Copper-catalyzed synthesis of 1,2-diketones via oxidation of alkynes

Article abstract of DOI:10.1016/j.tetlet.2015.01.195

The direct oxidation of internal alkynes proceeds efficiently in the presence of CuI as a catalyst to afford the corresponding 1,2-diketones in good yields. This strategy offers a simple and efficient route for the synthesis of 1,2-diketones from an inexpensive copper catalyst and easily available internal alkynes. The advantage of present protocol is further demonstrated by the synthesis of quinoxaline derivatives from alkynes and 1,2-diaminobenzene via one-pot procedure.

Full text of DOI:10.1016/j.tetlet.2015.01.195

Accepted Manuscript
Copper-catalyzed synthesis of 1,2-diketones via oxidation of alkynes
Ning Xu, Da-Wei Gu, Yan-Sheng Dong, Feng-Ping Yi, Liangzhen Cai, Xin-
Yan Wu, Xun-Xiang Guo
PII:
S0040-4039(15)00255-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.01.195
TETL 45875
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
2 December 2014
23 January 2015
30 January 2015
Please cite this article as: Xu, N., Gu, D-W., Dong, Y-S., Yi, F-P., Cai, L., Wu, X-Y., Guo, X-X., Copper-catalyzed
synthesis of 1,2-diketones via oxidation of alkynes, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/
j.tetlet.2015.01.195
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Tetrahedron Letters
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Copper-catalyzed synthesis of 1,2-diketones via oxidation of alkynes
a
Ning Xu , Da-Wei Gu , Yan-Sheng Dong , Feng-Ping Yi , Liangzhen Cai , Xin-Yan Wu *,
b
c
c
a
a,
b,
Xun-Xiang Guo *
a
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, Shanghai 200237, China.
b
Shanghai Center for Systems Biomedicine, Ministry of Education Key Laboratory of Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240,
China
c
School of Perfume and Aroma Technology, Shanghai Institute of Technology, Shanghai 201418, China
ARTICLE INFO
ABSTRACT
Article history:
Received
The direct oxidation of internal alkynes proceeds efficiently in the presence of CuI as a catalyst
to afford the corresponding 1,2-diketones in good yields. This strategy offers a simple and
efficient route for the synthesis of 1,2-diketones from an inexpensive copper catalyst and easily
available internal alkynes. The advantage of present protocol is further demonstrated by the
synthesis of quinoxaline derivatives from alkynes and 1,2-diaminobenzene via one-pot
procedure.
Received in revised form
Accepted
Available online
Keywords:
Copper
2
014 Elsevier Ltd. All rights reserved.
Oxidation
Alkynes
1
,2-Diketones
Quinoxalines
1,2-Diketones are one of important structural motifs in a
variety of molecules with interesting physiological and biological
copper complexes as catalysts, we report here a novel method for
the synthesis of 1,2-diketones through Cu-catalyzed oxidation of
internal alkynes. Using this reaction protocol, the 1,2-diketones
were obtained in good yields in the presence of inexpensive
copper catalyst from easily available internal alkynes.
1
activities. It is found that 1,2-diketones have been used as useful
2
building blocks in organic synthesis, particularly for the
construction of important heterocycles, such as quinoxalines, and
3
imidazoles.
Initially, we choose 1,2-diphenylethyne 1a as a model
substrate to test the reaction. The reaction of 1a in the presence of
A lot of synthetic protocols have been developed for the
synthesis of 1,2-diketones. As one of the most straightforward
4
2 2 2 8
20 mol% Cu(OAc) as a catalyst with 1.5 equiv of K S O as an
o
process for the synthesis of 1,2-diketones, the oxidation of
internal alkynes, which are easily accessible by the Sonogashira
oxidant in DMSO at 120 C for 24 hours afforded the desired
product 2a in 3% yield (Table 1, entry 1). The catalyst CuO gave
4% yield of 2a (Table 1, entry 2). The yield was increased to 35%
5
coupling, has received much attention in the past few years.
6-11
Among them, the transition-metal-catalyzed direct oxidation of
internal alkynes is particularly attractive and efficient. However,
most reported examples are use of expensive transition-metal
2
when CuCl was used in the reaction (Table 1, entry 3).
