Cu-catalyzed cross-dehydrogenative coupling reactions of (benzo)thiazoles with cyclic ethers

Article abstract of DOI:10.1021/ol4022113

Copper-catalyzed cross-dehydrogenative coupling (CDC) reactions of (benzo)thiazoles with cyclic ethers were developed under mild conditions. In particular, the formation of C-C bonds via the CDC reactions between non-benzo-fused azoles and ethers are reported for the first time. In addition, the acetals, known as the masked 2-thiazolecarboxaldehydes, could be successfully obtained by this CDC reaction. The preliminary mechanism and supportive DFT calculations are discussed as well.

Full text of DOI:10.1021/ol4022113

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Cu-Catalyzed Cross-Dehydrogenative
Coupling Reactions of (Benzo)thiazoles
with Cyclic Ethers
Zengyang Xie,† Yuping Cai,‡ Hongwen Hu,† Chen Lin,† Juli Jiang,*,† Zhaoxu Chen,*,‡
Leyong Wang,† and Yi Pan†
Key Laboratory of Mesoscopic Chemistry of MOE, Center for Multimolecular
Chemistry and Institute of Theoretical and Computational Chemistry, School of
Chemistry and Chemical Engineering, Nanjing University, Nanjing, P. R. China, 210093
jjl@nju.edu.cn; zxchen@nju.edu.cn
Received August 5, 2013
ABSTRACT
Copper-catalyzed cross-dehydrogenative coupling (CDC) reactions of (benzo)thiazoles with cyclic ethers were developed under mild conditions.
In particular, the formation of CꢀC bonds via the CDC reactions between non-benzo-fused azoles and ethers are reported for the first time.
In addition, the acetals, known as the masked 2-thiazolecarboxaldehydes, could be successfully obtained by this CDC reaction. The preliminary
mechanism and supportive DFT calculations are discussed as well.
Azoles, especially (benzo)thiazoles, are widespread in
various natural products1 from agriculture and pharma-
ceutical agents to material sciences.2 More recently, the
cleavageand functionalization of CꢀH bonds in azoles has
attracted considerable attention because of their potential
possibility to transform into other valuable compounds.3
In the past decades, inspiring progress on transition-metal-
catalyzed reactions of azoles has been made,4 where the
direct cross-dehydrogenative coupling (CDC) reactions
were of particular importance5 because the introduction
of oriented and activated functional groups in azoles were
avoided, making synthetic routes shorter and more atom-
economical.6
Numerous examples of CꢀC, CꢀN, and CꢀP bond
formations of azoles by CDC reactions have been reported,
such as arylation or aroylation of azoles with arenes7
and aldehydes;8 the CDC reactions of azoles with azoles;9
N-alkylation, N-arylation, amidation, or amination of
azoles with dimethylacetamide, benzylamine, secondary
amine, and formamides;10 and phosphonation of azoles
with phosphites.11 In the CDC reactions, transition
metals, especially noble metals, were widely used, but the
† Center for Multimolecular Chemistry.
‡ Institute of Theoretical and Computational Chemistry.
(1) (a) DeSimone, R. W.; Currie, K. S.; Mitchell, S. A.; Darrow,
J. W.; Pippin, D. A. Comb. Chem. High Throughput Screen 2004, 7, 473.
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(6) (a) Li, C. J. Acc. Chem. Res. 2009, 42, 335. (b) Scheuermann, C.
Chem. Asian J. 2010, 5, 436.
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2008, 41, 1013. (b) Corbet, J. P.; Mignani, G. Chem. Rev. 2006, 106, 2651.
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r
10.1021/ol4022113
XXXX American Chemical Society

application of inexpensive metals, such as copper and iron,
remains limited and is still a big challenge.
provided an aldehyde-free synthetic protocol for the acetals
of 2-thiazolecarboxaldehydes.
