High-performance hypoiodite/hydrogen peroxide catalytic system for the oxylactonization of aliphatic γ-oxocarboxylic acids

Article abstract of DOI:10.1246/cl.141110

Highly efficient hypoiodite-catalyzed oxylactonization of aliphatic γ-oxocarboxylic acids to the corresponding γ-acyl-γ-butyrolactones was developed. Highly dilute reaction conditions and slow addition of the oxidant are both highly effective for promotin

Full text of DOI:10.1246/cl.141110

Received: December 3, 2014 | Accepted: December 18, 2014 | Web Released: February 17, 2015
CL-141110
High-performance Hypoiodite/Hydrogen Peroxide Catalytic System
for the Oxylactonization of Aliphatic γ-Oxocarboxylic Acids
Muhammet Uyanik,1 Daisuke Suzuki,1 Mizu Watanabe,1 Hiroyasu Tanaka,2 Kikuo Furukawa,2 and Kazuaki Ishihara*1,3
1Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8603
2Mitsubishi Gas Chemical Co., Inc., Tokyo Research Laboratory, 1-1 Niijuku 6-chome, Katsushika-ku, Tokyo 125-8601
3Japan Science and Technology Agency (JST), CREST, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8603
(E-mail: ishihara@cc.nagoya-u.ac.jp)
Highly efficient hypoiodite-catalyzed oxylactonization of
aliphatic γ-oxocarboxylic acids to the corresponding γ-acyl-γ-
butyrolactones was developed. Highly dilute reaction conditions
and slow addition of the oxidant are both highly effective for
promoting the high-performance hypoiodite/hydrogen peroxide
catalytic oxidation system.
used (m-CPBA). To overcome some of these limitations, in
2011, we developed a hypoiodite catalytic system5,6 for the same
reaction using hydrogen peroxide as an inexpensive and atom-
economical oxidant (Scheme 1c).7 The highly chemoselective
oxylactonization reaction proceeded under milder conditions
and water was the only by-product derived from the oxidant.
(Hetero)aromatic γ-acyl-γ-butyrolactones were obtained in ex-
cellent yields. However, aliphatic γ-acyl-γ-butyrolactones were
obtained in only moderate yields even after prolonged reaction
times. Aliphatic γ-acyl-γ-butyrolactone derivatives are potent
substrates for industrial use, and there is strong demand for
an efficient synthetic method for these compounds. Here, we
developed high yield methods for the oxylactonization of
aliphatic γ-oxocarboxylic acids to the corresponding γ-acyl-γ-
butyrolactones (Scheme 1d). We found that dilute reaction
conditions and slow addition of the oxidant are both highly
effective for the promoting this high-performance hypoiodite/
hydrogen peroxide catalytic oxidation system.
γ-Acyl-γ-butyrolactones and their derivatives are significant
building blocks in synthetic organic chemistry.1 To date, several
methods have been developed for the synthesis of these
compounds.2 In 1990, Moriarty and colleagues reported the
hypervalent organoiodine(III)-mediated oxylactonization of var-
ious oxocarboxylic acids to the corresponding acyllactones
(Scheme 1a).3 In 2009, we developed a catalytic variant of the
Moriarty reaction using the in situ-generated PhIL2 species as
a catalyst and meta-chloroperbenzoic acid (m-CPBA) as an
oxidant (Scheme 1b).4 However, this organoiodine(III)-cata-
lyzed method was limited in scope to only (hetero)aryl ketones.
Moreover, low chemoselectivity was observed due to competi-
tion with the Baeyer-Villiger oxidation due to the strong oxidant
Initially, we reconsidered the catalytic mechanism of the
hypoiodite/hydrogen peroxide oxidation system (Figure 1).5-8
Based on our recent Raman spectroscopic analysis of a solution
of tetrabutylammonium iodide and tert-butyl hydroperoxide
(TBHP), we confirmed the in situ generation of the hypoiodite
a) Moriarty’s work (stoichiometric oxidation):3
¹
salt ([Bu4N]+[IO] ) as an unstable catalytic active species and
O
¹
the triiodide salt ([Bu4N]+[I3] ) as a stable inert species.8b
O
R1
PhI(OH)OTs (1 equiv)
CH2Cl2, reflux
+ PhI
+ TsOH
+ H2O
H
O
O
R1
Unfortunately, it was technically difficult to detect unstable
hypoiodite species by Raman measurements for hydrogen
peroxide due to its stronger oxidation ability than TBHP.