Interestingly, the copper (I) complex of CuCl also afforded
product 2a in 31% yield (Table 1, entry 4). To our delight, the
employment of CuI as a catalyst provided product 2a in 57%
yield (Table 1, entry 5). We applied CuI to examine other reaction
conditions. The use of benzoquinone (BQ) and TBHP afforded
trace amount of product 2a (Table 1, entries 6-7). Although
7
8
9
complexes, such as palladium, gold, and ruthenium, as the
catalyst. Recently, although the use of a combination of copper
powder and selectfluor as a catalyst has been reported for the
1
1
synthesis of 1,2-diketones, the reaction suffers from a limitation
of the use of toxic selectfluor. Therefore, the development of
efficient inexpensive transition-metal-catalyzed protocols to
access of 1,2-diketones is still highly desirable because of their
important biological and pharmacological properties.
PhI(OAc)
yield was increased to 68% when Na
2
gave product 2a in 34% yield (Table 1, entry 8), the
was used as an
2 2 8
S O
oxidant (Table 1, entry 9). We investigated several solvents. The
use of DMF, toluene, and 1,4-dioxane provided product 2a in
trace amount of yields (Table 1, entries 10-12). In the
We recently have developed Cu-catalyzed methods to
1
construct heterocycles. As our interests to focus on inexpensive
2
o
examination of reaction temperature, 140 C was found to be the
optimal one (Table 1, entries 13-14). The reaction also proceeds
_
_______
∗
Corresponding author. Tel.: +86-21-3420-4190
E-mail: xinyanwu@ecust.edu.cn (X.-Y. Wu)
well under N
2
to give 2a in 74% yield (Table 1, entry 15). In
addition, we found that the desired product 2a was obtained in 82%
xunxiang_guo@sjtu.edu.cn (X.-X. Guo)

2
Tetrahedron Letters
yield when the copper catalyst loading was decreased to 10 mol% Table 2. Copper-catalyzed oxidation of alkynes
Table 1, entry 16).
a,b
(
O
CuI (10 mol%)
R2
R1
R2
R1
Table 1. Copper-catalyzed oxidation of 1,2-diphenylethyne:
optimization of the reaction conditions
Na2S2O8 (1.5 equiv)
a
o
O
DMSO, 140 C, 24 h
1
air
2
O
reaction conditions
Ph
Ph
Ph
Ph
Me
OMe
O
O
O
O
Ph
1
a
2a
Ph
Ph
Ph
O
O
O
o
Temp ( C)
b
Yield (%)
Entry
[Cu]
Oxidant
2
a, 82%
2b, 65%
2c, 78%
1
2
3
4
5
6
7
8
Cu(OAc)
CuO
2
K
2
S
2
O
8
120
120
120
120
120
120
120
120
120
120
120
120
130
140
140
140
3
F
CO Me
2
K
2
S
2
O
8
4
O
O
CuCl
CuCl
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
2
K
2
S
2
O
8
35
Ph
Ph
Ph
O
d, 67%
O
K
2
S
2
O
8
31
2
2e, 79%c
K
2
S
2
O
8
57
BQ
TBHP
PhI(OAc)
trace
trace
34
O
O
Ph
N
O
2
O
9
Na
Na
Na
Na
Na
Na
Na
Na
2
2
2
2
2
2
2
2
S
S
S
S
S
S
S
S
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
8
8
8
8
8
8
8
8
68
2f, 61%
2g, 60%
c
1
1
1
1
1
1
0
1
2
3
4
5
6
trace
trace
trace
72
Me
OMe
d
e
O
O
O
O
MeO
MeO
2i, 89%c
2
h, 70%
80
f
74
F
O
O
g
1
82
a
Table reaction conditions: unless otherwise noted, the reactions were
performed in a tube with 1,2-diphenylethyne (0.2 mmol), catalyst (0.04
mmol), and oxidant (0.3 mmol) in DMSO (2.0 mL) in air for 24 h.
O
O
2k, 84%
MeO
MeO
b
2j, 67%
Isolated yield.
DMF was used instead of DMSO.
Toluene was used instead of DMSO.
c
d
e
1
Under N
,4-Dioxane was used instead of DMSO.
O
O
f
2
.
.02 mmol of CuI was used.
