Palladium-catalyzed oxidation of cyclohexanones to conjugated enones using molecular oxygen

Article abstract of DOI:10.1016/j.tetlet.2007.07.181

Oxidation of cyclohexanones into conjugated enones with molecular oxygen as oxidant was achieved by palladium catalysts. A catalyst system consists of 1 mol % Pd(OCOCF₃)₂ and 5,5′-dimethyl-2,2′-bipyridine accomplished maximum 84% yield for the oxidation of cyclohexanone and 51-78% yields for 4-substituted-cyclohexanones.

Full text of DOI:10.1016/j.tetlet.2007.07.181

Tetrahedron Letters 48 (2007) 6860–6862
Palladium-catalyzed oxidation of cyclohexanones to conjugated
enones using molecular oxygen
Makoto Tokunaga,*, Saki Harada, Tetsuo Iwasawa, Yasushi Obora and Yasushi Tsuji*,à
Catalysis Research Center and Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 001-0021,
Japan
CREST, Japan Science and Technology Agency (JST), Japan
Received 12 July 2007; revised 24 July 2007; accepted 26 July 2007
Available online 31 July 2007
Abstract—Oxidation of cyclohexanones into conjugated enones with molecular oxygen as oxidant was achieved by palladium cat-
alysts. A catalyst system consists of 1 mol % Pd(OCOCF3)2 and 5,50-dimethyl-2,20-bipyridine accomplished maximum 84% yield for
the oxidation of cyclohexanone and 51–78% yields for 4-substituted-cyclohexanones.
Ó 2007 Elsevier Ltd. All rights reserved.
Aerobic oxidation of organic molecules is a fundamental
and important transformation from the viewpoint of
environmentally benign synthesis.1 There is an increas-
ing demand for replacing stoichiometric oxidants with
more clean chemicals such as molecular oxygen and
hydrogen peroxide.2 In this context, we have developed
a Pd-catalyzed air-oxidation of alcohols1g and Cu- and
Brønsted acid-catalyzed oxidative C@C bond cleavage
using molecular oxygen.1b,d In the alcohol oxidation,1g
a remarkable steric effect of 2,3,4,5-tetraphenylphenyl
substituent3 was observed.1c,g A pyridine ligand bearing
this group at meta-position (1) successfully suppresses
the zero valent Pd oligomerization and deactivation.1c
methods have been developed over the years, employing
selenium reagents,5 hypervalent iodine reagents,6 and
others.7 Another popular method is the Pd-catalyzed
aerobic oxidation of silylenol ethers.8 However, direct
oxidation of parent ketones using Pd-catalysts suffered
from the deactivation of the catalysts and resulted in
poor yields.4,9 For example, in the oxidation of cyclo-
hexanone, two catalyst systems PdCl(NO2)(MeCN)2–
Ag(OSO2CF3) and Pd(OCOCF3)2–P(p-CH3C6H4)3 real-
ized only small turnover numbers of 114d and 5.9,4b
respectively. In these reports, only the turnover numbers
were presented, but they are corresponding to 27% and
1.9% chemical yields, respectively. In this Letter we
describe a new and active Pd-catalyst system for oxida-
tion of ketones into conjugated enones with mole-
cular oxygen, which realizes 84% chemical yield for
cyclohexenone.
Ph
Ph
Ph
Ph
The oxidation of cyclohexanone with various Pd precur-
sors and ligands was examined. Typically, 1 mol %
Pd(OCOCF3)2 was used as a Pd source under 1 atm oxy-
gen atmosphere at 100 °C (Table 1). Although phos-
phine ligands have been used in the previous studies,
pyridine ligands were found to be more efficient in this
reaction. The monodentate pyridine ligand 1, which
exhibited excellent performance in the alcohol oxida-
tion,1h was not so effective, although 1 gave better yield
than the unsubstituted pyridine (entries 1 and 2)
(Scheme 1).
