Selective oxidation of alcohols with alkali metal bromides as bromide catalysts: Experimental study of the reaction mechanism

Article abstract of DOI:10.1021/jo5008064

A bromide-catalyzed oxidation of alcohols was developed which proceeded in the presence of an alkali metal bromide and an oxidant under mild conditions. The reaction involved an organic-molecule-free oxidation using KBr and Oxone and a Br?nsted acid assisted oxidation using KBr and aqueous H ₂O₂ solution to provide a broad range of carbonyl compounds in high yields. Moreover, the bromide-catalyzed oxidation of primary alcohols enabled the divergent synthesis of carboxylic acids and aldehydes under both reaction conditions in the presence of TEMPO. A possible catalytic mechanism was suggested on the basis of various mechanistic studies.

Full text of DOI:10.1021/jo5008064

Article
pubs.acs.org/joc
Selective Oxidation of Alcohols with Alkali Metal Bromides as
Bromide Catalysts: Experimental Study of the Reaction Mechanism
Katsuhiko Moriyama,* Misato Takemura, and Hideo Togo*
Department of Chemistry, Graduate School of Science, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
S
* Supporting Information
ABSTRACT: A bromide-catalyzed oxidation of alcohols was developed which proceeded in the presence of an alkali metal
bromide and an oxidant under mild conditions. The reaction involved an organic-molecule-free oxidation using KBr and Oxone
and a Brønsted acid assisted oxidation using KBr and aqueous H2O2 solution to provide a broad range of carbonyl compounds in
high yields. Moreover, the bromide-catalyzed oxidation of primary alcohols enabled the divergent synthesis of carboxylic acids
and aldehydes under both reaction conditions in the presence of TEMPO. A possible catalytic mechanism was suggested on the
basis of various mechanistic studies.
report herein a halide-catalyzed selective oxidation of alcohols,
which involves the oxidation of an alkali metal halide with an
oxidant under mild conditions, as a biomimetic method for the
realization of a green sustainable process (Figure 1).
INTRODUCTION
■
The umpolung-based oxidative transformation of halides (I−,
Br−, and Cl−) into halonium ions (X+) by oxidants is a very
important tool for the biosynthesis of natural products1 and has
attracted much attention as a green sustainable method that is
expected to replace heavy metal reactions in modern organic
synthesis.2 As the oxidation of halides is catalyzed by
haloperoxidases in many organisms,3 the potential of oxidative
transformation through the oxidation of halides should be
examined to develop biomimetic processes. As one of the most
abundant natural resources on earth, alkali metal halides are
stable in air, easy to handle, neutral, and nontoxic, and
elaboration of the products does not pollute the environment.
We have developed ingenious transformations involving the
oxidation of alkali metal halides.4 Nevertheless, alkali metal
halide catalyzed oxidative transformation has not been
established and remains a daunting challenge in organic
chemistry. On the other hand, the catalytic oxidation of
alcohols is one of the economically important transformations
that provide corresponding carbonyl compounds.5
Figure 1. Alkali metal bromide catalyzed oxidation of alcohols with
aqueous hydrogen peroxide.
RESULTS AND DISCUSSION
■
First, we screened for solvents, metal bromides, and oxidants
for the bromide-catalyzed oxidation of 5-nonanol (1a) (Table
1).
Treatment of 1a with KBr (10 mol %) and Oxone (2KHSO5·
KHSO4·K2SO4) (1.0 equiv) in MeCN at room temperature
gave 2a in 89% yield (entry 1). Whereas the reaction in AcOEt
showed reactivity similar to that in MeCN, the reactions in
THF, MeNO2, and CH2Cl2 gave low yields of 2a (entries 2−5).