Me
Pr
g
0
Ph
Pr
O
O
With the optimal reaction conditions in hand (Table 1, entry
6), we investigated the scope of internal alkynes, and the results
2l, 0%
2m, 0%
1
are summarized in Table 2. It was found that a variety of 1,2-
disubstituted alkynes were suitable for the reaction to provide the
corresponding products in good yields. For example, the reaction
a
Table reaction conditions: unless otherwise noted, the reactions were
performed in a tube with alkyne (0.2 mmol), CuI (0.02 mmol), and Na
2
S
2
O
8
o
(0.3 mmol) in DMSO (2.0 mL) at 140 C for 24 h in air.
of 1a in the presence of 10 mol% of CuI as the catalyst with 1.5
S
b
o
as the oxidant in DMSO at 140 C for 24 hours
Isolated yield.
1
equiv of Na
2
2
O
8
c
o
20 C.
in air afforded the product 2a in 82% yield. The electronic effects
of alkynes have no significant influence on this oxidation, and
both electron-donating and electron-withdrawing substituted
internal alkynes gave the corresponding products in good yields
7
a,d,8,11
On the basis of previous reported,
mechanism of this reaction was proposed in Scheme 1. The
I
oxidation of Cu species in the presence of Na S O affords a
a plausible
(
Table 2, 2b-e and 2h-j). It is noteworthy that some functional
2 2 8
III
groups, such as nathphyl, and pyridyl groups are tolerated to
afford the corresponding products in good yields (Table 2, 2f-g
and 2k). However, no desired product (2l or 2m) was obtained
when the alkyne containing one or two alkyl substitutes was used
in the present reaction.
Cu species, which coordinates with the alkyne to give
intermediate A. The nucleophilic addition of DMSO to A forms
intermediate B. The addition of another DMSO to B generates
dimethyl sulfide (DMS) and intermediate C, which proceeds to
provide the corresponding 1,2-diketone product, DMS, and a
III
Cu species.

CuI
Supplementary data
O
Na S O
8
2
2
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
Ph
+
DMS
Me
Ph
CuIII
Ph
Ph
O
References and notes
+
Me
S
1. (a) Hatae, N.; Nakamura, J.; Okujima, T.; Ishikura, M.; Abe, T.; Hibino,
S.; Choshi, T.; Okada, C.; Yamada, H.; Uno, H.; Toyota, E. Bioorg.
Med. Chem. Lett. 2013, 23, 4637-4640; (b) Parkinson, E. I.; Hatfield, M.
J.; Tsurkan, L.; Hyatt, J. L.; Edwards, C. C.; Hicks, L. D.; Yan, B.;
Potter, P. M. Bioorg. Med. Chem. 2011, 19, 4635-4643; (c) Hyatt, J. L.;
Wadkins, R. M.; Tsurkan, L.; Hicks, L. D.; Hatfield, M. J.; Edwards, C.
C.; Ross II, C. R.; Cantalupo, S. A.; Crundwell, G.; Danks, M. K.; Guy,
R. K.; Potter, P. M. J. Med. Chem. 2007, 50, 5727-5734; (d) Wadkins, R.
M.; Hyatt, J. L.; Wei, X.; Yoon, K. J. P.; Wierdl, M.; Edwards, C. C.;
Morton, C. L.; Obenauer, J. C.; Damodaran, K.; Beroza, P.; Danks, M.
K.; Potter, P. M. J. Med. Chem. 2005, 48, 2906-2915.
Ph
Ph
Ph
O
O
CuIII
CuIII
Ph
A
C
DMSO
CuIII
Ph
DMS
O
Ph
2
.
(a) Babudri, F.; Fiandanese, V.; Marchese, G.; Punzi, A. Tetrahedron
Lett. 1995, 36, 7305-7308; (b) De Kimpe, N.; Stanoeva, E.; Boeykens,
M. Synthesis 1994, 427-431.
DMSO
S
+
Me
Me
B
3. For selected examples of application of 1,2-diketones, see: (a) Herrera,
A. J.; Rondón, M.; Suárez, E. J. Org. Chem. 2008, 73, 3384-3391; (b)
Deng, X.; Mani, N. S. Org. Lett. 2006, 8, 269-272; (c) Hui, X.; Desrivot,
J.; Bories, C.; Loiseau, P. M.; Franck, X.; Hocquemiller, R.; Figadère, B.