N
1
With regard to catalytic oxidation of ketones into conju-
gated enones with molecular oxygen, only a few reports
have been made.4 Since this transformation is very
important in organic synthesis, many stoichiometric
*
Corresponding authors. Tel./fax: +81 92 642 7528 (M.T.); tel.: +81
75 383 2515; fax: +81 75 383 2514 (Y.T.); e-mail addresses:
mtok.scc@mbox.nc.kyushu-u.ac.jp; ytsuji@scl.kyoto-u.ac.jp
Present address: Department of Chemistry, Graduate School of
Science, Kyushu University, Fukuoka, 812-8581, Japan.
à Present address: Department of Energy and Hydrocarbon Chemistry,
Graduate School of Engineering, Kyoto University, Kyoto, 615-8510,
Japan.
Strongly coordinating DMAP prevented Pd black forma-
tion but also inhibited the reaction (entry 3). Bipyridine
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.181

M. Tokunaga et al. / Tetrahedron Letters 48 (2007) 6860–6862
6861
Table 1. Pd-catalyzed oxidation of 2a into 3a with atmospheric
oxygena
R3
R3
N
N
R2
R2
Entry
Ligand
Solvent
Yield of
Yield of
6
3ab (%)
4ab (%)
N
N
R1
R1
Pyridinec
Toluene
Toluene
Toluene
Toluene
17
24
Trace
19
24
25
46
70 (84)f
11
27
10
2
11
42
3
13
29
0
2
0
0
1
0
4
Me
Me
1
2
3
4
5
6
7
8e
9
10
11
12
13
14
15e
16
17
5a: R1 = R2 = R3 = H
1c
5b: R1 = R3 = H, R2 = Me
DMAPd,c
5c: R1 = R2 = H, R3 = C9H19
N
N
7
5a
5a
5b
5b
5b
5c
5d
5e
5f
5g
6
5d: R1 = R2 = H, R3 =
t-Bu
Chlorobenzene
Toluene
Chlorobenzene
Chlorobenzene
Toluene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
N
N
5e: R1 = R2 = H, R3 = Ph
5f: R1 = R2 = H, R3 = OMe
5g: R2 = R3 = H, R1 = Me
N
N
2 (4)f
8
2
2
3
0
0
2
0
0
1
Figure 1. Pyridine ligands used in this study.
Next we examined the oxidation of various ketones under
the optimized condition using ligand 5b (Table 2). Substi-
tuted cyclohexanones at the 4-position (2b–e) gave good
yields (51–78%) of the products (3b–e) (entries 1–4).
The selectivity for the enone formation was generally
high, the product yields were near to the substrate conver-
sions in all cases. Thus only trace amount of correspond-
ing phenols 4b–e were formed. A bulky substituent did
not decrease the yield (entry 3, 78% yield for 2d:
R = tBu:).
6
7
8
a A mixture of 2a (1 mmol), Pd(OCOCF3)2 (0.01 mmol), ligand
(0.01 mmol), and solvent (0.9 mL) was stirred at 100 °C for 24 h
under 1 atm O2.10
b GC yield.11
c 8 mol % (0.08 mmol) ligand was used.
d DMAP: 4-(dimethylamino)pyridine.
e
˚
Molecular sieves 4 A (100 mg) was added.
f For 48 h.
On the other hand, substituent at the 2- or 3-position of
cyclohexanone decreased the yield of enones (<20%).
For example, 19% yield for 76 h with 2-t-butylcyclo-
hexanone, 9% yield for 54 h with 3,5-dimethylcyclohexa-
none, and trace yield for 24 h with, a- and b- tetralone
were observed. Other cyclic substrates also showed low
reactivity. Among them, the highest yield (26%) was
obtained with cyclopentanone. Acyclic substrates such
as 4-phenyl-2-butanone and nonyl phenyl ketone also
resulted in low yield (<20% for 24 h).
