Dioxygen activation under ambient conditions: Cu-catalyzed oxidative amidation-diketonization of terminal alkynes leading to α-ketoamides

Article abstract of DOI:10.1021/ja908911n

(Figure Presented) A novel Cu-catalyzed oxidative amidation-diketonization reaction of terminal alkynes leading to α-ketoamides has been developed. This chemistry offers a valuable mechanistic insight into this novel Cu catalysis via a radical process. O₂ not only participates as the ideal oxidant but also undergoes dioxygen activation under ambient conditions in this transformation.

Full text of DOI:10.1021/ja908911n

Published on Web 12/10/2009
Dioxygen Activation under Ambient Conditions: Cu-Catalyzed Oxidative
Amidation-Diketonization of Terminal Alkynes Leading to r-Ketoamides
Chun Zhang† and Ning Jiao*,†,‡
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniVersity, Xue
Yuan Road 38, Beijing 100191, China, and State Key Laboratory of Organometallic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, China
Received October 19, 2009; E-mail: jiaoning@bjmu.edu.cn
Table 1. Cu-Catalyzed Oxidative Amidation-Diketonization of 1a
with Alkyne 2aa
Dioxygen is an ideal oxidant and offers attractive academic and
industrial prospects.1 Significantly, dioxygen activation2 for the func-
tionalization of an organic molecule has been of long-standing interest
to organic chemists because of its tremendous importance in chemistry
as well as in biology.3 In the past decades, alkynes have been
extensively used in organic synthesis through transition-metal-catalyzed
reactions. Recent breakthroughs involving the cross-dehydrogenative
coupling (CDC)4 reaction of terminal alkynes via C-H activation (eq
1) have been developed by the research groups of Stahl,5a Li,5b and
Han.5c In these approaches, one new C-N, C-C, or C-P bond,
respectively, is formed with retention of the triple C-C bond, facilitated
by an oxidant such as O2.5a,c However, this kind of coupling using
molecular oxygen as the oxidant still remains a challenging research
area, and the oxidation of alkynes with dioxygen has very rarely been
investigated.6 The combination of using dioxygen as the oxidant and
as a reactant via dioxygen activation would substantially broaden the
field of cross-coupling and offer more functionalized products. Herein,
for the first time, we present a novel Cu-catalyzed oxidative
amidation-diketonization reaction of terminal alkynes using O2 as the
oxidant and as a reactant via dioxygen activation (eq 2). This chemistry
offers not only a new approach to R-ketoamides but also valuable
mechanistic insights into this novel Cu catalysis.
entry
catalyst
additive (equiv)
T (°C)
% yield of 3aab
c
CuCl2 ·2H2O
none
110
15
25
0
67
50
trace
1
2
3
4
CuCl2 ·2H2O
none
none
none
none
none
H2O (10)
H2O (10)
110
110
60
60
60
none
CuBr2
d
CuBr2
5
6
c d
,
CuBr2
CuBr2
CuBr2
7
60
60
77
90
e
8
a Reaction conditions: 1a (0.25 mmol), 2a (1.25 mmol), cat. (0.025
mmol), TEMPO (0.025 mmol), pyridine (1.0 mmol), H2O (2.5 mmol),
toluene (3 mL), O2 (1 atm), 18 h. b Isolated yields. c The reaction was
carried out in the absence of TEMPO. d The reaction was carried out
under air. e A 90% yield was obtained when 10 equiv of 2a was used.
in our cases could be transformed into the desired products. In
addition, a heteroaryl-substituted alkyne, 3-thienylacetylene (2i),
provided 3ai in 64% yield (Table 2, entry 9). It is noteworthy that
alkenyl-substituted alkynes such as 2l and 2m survived well, leading
to 3al (65%) and 3am (24%), respectively (entries 12 and 13).
