Wacker- type oxidation of alkynes into 1, 2-diketones using molecular oxygen

Article abstract of DOI:10.1021/ol900344g

An intriguing new Wacker- type oxidation of alkynes catalyzed by PdBr ₂ and CuBr₂ is described, which opens an efficient access to 1, 2-diketones using molecular oxygen. Under the optimized conditions, a variety of alkynes, including diarylalkynes, arylalkylalkynes, and dialkylalkynes, were compatible substrates in this transformation. The mechanism of this reaction was preliminarily investigated by control experiments.

Full text of DOI:10.1021/ol900344g

ORGANIC
LETTERS
2009
Vol. 11, No. 8
1841-1844
Wacker-Type Oxidation of Alkynes into
1,2-Diketones Using Molecular Oxygen
Wei Ren,† Yuanzhi Xia,† Shun-Jun Ji,† Yong Zhang,‡ Xiaobing Wan,*,† and
Jing Zhao§
Key Laboratory of Organic Synthesis of Jiangsu ProVince, College of Chemistry,
Chemical Engineering and Materials Science, Soochow UniVersity,
Suzhou 215123, P. R. China, Testing and Analysis Center of Soochow UniVersity,
Suzhou 215123, P. R. China, and State Key Laboratory of Pharmaceutical
Biotechnology, School of Life Sciences, Nanjing UniVersity,
Nanjing 210093, P. R. China
wanxb@suda.edu.cn
Received February 16, 2009
ABSTRACT
An intriguing new Wacker-type oxidation of alkynes catalyzed by PdBr2 and CuBr2 is described, which opens an efficient access to 1,2-diketones
using molecular oxygen. Under the optimized conditions, a variety of alkynes, including diarylalkynes, arylalkylalkynes, and dialkylalkynes, were
compatible substrates in this transformation. The mechanism of this reaction was preliminarily investigated by control experiments.
Pd-catalyzed Wacker oxidation of alkenes consists of one
of the most important industrial processes employing transi-
tion metal catalysts.1 Owing to its high selectivity and
excellent functional group tolerance, this transformation has
found widespread application in synthetic chemistry.2 Recent
research in this field mainly focused on asymmetric versions,3
the use of molecular oxygen as the sole oxidant,4 and/or
nucleophiles other than oxygen-based groups,5,6 which have
led to remarkable progress in this field.
Compared with the impressive development of alkenes,
Wacker-type oxidation of alkyne has not been explored thus
far.7 We speculate this dichotomy in progress between
alkenes and alkynes may be attributable to the differences
in the assumed catalytic cycles. It seems to us that ꢀ-hydride
elimination, the key step for Wacker oxidation of alkenes,
might be difficult for similar reactions of alkynes. Thus,
(3) For representative examples, see: (a) Hosokawa, T.; Uno, T.; Inui,
S.; Murahashi, S.-I. J. Am. Chem. Soc. 1981, 103, 2318–2323. (b) Uozumi,
Y.; Kato, K.; Hayashi, T. J. Am. Chem. Soc. 1997, 119, 5063–5064. (c)
Uozumi, Y.; Kato, K.; Hayashi, T. J. Org. Chem. 1998, 63, 5071–5075.
(d) Uozumi, Y.; Kyota, H.; Kato, K.; Ogasawara, M.; Hayashi, T. J. Org.
Chem. 1999, 64, 1620–1625. (e) Arai, M. A.; Kuraishi, M.; Arai, T.; Sasai,
H. J. Am. Chem. Soc. 2001, 123, 2907–2908. (f) Trend, R. M.; Ramtohul,
Y. K.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem., Int. Ed. 2003, 42, 2892–
2895. (g) Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc.
2005, 127, 17778–17788. (h) Wang, F.; Zhang, Y.; Yang, G.; Zhang, W.
Tetrahedron Lett. 2007, 48, 4179–4182.
† Soochow University.
‡ Testing and Analysis Center of Soochow University.
§ Nanjing University.
(1) For recent reviews, see: (a) Tsuji, J. Pure Appl. Chem. 1999, 71,
1539–1547. (b) Takacs, J. M.; Jiang, X. Curr. Org. Chem. 2003, 7, 369–
396. (c) Cornell, C. N.; Sigman, M. S. Inorg. Chem. 2007, 46, 1903–1909.
(d) Kotov, V.; Scarborough, C. C.; Stahl, S. S. Inorg. Chem. 2007, 46,
1910–1923.
(2) For representative examples, see: (a) Ba¨ckvall, J.-E.; Åkermark, B.;
Ljunggren, S. O. J. Chem. Soc., Chem. Commun. 1977, 264–265. (b) Zaw,
K.; Henry, P. M. J. Org. Chem. 1990, 55, 1842–1847. (c) Nelson, D. J.;
Li, R.; Brammer, C. J. Am. Chem. Soc. 2001, 123, 1564–1568. (d) Keith,
J. A.; Oxgaard, J.; Goddard, W. A., III. J. Am. Chem. Soc. 2006, 128, 3132–
3233. (e) Keith, J. A.; Nielsen, R. J.; Oxgaard, J.; Goddard, W. A., III
J. Am. Chem. Soc. 2007, 129, 12342–12343. (f) Cornell, C. N.; Sigman,
M. S. J. Am. Chem. Soc. 2005, 127, 2796–2797. (g) Hayashi, T.; Yamasaki,
K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036–3037.
(4) (a) ten Brink, G.-J.; Arends, I. W. C. E.; Papadogianakis, G.; Sheldon,
R. A. Chem. Commun. 1998, 2359–2360. (b) ten Brink, G.-J.; Arends,
I. W. C. E.; Papadogianakis, G.; Sheldon, R. A. Appl. Catal., A 2000,
194-195, 435–442. (c) Mun˜iz, K. AdV. Synth. Catal. 2004, 346, 1425–
1428. (d) Mitsudome, T.; Umetani, T.; Nosaka, N.; Mori, K.; Mizugaki,
T.; Ebitani, K.; Kaneda, K. Angew. Chem., Int. Ed. 2006, 45, 481–485. (e)
Cornell, C. N.; Sigman, M. S. Org. Lett. 2006, 8, 4117–4120. (f) Ref 3f.
(g) Ref 3g.
10.1021/ol900344g CCC: $40.75
Published on Web 03/25/2009
2009 American Chemical Society

