Facile aerobic photooxidative oxylactonization of oxocarboxylic acids in fluorous solvents

Article abstract of DOI:10.1039/c2gc36238d

We developed efficient aerobic photooxidative oxylactonizations of oxocarboxylic acids promoted by trifluoroacetic anhydride with molecular oxygen as the terminal oxidant in the fluorous solvent FC-72.

Full text of DOI:10.1039/c2gc36238d

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COMMUNICATION
Facile aerobic photooxidative oxylactonization of oxocarboxylic acids in
fluorous solvents†
Norihiro Tada, Lei Cui, Takafumi Ishigami, Kazunori Ban, Tsuyoshi Miura, Bunji Uno and Akichika Itoh*
Received 7th May 2012, Accepted 3rd September 2012
DOI: 10.1039/c2gc36238d
We developed efficient aerobic photooxidative oxylactoniza-
tions of oxocarboxylic acids promoted by trifluoroacetic
anhydride with molecular oxygen as the terminal oxidant in
the fluorous solvent FC-72.
Lactones are essential structural motifs in organic chemistry
because their frameworks are ubiquitously found in many bio-
logically active natural products. Various methods for the prep-
Scheme 1 Aerobic photooxidative cyclization with TFAA.
aration of lactones from many types of substrates have been
viewpoint of synthetic organic chemistry.11,12 Therefore, we
reported, and of these, the oxylactonization of 5- or 6-oxocar-
boxylic acids is one of the most interesting synthesis methods.
examined reaction conditions in fluorous solvents and success-
fully found that using TFAA as an additive with the fluorous
Several oxylactonizations have been described that use stoichio-
metric amounts of reagents such as (i) Br2,1 (ii) CuCrO4,2 (iii)
solvent FC-72 allowed us to carry out the aerobic photooxidative
lead acetate,3 and (iv) Koser’s reagent and its derivatives.4
lactonization of oxocarboxylic acid, proceeding through enol
Recently, the catalytic oxylactonization of oxocarboxylic acids to
lactone, under visible light irradiation from a general-purpose
oxolactones with in situ generated Koser’s reagent derivatives
fluorescent lamp (Scheme 1). We now report the details of this
reaction.
has been reported.5 Furthermore, Ishihara’s group showed that
tetrabutylammonium iodide was highly effective as a precatalyst
Initially, to explore the potential of TFAA-promoted aerobic
for the oxylactonization of oxocarboxylic acids with 30%
photooxidative oxylactonization, we chose 4-benzoylbutyric acid
(1a) as a test substrate to optimize the reaction conditions
(Table 1). Among the solvents examined, FC-72 appears to be
the most suitable, and in the presence of 3 equiv. of TFAA, 2a
aqueous hydrogen peroxide.6 However, to the best of our knowl-
edge, there is no reported oxylactonization of oxocarboxylic
acids that uses molecular oxygen as the terminal oxidant. Mo-
lecular oxygen has received much attention as a primary environ-
was obtained in a good yield (up to 71%) (entry 5). In contrast,
mentally benign oxidant because it is photosynthesized by
only a low yield was obtained in typical organic solvents (entries
1–3).13 These results suggest that high solubility of O2 and low
plants, produces little waste, is inexpensive, and has greater atom
efficiency than other oxidants.7 From this perspective, we have
polarity of fluorous solvent enable this reaction to proceed effec-
developed several catalytic photooxidation methods using mo-
tively. When the reaction was carried out under an air atmos-
phere, 2a was obtained in a low yield (entry 12). Note that 3,4-
dihydro-6-phenyl-2-pyrone (3a) was produced mainly under an
argon atmosphere or in the absence of light irradiation,
lecular oxygen as the terminal oxidant.8 In the course of our
further study, we have studied the oxylactonization using a
fluorous solvent of perfluorinated hydrocarbons to increase the
solubility of molecular oxygen. Fluorous solvents, such as
suggesting that enol lactone 3a is formed without light and
FC-72, are versatile9 because they afford high oxygen solubility
oxygen (entries 13 and 14). The reaction did not proceed
and are believed to be particularly suitable for oxidation.10 Fur-
without TFAA (entry 15). For this reaction, a 500 W xenon lamp
and a 400 W mercury lamp gave lower yields of 2a, probably
thermore, organic products often have low solubility in such sol-
vents, resulting in simple separation. Although these features
because the substrate decomposed (entries 16 and 17). It is note-
suggest that fluorous solvents would be useful for oxidation reac-
worthy that 3a was obtained predominantly in the presence of
tions, to the best of our knowledge, there are no reports of oxi-
galvinoxyl, indicating that the preparation of 3a from 1a pro-
ceeds through a nonradical mechanism, whereas the conversion
dation reactions carried out only in fluorous solvents from the
of 3a to 2a uses a radical mechanism.
With this optimized reaction condition, the scope and limit-
Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196,
Japan. E-mail: itoha@gifu-pu.ac.jp; Fax: (+81) 58-230-8108;
Tel: (+81) 58-230-8108
†Electronic supplementary information (ESI) available: Experimental
procedures, characterization of the compounds, 1H and 13C NMR
spectra. See DOI: 10.1039/c2gc36238d
ations of the reaction were explored using a series of oxocar-
boxylic acids (Table 2). Electron-deficient and electron-rich
