Oxidative dimerization of azoles via copper(II)/silver(I)-catalyzed CH homocoupling

Article abstract of DOI:10.1016/j.tetlet.2009.12.016

When several azole derivatives such as imidazole, thiazole, and oxazole are treated with a catalyst system of copper(II)/silver(I) under oxygen atmosphere, oxidative dimerization at the CH bond of the 2-position takes place to afford the corresponding bisazoles up to 86% yield.

Full text of DOI:10.1016/j.tetlet.2009.12.016

Tetrahedron Letters 51 (2010) 850–852
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Tetrahedron Letters
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Oxidative dimerization of azoles via copper(II)/silver(I)-catalyzed CH
homocoupling
*
Daiki Monguchi, Akira Yamamura, Taiki Fujiwara, Takashi Somete, Atsunori Mori
Department of Chemical Science and Engineering, Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
When several azole derivatives such as imidazole, thiazole, and oxazole are treated with a catalyst system
of copper(II)/silver(I) under oxygen atmosphere, oxidative dimerization at the CH bond of the 2-position
takes place to afford the corresponding bisazoles up to 86% yield.
Received 11 November 2009
Revised 3 December 2009
Accepted 4 December 2009
Available online 11 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
under an oxygen atmosphere as shown in Eq. 2. These results sug-
gest that the reaction conditions to give 3 are not effective for the
We have recently shown that CH, NH coupling of azoles occurs
with several amines and amides by the catalysisof copper(II) salt un-
der an oxygen atomosphere.1 The reaction was found to proceed
with thiazole, oxazole, and imidazole derivatives leading to the
2-aminated azoles, which were found in a variety of biologically
active compounds.2 During the course of our studies on further
understanding of the reaction details, we found that undesirable
dimerization of an imidazole derivative occurred to give the corre-
sponding imidazole dimer as a minor side product.3 Since azole
dimers are shown to serve as a supramolecular compound as well
as bidentate ligand of transition metals,4 development of an efficient
synthetic protocol toward such molecules are of significant interest
in organic synthesis. Nevertheless, catalytic dimerization of azoles
that occurs at the electron-deficient CH bond, in a reasonable yield
has not yet been shown to the best of our knowledge.5–7 It is thus
intriguing if such a catalytic CH, CH coupling is achieved in a facile
manner. Herein, we report that a catalyst system with Cu(II)/Ag(I)
is highly effective for the oxidative dimerization of azoles.
homocoupling of 1a. However, the yield of homocoupling was
found to improve to 86% when the additive base was switched to
silver(I) carbonate8 in place of NaOAc. With such highly effective
homocoupling in hand, the reaction conditions were examined as
summarized in Table 1. Lower silver(I) carbonate loading
(20 mol %) also afforded 2a in 75% yield suggesting that the silver
reagent did not serve as a base but as an oxidant. The yield was, in-
deed, decreased to 44ꢀ47% when the reaction was performed un-
der a nitrogen atmosphere. The addition of PPh3 as a ligand of
copper was not crucial to undergo the CꢀH homocoupling. Thus,
2a was afforded in 71% yield. The use of other copper catalysts,
including Cu2O, CuF2, and Cu was found to promote the reaction
although the yield was slightly inferior to that of Cu(OAc)2.
Table 1
a
Oxidative dimerization of 1-methylbenzimidazole (1a)
b
Cu (equiv)
Ag (equiv)
O2
% Yield
Cu(OAc)2–2PPh3 (0.1)
Cu(OAc)2–2PPh3 (0.1)
Cu(OAc)2–2PPh3 (0.1)
Cu(OAc)2–2PPh3 (0.1)
Cu(OAc)2 (0.1)
Cu2O (0.1)
Ag2CO3 (1.1)
Ag2CO3 (0.2)
Ag2CO3 (1.1)
Ag2CO3 (0.2)
Ag2CO3 (0.2)
Ag2CO3 (0.2)
Ag2CO3 (0.2)
Ag2CO3 (0.2)
AgF (0.2)
+
+
ꢀ
ꢀ
+
+
+
+
+
+
+
+
+
86
75c
47c
44
71
Trace
62
69
69
24
82
13
0
2. Results and discussion
When the oxidative amination of 1-methylbenzimidzole (1a)
was carried out in the presence of 20 mol % of copper(II) acetate
with N-methylaniline, homocoupled product 2a was obtained in
<10% along with the aminated product 3 (51%) as shown in
Eq. 1.1 It was found that such dimerization to give 2a took place
in the absence of the amine reagent to result in 11% yield when
the reaction of 1a was carried out in the presence of copper(II) ace-
tate (10 mol %)/PPh3 (20 mol %) and 1.1 equiv of sodium acetate
CuF2 (0.1)
Cu (0.1)
Cu(OAc)2 (0.1)
Cu(OAc)2 (0.1)
Cu(OAc)2 (0.1)
Cu(OAc)2 (0.1)
—
AgNO3 (0.2)
Ag2O (0.2)
—
Ag2CO3 (0.2)
a
Unless noted, the reaction was performed with 1 (0.2 mmol) in 1 mL of xylene
at 140 °C for 24 h under 1 atm of O2.
