Pd/C-catalyzed direct α-oxygenation of 1,3-dicarbonyl compounds using molecular oxygen

Article abstract of DOI:10.1055/s-2008-1078023

A hydroxyl group was readily and directly introduced into the α-position of a variety of β-dicarbonyl compounds by heterogeneous Pd/C-catalyzed oxygenation using molecular oxygen. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078023

LETTER
2291
Pd/C-Catalyzed Direct a-Oxygenation of 1,3-Dicarbonyl Compounds Using
Molecular Oxygen
P
d/C-Catalyzed
a
-
a
O
xygenatio
s
n of
b
-D
i
u
carbonyl Com
n
pounds with
a
O
xygen ri Monguchi, Tohru Takahashi, Yusuke Iida, Yuta Fujiwara, Yuya Inagaki, Tomohiro Maegawa,
Hironao Sajiki*
Department of Medicinal Chemistry, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu, 502-8585, Japan
Fax +81(58)2375979; E-mail: sajiki@gifu-pu.ac.jp
Received 12 May 2008
Table 1 a-Oxygenation of Diethyl Phenylmalonate
Abstract: A hydroxyl group was readily and directly introduced
into the a-position of a variety of b-dicarbonyl compounds by het-
erogeneous Pd/C-catalyzed oxygenation using molecular oxygen.
CO2Et
CO2Et
catalyst (30 wt% of 1)
Ph
Ph
HO
EtOH, r.t.
CO2Et
CO2Et
Key words: heterogeneous catalysis, palladium, oxygenation, oxy-
gen, ketones
1
2
Entry Catalyst
Base (equiv) Gas
Time (h) 1/2a
1
2
10% Pd/C
10% Rh/C
10% Ru/C
10% Ni/C
10% Pt/C
10% Ir/C
10% Au/C
Norit
–
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
Air
O2
Ar
12
12
12
12
12
12
12
12
6
39:61
98:2
The direct introduction of a hydroxyl group at the a-posi-
tion of the carbonyl compounds is a useful technique to
construct the a-ketoalcohol functionality, which could be
applied as a synthon of a variety of molecules including
natural products.1 A number of methods for such a trans-
formation has been developed using stoichiometric
amounts of oxidants such as MoOPH,2 Pb(OAc)4,3 m-
chloroperbenzoic acid,4 dimethyldioxirane,5 N-sulfo-
nyloxaziridine derivatives,6 etc. Most of these reagents
are ecologically harmful and require the strong base, for
example, lithium amide. Then, molecular oxygen has
been applied as an environmentally benign oxygen source
with chiral phase-transfer catalysts7 or chiral aza-crown
ethers.8 Oxygenation of a-substituted b-dicarbonyl com-
pounds has also been achieved under oxygen atmosphere
with cesium fluoride or cesium carbonate as a base.9 Re-
cently, molecular oxygen was combined with a catalytic
amount of a transition-metal reagent, such as MnO2,10
CoCl2,11 and CeCl312 for the hydroxylation of a-substitut-
ed b-dicarbonyl compounds, although heterogeneous cat-
alysts were not yet applied.
–
3
–
98:2
4
–
57:43
100:0
92:8
5
–
6
–
7
–
90:10
88:12
8
–
9
10% Pd/C
10% Pd/C
10% Pd/C
–
Et3N (1.1)
Et3N (0.2)
Et3N (1.1)
Et3N (1.1)
–
0:100b
10
11c
12
13
12
12
39
12
14:86
11:89
100:0
100:0
10% Pd/C
a Determined by 1H NMR analysis.
b Compound 2 was isolated in 98% yield.
c The reaction was carried out under the open system.
The use of the carbon-supported transition-metal cata-
lysts, which are easily available, have been investigated
for a wide range of reactions, because of their reliable re-
cyclability and easy removal from reaction media.13 In
this paper, we report the a-oxygenation of b-dicarbonyl
compounds catalyzed by palladium on carbon (Pd/C).