NaBr was an effective bromo source for the oxidation of 1a,
whereas CaBr2 was much less effective than alkali metal
bromides (entries 6 and 7). Other oxidants, such as H2O2, t-
BuOOH (TBHP), and t-BuOCl, were much less effective than
Recently, the catalytic oxidation of alcohols was accom-
plished by using numerous transition metal catalysts6 and
organocatalysts.7,8 The halogen reagent catalyzed oxidation of
alcohols typically requires toxic reagents, such as Br2 and HBr.9
Moreover, the use of alkali metal halides for oxidation has also
been reported.10,11 However, this method requires organic
oxidants such as hypervalent iodines, which produce a
stoichiometric amount of the corresponding organic waste, or
shows a limitation of substrate versatility and lower chemo-
selectivity. In addition, oxidations with halogen reagents and
alkali metal halides cannot be used for the divergent synthesis
of carboxylic acids and aldehydes from primary alcohols. We
Received: April 10, 2014
© XXXX American Chemical Society
A
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Table 1. Screening for Metal Halides, Oxidants, and Solvent
for Alkali Metal Halide Catalyzed Oxidation of 1a
Table 2. Screening for Metal Bromides, Additives, and
Solvents for Alkali Metal Halide Catalyzed Oxidation of 1a
with Aqueous H2O2 as Oxidant
a
entry
MX
oxidant
solvent
MeCN
time (h) yield (%)
1
KBr
KBr
KBr
KBr
KBr
NaBr
CaBr2
KBr
KBr
KBr
KCl
KI
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
H2O2
5
7
89
86
a
entry
MX
additive
PhSO3H
solvent
yield (%)
2
AcOEt
3
THF
24
5
25 (51)
68
1
2
3
4
5
6
7
KBr
KBr
KBr
KBr
KBr
LiBr
NaBr
CaBr2
KCl
KI
MeCN/H2O (9/1)
AcOEt/H2O (9/1)
CH2Cl2:H2O (9/1)
CH2Cl2/H2O (4/1)
CH2Cl2/H2O (19/1)
CH2Cl2/H2O (9/1)
CH2Cl2/H2O (9/1)
CH2Cl2/H2O (9/1)
CH2Cl2/H2O (9/1)
CH2Cl2/H2O (9/1)
CH2Cl2/H2O (9/1)
CH2Cl2/H2O (9:1)
CH2Cl2:H2O (9/1)
CH2Cl2/H2O (9/1)
CH2Cl2/H2O (9/1)
CH2Cl2/H2O (9/1)
CH2Cl2/H2O (9/1)
23 (70)
35 (64)
97
4
MeNO2
CH2Cl2
MeCN
PhSO3H
5
10
7
70
PhSO3H
6
80
PhSO3H
64 (27)
81
7
MeCN
5
69
PhSO3H
8
MeCN
24
24
24
24
24
2
0 (>99)
5 (93)
45 (33)
53 (36)
0 (>99)
>99
PhSO3H
92
9
TBHP
t-BuOCl
Oxone
Oxone
Oxone
Oxone
MeCN
PhSO3H
93
b
10
11
12
13
14
MeCN
8
PhSO3H
89
MeCN
9
PhSO3H
0 (>99)
0 (97)
89
MeCN
10
11
12
13
14
15
PhSO3H
KBr
-
MeCN/H2O (9/1)
MeCN
KBr
KBr
KBr
KBr
KBr
KBr
MeSO3H
(PhO)2P(O)OH
p-NO2-C6H4SO3H
CF3CO2H
PhCO2H
PhSO3H
24
0 (>99)
3 (87)
80
a
Values in parentheses indicate the recovery of 1a.
82
1 (94)
59 (41)
0 (>99)
0 (>99)
Oxone (entries 8−10). Use of KCl and KI instead of KBr
decreased the yields of 2a (entries 11 and 12). The addition of
H2O to MeCN promoted the oxidation of 1a to give 2a in a
quantitative yield (entry 13). The oxidation of 1a did not
proceed in the absence of KBr (entry 14).
On the other hand, the use of aqueous hydrogen peroxide as
an oxidant is the most attractive for various oxidations because
it has higher atom economy and is milder than the other
oxidants, producing only water as the byproduct of an organic
reaction. Thus, we attempted to perform an atom-economical
bromide-catalyzed oxidation of alcohols by using aqueous
hydrogen peroxide as the oxidant (Scheme 1).
c
16
17
18
PhSO3H
KBr
CH2Cl2/H2O (9/1)
a
b
Values in parentheses indicate the recovery of 1a. CaBr2 (10 mol %)
c
was used. KBr (10 mol %) was used.