b
In the absence of O2, the reaction was performed under a N2 atmosphere.
The reaction period: 20 h.
* Corresponding author. Tel./fax: +81 788036181.
E-mail address: amori@kobe-u.ac.jp (A. Mori).
c
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.016

D. Monguchi et al. / Tetrahedron Letters 51 (2010) 850–852
851
Cu(OAc)2 -2PPh3
(20 mol%)
Table 3
CꢀH homocoupling of azolesa
N
HNMePh
+
H
Entry
Azole–H
Product
Yieldb (%)
N
Me
1a
NaOAc (4.0 eq.)
xylene, O2
140 ºC, 20 h
N
N
N
H
H
ð1Þ
ð2Þ
1
22
0
O
O
O
N
N
N
4
5
7
+
NMePh
N
Me
N
Me
N
Me
3
(51%)
N
N
N
2
3
S
2a
S
S
(<10%)
6
Cu cat.
N
N
N
Me
Me
Me
H
N
N
S
N
N
N
Me
N
Me
NaOAc
H
43
xylene, O2
140 ºC, 24 h
Me
S
S
S
N
2a (11%)
1a
8
Me
10
Me
Me
Me
The use of silver(I) fluoride and oxide instead of carbonate similarly
promoted the reaction to afford 69% and 82% of the dimerized prod-
uct, respectively, while the yield was significantly decreased when
silver(I) nitrate was employed. It appeared to be important to carry
out the reaction with catalytic amounts of both copper and silver.
The yield was decreased to 13% when the reaction was performed
without silver, and no reaction took place without copper catalyst.
Table 2 summarizes the effect of the substituent on the nitrogen
atom at the 1-position. Several benzimidazole derivatives (1a–h)
with different substituents were subjected to the homocoupling
reaction. The use of allyl (1b)-, and benzyl (1c)-substituted deriva-
tives effected the reaction to afford the corresponding 2,2’-bis(benz-
imidazole). It was found that the N-arylated (4-methylphenyl)
derivative 1d also effected homocoupling in a moderate yield. The
reaction with CH2COOEt 1e-substituted one resulted in a lower
yield. By contrast, benzimidazoles bearing an electron-withdrawing
substituent did not promote the reaction at all under similar condi-
tions. The use of t-butoxycarbonyl (1f: Boc), benzoyl (1g: Bz), and
4-toluenesulfonyl (1h: Ts) derivatives resulted in completely no
reaction.
In addition to benzimidazoles, CH homocoupling of several
other azoles are examined as shown in Table 3. Benzoxazole (4)
underwent the dimerization to give 5 in a poor yield (22%) and
benzothiazole (6) resulted in no reaction, these results contrasted
to that of imidazole derivatives. However, several methylated thi-
azole derivatives such as 4-methylthiazole (8) and 4,5-dimethyl-
thiazole (9) were found to induce homocoupling to afford the
corresponding dimerized product 10 and 11, respectively, although
the yield was slightly inferior (42% and 43%). The reaction of a mix-
ture of 1-benzyl-4- and 5-methyl-imidazoles (12), which was ob-
tained by the reaction of 4-methylimidazole with benzyl bromide
to give ca. 1:2 of the mixture,9 also effected homocoupling highly
efficiently although the product 13 was a statistic amount of mix-
ture. These results suggest that the order of the reactivity of oxida-
N
N
42c
82
Me
H
Me
4
5
S
S
11
9
N
N
N
Me
Me
Me
H
N
Bn
N
N
Bn
12
Bn
13
a
Reaction conditions: Azole–H (0.2 mmol), Cu(OAc)2 (10 mol %), and Ag2CO3
(20 mol %), under 1 atm of O2, 1 mL of xylene, at 140 °C for 24 h.
b
Isolated yield.