However, our control experiments suggested that the hypoiodite
salt might be a catalytic active species for both the TBHP and
hydrogen peroxide oxidation systems (Figure 1).9 In contrast,
the main inactivation path for the hydrogen peroxide oxidation
system might be the catalytic decomposition of hydrogen
peroxide by the hypoiodite (or hypoiodous acid)/iodide couple
(shown in blue, Figure 1) (vide infra).10,11
R2
36–81% yield
R2 CO2H
R1= Aryl or alkyl
b) Our previous work-1 (organoiodine(III)-catalysis):4
PhI (10 mol%)
O
O
·
TsOH H2O (20 mol%)
H
+ m-CBA
+ H2O
O
O
Ar
Ar
m-CPBA (1.4–2.4 equiv)
CH3NO2, 50 °C
R2
R2 CO2H
38–81% yield
Limitations: Only (hetero)aryl ketones, side-reactions (Baeyer–Villiger, etc.).
c) Our previous work-2 (hypoiodite-catalysis):7
Bu4NI (10 mol%)
O
O
R1
O
30% H2O2 (2 equiv)
H
[Bu4N]+[IO]–
H
O
O
+ H2O
R1
H2O
CO2H
R1
active species
EtOAc, RT
R2
R2 CO2H
R2
1
R1 = (Hetero)aryl: 92–99% yield
H2O2
R1 = Alkyl: 30–46% yield (limitations)
fast (R1 = Aryl)
slow (R1 = Alkyl)
fast
fast
d) This work:
H2O + O2
[Bu4N]+I–
Bu4NI (5 or 20 mol%)
30% H2O2 (1.1–2.5 equiv)
O
O
O
O
O
+ H2O
O
H2O2
R1
O
EtOAc, 50 °C
dilute conditions or
slow additon of oxidant
High-performance hypoiodite/H2O2 catalytic system
R2
CO2H
H2O
productive path
2
1
2, high yield
nonproductive path
Figure 1. Proposed hypoiodite/hydrogen peroxide catalytic mech-
anism for the oxylactonization of oxocarboxylic acids.
Scheme 1. Oxylactonization of oxocarboxylic acids.
Chem. Lett. 2015, 44, 387–389 | doi:10.1246/cl.141110
© 2015 The Chemical Society of Japan | 387

Table 1. Investigation of oxidant for the oxylactonization of 1a
A
B
O
O
Bu4NI (5 mol%)
Bu4NI (5 mol%)
Bu4NI (5 mol%)
oxidant (2 equiv)
30% H2O2 (2+1 equiv)
TBHP (2+1 equiv)
O
1a
2a
1a
2a
O
CO2H
EtOAc (0.02 M), 50 °C
EtOAc (1 M), 50 °C
EtOAc, 50 °C
1a
2a
100"
80"
60"
40"
20"
0"
Entry
Oxidant
EtOAc/M
Time/h
2a, Yield/%a
100"
80"
60"
40"
20"
0"
+ H2O2 (1 equiv)
1
2
3
4
5
6
30% H2O2
TBHP
TBHP
TBHP
70% TBHPd
CHP
0.02
0.02
0.1
1
0.1
0.1
1.5
14
4
2
4
63b,c
76
73
50b
73
+ TBHP (1 equiv)
3
78
H2O2 (2 equiv)
TBHP (2 equiv)
aIsolated yield. bEvaluated by 1H NMR analysis. cThe reaction did not
proceed further and the yield of 2a did not change even after 12 h.
dAqueous solution. For details, see the Supporting Information.
0"
1"
2"
3"
4"
5"
0"
1"
2"
3"
4"
5"
Time/h
Time/h
H2O2
H2O2
TBHP
TBHP
The oxylactonization of aliphatic γ-oxocarboxylic acids
proceeded much more slowly than that of their aromatic
counterparts, and consequently the nonproductive path prefer-
entially proceeded under the present conditions (Figure 1).12 For
the construction of a high-performance catalytic system for
oxylactonization, the cyclization step should not be rate limiting.
To address this issue, the generation of hypoiodite should be
decelerated or the decomposition of hydrogen peroxide should
be suppressed.
