Direct C-H iodination of 1,3-azoles catalysed by CuBr2

Article abstract of DOI:10.1016/j.tetlet.2014.12.029

A mild method was developed for the direct C-H iodination of 1,3-azoles catalysed by CuBr₂. Compared with the traditional metalation/iodination sequences carried out with nBuLi or TMPLi (TMP = 2,2,6,6-tetramethylpiperidino), a relatively weaker base, LiOtBu, was used in the presence of 1,10-phenanthroline. Five series of 1,3-azoles, including benzoxazole, benzothiozole, N-methyl-benzoimidazole, 5-phenyloxazole and 2-phenyl-1,3,4-oxadiazole were tested and afforded the corresponding iodination products.

Full text of DOI:10.1016/j.tetlet.2014.12.029

Tetrahedron Letters 56 (2015) 511–513
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Tetrahedron Letters
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Direct C–H iodination of 1,3-azoles catalysed by CuBr2
a,
⇑
b
b
b
a
a
b,
⇑
Xia Zhao , Fang Ding , Jingyu Li , Kui Lu , Xiaoyu Lu , Bin Wang , Peng Yu
a
College of Chemistry, Tianjin Key Laboratory of Structure and Performance for Functional Molecules, Tianjin Normal University, Tianjin 300387, China
College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild method was developed for the direct C–H iodination of 1,3-azoles catalysed by CuBr . Compared
2
Received 8 October 2014
Revised 27 November 2014
Accepted 8 December 2014
Available online 13 December 2014
with the traditional metalation/iodination sequences carried out with nBuLi or TMPLi (TMP = 2,2,6,
6-tetramethylpiperidino), a relatively weaker base, LiOtBu, was used in the presence of 1,10-phenanthro-
line. Five series of 1,3-azoles, including benzoxazole, benzothiozole, N-methyl-benzoimidazole, 5-phenyl-
oxazole and 2-phenyl-1,3,4-oxadiazole were tested and afforded the corresponding iodination products.
Ó 2014 Published by Elsevier Ltd.
Keywords:
1
,3-Azole
CuBr -catalysed
2
Iodination
Introduction
N
O
N
O
1) n-BuLi, MgBr2
I
I
Ref. 9b
2) I2
Substituted 1,3-azoles are essential structure units found in nat-
ural products, pharmaceutical compounds, agricultural chemicals
and organic materials. In the past few years, several attempts have
1a
2a
N
N
1
)TMPLi
1
M
N
O
N
O
Cl
Cl
Ref. 9e, 9f and 9h
this work
been made to develop efficient methods for the functionalization of
these types of heterocycles.2
–7
Among these methods, direct
1a
2) I
2
2a
halogenation has received much attention from organic chemists,
because the corresponding halide can be converted to other func-
tional groups by transition metal-catalysed cross-coupling reac-
LiOtBu
N
O
N
O
1
,10-phenanthroline
I
CuBr , I
2
2
1a
2a
tions. In 2009, Daugulis reported the preparation of 2-bromo- and
8
2
-chloro-1,3-azoles by direct halogenation using LiOtBu as a base;
Scheme 1. Iodination of benzoxazole.
however, to the best of our knowledge, strong bases, such as nBuLi
together with MgBr , or TMPLi (TMP = 2,2,6,6-tetramethylpiperidi-
no) together with CdCl (TMEDA), or ZnCl (TMEDA) (TMEDA =
2
2
2
0
0
nately, this approach did not lead to the formation of the desired
product. The starting material was then partly recovered from
decomposition of benzoxazole that occurred at 100 °C (Table 1,
entry 1); when 12-crown-4 was added to increase the basicity of
LiOtBu, 2-iodo-benzoxazole was obtained in 16% yield (entry 2).
Other additives such as HMPA (HMPA = Hexamethylphosphora-
mide) and 1,10-phenanthroline were tested; the latter gave 60%
yield (entries 3 and 4). However, combination of KOtBu and 18-
crown-6 gave no desired product (entry 5). In order to optimise
the reaction, the effect of a series of solvents, including DMF,
N,N,N ,N -tetramethylethylenediamine) are required for the direct
9
iodination of the 2-position C–H in 1,3-azoles (Scheme 1). Such
strong basic conditions undermine the tolerance of specific func-
tional groups, limiting its further application to synthesising com-
plex molecules. Herein, we report a copper-catalysed direct C–H
iodination of 1,3-azoles using a basic mixture of LiOtBu and
1
,10-phenanthroline.
