Ruthenium-catalyzed oxidation of alkynes to 1,2-diketones under room temperature and one-pot synthesis of quinoxalines

Article abstract of DOI:10.1016/j.tetlet.2012.11.142

A ruthenium-catalyzed alkyne oxidation to 1,2-diketones using Oxone under room temperature is reported. Both substrate scope and mechanism were discussed. Notably, combination of the alkyne oxidation and condensation cyclization in one pot offers a very efficient and convenient entry into quinoxaline derivatives.

Full text of DOI:10.1016/j.tetlet.2012.11.142

Tetrahedron Letters 54 (2013) 642–645
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Tetrahedron Letters
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Ruthenium-catalyzed oxidation of alkynes to 1,2-diketones under room
temperature and one-pot synthesis of quinoxalines
⇑
Yuan Xu, Xiaobing Wan
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering, and Materials Science, Soochow University, 199 RenAi Road, Suzhou,
Jiangsu 215123, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A ruthenium-catalyzed alkyne oxidation to 1,2-diketones using Oxone under room temperature is
reported. Both substrate scope and mechanism were discussed. Notably, combination of the alkyne oxi-
dation and condensation cyclization in one pot offers a very efficient and convenient entry into quinox-
aline derivatives.
Received 19 September 2012
Revised 22 November 2012
Accepted 30 November 2012
Available online 5 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Ruthenium
Alkynes
Oxidation
1,2-Diketones
Quinoxalines
Introduction
work, we investigated the Ru-catalyzed oxidation of 1,2-diph-
enylethyne 1a for benzil 2a using Oxone as the oxidant under
1,2-Diketones appear frequently as structural sub-units in mol-
ecules of biological and medicinal interest1 and are versatile build-
room temperature. Sodium bicarbonate was used as the buffer
to maintain the neutral conditions.5 To our delight, a small
amount of benzil 2a was formed in the catalytic system (Table 1,
entry 11). Interestingly, the use of TEMPO as a cocatalyst en-
hanced the conversion in a remarkable manner, resulting in the
product 2a in excellent yield. The catalyst is capable of up to
4600 turnovers with the substrate 1a (Table 1, entry 1). In sharp
contrast with Yang’s work, no carboxylic acid was detected in this
transformation. Negligible product 2a was generated in the ab-
sence of Ru catalyst (Table 1, entry 10). When other Ru catalysts
were used, product 2a was achieved in moderate yield (Table 1,
entries 13 and 14). In addition to Oxone, various oxidants were
also employed in this study. The results are shown in Table 1,
which indicated that Oxone is the best oxidant for the transfor-
mation (Table 1, entries 15–18). The effect of the solvent was also
dramatic. Among the various solvents examined, MeNO2/H2O was
the most suitable for the transformation under the catalytic sys-
tem. Replacement of MeNO2/H2O with other solvents leads to a
drop in yield (Table 1, entries 2–9). Finally, when the transforma-
tion was scaled up to 10 mmol, product 2a was still achieved in
excellent yield (Table 1, entry 19).
ing blocks capable of undergoing
a variety of chemical
transformations, especially for the synthesis of heterocyclic com-
pounds.2 The direct oxidation of properly substituted alkynes,
which are prepared via Sonogashira coupling, might be the most
straightforward method to synthesize the 1,2-diketone derivatives.
The stoichiometric oxidation of alkynes has been widely studied,
which suffers from generation of large amounts of wastes. Re-
cently, the development of catalytic methods for the oxidation of
alkynes to 1,2-diketones has been an attractive research area in or-
ganic chemistry.3 In addition, C–C bond cleavage of 1,3-diketones
represents another promising method for producing 1,2-dike-
tones.4 Despite these great achievements, from the standpoint of
environmental benignity and overall cost, pursuing more efficient
and practical catalytic systems with improved turnover is para-
mount. As part of our ongoing project to investigate new oxidation
methods for 1,2-diketone,3j,l,n we attempted to develop a mild pro-
cess catalyzed by ruthenium with low catalyst loadings.
Results and discussions
With the optimized oxidation conditions available, we em-
barked on the investigation of the alkynes’ scope. A series of al-
kynes with different substituents on the aromatic ring were
examined (Table 2). To our delight, aromatic alkynes bearing both
electron-rich and electron-poor functional groups were oxidized to
the corresponding 1,2-diketones in moderate to excellent yields.
Recently, Yang et al. reported a Ru-catalyzed oxidative cleav-
age of alkynes to carboxylic acids using Oxone.5a Inspired by this
⇑
Corresponding author. Tel./fax: +86 512 65880334.
E-mail address: wanxb@suda.edu.cn (X. Wan).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.142