Bioorg. Med. Chem. Lett. 2006, 16, 815-820; (d) Bhosale, R. S.; Sarda,
S. R.; Ardhapure, S. S.; Jadhav, W. N.; Bhusare, S. R.; Pawar, R. P.
Tetrahedron Lett. 2005, 46, 7183-7186; (e) Wolkenberg, S. E.;
Wisnoski, D. D.; Leister, W. H.; Wang, Y.; Zhao, Z.; Lindsley, C. W.
Org. Lett. 2004, 6, 1453-1456; (f) Singh, S. K.; Saibaba, V.; Ravikumar,
V.; Rudrawar, S. V.; Daga, P.; Rao, C. S.; Akhila, V.; Hegde, P.; Rao, Y.
K. Bioorg. Med. Chem. 2004, 12, 1881-1893; (g) McKenna, J. M.;
Halley, F.; Souness, J. E.; McLay, I. M.; Pickett, S. D.; Collis, A. J.;
Page, K.; Ahmed, I. J. Med. Chem. 2002, 45, 2173-2184; (h) Barta, T.
E.; Stealey, M. A.; Collins, P. W.; Weier, R. M. Bioorg. Med. Chem.
Lett. 1998, 8, 3443-3448; (i) Prasad, K. R. K.; Joshi, N. N. J. Org. Chem.
Scheme 1. Proposed mechanism.
The obtained 1,2-diketones can be efficiently transformed into
quinoxaline derivatives by the reaction with 1,2-diamines. In
order to show advantages of present oxidation reaction, we
explored the synthesis of quinoxaline derivatives from alkynes
and 1,2-diamines via a one-pot procedure. As shown in Scheme
2, the oxidation of 1a under the optimized conditions followed by
the addition of 3 equiv of 1,2-diaminobenzene afforded the
quinoxaline derivative 3a in 70% yield.
1
For selected examples of synthesis of 1,2-diketones, see: (a) Deshidi, R.;
996, 61, 3888-3889.
4
.
Kumar, M.; Devari, S.; Shah, B. A. Chem. Commun. 2014, 50, 9533-
9
1
) CuI (10 mol%)
535; (b) Zhang, Z.; Jiang, X. Org. Lett. 2014, 16, 4400-4403; (c) Shi,
Na S O (1.5 equiv)
2
2
8
S.; Wang, T.; Yang, W.; Rudolph, M.; Hashmi, A. S. K. Chem. Eur. J.
2013, 19, 6576-6580; (d) Zhang, C.; Jiao, N. J. Am. Chem. Soc. 2010,
132, 28-29; (e) Tada, N.; Shomura, M.; Nakayama, H.; Miura, T.; Itoh,
A. Synlett 2010, 1979-1983; (f) Bouma, M.; Masson, G.; Zhu, J. J. Org.
Chem. 2010, 75, 2748-2751; (g) Joo, C.; Kang, S.; Kim, S. M.; Han, H.;
Yang, J. W. Tetrahedron Lett. 2010, 51, 6006-6007; (h) Kashiwabara,
T.; Tanaka, M. J. Org. Chem. 2009, 74, 3958-3961.
o
DMSO, 140 C
4 h, air
N
Ph
Ph
2
Ph
Ph
2) 1,2-diaminobenzene
rt, 24 h
N
1
a
3a
5
6
.
.
(a) Doucet, H.; Hierso, J.-C. Angew. Chem., Int. Ed. 2007, 46, 834-871;
(b) Chinchilla, R.; Nájera, C. Chem. Rev. 2007, 107, 874-922.
70%
For selected examples of synthesis of 1,2-diketones via metal-free
oxidation of internal alkynes, see: (a) Chikugo, T.; Yauchi, Y.; Ide, M.;
Iwasawa, T. Tetrahedron 2014, 70, 3988-3993; (b) Chen, C.-Y.; Hu,
W.-P.; Liu, M.-C.; Yan, P.-C.; Wang, J.-J.; Chung, M.-I. Tetrahedron
Scheme 2. Synthesis of quinoxaline derivative 3a.
2
013, 69, 9735-9741; (c) Sakthivel, K.; Srinivasan, K. Eur. J. Org.
Chem. 2013, 3386-3396; (d) Matsumoto, S.; Shibata, H.; Akazome, M.