development of a Wacker-type procedure for alkyne oxida-
tion would not only expand the scope of the Wacker reaction
but also pose an interesting mechanistic question. Further-
more, the 1,2-diketones, oxidation products of alkynes, are
very important structural moieties in numerous biologically
interesting compounds8 and are broadly utilized for construc-
tion of complex structures in organic synthesis.9 Although
several methods have been reported for the oxidation of
alkynes,10 these reactions are still suffering from drawbacks
such as harsh conditions, narrow substrate scope, low yield,
and/or chemoselectivity. Thus, developing a new and efficient
protocol for clean catalytic oxidation of alkynes is still highly
desirable. In this communication, we report the Wacker-type
oxidation of alkynes, which affords 1,2-diketones using
molecular oxygen as the stoichiometric oxidant under mild
conditions.
We launched our efforts to develop the Wacker-type
oxidation of alkynes under typical conditions employed for
alkenes. Reaction of 1,2-diphenylethyne in DMF/H2O in the
presence of a catalytic amount of PdCl2 and CuCl2 afforded
benzyl 2a in 21% yield (Table 1, entry 1). Despite the modest
yield obtained, the initial test result was quite encouraging
since it attested the feasibility of Wacker-type oxidation of
alkynes. An extensive screening of the reaction parameters
indicated that the catalysts, cocatalysts, oxidants, and solvents
all play critical roles on the reaction efficiency. The best
result was obtained by treating 1,2-diphenylethyne with 5
mol % of PdBr2 and 10 mol % of CuBr2 in dioxane/H2O
under 1 atm of oxygen atmosphere, with a yield of 97% for
2a. It should be noted that using air in place of oxygen could
also give good yield of the product (Table 1, entry 16). Next,
the practical utility of this oxidation process was evaluated,
and up to 91% yield could be achieved on a scale of 60
mmol 1a (Table 1, entry 22). Another feature of the reaction
was that the use of molecular oxygen as the oxidant was
essential for high conversion, as demonstrated by the fact
that the yields decreased when other oxidants were employed
(Table 1, entries 17-21).
Table 1. Optimization of Reaction Conditionsa
entry Pd(OAc02 cocatalyst
oxidant
solvent
yieldb
1
PdCl2
CuCl2
O2
DMF/H2O
DMF/H2O
DMF/H2O
21%
0%
72%
2
Pd(OAc)2 Cu(OAc)2 O2
3
PdBr2
PdBr2
-
CuBr2
CuBr2
CuBr2
-
O2
O2
O2
-
4
Dioxane/H2O 97%
5
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
THF/H2O
0%
6
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
0%c
8%
7
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
-
8
O2
O2
O2
O2
O2
O2
O2
O2
air
48%
72%
52%
15%
15%
28%
0%
18%
76%
89%
30%
12%
18%
14%
91%
9
DMF/H2O
10
11
12
13
14
15
16
17
18
19
20d
21
22e
DME/H2O
EA/H2O
iPrOH/H2O
MeCN/H2O
CH3NO2/H2O
Acetone/H2O
Dioxane/H2O
benzoquinone Dioxane/H2O
PhI(OAc)2
H2O2
TBHP
DMSO
O2
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
a 0.2 mmol 1a, 5 mol % catalyst, 10 mol % cocatalyst. b Isolated yield.
c Deoxybenzoin 3 was achieved in 30% yield. d TBHP: tert-butyl
hydroperoxide. e 60 mmol 1a was used.
functional groups, including halide, ketone, aldehyde, nitro,
benzylic C-H bond, trifluoromethyl, ester, etc., could be
tolerated. Apart from the diarylalkynes, alkynes bearing one
or two aliphatic substituents were also suitable substrates
under standard oxidation conditions, affording the corre-