O
O
OH
1 mol% Pd(OCOCF3)2
1 mol% Ligand
Solvent, O2 (1 atm)
100 °C
+
R
R
R
2a: R = H
3
4
2b: R = Me
2c: R = Et
2d: R = tBu
2e: R = Ph
Although a precise mechanism of the present reaction is
unclear, ketonic substrates would react with Pd in a sim-
ilar manner to the previous report.4b–d Thus probably
the reaction include the formation of palladium C-eno-
late followed by b-H elimination to give Pd0 species.
During the course of the reoxidation of Pd, aggregation
and deactivation of the catalyst takes place. The bipyridine
Scheme 1. Pd-catalyzed oxidation of 2 into 3 with atmospheric
oxygen.
ligands (5) and structurally related ligands provided
favorable results in terms of catalyst lifetime and activity
(entries 4–17) (Fig. 1). Particularly, 5,50-dimethyl-2,20-
bipyridine 5b exhibited highest performance. Using
1 equiv of 5b as ligand to Pd, yield of 3 was improved
to 46% by the use of chlorobenzene as solvent and
Table 2. Pd(OCOCF3)2/5b-catalyzed oxidation of 2b–d with atmo-
spheric oxygena
Entry
1
Substrate
Time (h)
Yield of 3ab (%)
˚
70% in the presence of molecular sieves 4 A (entries 7
2b
24
96
53
72
and 8). The catalyst was still active under the condition
and 84% yield was obtained with prolonged reaction
time (48 h, entry 8). Amount of the molecular sieves
affected the reaction; the highest yield was obtained in
entry 8. Gradual decrease of yield was observed with a
larger or a lesser amount of the molecular sieves. The
addition of molecular sieves was not always favorable,
and lower activity was observed when 2,20-biquinoline
6 was employed as ligand (entry 15). Other Pd precur-
sors such as Pd(OAc)2 showed slightly lower activity
but almost no reaction occurred when PdCl2(PhCN)2
was used. The addition of basic salts, such as NaOAc,
K2CO3, and NaOtBu, decreased the activity.
2
2c
24
48
95
55
69
78
3
4
2d
2e
20
44
53
78
20
48
47
51
a A mixture of
2
(1 mmol), Pd(OCOCF3)2 (0.01 mmol), 5b
˚
(0.01 mmol), molecular sieves 4 A (100 mg), and chlorobenzene
(0.9 mL) was stirred at 100 °C under 1 atm O2.
b GC yield.11,12

6862
M. Tokunaga et al. / Tetrahedron Letters 48 (2007) 6860–6862
4. (a) Hwang, S. W.; Park, Y. W. J. Ind. Eng. Chem. 2000, 6,
125–128; (b) Park, Y. W.; Oh, H. H. Bull. Korean Chem.
Soc. 1997, 18, 1123–1124; (c) Fuchita, Y.; Harada, Y.
Inorg. Chim. Acta 1993, 208, 43–47; (d) Wenzel, T. T. J.
Chem. Soc., Chem. Commun. 1989, 932–933; (e) Theissen,
R. J. J. Org. Chem. 1971, 36, 752–757.
ligands may stabilize Pd active species and prevent their
aggregation to extend the catalyst lifetime.
In conclusion, we have achieved catalytic transfor-
mation of cyclohexanone derivatives into correspond-
ing enones up to 84% yield with molecular oxygen as
oxidant.
5. Reich, H. J.; Renga, J. M.; Reich, I. L. J. Am. Chem. Soc.
1975, 97, 5434–5447.
6. Nicolaou, K. C.; Montagnon, T.; Baran, P. S. Angew.
Chem., Int. Ed. 2002, 41, 1386–1389.
References and notes
7. Allyl phosphate was used as a stoichiometric oxidant for
this transformation catalyzed by Pd complexes. Shvo, Y.;
Arisha, A. H. I. J. Org. Chem. 1998, 63, 5640–5642.
8. (a) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43,
1011–1013; (b) Larock, R. C.; Hightower, T. R.; Kraus,
G. A.; Hahn, P.; Zheng, D. Tetrahedron Lett. 1995, 36,
2423–2426.