Tetrahydrofuran (THF) and dioxane are important
chemical raw materials and usually used as common
solvents in various chemical reactions for their chemical
inertness.12 Thus, there were some inherent difficulties
in the activation of THF and dioxane, and only a few
examples were reported based on the activation of THF
and dioxane. For example, Wan13 and Reddy14 reported
the formation of CꢀO bond via the activation of CꢀH
bonds of cyclic ethers. Li and co-workers15 reported the
formation of CꢀN bonds catalyzed by Fe. However, the
direct formation of CꢀC bonds between azoles and cyclic
ethers was very rarely reported, and the only example was
reported by Wang and co-workers,16 in which the CꢀC
bonds between benzoazoles (including benzoxazole, ben-
zothiazole, and benzimidazole) and ethers were formed
via the CDC reactions. In particular, there is no reported
example on the formation of the CꢀC bonds between
ethers and non-benzo-fused azoles via the CDC reactions
for the following possible reasons: (a) non-benzo-fused
azoles are more π-electron-deficient and show weaker
acidity than benzoazoles;17 (b) non-benzo-fused azoles
may generate more regioisomeric products with more
active sites than benzoazoles; and (c) for non-benzo-fused
azoles, oxidative homocoupling more easily occurred than
CDC reaction.18 Followed by our recent work on Cu-
catalyzed direct CꢀH bond activation,19 here we report a
novel Cu-catalyzed CDC reaction between (benzo)thiazoles
and cyclic ethers, especially, to the best of our knowledge,
with the first example of the formation of CꢀC bonds
between non-benzo-fused azoles and cyclic ethers so far.
More interestingly, while dioxolane was used as a special
cyclic ether in this CDC reaction, the acetals of 2-thiazole-
carboxaldehydes were also obtained successfully, which
In our initial study, 4,5-dimethylthiazole (1a) and THF
(2a) were selected to test the CDC reactions. As shown in
Table 1, up to 17 types of simple copper salts were tested
(entries 1ꢀ17), where all the monovalence copper salts
(CuCl, CuBr, CuI, CuCN, and Cu2O) failed to obtain any
product, and in the case of divalent copper salts
(CuSO4 5H2O, Cu(acac)2, and CuO), the corresponding
3
products were obtained with low yields. However, 80%
and 82% of yields were obtained when Cu(OTf)2 and
Cu(ClO4)2 were used, respectively (Table 1, entries 12
and 17). Although Cu(ClO4)2 afforded a slightly higher
yield than Cu(OTf)2, we prefer Cu(OTf)2 as the optimal
catalyst, considering the safety of large-scale production.
Next, the oxidant effect in this reaction was investigated,
and more than 10 oxidants were tested (Table 1, entries 12
and 18ꢀ27), in which K2S2O8 afforded the highest yield. In
addition, we also found that inert gas was favorable to this
Table 1. Cu-Catalyzed CDC Reactions of Thiazole with THFa
entry
copper salts
CuCl
oxidants
yieldb (%)
1
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
Ag2CO3
TBHP
Ag2O
0
2
CuBr
CuI
0
3
trace
0
4
CuCN
CuBr2
CuCl2
5
trace
trace
trace
30
0
6
7
CuCl2 2H2O
3
8
CuSO4 5H2O
3
9
Cu(OAc)2
(10) (a) Xia, Q. Q.; Chen, W. Z. J. Org. Chem. 2012, 77, 9366. (b)
Sang, P.; Xie, Y. J.; Zou, J. W.; Zhang, Y. H. Org. Lett. 2012, 14, 3894.
(c) Wang, Q.; Schreiber, S. L. Org. Lett. 2009, 11, 5178. (d) Li, Y. M.;
Xie, Y. S.; Zhang, R.; Jin, K.; Wang, X. N.; Duan, C. Y. J. Org. Chem.
2011, 76, 5444. (e) Wang, J.; Hou, J. T.; Wen, J.; Zhang, J.; Yu, X. Q.
