.059 g), brown oil: Rf = 0.30 (hexane/AcOEt = 4:1);
IR (KBr) 3402, 2931, 2858, 2168, 1631, 1503, 1349, 1247, 797, 740,
1,1′-Bis(4-trifluoromethylphenylethynyl)-3,3′-biimidazo-
[1,5-a]pyridinyl (5b). 11% yield (0.013 g), yellow solid: mp 268−
269 °C, Rf = 0.53 (hexane/AcOEt = 4:1); IR (KBr) 3446, 3110, 2925,
1
2201, 1611, 1499, 1328, 1171, 1119, 756 cm−1; H NMR (CDCl3) δ
1
678 cm−1; H NMR (CDCl3) δ 1.59−1.72 (m, 4H), 2.14−2.19 (m,
6.93 (dd, J = 7.6, 6.1 Hz, 2H), 7.11 (dd, J = 9.3, 6.1 Hz, 2H), 7.62 (d,
J = 8.3 Hz, 4H), 7.71 (d, J = 8.3 Hz, 4H), 7.78 (d, J = 9.3 Hz, 2H),
9.95 (d, J = 7.3 Hz, 2H); 13C NMR (CDCl3) δ 85.3, 91.7, 113.6, 114.8,
117.8, 123.1 (Ar), 124.0 (q, J = 271.8 Hz), 125.3 (q, J = 3.3 Hz),
2H), 2.25−2.30 (m, 2H), 6.33−6.35 (m, 1H), 6.68 (dd, J = 7.1,
5.9 Hz, 1H), 6.80 (dd, J = 9.3, 5.9 Hz, 1H), 7.45−7.47 (m, 2H), 8.07
(d, J = 7.1 Hz, 1H); 13C NMR (CDCl3) δ 21.4, 22.2, 25.8, 28.8, 75.5,
97.5, 113.3, 118.3, 119.9, 120.0, 120.9, 122.6, 122.9, 130.8, 136.7; MS
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(EI) m/z 222 (M+); HRMS (EI) m/z calcd for C15H14N2 (M+),
222.1157, found 222.1147.
138.5, 139.1, 148.2; MS (EI) m/z 299 (M+); HRMS (EI) m/z calcd
for C20H13NS (M+), 299.0769, found 299.0776.
3-(4-Bromophenylethynyl)imidazo[1,5-a]pyridine (7g). 62%
yield (0.092 g), brownish solid: mp 127−130 °C, Rf = 0.23 (hexane/
AcOEt = 4:1); IR (KBr) 3443, 2924, 2853, 2203, 1631, 1503, 1454,
Synthesis of 1,3-Bis(phenylethynyl)imidazo[1,5-a]pyridine
(20) That Appeared in Figures 2 and 3. To a solution of 1,3-
dibromoimidazo[1,5-a]pyridine (19) (0.5 mmol, 0.138 g) in MeCN
(4 mL) were added PdCl2(NCPh)2 (0.038 g, 20 mol %), tBu3PH·BPh4
(0.105 g, 40 mol %), CuI (0.019 g, 20 mol %), phenylacetylene (0.220 mL,
4 equiv), and iPr2NEt (0.522 μL, 6 equiv) under Ar atmosphere. The
resulting mixture was stirred at 60 °C for 24 h. The resulting mixture
was cooled at room temperature and directly purified by flash column
chromatography on silica gel (hexane/EtOAc = 2:1 then 1:1) to give a
1,3-bis(phenylethynyl)imidazo[1,5-a]pyridine (20) (0.040 g, 25%) as
a yellow solid: mp 160−162 °C, Rf = 0.38 (hexane/AcOEt = 4:1); IR
(KBr) 3448, 3050, 2924, 2854, 2204, 1627, 1596, 1487, 1309, 1243,
753, 689 cm−1; 1H NMR (CDCl3) δ 6.82 (t, J = 6.8 Hz, 1H), 7.00 (dd,
J = 9.0, 6.8 Hz, 1H), 7.33−7.39 (m, 6H), 7.56−7.62 (m, 4H), 7.72 (d,
J = 9.0 Hz, 1H), 8.22 (d, J = 6.8 Hz, 1H); 13C NMR (CDCl3) δ 77.5,
82.2, 92.2, 95.8, 114.6, 115.6, 118.5, 121.7, 122.2, 123.2, 123.3, 128.1,
128.3, 128.5, 129.2, 131.4, 131.6 (some of peaks are overlapped); MS
(EI) m/z 318 (M+); HRMS (EI) m/z calcd for C23H14N2 (M+),
318.1157, found 318.1148.