11−15). Decreasing the amount of KBr (10 mol %) did not
promote the oxidation of 1a (entry 16). The oxidation did not
proceed in the absence of KBr or PhSO3H (entries 17 and 18).
To explore the scope of the alkali metal bromide catalyzed
oxidation of alcohols, various secondary alcohols 1 and primary
alcohols 3 were examined under the optimum conditions for
the organic-molecule-free oxidation using Oxone (method A)
and the catalytic Brønsted acid assisted oxidation using
hydrogen peroxide (method B), respectively (Table 3). When
1-arylethanols bearing 4-Me (1b), 4-Cl (1c), 4-NO2 (1d), 3-Cl
(1e), and 2-Cl (1f) groups on the aromatic ring were used
under both conditions, aryl methyl ketones 2b−f were obtained
in excellent yields (86 to >99%) (entries 1−5). The reaction of
benzyl alcohols bearing various alkyl or aryl groups at the α
position, such as Et (1g), i-Pr (1h), t-Bu (1i), and Ph (1j), also
gave the corresponding ketones 2g−j in excellent yields (96 to
>99%) (entries 6−9). In contrast to the organic-molecule-free
oxidation using Oxone (method A) of 1-tetralol (1k) that
provided 1-tetralone (2k) in 89% yield, the Brønsted acid-
assisted oxidation using aqueous H2O2 (method B) did not
proceed at all (entry 10). The reaction of aliphatic alcohols,
such as 2-octanol (1l), cyclododecanol (1m), 4-tert-butylcyclo-
hexanol (1n), (−)-menthol (1o), and β-cholestanol (1p),
under method A conditions also occurred to give the
corresponding ketones 2l−p in high yields (62 to >99%)
(entries 11−15, method A). However, method B conditions
were much less effective than method A conditions for the
transformation of 1 into 2 (entries 13−15, method B). Bulky
aliphatic alcohols 1q,r were also oxidized under both conditions
to give the desired ketones 2q,r in high yields (78−98%),
respectively (entries 16 and 17). Furthermore, the same
treatment of various alcohols bearing such functional groups
Scheme 1. Alkali Metal Bromide Catalyzed Oxidation of
Alcohols with Aqueous H2O2 as Oxidant
In our previous work, we showed that hydrogen peroxide was
ineffective for alkali metal bromide based oxidations (Table 1,
entry 8).4 Therefore, the bromide-catalyzed oxidation of 5-
nonanol (1a) in the presence of an additive, such as a Brønsted
acid, was examined by using aqueous hydrogen peroxide as the
oxidant (Table 2).
The addition of a catalytic amount of PhSO3H (10 mol %) to
a mixture of KBr (20 mol %) and aqueous H2O2 (1.5 equiv) in
MeCN and H2O (9/1) at room temperature furnished 5-
nonanone (2a) in 23% yield (entry 1). The reaction in CH2Cl2
instead of MeCN provided 2a in 97% yield (entry 3), whereas
the reaction in AcOEt showed reactivity similar to that in
MeCN (entry 2). Both an increase and a decrease in the
amount of H2O in CH2Cl2 reduced the yield of 2a (entries 4
and 5). LiBr, NaBr, and CaBr2 were effective bromo sources for
the oxidation of 1a, whereas the use of KCl and KI did not give
any product (entries 6−10). Other Brønsted acids, such as
MeSO3H, (PhO)2P(O)OH, p-NO2-C6H4SO3H, CF3CO2H,
and PhCO2H, were much less effective than PhSO3H (entries
B
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Table 3. Screening for Substrates and Optimum Conditions for Alkali Metal Bromide Catalyzed Oxidation of 1a
a
b
c
Values in parentheses indicate the recovery of 1. Cs2CO3 (1.0 equiv) was added. The reaction was carried out in a mixture of AcOEt and H2O (9/
d
e
f
1) (2 mL). KBr (20 mol %), aqueous H2O2 (3.0 equiv), and PhSO3H (20 mol %) were used. The reaction was carried out in MeCN. KBr (20 mol
%) and Oxone (2.0 equiv) were used. The reaction was carried out under fluorescent light irradiation. KBr (30 mol %), aqueous H2O2 (3.0 equiv),
and PhSO3H (30 mol %) were used. KBr (20 mol %) and Oxone (2.5 equiv) were used. The reaction was carried out in a mixture of MeCN and
H2O (9/1) (2 mL). The value in parentheses indicates the yield of octyl octanoate.
