2-Hydroxylation of 1,3-Diketones with Atmospheric Oxygen

Article abstract of DOI:10.1055/s-0035-1560647

An efficient method for the 2-hydroxylation of 1,3-diketones by using atmospheric oxygen as an oxidant under transition-metal-free condition is described. The protocol has the advantages of using an inexpensive and stable oxidant, producing high yields, and requiring ecofriendly conditions.

Full text of DOI:10.1055/s-0035-1560647

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2863–2865
letter
2863
Z. Li et al.
Letter
Synlett
2-Hydroxylation of 1,3-Diketones with Atmospheric Oxygen
Zheng Li*
Tianpeng Li
O
O
O
O
air, H2O
one step
Jiasheng Li
Lili He
R1
R2
R1
R2
Xianggui Jia
Jingya Yang
80–95% yield
14 examples
OH
R1, R2 = aryl, heteroaryl
College of Chemistry and Chemical Engineering, Northwest
Normal University, Lanzhou, Gansu 730070, P. R. of China
lizheng@nwnu.edu.cn
Received: 26.07.2015
Accepted after revision: 05.09.2015
Published online: 22.09.2015
lution. Therefore the exploration of the reaction using air as
an oxidant without heavy metals and the enlargement of
the substrate scope are still necessary. Here we report a 2-
hydroxylation of 1,3-diketones by using air as an oxidant in
the absence of heavy metals.
Initially, the required 1,3-diarylpropane-1,3-diones 1
were prepared by the reaction of methyl benzoates with ac-
etophenones in the presence of sodium methoxide in xy-
lene (Scheme 1).
DOI: 10.1055/s-0035-1560647; Art ID: st-2015-w0579-l
Abstract An efficient method for the 2-hydroxylation of 1,3-diketones
by using atmospheric oxygen as an oxidant under transition-metal-free
condition is described. The protocol has the advantages of using an in-
expensive and stable oxidant, producing high yields, and requiring
ecofriendly conditions.
Key words diketones, hydroxylations, oxidations, green chemistry
O
O
O
O
MeONa
+
R1
R2
2-Hydroxy-1,3-dicarbonyl compounds are widely used
as synthetic intermediates, and the 2-hydroxy-1,3-dicar-
bonyl group is a common structural motif in many natural
products and pharmaceuticals.1 The most convenient syn-
thetic route to 2-hydroxy-1,3-dicarbonyl compounds is the
direct oxidation of the corresponding 1,3-dicarbonyl com-
pounds with various oxidants, such as m-chloroperbenzoic
acid,2 dimethyldioxirane,3 oxaziridines,4 cumene hydroper-
oxide,5 or nitrosobenzene.6 However, such oxidants have
disadvantages in terms of their instability and high cost.
With respect to the synthesis of 2-hydroxy-1,3-diketones,
Labat and Meunier reported a peroxidase route for the hy-
droxylation of dimedone (5,5-dimethylcyclohexane-1,3-di-
one) with hydroperoxide as an oxidant.7 Suzuki and co-
workers reported a two-step method involving the hydrox-
ylation of isoxalium salts by using sodium hypochlorite as
an oxidant.8 Recently, oxidation by molecular oxygen cata-
lyzed by transition-metal catalysts (manganese,9 cerium,10
or palladium11) or by diiodine12 has been used to synthesize
2-hydroxy-1,3-dicarbonyl compounds. From an economic
and ecological point of view, the oxidation of dicarbonyl
compounds by air is optimal. However, these reactions are
still limited by the restricted scope of the substrates, such
as β-keto esters. A heavy-metal catalyst loading of at least 5
mol% is still required, which can cause environmental pol-
OMe
R2
R1
Me
xylene, reflux
1
R1, R2 = aryl, heteroaryl
Scheme 1 Synthesis of 1,3-diarylpropane-1,3-diones
In the investigations on the 2-hydroxylation of 1,3-dike-
tones, 1,3-diphenylpropane-1,3-dione (1a) was selected as
a substrate. The reaction was conducted by using air as an
oxidant under various conditions involving a range of cata-
lysts, bases, and solvents. In the absence of a catalyst, no 2-
hydroxy-1,3-diphenylpropane-1,3-dione (2a) was obtained
(Table 1, entry 1). The reaction also failed in the presence of
the transition-metal catalyst copper(I) iodide (entry 2). For-
tunately, further research showed that several alkali metal
halides, such as sodium iodide, potassium iodide, potassi-
um bromide, and potassium chloride were efficient cata-
lysts for the reaction, giving 2a in good yields (entries 3−6).
In particular, potassium fluoride, cesium fluoride, calcium
fluoride, and tetrabutylammonium fluoride trihydrate gave
the hydroxy compound 2a in high yields (entries 7−10). Of
these catalysts, potassium fluoride afforded the best yield
(entry 7). The choice of base also had an effect on the reac-
tion of dione 1a. Product 2a was not obtained in the ab-
sence of a base (entry 13). When calcium hydroxide, sodi-
um tert-butoxide, or sodium hydroxide was used as the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2863–2865