Y. Xu, X. Wan / Tetrahedron Letters 54 (2013) 642–645
643
Table 1
Optimization of reaction conditionsa
O
catalyst, cocatalyst
oxidant, solvent
O
1a
2a
Entry
Catalyst
Cocatalyst
Oxidant
Solvent
Yieldb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
[Ru(cymene)Cl2]2
[Ru(cymene)Cl2]2
[Ru(cymene)Cl2]2
[Ru(cymene)Cl2]2
[Ru(cymene)Cl2]2
[Ru(cymene)Cl2]2
[Ru(cymene)Cl2]2
[Ru(cymene)Cl2]2
[Ru(cymene)Cl2]2
—
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
—
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
O2
MeNO2/H2O
DMF/H2O
DME/H2O
92%
<5%
<5%
<5%
35%
<5%
<5%
<5%
<5%
<5%
26%
N.O.c
41%
67%
N.O.
N.O.
40%
N.O.
94%d
EA/H2O
tBuOH/H2O
MeCN/H2O
Dioxane/H2O
Toluene/H2O
DCE/H2O
MeNO2/H2O
MeNO2/H2O
MeNO2/H2O
MeNO2/H2O
MeNO2/H2O
MeNO2/H2O
MeNO2/H2O
MeNO2/H2O
MeNO2/H2O
MeNO2/H2O
[Ru(cymene)Cl2]2
—
RuCl2(PPh3)3
—
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
RuCl3
[Ru(cymene)Cl2]2
[Ru(cymene)Cl2]2
[Ru(cymene)Cl2]2
[Ru(cymene)Cl2]2
[Ru(cymene)Cl2]2
Benzoquinone
PhI(OAc)2
H2O2
Oxone
a
All reactions were carried out in the scale of 0.2 mmol in 4.0 mL of nitromethane and 0.5 mL of water in the presence of 0.5 mmol NaHCO3, 10 mol % TEMPO, and
0.02 mol % Ru catalyst using Oxone (330 mg, 5% active oxygen) under room temperature for 12 h unless noted otherwise.
b
Isolated yield.
Not observed.
10 mmol substrate was used.
c
d
Table 2
Ru-catalyzed alkyne oxidation for 1,2-diketonesa
O
O
O
F
I
Br
Cl
O
O
O
2b, 94%
O
2c, 80%
O
2d, 88%
O
OMe
CO2Me
O
O
O
2g
2e, 93%
, 85%
2f
, 92%
O
O
O
Ph
O
O
O
O
2j
, 76%
2h, 80%
2i, 75%
O
O
O
CF3
CN
NO2
O
O
O
[b]
2m, 91%b
2k
, 93%
2l
, 81%
C6H13
N
O
O
O
O
O
Ph
MeO
O
2p
, 51%
2o, 62%
b
2n
, 62%
O
O
CN
O
Bu
C12H25
O
O
O
2s
, 52%
2r
, 71%
2q
, 56%
b
50 °C.
a
All reactions were carried out in the scale of 0.2 mmol in 4.0 mL of nitromethane and 0.5 mL of water in the presence of 0.5 mmol NaHCO3, 10 mol % TEMPO, and
0.02 mol % [Ru(cymene)Cl2]2 using Oxone (330 mg, 5% active oxygen) under room temperature for 12 h unless noted otherwise.