substrates gave the corresponding oxolactones in good yields
(2a, 2b, 2c, 2d, and 2e). In contrast, the methoxy group, a stron-
ger electron-donating group, retarded the reaction, and 2f was
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Table 1 Study of reaction conditions in a fluorous solventa
Table 2 Scope and limitationsa
Entry
Additive (equiv.)
Time (h)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
TFAA (3)
TFAA (3)
TFAA (3)
TFAA (3)
TFAA (3)
TFAA (3)
TFA (3)
Ac2O (3)
TFAA (2)
TFAA (4)
TFAA (3)
TFAA (3)
TFAA (3)
TFAA (3)
—
15
15
15
15
15
15
15
15
15
15
1
15
15
15
15
15
15
15
THF
Trace
17
43
40
71 (69)
19
0
0
43
EtOAc
Hexane
FC-77c
FC-72d
Neat
FC-72
FC-72
FC-72
FC-72
FC-72
FC-72
FC-72
FC-72
FC-72
FC-72
FC-72
FC-72
9
10
11
12
13
14
15
16
17
18
57
Tracee
21f
9g
0h
0
TFAA (3)
TFAA (3)
TFAA (3)
45i
41j
Tracek
a 1 (0.3 mmol), TFAA (3 equiv.), FC-72 (5 mL) with O2 balloon
irradiation with two 22 W fluorescent lamps. b Isolated yields. c This
reaction was carried out with 6.0 equiv. of TFAA. d This reaction was
carried out under irradiation by a 400 W high pressure mercury lamp.
a Reaction conditions: 1a (0.3 mmol), additive, solvent (5 mL) with O2
balloon irradiation with two 22 W fluorescent lamps. b 1H NMR yields.
Number in parentheses denotes isolated yield. c FC-77 is
a
perfluorooctane and
a
cyclic perfluorooctyl ether mixture
((C8F18)n·(C8F16O)m). d FC-72 is a perfluorohexane (C6F14). e 3,4-
Dihydro-6-phenyl-2-pyrone (3a) (89%) was detected by 1H NMR. f This
reaction was carried out under an air atmosphere. g This reaction was
carried out under an argon atmosphere. 3a (59%) was detected by 1H
NMR. h This reaction was carried out in the dark. 3a (65%) was detected
by 1H NMR. i This reaction was carried out through irradiation with a
Table 3 Study of the reaction mechanisma
j
500 W Xe lamp. This reaction was carried out through irradiation with
a 400 W Hg lamp. k This reaction was carried out in the presence of
galvinoxyl (0.1 equiv.). 3a (80%) was detected by 1H NMR.
Yieldb (%)
Entry
Additive (equiv.)
Solvent
2a
1a
3a
obtained in low yield. Sterically hindered substrates possessing
two methyl groups on the aromatic ring gave the corresponding
oxolactones in good yields (2g and 2h). 4-(2-Naphthoyl)butyric
acid (1i) gave the corresponding oxolactone in moderate yield
(2i). Unfortunately, 4-acetylbutyric acid (1j), 3-benzoylpropionic
acid (1k), and 5-benzoylpentanoic acid (1l) were poor substrates.
Regarding the method using TFAA in FC-72, we found that
enol lactone 3a was produced in the reaction.14 Thus, to clarify
the mechanism, we used 3a as the substrate (Table 3). We found
that TFAA can promote oxylactonization (entries 1 and 2), but in
the presence of TFA, 1a was obtained (entry 3). Furthermore,
FC-72 is the best solvent in this step (entries 1 and 4–6). This
result is probably because of the high solubility of molecular
oxygen in FC-72. Note that light and molecular oxygen are
essential (entries 7 and 8).
We assumed that the light of UV-vis absorption corresponds
to HOMO → LUMO excitation. So we calculated the HOMO
and LUMO of 3a by HF/6-31G(d). The high electron density at
the HOMO of 3a exists at the C1–C2 bond. On the other hand,
the LUMO was anti-bonding (Fig. 1). Therefore, HOMO →
LUMO excitation of 3a can form 4a, as shown in Scheme 2.
Then 4a traps molecular oxygen at the non-benzylic position to
give 5a. At the next stage no detailed mechanistic information is
1
2
3
4
TFAA (3)
—
FC-72
FC-72
FC-72
FC-77
Neat
Hexane
FC-72
FC-72
60
28
24
42
34
29
0
0
9
60
Trace
Trace
64
11
28
Trace
38
0
22
17
0
TFA (3)
TFAA (3)
TFAA (3)
TFAA (3)
TFAA (3)
TFAA (3)
5
6
7c
8d
77
55
Trace
a Reaction conditions: 3a (0.3 mmol), additive, solvent (5 mL) with O2
balloon irradiation with two 22 W fluorescent lamps for 15 h. b 1H NMR
yields. c This reaction was carried out under an argon atmosphere. d This
reaction was carried out without irradiation by the fluorescent lamp.
available, but it is considered rational that a reaction pathway
includes the peroxy radical (ROO˙) bond to carbonyl carbon
with cleavage of the C–O bond of an ester to give 6a, which can
be converted to 2a in the presence of TFA generated in situ.15
The yields of 2k and 2l, shown in Table 2, are low because of
the difficulties associated with the formation of the 4-membered
ring product and the 7-membered ring intermediate, respectively.
The experimental and theoretical results suggest that oxocar-
boxylic acid 1a reacts with TFAA to form enol lactone 3a which
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In conclusion, we have developed a convenient method for the
direct synthesis of oxolactones from oxocarboxylic acids that is
promoted by TFAA. This method represents the first successful
oxidation in a fluorous solvent and direct oxylactonization via an
enol lactone intermediate under visible light irradiation. Further-
more, this method is of great value from a green chemistry per-
spective and organic synthesis because of its use of visible light
irradiation and molecular oxygen as the terminal oxidant. Appli-
cations of the photooxidation system as well as further mechanis-
tic investigations are ongoing in our laboratory.
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This journal is © The Royal Society of Chemistry 2012
Green Chem.