Replacement of Pd/C with other carbon-supported transi-
tion-metal catalysts, such as Rh/C, Ru/C, Ni/C, Pt/C, Ir/C,
and Au/C, significantly dropped the yield of 2 (entries 2–
7). The use of an activated carbon (Norit) with no metal
embedded14 only slightly produced the conversion (entry
8). On the other hand, the addition of 1.1 equivalents of
Et3N as a weak base to the Pd/C-catalyzed reaction system
remarkably enhanced the reaction rate and the hydroxyl-
ation was completed within six hours to give 2 in a 98%
isolated yield.15 The reaction was expedited by the addi-
tion of even a catalytic amount of Et3N (entry 10 vs. 1).
The use of air instead of oxygen was available but not so
efficient for the reaction progress (entry 11). Since the re-
action never takes place without 10% Pd/C (entry 12) or
oxygen (entry 13), it is obvious that Pd/C is necessary for
Stirring diethyl phenylmalonate (1) in EtOH at room tem-
perature under an oxygen atmosphere (balloon) in the
presence of a catalytic amount of 10% Pd/C (10 wt% of 1)
led to a moderate generation of an a-oxygenated product
(2) to give a mixture of 1 and 2 in the ratio of 39:61 (entry
1, Table 1).
SYNLETT 2008, No. 15, pp 2291–2294
1
5
.0
9
.2
0
0
8
Advanced online publication: 31.07.2008
DOI: 10.1055/s-2008-1078023; Art ID: U04908ST
© Georg Thieme Verlag Stuttgart · New York

2292
Y. Monguchi et al.
LETTER
Table 3 a-Oxygenation of Various b-Dicarbonyl Compounds
the reaction and molecular oxygen works as the oxygen
source.
O2 (balloon)
10% Pd/C (30 wt% of the substrate)
Et3N (1.1 equiv)
O
O
O
O
Although the present reaction using 10% Pd/C and O2 was
applied to the a-oxygenation of diethyl benzylmalonate
(3a), no reaction took place with or without 1.1 equiva-
lents of Et3N (entries 1 and 2, Table 2).
R1
R3
R1
R3
EtOH, r.t.
R2 OH
R2
Entry
1
Substrate
Time (h)
16
Yield (%)a
76
Table 2 a-Oxygenation of a-Substituted Diethyl Malonates
O
O
O
O2 (balloon)
10% Pd/C (30 wt% of 3)
base
Me
OEt
OEt
CO2Et
CO2Et
CO2Et
CO2Et
R
Bn
R
HO
EtOH, r.t., 24 h
O
2
3
24
56
86
3
4
Me
Me
O
Entry
R
Base (equiv)
Isolated yield (%)
O
1
Bn (3a)
Bn (3a)
Bn (3a)
Bn (3a)
Et (3b)
–
0a
0b
3.5
OEt
2
Et3N (1.1)
O
O
O
3
EtONa (0.15)
EtONa (0.15)
EtONa (0.15)
94
0d
84
4
5
6
36
24
38
61
57
88
OEt
4c
5
O
a Compound 3a was quantitatively recovered.
Me
b No reaction took place; 94% of 3a was recovered.
c The reaction was carried out in the absence of 10% Pd/C.
d No reaction took place; 87% of 3a was recovered.
O
Me
Instead, the use of EtONa as a stronger base significantly
improved the reactivity, and the oxygenated product 4a
was obtained even with a catalytic amount (0.15 equiv) of
EtONa in 94% yield (entry 3). Furthermore, Pd/C was
found to be essential for the reaction (entry 4). The a-ox-
ygenation of diethyl ethylmalonate (3b) was also
achieved using 0.15 equivalents of EtONa (entry 5).
a Isolated yield.
ceeded without base, regardless of the protection at the
N1-position (Scheme 1).