644
Y. Xu, X. Wan / Tetrahedron Letters 54 (2013) 642–645
Table 3
Synthesis of quinoxaline derivatives via a one-pot procedurea
Ar1
Ar2
1) 0.02 mol % [Ru(cymene)Cl2]2 ,10 mol %
TEMPO, 2.5 equiv Oxone, 2.5 equiv NaHCO3
N
N
Ar1
Ar2
2) 3.0 equiv benzene-1,2-diamine
1
3
N
N
N
N
N
N
F
Cl
3c, 59%
3a, 95%
3b, 96%
N
N
N
N
N
N
Br
I
OMe
3d,
3f,
82%
3e,
78%
95%
N
N
N
N
N
N
Ph
CO2Me
CN
O
3i, 72%
3g, 88%
3h, 79%
a
Step 1: 0.2 mmol alkynes in 5.0 mL of nitromethane and 0.8 mL of water in the presence of 0.5 mmol NaHCO3, 10 mol % TEMPO, and 0.02 mol % Ru catalyst using Oxone
(330 mg, 5% active oxygen) under room temperature for 12 h. Step 2: 3.0 equiv of benzene-1,2-diamine, room temperature for 24 h.
Notably, the presence of halogen substituents on the aromatic
rings did not interfere with the triple bond oxidation process,
affording products that could be further functionalized by transi-
tion-metal-catalyzed cross-coupling reactions (products 2b–2e).
Heteroarenes such as carbazole also underwent clean oxidation
to give the corresponding 1,2-diketone 2n in satisfactory yield.
Usually, alkyl-substituted alkynes were not suitable partners for
1,2-diketone synthesis.3 In sharp contrast, when alkyl-substituted
alkynes were employed under the optimized conditions, products
2o–2s were achieved in moderate to good yields.
Quinoxalines occur widely in biologically active compounds,
functional material, and therapeutic drug molecules.6 With high
efficiency and mild conditions of the oxidation reaction in our
hand, we next explored the possibility of the construction of
quinoxalines directly from alkynes and 1,2-diamine via a one-
pot two-step procedure. The alkyne oxidation was carried out
under the optimized conditions, followed by condensation
cyclization with benzene-1,2-diamine, affording the correspond-
ing quinoxalines in moderate to excellent yields. As shown
in Table 3, several functional groups, such as methoxy, halide,
ester, CN, and benzoyl, on the aromatic moiety were well-
tolerated.
Acknowledgments
A Project Funded by the Priority Academic Program Develop-
ment of Jiangsu Higher Education Institutions (PAPD). This re-
search was also supported by the National Natural Science
Foundation of China (20802047, 21072142).
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
11.142.
References and notes
1. For example, see: (a) 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; (b) Ngadjui, B. T.;
Kouam, S. F.; Dongo, E.; Kapche, G. W. F.; Abegaz, B. M. Phytochemistry 2000, 55,
915–919.
2. For example, see: (a) Deng, X.; Mani, N. S. Org. Lett. 2005, 8, 269–272; (b)
Wolkenberg, S. E.; Wisnoski, D. D.; Leister, W. H.; Wang, Y.; Zhao, Z.; Lindsley, C.
W. Org. Lett. 2004, 6, 1453–1456; (c) 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; (d) Herrera, A. J.; Rondón, M.; Suárez, E. J. Org. Chem. 2008, 73,
3384–3391.
3. For representative alkynes oxidation for 1,2-diketones, see: (a) Zhu, Z.;
Espenson, J. H. J. Org. Chem. 1995, 60, 7728–7732; (b) Dayan, S.; Ben-David, I.;
Rozen, S. J. Org. Chem. 2000, 65, 8816–8818; (c) Murray, R. W.; Singh, M. J. Org.
Chem. 1993, 58, 5076–5080; (d) Wan, Z.; Jones, C. D.; Mitchell, D.; Pu, J. Y.;
Zhang, T. Y. J. Org. Chem. 2005, 71, 826–828; (e) Yusubov, M. S.; Zholobova, G. A.;
Vasilevsky, S. F.; Tretyakov, E. V.; Knight, D. W. Tetrahedron 2002, 58, 1607–
1610; (f) Giraud, A.; Provot, O.; Peyrat, J.-F.; Alami, M.; Brion, J.-D. Tetrahedron
2006, 62, 7667–7673; (g) Mousset, C.; Provot, O.; Hamze, A.; Bignon, J.; Brion, J.-
D.; Alami, M. Tetrahedron 2008, 64, 4287–4294; (h) Niu, M.; Fu, H.; Jiang, Y.;
Zhao, Y. Synthesis 2008, 2879–2882; (i) Tan, K. J.; Wille, U. Chem. Commun. 2008,
6239–6241; (j) Ren, W.; Xia, Y.; Ji, S.-J.; Zhang, Y.; Wan, X.; Zhao, J. Org. Lett.
2009, 11, 1841–1844; (k) Al-Rashid, Z. F.; Johnson, W. L.; Hsung, R. P.; Wei, Y.;
Conclusion
In summary, we have developed a new protocol for the 1,2-
diketone synthesis through alkyne oxidation catalyzed by ruthe-
nium under room temperature. The mild and neutral conditions,
wide substrate scope, and relatively safe oxidant, as well as its
application in one-pot synthesis of quinoxalines, render this meth-
od a powerful alternative to previous approaches. Further investi-
gations of detailed mechanism and related processes are ongoing
in our laboratories.