sponding diketone products in moderate to good yields (Table
2, entries 9-12). Although alkyne with a fused aromatic ring
showed lower reactivity under the optimal conditions, product
2g was isolated in high yield at elevated temperature (Table
2, entry 6).
It is remarkable that the aryl bromide was a compatible
substrate in this transformation given its important synthetic
application, as C-Br of the product could be further
functionalized (Table 2, entry 2). It was also mechanistically
interesting, as it is well-known that the C-Br bond is quite
sensitive under a Pd(0)/(II) catalytic cycle. Furthermore,
when alcohol and aldehyde, usually reactive under tradi-
With the optimized reaction conditions in hand, we began
to examine the scope of this new Wacker-type oxidation of
alkynes. As shown in Table 2, this transformation was highly
efficient for a broad scope of substrates, wherein various
(5) (a) Hegedus, L. S.; Allen, G. F.; Bozell, J. J.; Waterman, E. L. J. Am.
Chem. Soc. 1978, 100, 5800–5807. (b) Hosokawa, T.; Takano, M.; Kuroki,
Y.; Murahashi, S.-I. Tetrahedron Lett. 1992, 33, 6643–6646. (c) Larock,
R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem.
1996, 61, 3584–3585. (d) Lei, A.; Liu, G.; Lu, X. J. Org. Chem. 2002, 67,
974–980. (e) Bar, G. L. J.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. J. Am.
Chem. Soc. 2005, 127, 7308–7309. (f) Yip, K.-T.; Yang, M.; Law, K.-L.;
Zhu, N.-Y.; Yang, D. J. Am. Chem. Soc. 2006, 128, 3130–3131. (g) Zhang,
Z.; Tan, J.; Wang, Z. Org. Lett. 2008, 10, 173–175.
(10) For representative alkyne oxidation methods, 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) Wolfe, S.; Ingold, C. F.
J. Am. Chem. Soc. 1983, 105, 7755–7757. (e) Wan, Z.; Jones, C. D.;
Mitchell, D.; Pu, J. Y.; Zhang, T. Y. J. Org. Chem. 2006, 71, 826–828. (f)
Yusubov, M. S.; Zholobova, G. A.; Vasilevsky, S. F.; Tretyakov, E. V.;
Knight, D. W. Tetrahedron 2002, 58, 1607–1610. (g) Giraud, A.; Provot,
O.; Peyrat, J.-F.; Alami, M.; Brion, J.-D. Tetrahedron 2006, 62, 7667–
7673. (h) Mousset, C.; Provot, O.; Hamze, A.; Bignon, J.; Brion, J.-D.;
Alami, M. Tetrahedron 2008, 64, 4287–4294. (i) Yusubov, M. S.;
Filimonov, V. D. Synthesis 1991, 131–132. (j) Yusubov, M. S.; Kras-
nokutskaya, E. A.; Vasilyeva, V. P.; Filimonov, V. D.; Chi, K. W. Bull.
Korean Chem. Soc. 1995, 16, 86–88. (k) Chi, K.-W.; Yusubov, M. S.;
Filimonov, V. D. Synth. Commun. 1994, 24, 2119–2122. (l) Che, C.-M.;
Yu, W.-Y.; Chan, P.-M.; Cheng, W.-C.; Peng, S.-M.; Lau, K.-C.; Li, W.-
K. J. Am. Chem. Soc. 2000, 122, 11380–11392.
(6) (a) Fix, S. R.; Brice, J. L.; Stahl, S. S. Angew. Chem., Int. Ed. 2002,
41, 164–166. (b) Timokhin, V. I.; Anastasi, N. R.; Stahl, S. S. J. Am. Chem.
Soc. 2003, 125, 12996–12997. (c) Brice, J. L.; Harang, J. E.; Timokhin,
V. I.; Anastasi, N. R.; Stahl, S. S. J. Am. Chem. Soc. 2005, 127, 2868–
2869. (d) Timokhin, V. I.; Stahl, S. S. J. Am. Chem. Soc. 2005, 127, 17888–
17893. (e) Rogers, M. M.; Kotov, V.; Chatwichien, J.; Stahl, S. S. Org.
Lett. 2007, 9, 4331–4334. (f) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007,
129, 6328–6335.
(7) For Pd-catalyzed cleavage reaction of alkynes, see: Wang, A.; Jiang,
H. J. Am. Chem. Soc. 2008, 130, 5030–5031.
(8) Maurya, R.; Singh, R.; Deepak, M.; Handa, S. S.; Yadav, P. P.;
Mishra, P. K. Phytochemistry 2004, 65, 915–920.
(9) Deng, X.; Mani, N. Org. Lett. 2006, 8, 269–272.
1842
Org. Lett., Vol. 11, No. 8, 2009