When 2-phenyl-1,3-indanedione was employed as the
substrate, the homocoupling reaction preferably took
place rather than the desired oxygenation to give a dimer
in 94% yield (Scheme 2), suggesting the existence of a
radical intermediate at the 2-position.16,17 Interestingly,
the oxygenation reaction of 1,3-dicarbonyl compounds
bearing no substituent at the 2-position, such as diethyl
malonate, never proceeded. It is rational to consider that
the present a-oxygenation reaction is mediated by the rad-
ical intermediate since a radical on the tertiary carbon is
more stable than a radical on the secondary carbon, as
generated on the 2-unsubstituted 1,3-dicarbonyl com-
pounds.
The a-oxygenation of a variety of 1,3-dicarbonyl com-
pounds was then investigated (Table 3).
Both acyclic and cyclic a-substituted-b-ketoesters were
smoothly oxygenated at the a-position to give the corre-
sponding secondary alcohols in good yields (entries 1–4,
Table 3). 2-Acetyl-tetralone as a 1,3-diketone (entry 5)
could also be applied to the reaction. It is noteworthy that
a hydroxyl group was successively introduced to the a-po-
sition of 2-methylindanone, which is a monocarbonyl
compound, under such mild conditions (entry 6).
We next investigated the Pd/C-catalyzed oxygenation of
the biomolecular uridine derivatives, which has a mal-
onate moiety at the 5-position. This reaction easily pro-
In summary, we have developed a heterogeneous Pd/C-
catalyzed a-oxygenation of 1,3-dicarbonyl compounds
using molecular oxygen as the oxygen source. The present
EtO2C
HO
EtO2C
EtO2C
HO
O
O
N
R
O
R
O
O2 (balloon)
N
N
EtO2C
HO
10% Pd/C (30 wt% of the substrate)
N
MeOH, r.t.
R = H: 72%
R = BOM: 73%
O
O
HO
HO
Scheme 1 Application to the oxygenation of uridine derivatives
Synlett 2008, No. 15, 2291–2294 © Thieme Stuttgart · New York

LETTER
Pd/C-Catalyzed a-Oxygenation of b-Dicarbonyl Compounds with Oxygen
2293
O2 (balloon)
10% Pd/C (30 wt% of the substrate)
Et3N (1.1 equiv)
O
O
O
O
Ph
Ph
Ph
EtOH, r.t., 12 h
94%
O
O
Scheme 2 Oxidative homocoupling of 2-phenyl-1,3-indanedione
1.63 (3 H, m), 1.30 (3 H, t, J = 7.2 Hz). MS (EI): m/z (%) = 186 (50)
[M+], 142 (60), 85 (100). HRMS (EI): m/z calcd for C9H14O4 [M+]:
186.08921; found: 186.08839.
reaction efficiently proceeds in the presence of a stoichio-
metric amount of Et3N or a catalytic amount of EtONa un-
der ambient pressure and temperature.
2-Acetyl-3,4-dihydro-2-hydroxy-1-naphthalene21
1H NMR (400 MHz, CDCl3): d = 7.94 (1 H, d, J = 7.7 Hz), 7.46 (1
H, dd, J = 7.7, 7.4 Hz), 7.27 (1 H, dd, J = 7.4, 7.1 Hz), 7.18 (1 H, d,
J = 7.1 Hz), 4.53 (1 H, s), 3.06–3.03 (2 H, m), 2.53 (1 H, m), 2.20
(3 H, s), 2.12 (1 H, m). MS–FAB (Gly): m/z (%) = 205 (3) [M+ +
H]. HRMS–FAB: m/z calcd for C12H13O3 [M+ + H]: 205.08648;
found: 205.08740.
General Procedure for the a-Oxygenation of 1,3-Dicarbonyl
Compounds
To a test tube with a stir bar were added the 1,3-dicarbonyl com-
pound (0.250 mmol), EtOH (1 mL), 10% Pd/C (30% of the sub-
strate weight), and Et3N (38.3 mL, 0.275 mmol). The system was
sealed with a septum and the air inside was replaced with O2 (bal-
loon) by five vacuum and oxygen cycles. The mixture was stirred at
r.t. for 12 h and passed through a 0.45 mm membrane filter (Milli-
pore, Millex®–LH). The filter was washed with EtOH (3 × 10 mL)
and the combined filtrates were concentrated in vacuo. The residue
was purified by flash column chromatography on SiO2 (hexane–
EtOAc) to give the a-oxygenated product.