Chem. Commun. 2011, 47, 3652. (f) Kim, J. Y.; Cho, S. H.; Joseph, J.;
Chang, S. Angew. Chem., Int. Ed. 2010, 49, 9899.
(11) (a) Hou, C. D.; Ren, Y. L.; Lang, R.; Hu, X. X.; Xia, C. G.; Li,
F. W. Chem. Commun. 2012, 48, 5181. (b) Xiang, C. B.; Bian, Y. J.; Mao,
X. R.; Huang, Z. Z. J. Org. Chem. 2012, 77, 7706. (c) Mu, X. J.; Zou,
J. P.; Qian, Q. F.; Zhang, W. Org. Lett. 2006, 8, 5291.
(12) Liu, D.; Liu, C.; Li, H.; Lei, A. W. Angew. Chem., Int. Ed. 2013,
52, 4453.
(13) Chen, L.; Shi, E. B.; Liu, Z. J.; Chen, S. L.; Wei, W.; Li, H.; Xu,
K.; Wan, X. B. Chem.;Eur. J. 2011, 17, 4085.
(14) Kumar, G. S.; Pieber, B.; Reddy, K. R.; Kappe, C. O. Chem.;
Eur. J. 2012, 18, 6124.
(15) Pan, S. G.; Liu, J. H.; Li, H. R.; Wang, Z. Y.; Guo, X. W.; Li,
Z. P. Org. Lett. 2010, 12, 1932.
(16) He, T.; Yu, L.; Zhang, L.; Wang, L.; Wang, M. Org. Lett. 2011,
13, 5016.
(17) Sheng, K.; Fu, Y.; Li, J. N.; Liu, L.; Guo, Q. X. Tetrahedron
2007, 63, 1568.
(18) (a) Zhu, M.; Fujita, K.; Yamaguchi, R. Chem. Commun. 2011,
47, 12876. (b) Li, Y.; Jin, J.; Qian, W.; Bao, W. Org. Biomol. Chem. 2010,
8, 326. (c) Monguchi, D.; Yamamura, A.; Fujiwara, T.; Somete, T.;
Mori, A. Tetrahedron Lett. 2010, 51, 850.
(19) (a) Huang, G. L.; Sun, H. S.; Qiu, X. J.; Jin, C.; Lin, C.; Shen,
Y. Z.; Jiang, J. L.; Wang, L. Y. Org. Lett. 2011, 13, 5224. (b) Xie, Z. Y.;
Zhu, X. J.; Guan, Y. F.; Zhu, D. R.; Hu, H. W.; Lin, C.; Pan, Y.; Jiang,
J. L.; Wang, L. Y. Org. Biomol. Chem. 2013, 11, 1390.
10
11
12
13
14
15
16
17
18
19c
20
21
22
23
24
25
26d
27
28e
29d
Cu(OAc)2 H2O
0
3
Cu(acac)2
Cu(OTf)2
Cu(OH)2
Cu
20
80
trace
0
CuO
25
0
Cu2O
Cu(ClO4)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
82
0
62
0
Oxone
BQ
55
0
H2O2
0
Air
0
m-CPBA
O2
0
0
DDQ
0
K2S2O8
K2S2O8
86
45
a Unless otherwise indicated, a mixture of 1a (0.5 mmol), copper salt
(10 mol %), and oxidant (2 equiv) in THF (2 mL) was stirred at 60 °C for
14 h under air. b Yield of isolated 3aa. c 70% in water. d O2 balloon was
used. e Under N2 atmosphere.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 1. Cu-Catalyzed CDC Reactions of Thiazoles with
Ethersa
Scheme 2. Cu-Catalyzed CDC Reactions of Benzothiazoles
with Ethersa
a The reaction was performed with 1 (0.5 mmol), K2S2O8 (2.0 equiv),
and Cu(OTf)2 (10 mol %) in 2 mL of ether (2) under N2 at 60 °C for 14 h.