Results and discussion
toluene, CH
3
CN and 1,2-dichlorethane (DCE) (entries 6–9) was
At the outset of our investigation, we explored the direct iodin-
ation of benzoxazole by iodine in the presence of LiOtBu. Unfortu-
examined; we found that all solvents were less effective than
1
,4-dioxane.
Further optimisation revealed that addition of catalytic CuBr
0.2 equiv) to the reaction system slightly improved the yield
Table 2, entry 1); this may be due to a stabilisation of the benzox-
2
⇑
Corresponding authors. Tel.: +86 22 23766531; fax: +86 22 23766531 (X.Z.);
tel.: +86 22 60601268; fax: +86 22 60602298 (P.Y).
(
(
E-mail addresses: hxxyzhx@mail.tjnu.edu.cn (X. Zhao), yupeng@tust.edu.cn
(
P. Yu).
2
azole anion species promoted by CuBr through the formation of
http://dx.doi.org/10.1016/j.tetlet.2014.12.029
040-4039/Ó 2014 Published by Elsevier Ltd.
0

5
12
X. Zhao et al. / Tetrahedron Letters 56 (2015) 511–513
Table 1
Table 3
a
a
Optimisation of iodination of benzoxazole
Scope of direct C–H iodination of 1,3-azoles
Entry
Arene
Product
Yieldb (%)
74
Base (2.0 eq)
N
O
Additive (1.0eq)
N
O
t-Bu
N
O
t-Bu
N
O
+
I
2
I
1
1b
2b
I
Solvent 100 o
C
1
a
2a
Me
1
.0 eq
1.5 eq
Base
Me
Br
N
N
2
3
4
5
6
7
1c
1d
1e
1f
2c
2d
2e
2f
I
84
Entry
Solvent
Additive
Yieldb (%)
O
O
Br
N
N
1
2
3
4
5
6
7
8
9
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
DMF
LiOtBu
LiOtBu
LiOtBu
LiOtBu
KOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
—
0
16
10
60
0
0
0
8
6
50c
I
I
12-Crown-4
HMPA
1,10-Phenanthroline
18-Crown-6
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
1,10-Phenanthroline
O
N
O
N
Cl
Cl
50c
O
O
NC
MeO
N
NC
MeO
N
Toluene
I
20c
73
60
CH
3
CN
O
O
DCE
N
N
a
I
Reaction conditions: benzoxazole (0.50 mmol), iodine (0.75 mmol), base
1.0 mmol), additive (0.50 mmol), solvent (2 mL).
1g
1h
2g
2h
O
N
O
N
(
b
Isolated yield.
I
O
Me
O
I
Me
N
O
N
O
8
9
1i
2i
88
79
Table 2
a
Optimisation of metal salts for the iodination of benzoxazole
Me
Me
Me
Me
LiOtBu (2.0 eq)
N
O
N
O
1j
2j
N
N
O
I
1
,10-Phenanthroline (1.0 eq)
+
I
2
I
O
Catalyst, 1,4-Dioxane
tBu
tBu
1
a
2a
1
.0 eq
1.5 eq
N
N
10
1k
2k
85
I
Yieldb (%)
O
N
O
N
Entry
Catalyst (equiv)
Temperature (°C)
1
2
3
4
5
6
7
8
9
CuBr
CuCl
2
(0.2)
(0.2)
100
100
100
100
100
100
100
100
120
80
67
44
16
33
0
22
0
28
0
I
55c
1
1
2
1l
2l
2
S
N
S
Cu(OAc)
2
(0.2)
N
CuBr (0.2)
I
1
1m
N
Me
2m
15c
FeCl
FeCl
ZnCl
MgCl
CuBr
CuBr
CuBr
CuBr
3
2
(0.2)
(0.2)
(0.2)
N
Me
N
2
N
2
(0.2)
(0.2)
(0.2)
(0.2)
(0.1)
1
3
4
1n
1o
2n
2o
I
55
2
Ph
N
O
Ph
O
10
11
12
2
2
2
87
43
89
N
N
N
60
80
76d
1
I
Ph
O
Ph
O
a
a
Reaction conditions: benzoxazole (0.50 mmol), iodine (0.75 mmol), LiOtBu
1.0 mmol), 1,10-phenanthroline (0.50 mmol), metal salt (0.05–0.10 mmol), 1,4-
Reaction conditions: 1,3-azole (0.50 mmol), iodine (0.75 mmol), LiOtBu
(
2
(1.0 mmol), 1,10-phenanthroline (0.50 mmol), CuBr (0.05 mmol), 1,4-dioxane
dioxane (2 mL).