Y. Xu, X. Wan / Tetrahedron Letters 54 (2013) 642–645
645
Yao, P.-Y.; Liu, R.; Zhao, K. J. Org. Chem. 2008, 73, 8780–8784; (l) Ren, W.; Liu, J.;
Chen, L.; Wan, X. Adv. Synth. Catal. 2010, 352, 1424–1428; (m) Mori, S.; Takubo,
M.; Yanase, T.; Maegawa, T.; Monguchi, Y.; Sajiki, H. Adv. Synth. Catal. 2010, 352,
1630–1634; (n) Chen, S.; Liu, Z.; Shi, E.; Chen, L.; Wei, W.; Li, H.; Cheng, Y.; Wan,
X. Org. Lett. 2011, 13, 2274–2277; (o) Xu, C.-F.; Xu, M.; Jia, Y.-X.; Li, C.-Y. Org. Lett.
2011, 13, 1556–1559; (p) Tingoli, M.; Mazzella, M.; Panunzi, B.; Tuzi, A. Eur. J.
Org. Chem. 2011, 399–404; (q) Wang, A.; Jiang, H.; Li, X. J. Org. Chem. 2011, 76,
6958–6961; (r) Jacques, M. J. Mol. Catal. A: Chem. 2011, 338, 7–17; (s) Sawama,
Y.; Takubo, M.; Mori, S.; Monguchi, Y.; Sajiki, H. Eur. J. Org. Chem. 2011, 3361–
3367.
5. (a) Yang, D.; Yip, Y.-C.; Tang, M.-W.; Wong, M.-K.; Cheung, K.-K. J. Org. Chem.
1998, 63, 9888–9894; (b) Yang, D.; Zhang, C. J. Org. Chem. 2001, 66, 4814–4818;
(c) Yang, D.; Chen, F.; Dong, Z.-M.; Zhang, D.-W. J. Org. Chem. 2004, 69, 2221–
2223.
6. For example: see: (a) Burguete, A.; Pontiki, E.; Hadjipavlou-Litina, D.; Ancizu, S.;
Villar, R.; Solano, B.; Moreno, E.; Torres, E.; Pérez, S.; Aldana, I.; Monge, A. Chem.
Biol. Drug Des. 2011, 77, 255–267; (b) Wang, E.; Hou, L.; Wang, Z.; Hellström, S.;
Zhang, F.; Inganäs, O.; Andersson, M. R. Adv. Mater. 2010, 22, 5240–5244; (c)
Kitamura, C.; Tanaka, S.; Yamashita, Y. Chem. Mater. 1996, 8, 570–578; (d) Zhang,
J.; Cai, W.; Huang, F.; Wang, E.; Zhong, C.; Liu, S.; Wang, M.; Duan, C.; Yang, T.;
Cao, Y. Macromolecules 2011, 44, 894–901; (e) You, L.; Cho, E. J.; Leavitt, J.; Ma,
L.-C.; Montelione, G. T.; Anslyn, E. V.; Krug, R. M.; Ellington, A.; Robertus, J. D.
Bioorg. Med. Chem. Lett. 2011, 21, 3007–3011; (f) Qi, C.; Jiang, H.; Huang, L.; Chen,
Z.; Chen, H. Synthesis 2011, 387–396; (g) Noolvi, M. N.; Patel, H. M.; Bhardwaj,
V.; Chauhan, A. Eur. J. Med. Chem. 2011, 46, 2327–2346.
4. (a) Tada, N.; Shomura, M.; Nakayama, H.; Miura, T.; Itoh, A. Synlett 2010, 1979–
1983; (b) Karlsson, I.; Hillerstrom, L.; Stenfeldt, A.-L.; Martensson, J.; Borje, A.
Chem. Res. Toxicol. 2009, 22, 1881–1892; (c) Huang, L.; Cheng, K.; Yao, B.; Xie, Y.;
Zhang, Y. J. Org. Chem. 2011, 76, 5732–5737; (d) Yuan, Y.; Zhu, H. Eur. J. Org.
Chem. 2012, 329–333.