1 min 1.5 h
2.5 h
1 min 2 h
3 h
Figure 2. Comparison of the hypoiodite-catalyzed oxylactonization
of 1a with hydrogen peroxide (A) or TBHP (B).
a
Table 2. Investigation of the conditions for using 30% H2O2
Bu4NI (5 or 20 mol%)
30% H2O2 (2 equiv)
1a
Bu4NI
2a
Solvent, 50 °C
First, as well as considering our previous studies,8b we
investigated the oxidant to decelerate the generation of active
species (Table 1). The oxylactonization of 3-(2-oxocyclohex-
yl)propanoic acid (1a) under the previous conditions, using
5 mol % Bu4NI and 30% hydrogen peroxide in ethyl acetate
(0.02 M) at 50 °C, gave spirolactone 2a in 63% yield (Entry 1).
The reaction did not proceed further and the yield of 2a did not
change even after 12 h. As expected, the use of TBHP or cumene
hydroperoxide (CHP) as weaker oxidants,13 instead of hydrogen
peroxide, gave a higher yield even under concentrated con-
ditions (Entries 2-6).
Method,b
Time/h
Entry
Solvent (M)
2a, Yield/%c
/mol %
1
2
3
4
5
5
5
5
5
5
EtOAc (0.1)
A, 3
A, 4
A, 4
A, 4
A, 24
A, 24
A, 3
B, 3
38d
EtOAc (0.01)
EtOAc (0.005)
Dioxane (0.005)
Toluene (0.005)
CH3CN (0.005)
EtOAc (0.1)
EtOAc (0.1)
EtOAc (0.5)
EtOAc (0.5)
90 (85)
90 (86)
90 (82)
60
6
5
40
7e
8f
9f
10g
20
20
20
20
46 (42)
82 (69)
64 (54)
74 (63)
B, 3
C, 5.5
Here, the nonproductive path for the hydrogen peroxide
oxidation system (regeneration of iodide without product
formation) was confirmed by control experiments. Thus, after
the reaction stopped due to the decomposition of hydrogen
peroxide, oxylactonization started again with the second
addition of hydrogen peroxide (Figure 2A). On the other hand,
once the reaction stopped, the reaction did not proceed further
with the second addition of TBHP, because triiodide was
generated as an inert species (Figure 2B). The distinct features
of these two inactivation paths were also confirmed by color
changes (Figure 2, down). For hydrogen peroxide oxidation, the
color disappeared to regenerate iodide when the reaction
stopped, and the reaction mixture turned pale yellow again with
the second addition of hydrogen peroxide. In contrast, there was
no color change for TBHP oxidation. This result indicates the
generation of triiodide.
Next, we sought to establish a high-performance hypoio-
dite/hydrogen peroxide catalytic oxidation system (Table 2).
The reaction of 1a in ethyl acetate at high concentration (0.1 M),
under otherwise identical conditions, gave 2a in lower chemical
yield (Table 2, Entry 1 versus Table 1, Entry 1).14 In sharp
contrast, to our delight, the oxidation proceeded efficiently under
dilute conditions (0.01 M), and 2a was obtained in high
chemical yields (Entry 2 versus Entry 1). A brief screening of
aUnless otherwise noted, a solution of 1a (0.1 mmol) and 30 wt % H2O2
(see Method) in EtOAc was stirred in the presence of Bu4NI at 50 °C.
b30 wt % H2O2 was added all-at-once (Method A), portionwise
(5 © 0.36 equiv/0.5 h, Method B), or dropwise (over 5 h, Method C).
cEvaluated by 1H NMR (Entries 1-6) or GC analysis (Entries 7-10).
The isolated yields are shown in parentheses. dThe reaction did not
proceed further and the yield of 2a did not changed even after 24 h.
f
e1-g scale, 30% H2O2 (1.8 equiv). 10-g scale, 30% H2O2 (1.8 equiv).
g30-g scale, 30% H2O2 (1.05 equiv). For details, see the Supporting
Information.
the solvents revealed that the best result was obtained in ethyl
acetate, as previous studies (Entries 3-6).7 We next sought to
identify practical conditions at high concentration with respect
to industrial applicability. An increase in the amount of catalyst
did not lead to a considerable increase in activity or chemical
yield (Entry 7 versus Entry 1). Encouraged by the good results
under dilute conditions (Entries 2 and 3) or with further addition
of hydrogen peroxide (Figure 2A), we decided to use the slow
addition of hydrogen peroxide. As a result, the oxidation at a
high concentration (0.1 M) was completed and 2a was obtained
in high yield, when hydrogen peroxide was added portionwise
(Method B, Entry 8). The dropwise addition of hydrogen
peroxide using a syringe-pump (Method C) was superior to
388 | Chem. Lett. 2015, 44, 387–389 | doi:10.1246/cl.141110
© 2015 The Chemical Society of Japan

Bu4NI (5 mol%)
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O
O
30% H2O2 (1.1–2.5 equiv)
R1
R1
O
O
O
EtOAc (0.01 or 0.1M), 50 °C
R2 CO2H
R2
1
2
2
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O
O
O
O
O
2ba
2ca
A: 5 h, 89% yield (50% yield)b
B: 5 h, 60% yield
A: 8 h, 52% yield (18% yield)b
B: 10 h, 50% yieldc
O
O
O
O
O
O
O
3
4
O
2d
2e
A: 12 h, 58% yield (30% yield)b
B: 10 h, 60% yield
B: 5 h, 70% yieldd
A: 4 h, 84% yield (70% yield)b
C: 4 h, 87% yield
Scheme 2. Oxylactonization of various aliphatic oxocarboxylic
acids 1 under the optimized conditions. Products, methods (see
Table 2 footnote), reaction times and isolated yields of 2 are shown.
aThe reaction of either isomerically pure or mixture of 1 gave product
2 as a diastereomeric mixture. bThe yields for the oxidation at high
concentration (0.1 M) are shown in parentheses. cReaction was
performed at 70 °C using 20 mol % of Bu4NI. d20 mol % of Bu4NI
was used.
5
6
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portionwise addition at higher concentration (0.5 M, Entry 10
versus Entry 9). Notably, these reactions were scalable and
practical (Entries 8-10).15
We examined the oxylactonization of other aliphatic
γ-oxocarboxylic acids
1 under the optimized conditions
(Scheme 2).9 The oxidation of methyl-substituted cyclohexa-
none-derived 1b and 1c, cyclopentanone-derived 1d, and β-
oxoester 1e gave the corresponding spirolactones 2b-2e in
good to high yields using method A (all-at-once addition), B
(portionwise addition), or C (dropwise addition).
In summary, we have developed a high-performance
hypoiodite/hydrogen peroxide catalytic oxidation system for
the oxylactonization of aliphatic γ-oxocarboxylic acids to the
corresponding γ-acyl-γ-butyrolactones by using highly dilute
reaction conditions or slow addition of the oxidant.
7
8
9
M. Uyanik, D. Suzuki, T. Yasui, K. Ishihara, Angew. Chem., Int. Ed.
2011, 50, 5331.
a) M. Uyanik, H. Okamoto, T. Yasui, K. Ishihara, Science 2010, 328,
1376. b) M. Uyanik, H. Hayashi, K. Ishihara, Science 2014, 345, 291.
For details, see the Supporting Information.
Financial support for this project was partially provided by
JSPS, KAKENHI (Nos. 24245020 and 25105722), and the
Program for Leading Graduate Schools: IGER Program in Green
Natural Sciences (MEXT).
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11 It is important to note that we could not completely rule out the catalytic
Supporting Information is available electronically on J-STAGE.
¹
¹
role of [IO2] or the generation of other inert species ([IO3] and
¹
[IO4] ) under our reaction conditions.
References and Notes
12 Although the reaction mechanism is not clear yet, low reactivity of
aliphatic ketones might be attributed to lower acidity of its α-proton
than that of aromatic ketones.
13 R. D. Cadle, H. Huff, J. Phys. Chem. 1950, 54, 1191.
14 Although the reaction of 1a at higher temperatures such as 70 °C gave
2a in higher yields, further investigation was conducted at lower
temperature for safety reason.
15 However, the isolated yields of 2a for large-scale reactions were lower
than those indicated by in situ GC analysis due to some decomposition
of the product during work-up procedures, which requires further
investigations.
1
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Chem. Lett. 2015, 44, 387–389 | doi:10.1246/cl.141110
© 2015 The Chemical Society of Japan | 389