J. Org. Chem. 2013, 78, 1650-1654; (e) Sakthivel, K.; Srinivasan, K.
Eur. J. Org. Chem. 2011, 2781-2784; (f) Tingoli, M.; Mazzella, M.;
Panunzi, B.; Tuzi, A. Eur. J. Org. Chem. 2011, 399-404; (g) Chen, M.;
Zhao, Q.; She, D.-B.; Yang, M.-Y.; Hui, H.-H.; Huang, G.-S. J. Chem.
Sci. 2008, 119, 347-351; (h) Yusubov, M. S.; Filimonov, V. D.
Synthesis 1991, 131-132.
In conclusion, we developed an efficient Cu-catalyzed
oxidation of internal alkynes. The corresponding 1,2-diketones
were obtained in good yields using CuI as a catalyst. The present
protocol was further explored for the synthesis of quinoxaline
derivatives from alkynes and 1,2-diaminobenzene via a one-pot
procedure. The use of catalytic amount of inexpensive copper
catalyst combining with good functional group tolerance of
substrates from easily available internal alkynes should make the
present reaction to become a useful method for the synthesis of
7
.
(a) Gao, A.; Yang, F.; Li, J.; Wu, Y. Tetrahedron 2012, 68, 4950-4954;
(b) Sawama, Y.; Takubo, M.; Mori, S.; Monguchi, Y.; Sajiki, H. Eur. J.
Org. Chem. 2011, 3361-3367; (c) Chandrasekhar, S.; Reddy, N. K.;
Kumar, V. P. Tetrahedron Lett. 2010, 51, 3623-3625; (d) Mori, S.;
Takubo, M.; Yanase, T.; Maegawa, T.; Monguchi, Y.; Sajiki, H. Adv.
Synth. Catal. 2010, 352, 1630-1634; (e) Ren, W.; Xia, Y.; Ji, S.-J.;
Zhang, Y.; Wan, X.; Zhao, J. Org. Lett. 2009, 11, 1841-1844.
1
,2-diketones.
8
9
.
.
Xu, C.-F.; Xu, M.; Jia, Y.-X.; Li, C.-Y. Org. Lett. 2011, 13, 1556-1559.
(a) Daw, P.; Petakamsetty, R.; Sarbajna, A.; Laha, S.; Ramapanicker, R.;
Bera, J. K. J. Am. Chem. Soc. 2014, 136, 13987-13990; (b) Miao, Y.;
Dupé, A.; Bruneau, C.; Fischmeister, C. Eur. J. Org. Chem. 2014, 5071-
Acknowledgements
This work was supported by the Natural Science Foundation
of China (No. 21172142).
5077; (c) Xu, Y.; Wan, X. Tetrahedron Lett. 2013, 54, 642-645; (d) Ren,
W.; Liu, J.; Chen, L.; Wan, X. Adv. Synth. Catal. 2010, 352, 1424-1428.
1
0. For the synthesis of 1,2-diketones from oxidation of internal alkynes
with Mercuric salts, see: Jung, M. E.; Deng, G. Org. Lett. 2014, 16,

4
Tetrahedron Letters
2
1. Zhang, W.; Zhang, J.; Liu, Y.; Xu, Z. Synlett 2013, 2709-2714.
142-2145.
1
1
2. (a) Guo, X.-X.; Gu, D.-W.; Wu, Z.; Zhang, W. Chem. Rev. 2015, DOI:
1
2
1
0.1021/cr500410y; (b) Gu, D.-W.; Guo, X.-X. Org. Biomol. Chem.
014, 12, 6114-6120; (c) Guo, X.-X. J. Org. Chem. 2013, 78, 1660-
664.
Graphical Abstract
The direct oxidation of internal alkynes proceeds efficiently
in the presence of CuI as
Copper-catalyzed synthesis of 1,2-diketones
via oxidation of alkynes
a catalyst to afford the
Ning Xu, Da-Wei Gu, Yan-Sheng Dong, Feng-Ping Yi,
Liangzhen Cai, Xin-Yan Wu, Xun-Xiang Guo
1
) CuI (10 mol%)
Na S O (1.5 equiv)
2
2
8
o
DMSO, 140 C
24 h, air
O
R1
N
N
CuI (10 mol%)
R2
R1
R2
R1
Na S O (1.5 equiv)
2
2) 1,2-diaminobenzene
rt, 24 h
2
8
R2
O
o
DMSO, 140 C
4 h, air
2