g
h
i
j
k
as esters (1s−u), chloro (1v), and amide (1w) provided the
corresponding products 2s−w in high yields (89 to >99%),
respectively (entries 18−22). In the present oxidation with KBr
and oxidant, a benzylic hydrogen atom could be abstracted by a
bromo radical to provide various benzylic substitution
products.4b Fortunately, 4-phenyl-2-butanol (1x) was efficiently
and selectively oxidized under method A conditions to give 4-
phenyl-2-butanone (2x) in 78% yield (entry 23). The oxidation
of benzyl alcohols bearing 4-Me (3a), 4-F (3b), 4-Cl (3c), 3-Cl
(3d), and 2-Cl (3e) groups on the aromatic ring with twice the
amount of oxidant under both conditions provided carboxylic
acids in high yields (67 to >99%), respectively (entries 24−28).
C
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Whereas method A conditions for the oxidation of 1-octanol
(3f) at a concentration of 0.25 M provided caprylic acid (4f) in
85% yield, method B conditions gave a lower yield of the same
transformation product (entry 29). From the results in Table 3,
the organic-molecule-free oxidation using Oxone (method A) is
much more effective than the Brønsted acid assisted oxidation
using aqueous H2O2 (method B) for the alkali metal bromide
catalyzed oxidation of alcohols. Moreover, when the reaction
was conducted on a 30 mmol scale of 1a (4.33 g) under both
conditions (methods A and B), KBr showed high catalytic
activity and 2a was obtained in 98% and 99% yields,
respectively (Scheme 2).
of MeCN and H2O showed reactivity similar to that in the
absence of TEMPO (entry 1 vs 3), the oxidation in MeCN
increased the yield of desired aldehyde 5c in the bromide
catalyzed oxidation (entry 2 vs 4). Optimization experiments of
the solvent and the amount of TEMPO demonstrated that the
use of TEMPO (10 mol %) in AcOEt gave the best conditions
for the bromide catalyzed transformation into aldehyde 5c with
KBr/Oxone (entries 5−8). On the other hand, those reactions
conducted under method B conditions also provided 4c as the
major product (entries 10−12). The addition of TEMPO and
the removal of water in the chemoselective oxidation with KBr/
H2O2/PhSO3H improved the yields (entries 13 and 14), and
the oxidation with KBr (20 mol %), aqueous H2O2 (2.0 equiv),
PhSO3H (20 mol %), and consequently TEMPO (10 mol %)
in CH2Cl2 generated the desired product 5c in a quantitative
yield (entry 15). The oxidation of 3c into 5c did not proceed in
the absence of KBr under both conditions (entries 9 and 16).
To explore the scope of the alkali metal bromide catalyzed
oxidative transformation of alcohols into aldehydes, various
primary alcohols 3 were examined under the optimum
conditions of methods C and D (Scheme 3).
a
Scheme 2. Catalytic Gram-Scale Oxidation of 1a
a
The oxidation of benzyl alcohols 3a−e bearing a substituent
on the aromatic ring produced the corresponding aldehydes
5a−e in high yields under both conditions (methods C and D)
(77 to >99%), respectively. The oxidation of aliphatic alcohol
3f provided the desired aldehyde 5f in low yields (40% and
32%) under both conditions due to side reactions (i.e.,
formation of octyl octanoate via oxidative dimerization).