1
1351, 1249, 823 cm−1; H NMR (CDCl3) δ 6.78 (t, J = 6.8 Hz, 1H),
6.89 (dd, J = 8.8, 6.8 Hz, 1H), 7.46 (d, J = 8.3 Hz, 2H), 7.50−7.54 (m,
4H), 8.19 (d, J = 6.8 Hz, 1H); 13C NMR (CDCl3) δ 79.3, 94.7, 113.8,
118.5, 120.5, 121.0, 121.5, 122.6, 123.1, 131.7, 132.7 (some of peaks
are overlapped); MS (EI) m/z 296 (100, M+), 298 (98, M+ + 2);
HRMS (EI) m/z calcd for C15H9BrN2 (M+), 295.9949, found
295.9948.
General Procedure for the Oxidative Coupling of Azoles and
Phenylacetylene (Chart 2). To a solution of azoles (0.5 mmol), Pd
cat 10 (0.5 mol %), Ag2CO3 (150 mol %), AcOH (100 mol %), and
phenylacetylene (X equiv) in a mixture of DMF (1.0 mL) and DMSO
(0.1 mL) was added dropwise a solution of terminal alkyne (2−X
equiv) in DMF (1.0 mL) in T min at 120 °C. The resulting mixture
was cooled at room temperature, filtered, and concentrated in vacuo.
The residue was purified by flash column chromatography on silica gel
to give coupling products.
2-(Phenylethynyl)benzo[d]oxazole (9a). The compound was
identified by comparison with 1H NMR data of previous report.16 59%
yield (0.065 g): 1H NMR (CDCl3) δ 7.35−7.47 (m, 5H), 7.53 (d, J =
7.3 Hz, 2H), 7.65 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H).
2-(Phenylethynyl)benzo[d]thiazole (9b). The compound was
identified by comparison with 1H NMR data of previous report.16 51%
yield (0.060 g): 1H NMR (CDCl3) δ 7.38−7.53 (m, 5H), 7.63 (dd, J =
7.8 Hz, 2H), 7.85 (d, J = 8.3 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H).
2-(Phenylethynyl)thiazole (9c). The compound was identified by
comparison with 1H NMR data of previous report.17 34% yield (0.031
ASSOCIATED CONTENT
* Supporting Information
Tables S1 and S2, copies of NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: fshiba@gifu-u.ac.jp; mtoshi@gifu-u.ac.jp.
Notes
■
1
g): H NMR (CDCl3) δ 7.36−7.39 (m, 4H), 7.63 (dd, J = 7.8 Hz,
2H), 7.56−7.59 (m, 2H), 7.84 (d, J = 2.9 Hz, 1H).
1-Benzyl-2-(phenylethynyl)-1H-benzo[d]imidazole (9d). 62%
yield (0.095 g), colorless solid: mp 175−177 °C, Rf = 0.20 (hexane/
AcOEt = 4:1); IR (KBr) 3436, 3059, 3030, 2925, 2360, 1675, 1596,
1496, 1450, 1398, 745 cm−1; 1H NMR (CDCl3) δ 5.53 (s, 2H), 7.26−
7.43 (m, 11H), 7.59 (d, J = 6.3 Hz, 2H), 7.80 (d, J = 6.3 Hz, 1H); 13C
NMR (CDCl3) δ 48.3, 78.8, 95.1, 110.1, 120.2, 121.0, 123.0, 124.0,
127.0, 128.0, 128.5, 128.8, 129.7, 132.0, 134.1, 135.7, 137.4, 143.1; MS
(EI) m/z 308 (M+); HRMS (EI) m/z calcd for C22H16N2 (M+),
308.1313, found 308.1311.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by Grant-in-Aids for Scientific
Research from the MEXT and JSPS and Research Foundation
for the Electrotechnology of Chubu.
REFERENCES
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■
1-Benzyl-2-(phenylethynyl)-1H-imidazole (9e). 42% yield
(0.054 g), colorless solid: mp 59−61 °C, Rf = 0.38 (hexane/AcOEt
= 1:1); IR (KBr) 3437, 3137, 3031, 2928, 2353, 2218, 1956, 1886,
1810, 1513, 1454, 1281, 1119, 755 cm−1; 1H NMR (CDCl3) δ 5.28 (s,
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6H), 7.51−7.54 (m, 2H); 13C NMR (CDCl3) δ 50.5, 78.6, 92.8, 120.4,
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7.55−7.57 (m, 2H).
2-(Phenylethynyl)-4-(p-tolylethynyl)thiazole (15). To a sol-
ution of 4-bromo-2-(phenylethynyl)thiazole (14) (0.080 g, 0.3 mmol)
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= 20:1 then 10:1) to give 2-(phenylethynyl)-4-(p-tolylethynyl)thiazole
(15) (0.052 g, 58%) as a colorless solid: mp 140−142 °C, Rf = 0.35
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