The scope of the Cu-catalyzed oxidative amidation-diketonization
reaction was further expanded to a variety of substituted anilines 1
(Table 3). These results indicate that anilines with electron-donating
groups proceeded more efficiently than anilines containing electron-
withdrawing groups. It is noteworthy that halo-substituted anilines
During our investigation of indole synthesis via Pd-catalyzed
reactions of anilines and alkynes using dioxygen as the oxidant,7a we
discovered the rather surprising formation of 2-oxo-2-phenyl-N-p-
toylacetamide (3aa) from 4-methylaniline (1a) and phenylacetylene
(2a) when copper salts were used as catalyst precursors (Table 1, entry
1). To the best of our knowledge, the synthesis of R-ketoamides from
alkynes via diketonization has not been reported to date. We envisioned
that a radical process7b,c was possibly involved. The presence of 10
mol % 2,2,6,6-tetramethylpiperadine-1-oxyl (TEMPO)8 promoted the
yield of 3aa to 25% (entries 1 and 2). However, this reaction did not
work in the absence of Cu catalyst (entry 3). Gratifyingly, 3aa was
formed in 67% yield when catalyzed by CuBr2 and TEMPO using O2
at ambient pressure as the oxidant in toluene at 60 °C (entry 4). Attempts
to use other metal catalysts such as Ag, Au, and Mn were not successful
[see the Supporting Information (SI)]. After a great deal of screening of
different parameters (see Table 1 and the SI), the highest yield (90%)
was achieved when 10 equiv of 2a was employed (entry 8).
Table 2. Cu-Catalyzed Oxidative Amidation-Diketonization of 1a
with Alkynes 2a
entry
R (2)
% yieldb (3)
1
2
Ph (2a)
77 (3aa)
67 (3ab)
51 (3ac)
62 (3ad)
71 (3ae)
56 (3af)
57 (3ag)
55 (3ah)
64 (3ai)
63 (3aj)
70 (3ak)
65 (3al)
24 (3am)
0 (3an)
4-Me-C6H4 (2b)
3-Me-C6H4 (2c)
2-Me-C6H4 (2d)
4-F-C6H4 (2e)
3
4
5
6
4-Br-C6H4 (2f)
2,4-F2-C6H4 (2g)
3,5-F2-C6H4 (2h)
3-thienyl (2i)
4-MeO-C6H4 (2j)
4-Et-C6H4 (2k)
styrenyl (2l)
7
8
9
10
11
12
13
14
Under these optimized conditions, the scope of aryl-substituted
alkynes was investigated (Table 2). Notably, both electron-rich
(para-, meta-, and ortho-substituted) and electron-deficient substrates
1-cyclohexenyl (2m)
n-octyl (2n)
a Standard reaction conditions: 1a (0.25 mmol), 2 (1.25 mmol),
CuBr2 (0.025 mmol), TEMPO (0.025 mmol), pyridine (1.0 mmol), H2O
(2.5 mmol), toluene (3 mL), 60 °C, O2 (1 atm), 18 h. b Isolated yields.
† Peking University.
‡ Chinese Academy of Sciences.
9
28 J. AM. CHEM. SOC. 2010, 132, 28–29
10.1021/ja908911n  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Cu-Catalyzed Oxidative Amidation-Diketonization of 1 with 2aa
Scheme 1. Proposed Mechanism for the Direct Transformation
entry
R (1)
% yieldb (3)
1
2
4-Me-C6H4 (1a)
3-Me-C6H4 (1b)
2-Me-C6H4 (1c)
4-CF3O-C6H4 (1d)
Ph (1e)
2-naphthyl (1f)
4-MeO-C6H4 (1g)
4-F-C6H4 (1h)
4-Cl-C6H4 (1i)
4-Br-C6H4 (1j)
4-COOEt-C6H4 (1k)
n-butyl (1l)
77 (3aa)
50 (3ba)
40 (3ca)
36 (3da)
47 (3ea)
51 (3fa)
77 (3ga)
47 (3ha)
41 (3ia)
32 (3ja)
22 (3ka)
0 (3la)
3
4
5
6
7
8
9
10
11
12
In conclusion, we have demonstrated the first Cu-catalyzed
oxidative amidation-diketonization reaction of terminal alkynes
leading to R-ketoamides. O2 not only participates as the ideal
oxidant but also undergoes dioxygen activation under ambient
conditions via a radical process. This chemistry also offers a
valuable mechanistic insight into this novel Cu catalysis. Further
studies to clearly understand the reaction mechanism and the
synthetic applications are ongoing in our laboratory.
a The standard reaction conditions are given in Table 2, footnote a.
b Isolated yields.
survived well, leading to halo-substituted R-ketoamides (Table 3,
entries 8-10), which could be used for further transformations.