2-Hydroxy-2-methyl-1-indanone22
1H NMR (400 MHz, CDCl3): d = 7.77 (1 H, d, J = 7.6 Hz), 7.63 (1
H, d, J = 7.6 Hz), 7.43 (1 H, d, J = 7.6 Hz), 7.39 (1 H, t, J = 7.6 Hz),
3.28 (1 H, d, J = 16.7 Hz), 3.22 (1 H, d, J = 16.7 Hz), 3.21 (1 H, s),
1.45 (3 H, s). MS (EI): m/z (%) = 162 (100) [M+], 120 (68), 91 (55).
HRMS (EI): m/z calcd for C10H10O2 [M+]: 162.06808; found:
162.06755.
Diethyl 2-Hydroxy-2-phenylmalonate18
1H NMR (400 MHz, CDCl3): d = 7.65 (2 H, dd, J = 8.0, 1.7 Hz),
7.39–7.26 (3 H, m), 4.38 (1 H, s), 4.38 (1 H, s), 4.29 (4 H, m), 1.28
(6 H, t, J = 7.0 Hz). MS (EI): m/z (%) = 252 (1) [M+], 179 (29), 105
(100). HRMS (EI): m/z calcd for C13H16O5 [M+]: 252.09977; found:
252.10066.
5-(1,1-Diethoxycarbonyl-1-hydroxymethyl)-2¢-deoxyuridine
1H NMR (400 MHz, DMSO-d6): d = 11.47 (1 H, s), 7.79 (1 H, s),
6.64 (1 H, br s), 6.18 (1 H, m), 5.25 (1 H, d, J = 4.1 Hz), 4.91 (1 H,
t, J = 5.1 Hz), 4.17–4.06 (5 H, m), 3.79 (1 H, m), 3.54–3.48 (2 H,
m), 2.03 (1 H, m), 1.97 (1 H, m), 1.15 (6 H, t, J = 7.2 Hz). MS–FAB
(NBA): m/z (%) = 403 (8) [M+], 176 (6), 154 (100). HRMS–FAB
(NBA): m/z calcd for C16H23N2O10 [M+]: 403.13523; found:
403.13589.
Diethyl 2-Benzyl-2-hydroxymalonate19
1H NMR (400 MHz, CDCl3): d = 7.25–7.24 (5 H, m), 4.24 (4 H, q,
J = 7.3 Hz), 3.73 (1 H, s), 3.35 (2 H, s), 1.28 (6 H, t, J = 7.3 Hz). MS
(EI): m/z (%) = 266 (1) [M+], 248 (36), 91 (100). HRMS (EI): m/z
calcd for C14H18O5 [M+]: 266.11542; found: 266.11645.
3-Benzyloxymethyl-5-(1,1-diethoxycarbonyl-1-hydroxymeth-
yl)-2¢-deoxyuridine
1H NMR (400 MHz, DMSO-d6): d = 7.92 (1 H, s), 7.30 (5 H, m),
6.76 (1 H, s), 6.20 (1 H, m), 5.31 (1 H, s), 5.28 (1 H, d, J = 4.1 Hz),
4.94 (1 H, t, J = 5.1 Hz), 4.56 (2 H, s), 4.21 (1 H, m), 4.14 (4 H, q,
J = 7.2 Hz), 3.82 (1 H, m), 3.53 (2 H, m), 2.17 (1 H, m), 2.03 (1 H,
m), 1.15 (6 H, t, J = 7.2 Hz). MS–FAB (NBA): m/z (%) = 523 (6)
[M+], 154 (100). HRMS–FAB (NBA): m/z calcd for C24H31N2O11
[M+]: 523.19283; found: 523.19109.