Yields refer to isolated yields.
reaction, the yield was improved to 86% when the reaction
was carried out under an atmosphere of dry nitrogen
(Table 1, entry 28).
a The reaction was performed with 4 (0.5 mmol), K2S2O8 (2.0 equiv),
and Cu(OTf)2 (10 mol %) in 2 mL of ether (2) under N2 at 60 °C for 14 h.
Yields refer to isolated yields.
Subsequently, we explored the effects of reaction tem-
perature, Cu-catalyst loading, and oxidant loading, respec-
tively (see the Supporting Information). The reaction did
not occur at ambient temperature (approximately 25 °C),
and the yield of the reaction increased when the tempera-
ture was raised to 60 °C, whereas the yield did not increase
when the temperature reached to 100 °C from 60 °C.
Moreover, we also found that no product was obtained
in the absence of the Cu catalyst, and when the Cu(OTf)2
catalyst loading was reduced from 10 to 5 mol %, the yield
was lowered from 86% to 62%. But when the Cu(OTf)2
loading was raised to 15 mol %, the yield did not increase
obviously. Next, under the above-mentioned conditions,
the effect of oxidant loading was investigated. Finally, the
addition of additive ligands (TMEDA, DMEDA, 2,20-
bipyridyl, and phen) and other solvents (DMF, CH3CN,
DCE, toluene, and hexane) were found to be ineffective to
improve the yield. The above experiments clearly demon-
strated that the optimized conditions for the CDC reaction
of 4,5-dimethylthiazole and THF were shown as follows:
Cu(OTf)2 (10 mol %) and K2S2O8 (2 equiv) in THF (2 mL)
at 60 °C under N2 for 14 h.
Next, as shown in Scheme 1, various thiazoles 1 were
reacted with three types of cyclic ethers (2aꢀc), and the
corresponding products 3 were obtained in moderate to
excellent yields. It was noteworthy that the reactivity of
5-methylthiazole was much better than 4-methylthiazole
(3ca vs 3ba; 3cb vs 3bb). We also found electron-rich
thiazoles gave slightly higher yields than electron-deficient
ones (3ca vs 3ea; 3cb vs 3eb). Interestingly, the CDC
reaction could smoothly occur with dioxolane as the cyclic
ether, where the corresponding products 3dc could be
achieved with the 54% yield and it could be transformed
to 2-thiazolecarboxaldehyde by simple hydrolysis. We
then tried to extend non-benzo-fused thiazoles 1 to benzo-
thiazoles 4 in the CDC reaction. As displayed in Scheme 2,
the desired products 5 were obtained in satisfactory yields
under the same conditions, and the substituent group on
benzothiazoles 4 caused a certain influence on the product
yield. From the results listed in Scheme 2, we could find
that 6-methoxybenzothiazole (5ba) afforded a much high-
er yield than benzothiazole with a halide substituent group
(5ca, 5da, 5ea). Among the benzothiazoles with various
electron-withdrawing substituents, 6-fluorobenzothiazole
afforded the corresponding products with the lowest
yields (Scheme 2, 5ca, 5cb, 5cc). However, in the case of
more electron-deficient 6-nitrobenzothiazole and THF,
no desired product was found. The scope of 1,3-dioxolane
with various benzothiazole 4 were also screened, and all
theseexamplesgavethe corresponding acetalsin acceptable
yields (Scheme 2, 5acꢀdc).
To understand the mechanism of this CDC reaction,
TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl), as a radi-
cal-trapping reagent, was added into the reaction system to
investigate the intermediates under the optimized condi-
tions. No desired product 3aa was found upon addtion
of TEMPO, whereas the TEMPOꢀTHF adduct 6 was
detected (Scheme 3). Moreover, neither 3aa nor 6 was
found with the addtion of TEMPO but without the pre-
sence of the oxidant K2S2O8. Therefore, radical inter-
mediate 7 might be formed through a dehydrogenation
of THF facilitated by sulfate radical anion that was
produced from the heated potassium peroxydisulfate.20
The possible catalytic cycle was then initially proposed in
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Mechanistic Consideration
Scheme 4. Possible Mechanism for Cu-Catalyzed CDC
Reactions between 1a and THF
Figure 1. (a) (Left) tetradentate copper. (Right) bidentate copper.