Performed with 20 mol % Ag2O.
c
tive dimerization (imidazole > thiazole ꢁ oxazole) is not consistent
with the palladium-catalyzed CH functionalization reactions with
organic halides, which we have shown previously.10,11
Scheme 1 shows a plausible reaction mechanism of the oxida-
tive homocoupling reaction. Although further studies are necessary
for the understanding of the mechanism, the reaction would be
reductive coupling of the intermediate copper bisazole complex I,
which is the resultant of CH substitution with copper. As discussed
in the CH, NH coupling of azoles,1 the reaction of Cu(OAc)2 and
azole in the presence of a base would form an organocopper spe-
cies bearing a carbon–metal bond at the 2-position of azole. Since
this process has shown to occur without a silver salt, the role of sil-
ver in the homocoupling reaction would be a kind of base to neu-
tralize thus formed HX. Formation of the dimerized product
accompanies Cu0, which would be oxidized by O2 to regenerate CuII
species. This step would also occur mediated by silver(I) carbonate
although the role of the silver salt has not been clear yet.
In conclusion, we have demonstrated the CH homocoupling of
azoles in the presence of catalytic amounts of copper and silver
species. The 1-substituted benzimidzole derivatives with an
Table 2
CꢀH homocoupling of N-substituted benzimidazoles 1a
H2O
2Azole
H
LnCuIIX2
1
Substrate
Substituent
% Yield
silver species
as a base
1a
1b
1c
1d
1e
1f
CH3
CH2CH@CH2
CH2C6H5
C6H4-p-CH3
CH2COOEt
81
83
62
52
11
0
AgI
O2
LnCu0
2HX
COOtBu (Boc)
COC6H5 (Bz)
SO2C6H4-p-CH3 (Ts)
Azole
Azole
1g
1h
0
0
Azole Azole
LnCuII
2
a
The reaction was carried out with 1-substituted benzimidazole (0.2 mmol),
Cu(OAc)2 (10 mol %), and Ag2CO3 (20 mol %), under 1 atm of O2, 1 mL of xylene, at
I
140 °C for 24 h.
Scheme 1.

852
D. Monguchi et al. / Tetrahedron Letters 51 (2010) 850–852
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Cho, S.-H.; Kim, J. Y.; Chang, S. Angew. Chem., Int. Ed. 2009, 48, 9127.
9. The ratio of 13 was ca. 1:3:4.
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electron-donating substituent afforded the homocoupled products
in good yields. It is worthy of note that a simple mixed catalyst sys-
tem undergoes oxidative dimerization at an acidic CH bond of
azoles. The reaction would be a complimentary coupling protocol
in addition to the palladium-catalyzed oxidative homocoupling of
thiophene and thiazoles (5-position),4 which occurs at the elec-
tron-enriched CH bond.12
Acknowledgments
This work was partially supported by a Grant-in-Aid for Scien-
tific Research on Priority Areas, ‘Advanced Molecular Transforma-
tion of Carbon Resources’ and by Special Coordination Funds for
Promoting Science and Technology, Creation of Innovation Centers
for Advanced Interdisciplinary Research Areas (Innovative Biopro-
duction Kobe), by the Ministry of Education, Culture, Sports, Sci-
ence and Technology (MEXT), Japan. The authors thank the
Support Network for Nanotechnology Research of Nara Institute
of Science and Technology supported by MEXT for the measure-
ment of high resolution mass spectra.
12. Typical procedure for the CH homocoupling: A solution of Cu(OAc)2 (9.1 mg,
0.05 mmol), 1-methylbenzimidazole 1 (66 mg, 0.5 mmol) and silver carbonate
(27.6 mg, 0.1 mmol) in 2.5 mL of xylene under O2 atmosphere was stirred at
140 °C for 24 h. After cooling to room temperature, the mixture was passed
through a CeliteÒ pad, which was washed with chloroform repeatedly. The
filtrate was washed with water three times. The organic layer was
concentrated under reduced pressure to leave a crude oil, which was purified
by chromatography on silica gel to afford 47 mg of 2 (71%).