tional10 or Pd-catalyzed oxidation conditions,11 were sub-
jected to the Wacker-type oxidation conditions, only the triple
bond oxidation products were isolated (Table 2, entries 7
and 8).
Table 2. Wacker-Type Oxidation of Alkynes
The current Wacker oxidation methodology shows several
advantages compared with previously reported alkyne oxida-
tion procedures,10 including: (1) the reaction is free of strong
oxidant, (2) it works under mild and neutral reaction
conditions, and (3) it affords clean conversion in high
efficiency. Accordingly, this PdBr2/CuBr2 combination in
dioxane/H2O extends the Wacker oxidation to triple bonds
and opens an efficient access to 1,2-diketones, which is an
attractive alternative to traditional alkyne oxidation methods.
While the results in Table 2 show the potential applications
of the transformation, understanding of the detailed reaction
mechanism would be useful for further expansion. Experi-
ments were carried out for mechanistic exploration, and the
results revealed the following facts: (1) isotopic labeling
experiments using H2O18 revealed that both oxygen atoms
of the 1,2-diketone product originated from water instead
of molecular oxygen (Scheme 1, eq 1); (2) deoxybenzoin 3
Scheme 1. Preliminary Study on Mechanism
and benzoin 4 seemed not to serve as intermediates in the
reaction, as none of them were observed in the catalytic
system and only a trace amount of product could be detected
when these species were introduced to the optimal reaction
conditions (Scheme 1, eq 2 and 3); (3) the presence of CuBr2
is crucial for the formation of the 1,2-diketone product, while
only about 30% yield of deoxybenzoin 3 was obtained in
the absence of this cocatalyst (Table 1, entry 6); (4) addition
of a radical trap, 2,2,6,6-tetramethyl-1-piperidinyloxy, to the
reaction medium hardly influenced this oxidation, suggesting
that the oxidation was not a radical process. Considering the
controversy surrounding the Wacker process of alkenes,1
further investigations on detailed mechanisms are underway
in our laboratory.
In summary, a new Wacker-type reaction of alkynes under
aerobic conditions has been developed. This transformation
a Isolated yield. b 80 °C for 24 h.
Org. Lett., Vol. 11, No. 8, 2009
(11) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400–3420.
1843

showed high efficiency and good functional group tolerance.
Further investigations on mechanistic understanding, sub-
strate scope expanding, and the use of molecular oxygen as
the sole oxidant are ongoing.
2047) and the Bureau of Education, Jiangsu Province
(08KJD150005).
Supporting Information Available: Experimental details
and 1H and 13C NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This research was supported by the
National Natural Science Foundation of China (2080-
OL900344G
1844
Org. Lett., Vol. 11, No. 8, 2009