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Z. Li et al.
Letter
Synlett
base (entries 7, 11−12), the best results were obtained with
sodium hydroxide (entry 7). The solvents also played an
important role in the reaction of dione 1a. The reaction in
aqueous dimethyl sulfoxide gave the desired product 2a in
good yield (entry 15). Aqueous N,N-dimethylformamide
was also an effective solvent for the reaction, giving the hy-
droxylated product in high yield (entry 7). Note that water
is indispensable for the reaction; in the absence of water,
product 2a was not obtained (entry 14). Other solvents that
were tested (ethanol, 1,4-dioxane, acetonitrile, toluene, tet-
rahydrofuran, and dichloromethane) did not give an effi-
cient reaction.
yields than the latter. 1,3-Diketones bearing heteroaryl
groups, such as thienyl or furyl, also reacted efficiently (en-
tries 13 and 14). Unfortunately, attempts to perform 2-hy-
droxylation of aliphatic 1,3-diketones such as pentane-2,4-
dione (1o, R1 = R2 = Me; entry 15), were unsuccessful, possi-
bly because, unlike aromatic 1,3-diketones, aliphatic 1,3-
diketones cannot form stable conjugate enol intermediates
during the reactions, making the hydroxylation more diffi-
cult.
Table 2 Scope of the 1,3-Diketones
O
O
O
O
KF, NaOH
R1
R2
Table 1 Optimization of the Reaction Conditions for the 2-Hydroxyl-
ation of Dione 1aa
R1
R2
air, DMF-H2O, 120 °C, 12 h
OH
1
2
R1, R2 = aryl, heteroaryl
O
O
O
O
catalyst, base
Entry
R1
Ph
R2
Product
Yield (%)
OH
2a
air, solvent
120 °C, 12 h
1
2
Ph
2a
2b
2c
2d
2e
2f
95
93
90
89
85
87
82
85
82
80
82
80
81
80
0
1a
Ph
4-Tol
Entry Catalyst
Base
Solvent
Time
(h)
Yieldb
(%)
3
Ph
4-MeOC6H4
4-Tol
4
4-Tol
4-Tol
Ph
1
2
−
NaOH
DMF–H2O (24:1)
24
24
12
12
12
12
12
12
12
12
12
12
24
24
12
0
0
5
4-MeOC6H4
3-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
4-ClC6H4
3-BrC6H4
2-thienyl
2-furyl
CuI
NaI
KI
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
Ca(OH)2
t-BuONa
−
DMF–H2O (24:1)
DMF–H2O (24:1)
DMF–H2O (24:1)
DMF–H2O (24:1)
DMF–H2O (24:1)
DMF–H2O (24:1)
DMF–H2O (24:1)
DMF–H2O (24:1)
DMF–H2O (24:1)
DMF–H2O (24:1)
DMF–H2O (24:1)
DMF–H2O (24:1)
DMF
6
3
75
80
84
87
95
93
89
90
78
89
0
7
Ph
2g
2h
2i
4
8
Ph
5
KBr
KCl
KF
9
Ph
6
10
11
12
13
14
15
4-Tol
4-Tol
Ph
2j
7
2k
2l
8
CsF
CaF2
9
Ph
2m
2n
2o
10
11
12
13
14
15
TBAF∙3H2O
Ph
KF
KF
KF
KF
KF
Me
Me
The following plausible mechanism is proposed for the
2-hydroxylation of 1,3-diketones (Scheme 2). First, the 1,3-
diketone 1 is converted into an enol isomer A by hydrogen
bonding to the fluoride ion of potassium fluoride. Enol A is
oxidized by air to form the epoxide intermediate B, which
undergoes nucleophilic attack by a hydroxy ion to give in-
termediate C through ring-opening of the epoxide moiety.
Intermediate C easily yields the final product 2 by loss of
fluoride and hydroxy ions.
In conclusion, novel method has been developed for the
2-hydroxylation of 1,3-diketones by using atmospheric ox-
ygen as an oxidant, potassium fluoride as a catalyst, and so-
dium hydroxide as a base under transition-metal-free con-
ditions. The advantages of this protocol are its use of an in-
expensive and stable oxidant, its high yield, and its
ecofriendly conditions.
NaOH
NaOH
0
DMSO–H2O (24:1)
70
a Reaction conditions: 1a (1 mmol), catalyst (0.1 mmol), base (0.2 mmol),
solvent (5 mL), 120 °C, air.
b Isolated yield.
On the basis of these promising findings, a series of 1,3-
diketones 1 were examined in the hydroxylation reaction to
give the corresponding 2-hydroxy-1,3-diketones 2 by using
potassium fluoride as the catalyst and sodium hydroxide as
the base in aqueous N,N-dimethylformamide under air (Ta-
ble 2).13 1,3-Diketones bearing either electron-donating
(methyl, methoxy) groups or electron-withdrawing (fluoro,
chloro, bromo) groups on the aromatic rings participated in
the reaction (Table 2, entries 2–12). However, the former
gave the desired 2-hydroxy-1,3-diketones in slightly higher
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2863–2865