Diethyl 2-Ethyl-2-hydroxymalonate19
1H NMR (400 MHz, CDCl3): d = 4.27 (4 H, q, J = 7.1 Hz), 3.75 (1
H, s), 2.06 (2 H, q, J = 7.3 Hz), 1.29 (6 H, t, J = 7.1 Hz), 0.91 (3 H,
t, J = 7.3 Hz). No molecular ion peak was observed, see ref. 17.
Ethyl a-Acetyl-a-hydroxy-benzenepropanoate12b
1H NMR (400 MHz, CDCl3): d = 7.28–7.21 (5 H, m), 4.22 (2 H, q,
J = 7.3 Hz), 4.07 (1 H, s), 3.41 (1 H, d, J = 14.4 Hz), 3.18 (1 H, d,
J = 14.4 Hz), 2.27 (3 H, s), 1.27 (3 H, t, J = 7.3 Hz). MS (EI): m/z
(%) = 236 (2) [M+], 194 (92), 91 (100). HRMS (EI): m/z calcd for
C13H16O4 [M+]: 236.10486; found: 236.10425.
2,2¢-Diphenyl-[2,2¢-biindane]-1,1¢,3,3¢-tetrone23
1H NMR (400 MHz, DMSO-d6): d = 7.88 (4 H, dd, J = 5.7, 3.0 Hz),
7.73 (4 H, dd, J = 5.7, 3.0 Hz), 7.33 (2 H, t, J = 7.6 Hz), 7.25 (4 H,
t, J = 7.6 Hz), 7.19 (4 H, d, J = 7.6 Hz). MS (EI): m/z (%) = 442 (45)
[M+], 221 (100). HRMS (EI): m/z calcd for C30H18O4 [M+]:
442.12051; found: 442.12028.
Ethyl 2-Hydroxy-2-methylacetoacetate20
1H NMR (400 MHz, CDCl3): d = 4.26 (2 H, q, J = 7.1 Hz), 4.17 (1
H, s), 2.28 (3 H, s), 1.59 (3 H, s), 1.30 (3 H, t, J = 7.1 Hz). No mo-
lecular ion peak was observed.
Acknowledgment
We sincerely thank the N. E. Chemcat Corporation for the gift of the
carbon-supported catalysts.
Ethyl 1-Hydroxy-2-oxo-1-cyclopentanecarboxylate10
1H NMR (400 MHz, CDCl3): d = 4.19 (2 H, q, J = 7.3 Hz), 3.71 (1
H, s), 2.45–2.36 (3 H, m), 2.10–1.99 (3 H, m), 1.22 (3 H, t, J = 7.3
Hz). MS (EI): m/z (%) = 172 (17) [M+], 145 (30), 99 (100). HRMS
(EI): m/z calcd for C8H12O4 [M+]: 172.07356; found: 172.07421.
References and Notes
(1) (a) Corey, E. J. Chem. Soc. Rev. 1998, 17, 111. (b) Davis,
F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919. (c) Chen,
B.-C.; Zhou, P.; Davis, F. A.; Ciganek, E. In Org. React.,
Vol. 62; Overman, L. E.; Boger, D.; Charette, A.; Denmark,
S. E.; Farina, V.; Hegedus, L.; Kiessling, L.; Martinelli, M.
Ethyl 1-Hydroxy-2-oxo-1-cyclohexanecarboxylate10
1H NMR (400 MHz, CDCl3): d = 4.34 (1 H, s), 4.25 (2 H, q, J = 7.2
Hz), 2.70–2.53 (3 H, m), 2.04 (1 H, m), 1.88–1.79 (2 H, m), 1.77–
Synlett 2008, No. 15, 2291–2294 © Thieme Stuttgart · New York

2294
Y. Monguchi et al.
LETTER
homepage on the web (http://www.norit-americas.com/
J.; McCombie, S. W.; Rajanbabu, T. V.; Rigby, J. H.;
Rychnovsky, S. D.; Smith, A. B. III.; Wipf, P., Eds.; John
Wiley and Sons, Inc.: Hoboken, 2003, 1–356.
norit-sxplus.html). The reason why a 12% conversion was
attained is not clear. A very small amount of residual metal
might have caused the reaction, or the charcoal itself might
have been activated that the reaction took place.