The transformation of 1a and 2a was tested in the presence of H218
O
(10 equiv). However, the 18O-labeled product 18O-3aa was not detected
(eq 3). Further investigation under an 18O2 atmosphere [using mass
spectrometry (MS) and high-resolution MS; see the SI] proved the
dioxygen activation, indicating that both oxygen atoms of the R-ke-
toamide originated from molecular dioxygen (eq 4).
Acknowledgment. Financial support from Peking University,
the National Natural Science Foundation of China (20702002,
20872003), and the National Basic Research Program of China (973
Program 2009CB825300) is greatly appreciated. We thank Prof.
Chaozhong Li, Jingfen Lu, Yufei Song, and Li-Zhu Wu for helpful
discussions. We thank Riyuan Lin in this group for reproducing
the results for 3ab, 3aj, 3ga, and 3ia.
Supporting Information Available: Experimental details and NMR
spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
References
(1) Dioxygen has been used as an ideal oxidant. For some reviews, see: (a)
Punniyamurthy, T.; Velusamy, S.; Iqbal, J. Chem. ReV. 2005, 105, 2329.
In the electron paramagnetic resonance (EPR) spectra monitored
with the addition of the radical trap 5,5-dimethyl-1-pyrroline
N-oxide (DMPO), the signal corresponding to DMPO-OO(H) was
identified9 [see the “a” peaks in trace 1 of Figure 1; they are 12
classical peaks, and the calculated hyperfine splittings are g0 (2.006),
RN (14.4 G), RꢀH (13.3 G), and RγH (2.4 G)]. Furthermore, the above
signal disappeared with the addition of superoxide dismutase (SOD)
(trace 2 in Figure 1). The EPR results (for more details, see the SI)
indicate that the superoxide radical 7 (Scheme 1) is a key
intermediate involved in this kind of transformation.
A hypothesized mechanism of this transformation is shown in
Scheme 1. The proposed initiated complex 4 would insert alkyne
2a to give CuII intermediate 5. Next, imine radical 6 would
potentially be generated, and this would be followed by the
formation of the key intermediate, superoxide radical 7. Further
intramolecular cycloaddition to the imine would form the corre-
sponding aminyl radical 8.10 Intermediate 8 would then undergo
the second hydrogen abstraction facilitated by TEMPO or oxygen,
resulting in intermediate 9,11 and the subsequent fragmentation6a,12
of 9 would produce the desired R-ketoamide 3ea.
(b) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400.
(2) For some reviews, see: (a) Special issue on dioxygen activation by
metalloenzymes and models: Acc. Chem. Res. 2007, 40, 465-634. (b)
Limberg, C. Angew. Chem., Int. Ed. 2003, 42, 5932.
(3) (a) Klinman, J. P. J. Biol. Inorg. Chem. 2001, 6, 1. (b) Bollinger, J. M.,
Jr.; Krebs, C. Curr. Opin. Chem. Biol. 2007, 11, 151.
(4) Li, C.-J. Acc. Chem. Res. 2009, 42, 335, and references therein.
(5) (a) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833. (b)
Zhao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2008, 47, 7075. (c) Gao, Y.;
Wang, G.; Chen, L.; Xu, P.; Zhao, Y.; Zhou, Y.; Han, L.-B. J. Am. Chem.
Soc. 2009, 131, 7956.