(2 mL), 80 °C.
b
b
Isolated yield.
Isolated yield.
c
CuBr
2
(0.10 mmol).
d
The reaction was carried out at 60 °C.
benzoxazole copper intermediates.10 To further explore this point,
other copper sources, including CuCl
–4) were tested together with other metal salts such as FeCl
FeCl , ZnCl and MgCl . None of these combinations improved
the yield obtained with CuBr . Finally, the effect of the temperature
and that of the amount of CuBr was examined. When the reaction
2
, Cu(OAc)
2
and CuBr (entries
the 5-position gave a poor to moderate yield (Table 3, entries
3–5); this occurred even when the catalyst loadings were increased
to 0.2 equiv. Benzothiozole and 5-phenyloxazole led to the desired
product in moderate yield (Table 3, entries 7 and 9) with 0.2 equiv
2
3
,
2
2
2
2
of CuBr
acterised by a relatively high pK
only 15% of the iodination product (Table 3, entry 8). 2-Phenyl-
2
; however, 1-methyl-1H-benzo[d]imidazole, which is char-
2
1
2
temperature was set to 120 °C, no desired product was observed,
a
value of the C–H bond, gave
because of the decomposition of the starting material and the
1
1
12
product. Notably, the yield was improved to 87% at 80 °C; the
yield diminished at lower temperatures. Regarding the copper cat-
alyst, a reduction of the loading to 10% mol scarcely showed an
effect on the yield.
a
1,3,4-oxadiazole, which has a relatively low pK value, decom-
posed under the optimised conditions, but gave moderate yield
when the reaction was carried out at 60 °C (Table 3, entry 10).
2
To further confirm the catalytic effect of CuBr , some control
To examine the generality and substrate scope of the reaction, a
series of benzoxazole substitutes and other 1,3-azoles were tested
under the optimised conditions. As shown in Table 3, benzoxazole
bearing an electron-donating group at 4-, 5-, 6- or 7-position
ensured a fair to good yield (Table 3, entries 1, 2 and 6–10). In
contrast, benzoxazole bearing an electron-withdrawing group at
reactions were tested using 1a, 1j, 1k and 1l as representative sub-
strates in the optimised conditions. The results showed that the
1
3
2
absence of CuBr led to the decrease of yields.
1
0
Based on previous studies and experimental observation, a
plausible mechanism was proposed (Scheme 2). Coordination of
copper salt with benzoxazole followed by deprotonation with

X. Zhao et al. / Tetrahedron Letters 56 (2015) 511–513
513
Soc. 2010, 132, 1822–1824; (c) Zhao, D.; Wang, W.; Yang, F.; Lan, J.; Yang, L.;
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N
[
Cu]
H
N
O Li
+δ -δ
Cu
N
O
N
O
N
O
I
I
[Cu]
I
9553–9556.
4.
Direct amination of 1,3-azoles: (a) Yotphan, S.; Beukeaw, D.; Reutrakul, V.
Tetrahedron 2013, 69, 6627–6633; (b) Wang, J.; Hou, J.-T.; Wen, J.; Zhang, J.; Yu,
X.-Q. Chem. Commun. 2011, 3652–3654; (c) Froehr, T.; Sindlinger, C. P.;
Kloeckner, U.; Finkbeiner, P.; Nachtsheim, B. J. Org. Lett. 2011, 13, 3754–3757;
I
Scheme 2. Proposed mechanism for the direct C–H iodination.