In order to elucidate the mechanism of the present reactions,
we investigated the bromide catalyzed oxidation of 1a in the
presence of a galvinoxyl free radical under each set of reaction
conditions (methods A−D) (Scheme 4).
Method A: KBr (10 mol %) and Oxone (1.0 equiv) in MeCN/H2O
(9/1) at room temperature. Method B: KBr (20 mol %), aqueous
H2O2 (1.5 equiv), and PhSO3H (10 mol %) in CH2Cl2/H2O (9/1) at
room temperature.
Next, we investigated the divergent transformation of
primary alcohols 3 into carboxylic acids 4 and aldehydes 5 by
the alkali metal bromide catalyzed oxidation. To this end, the
alkali metal bromide catalyzed chemoselective oxidation of 4-
chlorobenzyl alcohol (3c) into 4-chlorobenzaldehyde (5c) was
examinded (Table 4). The use of method A conditions for
secondary alcohol oxidation provided carboxylic acid 4c as the
major product (entries 1 and 2). Whereas the oxidation by
method A in the presence of TEMPO7 (5 mol %) in a mixture
The reaction using method A in MeCN/H2O (9/1)
provided the desired product 2a in 58% yield together with
38% recovery of 1a, whereas that in CH2Cl2/H2O (9/1) gave
Table 4. Screening for Optimum Conditions for Alkali Metal Bromide Catalyzed Selective Oxidation of 3c into Aldehyde 5c
a
yield (%)
entry
KBr (mol %)
oxidant (equiv)
PhSO3H (mol %)
TEMPO (mol %)
solvent
4c
63
5c
22
1
10
10
10
10
10
10
10
10
Oxone (1.0)
Oxone (1.0)
Oxone (1.0)
Oxone (1.0)
Oxone (1.0)
Oxone (1.0)
Oxone (1.0)
Oxone (1.0)
Oxone (1.0)
aq H2O2 (2.0)
aq H2O2 (2.0)
aq H2O2 (2.0)
aq H2O2 (2.0)
aq H2O2 (2.0)
aq H2O2 (2.0)
aq H2O2 (2.0)
MeCN/H2O(9/1)
MeCN
2
91
9
22
67
83
82
91
85
4
3
5
5
MeCN/H2O(9/1)
MeCN
58
4
14
5
5
AcOEt
0
6
5
CH2Cl2
0
7
10
10
10
AcOEt
0
0
8
CH2Cl2
9
AcOEt
0 (94)
75
10
11
12
13
14
15
16
20
20
20
20
20
20
10
20
20
20
20
20
20
CH2Cl2/H2O(9/1)
CH2Cl2/H2O(9/1)
CH2Cl2
10
27
14
81
79
>99
3
68
73
5
10
10
10
CH2Cl2/H2O(9/1)
CH2Cl2/H2O(9/1)
CH2Cl2
4
0 (21)
CH2Cl2
0 (92)
a
Values in parentheses indicate the recovery of 3c.
D
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oxidizability of the oxidant in addition to the solvent effect (eq
1 vs eq 2). In addition, the reactions with TEMPO (methods C
and D) in the presence of galvinoxyl free radical gave the
oxidative products under both reaction conditions (eq 3 and eq
4). In those cases, the oxidation with Oxone is more effective
(5c in 68% yield and 4c in 10% yield) than the oxidation with
H2O2/PhSO3H (5c in 16% yield) (eq 3 vs eq 4). These
observations support that the oxidation with H2O2 in a solution
of CH2Cl2/H2O mainly proceeds via a radical pathway. In
contrast, the oxidation with Oxone in a mixture of MeCN and
H2O (method A) and the addition of TEMPO (methods C and
D) involve simultaneous ionic reactions in addition to a radical
reaction. Furthermore, the use of TEMPO in the oxidation
increases the ionic character of the bromide catalyzed oxidation
(eq 1 vs eq 3 and eq 2 vs eq 4).