(15) 10% Pd/C could be simply recovered and reused for at least
five cycles with more than a 90% yield of 2 after the 5th run,
although the catalytic activity was gradually diminished.
(16) Oxidative coupling of 2-phenylindanedionyl radicals to
dimerization was reported: Harnack, C.; Krull, W.; Lehnig,
M.; Neumann, W. P.; Zarkadis, A. K. J. Chem. Soc., Perkin
Trans. 2 1994, 1247.
(17) Oxidative radical homocouplings of 2-substituted malonates
were also reported: (a) De Jongh, H. A. P.; De Jonge, D. R.
H. I.; DeKlein, W. J.; Huysmans, W. G. B.; Mijs, W. J.; Van
Den Hoek, W. J.; Smidt, J. J. Org. Chem. 1972, 37, 1960.
(b) Peek, R.; Streukens, M.; Thomas, H. G.; Vanderfuhr, A.;
Wellen, U. Chem. Ber. 1994, 127, 1257.
(2) Vedejs, E.; Engler, D. A.; Telschow, J. E. J. Org. Chem.
1978, 43, 188.
(3) Demir, A. S.; Jeganathan, A. Synthesis 1992, 235.
(4) Andriamialisoa, R. Z.; Langlois, N.; Langlois, Y.
Tetrahedron Lett. 1985, 26, 3563.
(5) Adam, W.; Smerz, A. Tetrahedron 1996, 52, 5799.
(6) (a) Davis, F. A.; Clark, C.; Kumar, A.; Chen, B.-C. J. Org.
Chem. 1994, 59, 1184. (b) Davis, F. A.; Liu, H.; Chen,
B.-C.; Zhou, P. Tetrahedron 1998, 54, 10481.
(7) Masui, M.; Ando, A.; Shioiri, T. Tetrahedron Lett. 1988, 29,
2835.
(8) De Vries, E. F. J.; Ploeg, L.; Colao, M.; Brussee, J.; Van der
Gen, A. Tetrahedron: Asymmetry 1995, 6, 1123.
(9) Watanabe, T.; Ishikawa, T. Tetrahedron Lett. 1999, 40,
7795.
(10) Christoffers, J. J. Org. Chem. 1999, 64, 7668.
(11) Baucherel, X.; Levoirier, E.; Uziel, J.; Juge, S. Tetrahedron
Lett. 2000, 41, 1385.
(12) (a) Christoffers, J.; Werner, T. Synlett 2002, 119.
(b) Christoffers, J.; Werner, T.; Unger, S.; Frey, W. Eur. J.
Org. Chem. 2003, 425.
(13) For reviews, see: (a) Yin, L.; Liebscher, J. Chem. Rev. 2007,
107, 133. (b) Seki, M. J. Synth. Org. Chem. Jpn. 2006, 64,
853. (c) Seki, M. Synthesis 2006, 2975.
(18) Citterio, A.; Finzi, C.; Santi, R.; Strologo, S. J. Chem. Res.,
Synop. 1988, 156.
(19) Pac, C.; Sakurai, H.; Shima, K.; Ogata, Y. Bull. Chem. Soc.
Jpn. 1975, 48, 277.
(20) Greiner, A. Tetrahedron Lett. 1992, 33, 1897.
(21) Yoshioka, M.; Nishioka, T.; Hasegawa, T. J. Org. Chem.
1993, 58, 278.
(22) Enders, D.; Niemeier, O. Synlett 2004, 2111.
(23) Kappe, T.; Brandner, A.; Stadlbauer, W. Monatsh. Chem.
1987, 118, 1177.
(14) Norit SX PLUS, an acid-washed, steam-activated carbon,
was used without further purification. See the Norit
Synlett 2008, No. 15, 2291–2294 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.