1. (a) Punniyamurthy, T.; Velusamy, S.; Iqbal, J. Chem. Rev.
2005, 105, 2329–2363; (b) Tokunaga, M.; Aoyama, H.;
Shirogane, Y.; Obora, Y.; Tsuji, Y. Catal. Today 2006,
117, 138–140; (c) Komano, T.; Iwasawa, T.; Tokunaga,
M.; Obora, Y.; Tsuji, Y. Org. Lett. 2005, 7, 4677–4679; (d)
Tokunaga, M.; Shirogane, Y.; Aoyama, H.; Obora, Y.;
Tsuji, Y. J. Organomet. Chem. 2005, 690, 5378–5382; (e)
Ebitani, K.; Motokura, K.; Mizugaki, T.; Kaneda, K.
Angew. Chem., Int. Ed. 2005, 44, 3423–3426; (f) Shimizu,
H.; Onitsuka, S.; Egami, H.; Katsuki, T. J. Am. Chem.
Soc. 2005, 127, 5396–5413; (g) Iwasawa, T.; Tokunaga,
M.; Obora, Y.; Tsuji, Y. J. Am. Chem. Soc. 2004, 126,
6554–6555; (h) Uozumi, Y.; Nakao, R. Angew. Chem., Int.
Ed. 2003, 42, 194–197; (i) Sheldon, R. A.; Arends, I. W. C.
E.; ten Brink, G.-J.; Dijksman, A. Acc. Chem. Res. 2002,
35, 774–781; (j) Nishimura, T.; Onoue, T.; Ohe, K.;
Uemura, S. Tetrahedron Lett. 1998, 39, 6011–6014.
2. (a) Noyori, R.; Aoki, M.; Sato, K. Chem. Commun. 2003,
1977–1986; (b) Usui, Y.; Sato, K.; Tanaka, M. Angew.
Chem., Int. Ed. 2003, 42, 5623–5625.
3. (a) Tsuji, Y.; Fujihara, T. Inorg. Chem. 2007, 46, 1895–
1902; (b) Tokunaga, M.; Aoyama, H.; Kiyosu, J.;
Shirogane, Y.; Iwasawa, T.; Obora, Y.; Tsuji, Y. J.
Organomet. Chem. 2007, 692, 472–480; (c) Aoyama, H.;
Tokunaga, M.; Kiyosu, J.; Iwasawa, T.; Obora, Y.; Tsuji,
Y. J. Am. Chem. Soc. 2005, 127, 10474–10475; (d) Watson,
9. Under the reaction condition, facile formation of phos-
phine oxides was observed.
10. Typical procedure for Pd-catalyzed oxidation of cyclo-
hexanone (Table 1, entry 8). A dry 20-mL Schlenk flask
˚
was charged with molecular sieves 4 A (100 mg, powder,
activated, 5 lm, Aldrich), then heated at 200 °C for 5 min
under reduced pressure. After cooled to room tempera-
ture, Pd(OCOCF3)2 (3.3 mg, 0.010 mmol), 5,50-dimethyl-
2,20-bipyridine (1.8 mg, 0.010 mmol) and chlorobenzene
(0.9 mL) were introduced under Ar atmosphere, then
stirred at 60 °C for 15 min. To this were added cyclohex-
anone (98.1 mg, 1.00 mmol) and tridecane (internal stan-
dard, 37.8 mg, 0.205 mmol) at room temperature, then the
flask was purged with 1 atm O2. The mixture was stirred at
100 °C for 48 h, and the yield of the product was
determined by GC analysis.
11. GC analysis was performed by Agilent GC 6850 equipped
with Agilent HP-1 column (length 30 m, 0.32 mm I.D.).
Commercially unavailable authentic samples of enones
were synthesized by literature procedure.12
12. Sharpless, K. B.; Lauer, R. F.; Teranishi, A. Y. J. Am.
Chem. Soc. 1973, 95, 6137–6139.
M. D.; Fechtenko¨tter, A.; Mullen, K. Chem. Rev. 2001,
¨
101, 1267–1300.