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Z. Li et al.
Letter
Synlett
F–
H
F–
H
(3) (a) Adam, W.; Smerz, A. K. Tetrahedron 1996, 52, 5799.
(b) Smith, A. M. R.; Rzepa, H. S.; White, A. J. P.; Billen, D.; Hii, K.
K. J. Org. Chem. 2010, 75, 3085.
(4) (a) Davis, F. A.; Chen, B. C. Chem. Rev. 1992, 92, 919. (b) Davis, F.
A.; Liu, H.; Chen, B. C.; Zhou, P. Tetrahedron 1998, 54, 10481.
(5) Odagi, M.; Furukori, K.; Yamamoto, Y.; Sato, M.; Iida, K.;
Yamanaka, M.; Nagasawa, K. J. Am. Chem. Soc. 2015, 137, 1909.
(6) Lu, M.; Zhu, D.; Lu, Y.; Zeng, X.; Tan, B.; Xu, Z.; Zhong, G. J. Am.
Chem. Soc. 2009, 131, 4562.
F–
H
O
O
O
O
O
O
O
O
air
F–
OH–
R1
–O
R2
R2
R1
R2
R2
R1
R1
O
OH
A
1
B
C
F–, OH-
(7) Labat, G.; Meunier, B. J. Chem. Soc., Chem. Commun. 1990, 1414.
(8) Takikawa, H.; Takada, A.; Hikita, K.; Suzuki, K. Angew. Chem. Int.
Ed. 2008, 47, 7446.
O
O
(9) Christoffers, J. J. Org. Chem. 1999, 64, 7668.
R1
R2
(10) Rössle, M.; Christoffers, J. Tetrahedron 2009, 65, 10941.
(11) Chuang, G. J.; Wang, W. K.; Lee, E.; Ritter, T. J. Am. Chem. Soc.
2011, 133, 1760.
OH
2
(12) Miao, C.-B.; Wang, Y.-H.; Xing, M.-L.; Lu, X.-W.; Sun, X.-Q.; Yang,
H.-T. J. Org. Chem. 2013, 78, 11584.
Scheme 2 A plausible mechanism for the hydroxylation reaction
(13) 2-Hydroxy-1,3-diketones 2; General Procedure
A mixture of 1,3-diketone 1 (1.0 mmol), KF (0.1 mmol), and
NaOH (0.2 mmol) in DMF (4.8 mL) and H2O (0.2 mL) was stirred
at 120 °C under air for 12 h. When the reaction was complete
(TLC), the mixture was cooled to r.t., diluted with EtOAc, and
washed with sat. aq Na2CO3. The resulting organic phase was
dried (MgSO4) and concentrated under reduced pressure. The
residue was purified by column chromatography [silica gel, PE–
EtOAc (20:1)]. Analytical data for representative products are
given below.
Acknowledgment
The authors thank the National Natural Science Foundation of China
(21462038, 21362034, 21162024) and the Key Laboratory of Eco-
Environment-Related Polymer Materials for Ministry of Education for
their financial support of this work.
Supporting Information
2-Hydroxy-1,3-diphenylpropane-1,3-dione (2a)
White solid; yield: 95%; mp 92–94 °C. 1H NMR (600 MHz,
CDCl3): δ = 7.99 (d, J = 7.8 Hz, 4 H, ArH), 7.47–7.55 (m, 6 H, ArH),
6.86 (s, 1 H, CH). 13C NMR (150 MHz, CDCl3): δ = 185.7, 135.5,
132.4, 126.7, 127.1, 93.1. Anal. Calcd for C15H12O3: C, 74.99; H,
5.03. Found: C, 74.86; H, 5.05.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560647.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
References and Notes
1-(2-Furyl)-2-hydroxy-3-phenylpropane-1,3-dione (2n)
White solid; yield: 80%; mp 76–78 °C. 1H NMR (600 MHz,
CDCl3) δ = 7.96 (d, J = 7.2 Hz, 2 H, ArH), 7.47–7.62 (m, 4 H, ArH
(1) (a) Christoffers, J.; Baro, A.; Werner, T. Adv. Synth. Catal. 2004,
346, 143. (b) Pritchard, D. R.; Wilden, J. D. Tetrahedron Lett.
2010, 51, 1819. (c) Siliphaivanh, P.; Harrington, P.; Witter, D. J.;
Otte, K.; Tempest, P.; Kattar, S.; Kral, A. M.; Fleming, J. C.;
Deshmukh, S. V.; Harsch, A.; Secrist, P. J.; Miller, T. A. Bioorg.
Med. Chem. Lett. 2007, 17, 4619.
and FuH), 7.23–7.27 (m, 2 H, ArH and FuH), 6.77 (s, 1 H, CH). 13
C
NMR (150 MHz, CDCl3): δ = 182.5, 177.7, 151.0, 146.1, 134.7,
132.4, 128.7, 127.0, 115.8, 112.7, 92.7. Anal. Calcd for C13H10O4:
C, 67.82; H, 4.38. Found: C, 67.74; H, 4.39.
(2) (a) Asahara, H.; Nishiwaki, N. J. Org. Chem. 2014, 79, 11735.
(b) Andriamialisoa, R.; Langlois, N.; Langlois, Y. Tetrahedron Lett.
1985, 26, 3563.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2863–2865