(6) For the Pd-catalyzed cleavage reaction of alkynes with molecular dioxygen,
see: (a) Wang, A.; Jiang, H. J. Am. Chem. Soc. 2008, 130, 5030. For Pd-
catalyzed diketonization of alkynes with H2O, see: (b) Ren, W.; Xia, Y.;
Ji, S.-J.; Zhang, Y.; Wan, X.; Zhao, J. Org. Lett. 2009, 11, 1841.
(7) (a) Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.; Cui, Y.; Jiao, N. Angew.
Chem., Int. Ed. 2009, 48, 4572. For our recent work on radical reactions,
see: (b) Zhou, W.; Zhang, L.; Jiao, N. Tetrahedron 2009, 65, 1982. (c)
Zhou, W.; Zhang, L.; Jiao, N. Angew. Chem., Int. Ed. 2009, 48, 7094.
(8) For some reviews of the application of TEMPO in synthesis, see: (a)
Vogler, T.; Studer, A. Synthesis 2008, 1979. (b) De Souza, M. V. N. Mini-
ReV. Org. Chem. 2006, 3, 155. (c) Bragd, P. L.; van Bekkum, H.; Besemer,
A. C. Top. Catal. 2004, 27, 49. (d) Geisslmeir, D.; Jary, W. G.; Falk, H.
Monatsh. Chem. 2005, 136, 1591. (e) Sheldon, R. A.; Arends, I. W. C. E.;
ten Brink, G.-J.; Dijksman, A. Acc. Chem. Res. 2002, 35, 774.
(9) (a) Yamakoshi, Y.; Sueyoshi, S.; Fukuhara, K.; Miyata, N.; Masumizu,
T.; Kohno, M. J. Am. Chem. Soc. 1998, 120, 12363. (b) Finkelstein, E.;
Rosen, G. M.; Rauckman, E. J. J. Am. Chem. Soc. 1980, 102, 4994. (c)
Samuni, A.; Murali Krishna, C.; Riesz, P.; Finkelstein, E.; Russo, A. Free
Radical Biol. Med. 1989, 6, 141. (d) Izzet, G.; Zeitouny, J.; Akdas-Killig,
H.; Frapart, Y.; Me´nage, S.; Douziech, B.; Jabin, I.; Mest, Y. L.; Reinaud,
O. J. Am. Chem. Soc. 2008, 130, 9514. (e) Zhao, H.; Joseph, J.; Zhang,
H.; Karoui, H.; Kalyanaraman, B. Free Radical Biol. Med. 2001, 31, 599.
(f) Ou, Z.-Z.; Chen, J.-R.; Wang, X.-S.; Zhang, B.-W.; Cao, Y. New
J. Chem. 2002, 26, 1130.
(10) (a) Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543. (b) Bowman,
W. R.; Bridge, C. F.; Brookes, P. J. Chem. Soc., Perkin Trans. 1 2000, 1.
(c) Stella, L. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P.,
Eds.; Wiley-VCH: Weinheim, Germany, 2001; Vol. 2, p 407. (d) Guindon,
Y.; Guerin, B.; Landry, S. R. Org. Lett. 2001, 3, 2293. (e) Liu, F.; Liu, K.;
Yuan, X.; Li, C. J. Org. Chem. 2007, 72, 10231.
(11) (a) Chen, Y.-X.; Qian, L.-F.; Zhang, W.; Han, B. Angew. Chem., Int. Ed.
2008, 47, 9330. (b) Speier, G.; Pa´rka´nyi, L. J. Org. Chem. 1986, 51, 218.
(12) (a) Sima´ndi, L.; Sima´ndi, T. M.; May, Z.; Besenyei, G. Coord. Chem. ReV.
2003, 245, 85. (b) Schank, K.; Beck, H.; Werner, F. HelV. Chim. Acta
2000, 83, 1611.
Figure 1. EPR spectra (X band, 9.7 GHz, room temperature) for reaction
mixtures in the presence of (1) the radical trap DMPO (2.5 × 10-2 M) and
(2) SOD (2.5 × 10-3 M) and DMPO (1.25 × 10-2 M).
JA908911N
9
J. AM. CHEM. SOC. VOL. 132, NO. 1, 2010 29