References and notes
1. (a) Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A. Org. Lett. 2009, 11, 1607;
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1,10-Allyl-2,20-bis(benzimidazole) (2b): 1H NMR (500 MHz, CDCl3) d 5.04 (d,
J = 17.3 Hz, 2H), 5.14 (d, J = 10.2 Hz, 2H), 5.60 (d, J = 5.4 Hz, 4H), 6.02–6.08 (m,
2H), 7.34–7.39 (m, 4H), 7.48 (d, J = 6.9 Hz, 2H), 7.88 (d, J = 7.1 Hz, 2H); 13C NMR
(125 MHz, CDCl3) d 47.8, 110.8, 117.2, 120.7, 123.0, 124.0, 133.2, 135.6, 142.84,
2. (a) Yoshida, S.; Shiokawa, S.; Kawano, K.; Ito, T.; Murakami, H.; Suzuki, H.; Sato,
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Just, B.; Kerphirique, R.; Gontier, S.; Hubert, P.; Laduron, P. M.; Blevec, J. L.;
Meunier, M.; Miquet, J.-M.; Nemecek, C.; Pasquet; Piot, M.; Pratt, J.; Rataud, J.;
Reibaud, M.; Stutzmann, J.-M.; Mignani, S. J. Med. Chem. 1999, 42, 2828; (c)
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3. (a) Wang, Q.; Schreiber, S. L. Org. Lett. 2009, 11, 5178; (b) Besselièvre, F.; Piguel,
S. Angew. Chem., Int. Ed. 2009, 48. doi:10.1002/anie.200904776.
142.86; IR (neat) 914, 1184, 1331, 1398, 1405, 1643, 2919, 2989, 3062 cmꢀ1
;
HRMS found: m/z 314.1532. Calcd for 314.1531.
1,10-Benzyl-2,2’-bis(benzimidazole) (2c): 1H NMR (500 MHz, CDCl3) d 6.25 (s,
4H), 7.03 (d, J = 6.3 Hz, 4H), 7.14–7.18 (m, 6H), 7.31–7.33 (m, 4H), 7.38–7.40
(m, 2H), 7.86–7.88 (m, 2H); 13C NMR (125 MHz, CDCl3) d 48.9, 111.2, 120.7,
123.1, 124.3, 127.0, 127.6, 128.8, 137.1; IR (neat) 732, 966, 1176, 1358, 1360,
1455, 1496, 2922, 2929, 2997 cmꢀ1; HRMS found: m/z 414.1842. Calcd for
414.1844.
1,10-p-Tolyl-2,20-bis(benzimidazole) (2d): 1H NMR (500 MHz, CDCl3) d 2.35 (s,
6H), 6.87 (d, J = 8.2 Hz, 4H), 7.03 (d, J = 8.0 Hz, 4H), 7.24–7.30 (m, 4H), 7.35 (t,
J = 7.2 Hz, 2H), 7.91 (d, J = 7.9 Hz, 2H); IR (neat) 742 822, 1271, 1452, 1513,
1715, 2849, 2919 cmꢀ1; HRMS found: m/z 414.1841. Calcd for 414.1844.
Compound 11: 1H NMR (500 MHz, CDCl3) d 2.38 (s, 6H), 2.39 (s, 6H); 13C NMR
(125 MHz, CDCl3) d 11.8, 14.6, 129.6, 149.2, 156.5; IR (neat) 918, 1014, 1089,
1210, 1375, 1531, 2847, 2915, 3368 cmꢀ1; HRMS found: m/z 224.0440. Calcd
for 224.0442.
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Bouhmaida, N.; Fenet, B.; Marsura, A. Eur. J. Inorg. Chem. 2004, 3172.
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Compound 13: 1H NMR (500 MHz, CDCl3) d 2.11 (s, 0.5H), 2.12 (s, 1.5H), 2.22 (s,
1.5H), 2.25 (s, 2.5H), 5.64 (s, 2.6H), 5.79 (s, 1.4H), 6.65 (s, 1H), 6.82-6.83 (m,
0.7H), 6.86–6.94 (m, 0.3H), 7.02–7.06 (m, 3H), 7.20–7.35 (m, 7H); 13C NMR
(125 MHz, CDCl3) d 10.1, 13.9, 50.58, 50.67, 117.9, 126.4, 126.5, 127.2, 127.58,
127.61, 127.63, 128.0, 128.69, 128.72, 128.8, 137.68, 137.73, 137.9; IR (neat)
691, 695, 965, 1103, 1388, 1404, 1424, 1557, 2905, 3041 cmꢀ1; HRMS found:
m/z 342.1849. Calcd for 342.1844.
Other coupling products 2a,4a 5,13 and 104b are known compound.
13. Tauer, E.; Grellmann, K. H. J. Org. Chem. 1981, 46, 4252.
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