(
1
4
d) Wertz, S.; Kodama, S.; Studer, A. Angew. Chem., Int. Ed. 2011, 50, 11511–
1515; (e) Kim, J. Y.; Cho, S. H.; Joseph, J.; Chang, S. Angew. Chem., Int. Ed. 2010,
9, 9899–9903.
LiOtBu in the presence of 1,10-phenanthroline afforded benzoxaz-
ole copper species that reacted with iodine to provide the product.
5. Direct oxidation and alkoxylation of 1,3-azoles: (a) Takemura, N.; Kuninobu, Y.;
Kanai, M. Org. Lett. 2013, 15, 844–847; (b) Liu, Q.; Wu, P.; Yang, Y.; Zeng, Z.; Liu,
J.; Yi, H.; Lei, A. Angew. Chem., Int. Ed. 2012, 51, 4666–4670.
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Direct thiolation of 1,3-azoles: (a) Dai, C.; Xu, Z.; Huang, F.; Yu, Z.; Gao, Y.-F. J.
Org. Chem. 2012, 77, 4414–4419; (b) Zhou, A.-X.; Liu, X.-Y.; Yang, K.; Zhao, S.-C.;
Liang, Y.-M. Org. Biomol. Chem. 2011, 9, 5456–5462; (c) Arisawa, M.; Toriyama,
F.; Yamaguchi, M. Tetrahedron Lett. 2011, 52, 2344–2347; (d) Williams, D. R.;
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Haga, M.; Ogata, K. Tetrahedron Lett. 2009, 50, 2374–2376.
Conclusion
In summary, we have developed a mild and efficient catalytic
system for the direct C–H iodination of 1,3-azoles. A combination
of LiOtBu and 1,10-phenanthroline was employed instead of the
currently used nBuLi or TMPLi for metalation/iodination
sequences. The relatively weak basic conditions required for the
method proposed in this work allowed not only an increase of
the functional groups tolerance, but also an extension of the
substrate scope of this new iodination protocol.
7
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Direct phosphonation and phosphorylations of 1,3-azoles: (a) Hou, C.; Ren, Y.;
Lang, R.; Hu, X.; Xia, C.; Li, F. Chem. Commun. 2012, 5181–5183; (b) Zou, L.-H.;
Dong, Z.-B.; Bolm, C. Synlett 2012, 1613–1616.
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Acknowledgments
The authors sincerely thank the financial support from the
National Science Foundation of China (Grants 21202119,
2
1202118, 21102101) and the China International Science and
Technology Cooperation Projects (2013DFA31160).
1
0280–10290; (i) Lu, L.; Yan, H.; Sun, P.; Zhu, Y.; Yang, H.; Liu, D.; Rong, G.;
Supplementary data
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1. General procedure of iodination reactions: To a flame-dried Schlenk tube was
added benzoxazole 1a (60 mg, 0.5 mmol), 1,10-phenanthroline (90 mg,
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
1
2.029.
0.5 mmol), LiOtBu (80 mg, 1.0 mmol), CuBr
2
(11 mg, 0.05 mmol) and iodine
(
191 mg, 0.75 mmol). Dry 1,4-dioxane (2 mL) was added to the mixture and
the mixture was heated to 100 °C by putting the reaction tube to a preheated
oil bath. The mixture was cooled to room temperature and filtered through a
short pad of silica gel. The silica gel was washed with EtOAc (20 mL) and the
combined the organic phase was concentrated under reduced pressure to give
a residue which was purified by silica gel column chromatography to afford
compound 2a (109 mg, 89%) as a white solid.
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13. See Supporting information for details.
Selected literature on transition-metal-catalyzed coupling of 1,3-azoles with
2
sp carbon: (a) Do, H.; Daugulis, O. J. Am. Chem. Soc. 2011, 133, 13577–13586;
(
b) Xi, P.; Yang, F.; Qin, S.; Zhao, D.; Lan, J.; Gao, G.; Hu, C.; You, J. J. Am. Chem.