Scheme 3. Divergent Transformation of 3 into 4 and 5 by
Alkali Metal Bromide Catalyzed Oxidation
To evaluate the in situ generation of a cationic bromo ion
from an alkali metal bromide, we investigated the bromination
of p-methoxytoluene (6) with KBr under all of the reaction
conditions (methods A−D) (Scheme 5).12 The treatment of 6
Scheme 5. Bromination of p-Methoxytoluene (6) with KBr
a
under Conditions of Methods A−D
a
b
The reaction was carried out in CH2Cl2 (2 mL).
Values in
parentheses indicate the yield of octyl octanoate. KBr (30 mol %),
aqueous H2O2 (3.0 equiv), and PhSO3H (30 mol %) were used.
d
e
Value in parentheses indicates the yield of 4f. Value in parentheses
indicates the recovery of 3f.
Scheme 4. Bromide-Catalyzed Oxidation of Alcohols by
Galvinoxyl Free Radical
a
Method A: KBr (1.2 equiv) and Oxone (1.0 equiv) in MeCN/H2O
(9/1). Method B: KBr (1.2 equiv), aqueous H2O2 (1.5 equiv), and
PhSO3H (10 mol %) in CH2Cl2/H2O (9/1). Method C: KBr (1.2
equiv), Oxone (1.0 equiv), and TEMPO (10 mol %) in AcOEt.
Method D: KBr (1.2 equiv), aqueous H2O2 (1.5 equiv), PhSO3H (10
b
mol %), and TEMPO (10 mol %) in CH2Cl2. Values in parentheses
indicate the recovery of 6.
with KBr and Oxone in a mixture of MeCN and H2O (method
A) promoted the bromination on the aromatic ring to give the
brominated product 7 in 85% yield, whereas the bromination
with H2O2 and PhSO3H in a mixture of CH2Cl2 and H2O
(method B) and those systems with TEMPO (method C and
D) gave little or no yield of 7. Above all, those reactions did not
produce the benzyl bromide via the radical reaction. The results
indicated that using Oxone in polar solvents for the oxidation of
bromide promotes the generation of bromonium ion from a
bromide.
Hammett plots for the oxidation of various secondary
alcohols under the conditions of nethods A and B (Figure 2a,b)
and primary alcohols (Figure 2c,d) under the conditions of
methods C and D with KBr are drawn.13 A linear relationship
was observed in all cases between log(kX/kH) and substituent
constant σ+, and the reaction constants ρ were −0.66 (method
A), −0.56 (method B), −1.29 (method C), and −1.11 (method
D). The negative reaction constants denote that a small positive
charge is found at the benzylic position of 1 and 3 in the
transition state. Moreover, the large absolute values (−1.29 and
−1.11) for the oxidation with TEMPO (methods C and D) in
comparison to those values (−0.66 and −0.56) for the
oxidation without TEMPO (methods A and B) indicate that
a
b
Value in parentheses indicates the recovery of 1. Value in
parentheses indicates the yield of 4c.
no product (eq 1). The reaction using method B did not
generate any oxidized products under both solvent conditions
(eq 2). The difference in reactivity may mainly come from the
E
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Table 5. Kinetic Isotope Effect on 1c and 3c in Alkali Metal
Bromide Catalyzed Oxidation
a
b
entry 1 or 3 method
time (h) product yield (%)
kH/kD
1
2
3
4
5
6
7
8
1c
A
A
B
1
1
3
3
5
5
3
3
2c
34 (66)
21 (79)
60 (40)
42 (58)
52 (48)
16 (84)
72 (28)
24 (76)
1.62
1c-d
1c
2c-d
2c
1.43
3.25
3.00
1c-d
3c
B
2c-d
5c
C
C
D
D
3c-d
3c
5c-d
5c
3c-d
5c-d
a
Method A: KBr (10 mol %) and Oxone (1.0 equiv) in MeCN/H2O
(9/1). Method B: KBr (20 mol %), aqueous H2O2 (1.5 equiv), and
PhSO3H (10 mol %) in CH2Cl2/H2O (9/1). Method C: KBr (10 mol
%), Oxone (1.0 equiv), and TEMPO (10 mol %) in AcOEt. Method
D: KBr (10 mol %), aqueous H2O2 (1.5 equiv), PhSO3H (10 mol %),
b
and TEMPO (10 mol %) in CH2Cl2. Values in parentheses indicate
the recovery of substrates.