(b) Molecular structures of 9 (left), H-transferred 9 (middle), and
90 (right).
˚
the CuꢀC (THF) length was 3.799 A, showing that there
was no any strong interaction between them. But when the
radical intermediate 7 was set to attack the C2 in 8, the
species 90 was formed (Scheme 4, right side, blue solid line),
and its energy was 250 and 143 kJ/mol lower than the
energy of species 9 and H-transferred 9, respectively, which
suggested that the species 90 can be thermodynamically
formed much more easily than 9 and H-transferred 9.
These results demonstrated that the intermediate to gen-
erate 3aa was very likely to be 90. Presumably, the initial
intermediate might be 10 generated by the addition of 7
to CdN bond in 8,22 which undergo the intramolecular
radical elimination to generate 90, and CuOTf eliminated
from 90 was further oxidized to Cu(OTf)2 by potassium
peroxydisulphate to continue the catalytic cycle. It was
also well understood that no less than 2 equiv of potassium
peroxydisulfate was necessary to complete the reaction.
In summary, an efficient copper-catalyzed method for
cross-dehydrogenative coupling reactions of (benzo)-
thiazoles with cyclic ethers was developed. This protocol
provided not only a new avenue to form new CꢀC bonds
between azoles, especially non-benzo-fused azoles, and
inactive ethers but also an aldehyde-free synthesis for the
acetals. Further research will focus on the more detailed
mechanism and the formation of the CꢀC bonds between
other azoles and acyclic ethers by CDC reactions.
Scheme 4 (left side, red dashed line) according to the
literature.17,21 First, organocopper species 8 was formed
by a CMD process,17 and then 9 was generated from
organocopper species 8 with the radical intermediate 7.
Finally, the desired CDC reaction product 3aa was obtained
by a reductive elimination from Cu(III)ꢀaryl species 9.
In order to further verify the above proposed mechan-
ism, we performed density functional calculations. First,
two stable configurations of 8 were generated (Figure 1a),
where the tetradentate copper complex (left) was calcu-
lated to be 0.7 kJ/mol more stable than the bidentate
one (right). Next, the structure of species 9 was optimized
(Figure 1b, left), in which the Cu atom was coordinated to
the C2 atom (in thiazole) and the O atom (in OTf), and the
˚
corresponding distances were 1.893 and 1.916 A, respec-
tively. The distance between Cu and the radical C in 7 was
Acknowledgment. We gratefully acknowledge financial
support from the National Basic Research Program of
China (2011CB808600) and the National Natural Science
Foundation of China (Nos. 21102073, 21072093, and
20932004).
˚
2.380 A. Our calculations indicated that one of H atoms of
species 7 could easily transfer to the N atom, forming the
H-transferred 9 (Figure 1b, middle). In H-transferred 9,
(20) Ledwith, A.; Russell, P. J.; Sutcliffe, L. H. J. Chem. Soc. D,
Chem. Commun. 1971, 964.
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Commun. 2013, 49, 819. (b) Cao, H.; Zhan, H. Y.; Lin, Y. G.; Lin, X. L.;
Du, Z. D.; Jiang, H. F. Org. Lett. 2012, 14, 1688.
(22) (a) Miyabe, H.; Ueda, M.; Nishimura, A.; Naito, T. Org. Lett.
2002, 4, 131. (b) Miyabe, H.; Yoshioka, E.; Kohtani, S. Curr. Org. Chem.
2010, 14, 1254. (c) Miyabe, H.; Ueda, M.; Fujii, K.; Nishimura, A.;
Naito, T. J. Org. Chem. 2003, 68, 5618. (d) Friestad, G. K. Tetrahedron
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Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX