Calcium iodide catalyzed photooxidative oxylactonization of oxocarboxylic acids using molecular oxygen as terminal oxidant

Article abstract of DOI:10.1016/j.tetlet.2012.11.014

We developed aerobic photooxidative oxylactonization of oxocarboxylic acids catalyzed by calcium iodide using molecular oxygen as the terminal oxidant under photo irradiation.

Full text of DOI:10.1016/j.tetlet.2012.11.014

Tetrahedron Letters 54 (2013) 256–258
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Calcium iodide catalyzed photooxidative oxylactonization of oxocarboxylic
acids using molecular oxygen as terminal oxidant
⇑
Norihiro Tada, Takafumi Ishigami, Lei Cui, Kazunori Ban, Tsuyoshi Miura, Akichika Itoh
Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We developed aerobic photooxidative oxylactonization of oxocarboxylic acids catalyzed by calcium
iodide using molecular oxygen as the terminal oxidant under photo irradiation.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 29 September 2012
Revised 30 October 2012
Accepted 2 November 2012
Available online 10 November 2012
Keywords:
Oxylactonization
Lactone
Photooxidation
Calcium iodide
Molecular oxygen
Molecular oxygen has received much attention as a primary
environmentally benign oxidant because it is photosynthesized
by plants, produces little waste, is inexpensive, and has greater
atom efficiency than other oxidants.1 From this perspective, we
have developed several catalytic photooxidation methods using
molecular oxygen as the terminal oxidant.2 In the course of our fur-
ther studies of aerobic photooxidations, we have successfully
found the efficient oxylactonization of oxocarboxylic acids to the
corresponding oxolactones under aerobic photooxidation condi-
tions using molecular oxygen as the terminal oxidant in combina-
tion with photo irradiation.
no reported catalytic oxylactonization of oxocarboxylic acids that
uses molecular oxygen as the terminal oxidant.
Recently, we reported the tandem oxidative conversion of 1,3-
diketones 1 to 1,2-diketones in the presence of a catalytic amount
of iodine.2o In this reaction, 1,3-diketones 1 are iodinated at the
a-
position to give iodide 2, and iodide 2 is then cleaved homolytically
to an iodine radical and radical species 3, which is subsequently
converted to 1,2-diketone (Scheme 1, Eq. 1). In contrast, the aero-
bic photooxidation of the iodine radical or hydrogen iodide, gener-
ated by the abstraction of hydride from a substrate or a solvent, to
iodine enables iodine-catalyzed oxidative conversion with molecu-
lar oxygen as the terminal oxidant. It occurred to us that a succes-
sive nucleophilic substitution of the iodine of iodide 5 by the
internal carboxylic acid and oxidation of the resulting iodide anion
to iodine under aerobic photooxidation conditions would enable
Lactones are essential structural motifs in organic chemistry be-
cause their frameworks are ubiquitously found in many biologi-
cally active natural products. Various methods for the
preparation of lactones from many types of substrates have been
reported, and of these, the oxylactonization of oxocarboxylic acids
is one of the most efficient synthetic methods. Several oxylacton-
izations have been described that use stoichiometric amounts of
homolytic
cleavage
reagents such as (i) Br2,3 (ii) (CF3CO)2O/hm 4 (iii) CuCrO4,5 (iv) lead
,
O
R1
O
O
R1
I2
O
O
O O
R2
hν
R2
(1)
acetate,6 and (v) Koser’s reagent and its derivatives.7 Recently, the
catalytic oxylactonization of oxocarboxylic acids to oxolactones
with in situ generated Koser’s reagent derivatives has been re-
ported.8 Furthermore, Ishihara’s group showed that tetrabutylam-
monium iodide was highly effective as a precatalyst for the
oxylactonization of oxocarboxylic acids with 30% aqueous hydro-
gen peroxide.9 However, to the best of our knowledge, there is
R1
R2
R1
R2
I
O
I
1
2
3
ν
O2, h
nucleophilic
CO2H
substitution
O
R1
O
R1
I2
O
CO2H
2
O
(2)
2
R1
O
I
I-
5
6
4
O2, hν
⇑
Corresponding author. Tel./fax: +81 58 230 8108.
E-mail address: itoha@gifu-pu.ac.jp (A. Itoh).
Scheme 1. Aerobic photooxidative oxylactonization with an iodine source.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.014

N. Tada et al. / Tetrahedron Letters 54 (2013) 256–258
257
Table 2
the synthesis of oxolactone 6 from oxocarboxylic acid 4 using
Scope and limitationsa
molecular oxygen as the terminal oxidant (Scheme 1, Eq. 2).
Initially, to explore the potential of iodine-catalyzed aerobic
photooxidative oxylactonization, we chose 4-benzoylbutyric acid
(4a) as a test substrate to optimize the reaction conditions
(Table 1). Although we examined this reaction under the optimized
conditions of our previous works,2l,o product 6a was either not ob-
tained or obtained in a low yield (entries 1 and 2). Among the sol-
vents, iodine sources, and additives examined, THF, CaI2, and K2CO3
appear to be the most suitable, respectively (entries 3–8). As a re-
sult of further optimization, the highest yield was obtained using
CaI2 (0.2 equiv), K2CO3 (0.1 equiv), and THF (5 mL) under irradia-
tion with a 400-W high-pressure mercury lamp for 20 h (entries
4, 9–11, 15, and 16). Surprisingly, this reaction proceeded even un-
der an air atmosphere (entry 12). In contrast, 6a was not obtained
in an Ar atmosphere or in the dark (entries 13 and 14). Further-
more, note that the reaction proceeded in a good yield even in
the presence of the radical scavenger galvinoxyl, indicating that
the reaction proceeded by a nonradical mechanism (entry 17).
With these optimized reaction conditions with the iodine
source, the scope and limitations of the reaction were explored
using a series of oxocarboxylic acids (Table 2).10 Electron-deficient
and electron-rich substrates gave the corresponding oxolactones
(6b, 6c, 6d, 6e, and 6f) in good yields. Sterically hindered sub-
strates possessing two methyl groups on the aromatic ring gave
the corresponding oxolactones (6g and 6h) in modest yields. 4-
(2-Naphthoyl)butyric acid (4i) gave the corresponding oxolactone
(6i) in good yield. Unfortunately, 4-acetylbutyric acid (4j), 3-ben-
ν
O2, h (400-W Hg lamp)
CaI2 (0.2 equiv)
K2CO3 (0.1 equiv)
substrate
product
THF
(0.3 mmol)
O
O
O
O
O
O
O
O
O
F
Cl
6a 63% (20 h)
6b 74% (10 h)
6c 64% (20 h)
O
O
O
O
O
O
O
O
O
Me
6d 58% (70 h)
Me O
t-Bu
MeO
6e 65% (40 h)
Me O
6f 58% (70 h)
O
O
O
O
O
O
O
Me
Me
6i 57% (70 h)
6g 36% (20 h)
6h 24% (20 h)
O
O
O
O
O
O
O
Me
O
O
6j 7% (20 h)
6l 16% (40 h)
6k 0% (20 h)
a
Isolated yields. Substrate (0.3 mmol), CaI2 (0.2 equiv), K2CO3 (0.1 equiv), THF
(5 mL), with O2 balloon, and irradiation with a 400-W high pressure mercury lamp.
zoylpropionic acid (4k), and 5-benzoylpentanoic acid (4l) were
poor substrates.
To clarify the reaction mechanism, we assayed the peroxides in
solution and found that 2-tetrahydrofuryl hydroperoxide (7,
0.17 mmol) is generated in THF under the optimized conditions
(Table 3, entry 1). Furthermore, 7 (0.51 mmol) was generated in
the absence of a substrate, a catalyst, and an additive, and 7
(0.13 mmol) was generated in the presence of oxygen only in the
dark (entries 2 and 4).11 Thus, we examined the reaction using
THF, which was irradiated with 400-W Hg lamp for 20 h before-
hand as the solvent, and found that the reaction proceeded in a
good yield under an optimized condition (Table 4, entry 1). In con-
trast, the reaction did not proceed in the absence of calcium iodide
(entry 2). Without light irradiation or molecular oxygen, 6a was
obtained in low yields (entries 3–5). These results suggest that
the iodide anion was oxidized to iodine partly by 2-tetrahydrofuryl
hydroperoxide, generated from THF under aerobic photooxidation
conditions,12 and partly by light irradiation and molecular oxygen.
Note that H2O2 was a poor oxidant under this condition, and 6a
Table 1
Study of reaction conditions with an iodine sourcea
O , h (400-W Hg lamp)
ν
2
iodine source
O
O
O
additive
O
OH
O
solvent, 20 h
4a
6a
Entry
Iodine source (equiv)
Additive (equiv)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
I2 (0.2)
Ca(OH)2 (0.5)
—
—
EtOAc
MeOH
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
0c
CaI2 (0.2)
CaI2 (0.2)
CaI2 (0.2)
I2 (0.2)
4c
25
57
52
50
49
25
54
K2CO3 (0.2)
K2CO3 (0.2)
K2CO3 (0.2)
Ca(OH)2 (0.5)
Et3N (0.2)
K2CO3 (0.2)
K2CO3 (0.1)
K2CO3 (0.05)
K2CO3 (0.1)
K2CO3 (0.1)
K2CO3 (0.1)
K2CO3 (0.1)
K2CO3 (0.1)
K2CO3 (0.1)
NIS (0.2)
CaI2 (0.2)
CaI2 (0.2)
CaI2 (0.1)
CaI2 (0.2)
CaI2 (0.2)
CaI2 (0.2)
CaI2 (0.2)
CaI2 (0.2)
CaI2 (0.2)
CaI2 (0.2)
CaI2 (0.2)
9
10
11
12
13
14
15
16
17
74 (63)
58
67d
0e
Table 3
Assay of 2-tetrahydrofuryl hydroperoxide
0f
conditions
20 h
O
O
OOH
43c
65g
72h
7
(5 mL)
a
Entry
1
Conditions
7a (mmol)
Reaction conditions: 4a (0.3 mmol), iodine source, additive, solvent (5 mL), with
O2 balloon, and irradiation with a 400-W high pressure mercury lamp for 20 h.
O2, h
m
(400-W Hg lamp), 4a (0.3 mmol)
0.17
(0.17)
0.51
(0.59)
0.01
0.13
b
1H NMR yields. Number in parenthesis denotes isolated yield.
This reaction was carried out through irradiation with four of 22-W fluorescent
CaI2 (0.2 equiv), K2CO3 (0.1 equiv)
c
2
O2, h
m
(400-W Hg lamp)
lamp.
d
This reaction was carried out under an air atmosphere.
This reaction was carried out under an Ar atmosphere.
This reaction was carried out in the dark.
This reaction was carried out through irradiation with a 500-W Xe lamp.
3
4
Ar, hm (400-W Hg lamp)
O2
e
f
g
Determined by iodometry. Numbers in parentheses were determined by 1H
NMR using internal standard.
a
h
This reaction was carried out in the presence of galvinoxyl (1.0 equiv).

258
N. Tada et al. / Tetrahedron Letters 54 (2013) 256–258
Table 4
Acknowledgments
Effect of 2-tetrahydrofuryl hydroperoxidea
O2, hν (400-W Hg lamp)
This work was supported by Grant-in-Aid for Young Scientists
CaI2 (0.2 equiv)
(B) (No. 24790015) from the Japan Society for the Promotion of Sci-
ence (JSPS). The authors would like to thank Enago (www.enago.jp)
for the English language review.
O
O
O
K2CO3 (0.1 equiv)
O
OH
O
THF, 20 h
4a
6a
Supplementary data
Entry
Change from standard conditions
Yieldb (%)
4a
6a
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
11.014.
1
2
3
4
5
6c
—
67
0
39
20
9
6
Without CaI2 and K2CO3
In the dark
Under Ar
In the dark, under Ar
H2O2 (1.2 equiv) was added, in the dark
95
55
53
90
72
References and notes
8
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a
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(5 mL: Before using, THF was irradiated with a 400-W high pressure mercury lamp
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pressure mercury lamp for 20 h.
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b
1H NMR yields.
c
THF was used without previous irradiation under an oxygen atmosphere.
O
OOH
7
O2, hν and
CaI2
I2
O
-
I
O
R1
R1
O
I2, K2CO3
O
R1
CO2H
2
O
O
O
I-
4
6
5
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10. Typical procedure: A solution of substrate (0.3 mmol), CaI2 (0.2 equiv), and
K2CO3 (0.1 equiv) in dry THF (5 mL) in a Pyrex test tube with O2 balloon is
stirred and irradiated externally with 400-W high pressure mercury lamp at
room temperature for the indicated time. The temperature of the reaction
mixture at the final stage of this reaction was about 50 °C. The product is
quenched with 0.5 M aq Na2S2O3. Then the solution is acidified with 0.5 M aq
HCl and extracted with EtOAc. The product is purified by PTLC.
Scheme 2. Plausible path.
was obtained in a low yield (entry 6). These results indicate the fol-
lowing reaction mechanism (Scheme 2): (1) Calcium iodide is oxi-
dized to iodine with light and molecular oxygen or 2-
tetrahydrofuryl hydroperoxide (7). (2) The enolate of the oxocarb-
oxylic acid 4 is formed with potassium carbonate, and reacts with
iodine to form iodide 5. (3) Iodide 5 cyclizes to form oxolactone 6
in the presence of potassium carbonate. (4) The reoxidation of the
iodide anion to iodine completes the catalytic cycle, thus enabling
the iodine-catalyzed reaction.
In conclusion, we have developed convenient methods for the
direct synthesis of oxolactones from oxocarboxylic acids catalyzed
by calcium iodide. This method is of great value from a green
chemistry perspective and organic synthesis because of its use of
molecular oxygen as the terminal oxidant.
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