Then, we investigated the competitive oxidation of secondary
alcohol 1c and primary alcohol 3c with Oxone (0.5 equiv) or
aqueous H2O2 (1.0 equiv) under each set of conditions (Table
6). The oxidation of 1c and 3c under all the reaction conditions
(methods A−D) occurred with comparable selectivity to give
the corresponding ketone 2c and aldehyde 5c (eqs 7 and 8).
For the oxidation in the absence of TEMPO (Methods A and
B), the oxidation of secondary alcohol (1c) has an advantage
over one of primary alcohol (3c) because it is likely to be
Figure 2. Hammett plots of log (kX/kH) versus σ+ for bromide-
catalyzed oxidation of 1° and 2° benzyl alcohols;: (a) method A, KBr
(10 mol %) and Oxone (0.5 equiv) in MeCN/H2O (9/1), log(kX/kH)
= −0.66, σ+ = −6.3 × 10−3 (r = 0.977); (b) method B, KBr (10 mol
%), aqueous H2O2 (1.0 equiv), and PhSO3H (10 mol %) in CH2Cl2/
H2O (9/1), log(kX/kH) = −0.56, σ+ = −3.8 × 10−3 (r = 0.974); (c)
method C, KBr (10 mol %), Oxone (0.5 equiv), and TEMPO (10 mol
%) in AcOEt, log(kX/kH) = −1.29, σ+ = −4.6 × 10−2 (r = 0.991); (d)
method D, KBr (10 mol %), aqueous H2O2 (1.0 equiv), PhSO3H (10
mol %), and TEMPO (10 mol %) in CH2Cl2, log(kX/kH) = −1.12, σ+
= −4.4 × 10−4 (r = 0.997).
Table 6. Competitive Reactions of Alcohols 1c and 3c in
a
Bromide-Catalyzed Oxidation
the use of TEMPO increases the positive charge at the benzylic
position of 1 and 3 in the transition state.
The deuterium kinetic isotope effect on the alkali metal
bromide catalyzed oxidation was evaluated in the competitive
reaction of a 1/1 mixture of 1c and 1-deuterio-1-(4-
chlorophenyl)ethanol (1c-d) or 3c and dideuterio(4-
chlorophenyl)methanol (3c-d) under each set of reaction
conditions (Table 5). The small kH/kD values of 1.62 (entries 1
and 2) and 1.43 (entries 3 and 4) indicate a hydrogen atom at
the α-carbon of a hypobromite intermediate, which is formed
via a substitution of bromide from alcohols in a concerted
fashion, not the direct C−H abstraction of alcohol, is the rate-
determining step for the oxidation in the absence of TEMPO
(methods A and B). In contrast, the large kH/kD values of 3.25
(entries 5 and 6) and 3.00 (entries 7 and 8) confirm that
oxidation with TEMPO (methods C and D) directly promotes
hydrogen transfer from the hydrogen at the α-carbon of the
alcohol in the rate-determining step.
a
Method A: KBr (10 mol %) and Oxone (0.5 equiv) in MeCN/H2O
(9/1). Method B: KBr (10 mol %), aqueous H2O2 (1.0 equiv), and
PhSO3H (10 mol %) in CH2Cl2/H2O (9/1). Method C: KBr (10 mol
%), Oxone (0.5 equiv), and TEMPO (10 mol %) in AcOEt. Method
D: KBr (10 mol %), aqueous H2O2 (1.0 equiv), PhSO3H (10 mol %),
and TEMPO (10 mol %) in CH2Cl2.
F
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Figure 3. Plausible reaction mechanism.
caused by the stability of positive charge at α-carbon of a
hypobromite intermediate (eq 7). In particular, in the oxidation
with TEMPO, the primary alcohol is oxidized more rapidly
than the secondary alcohol (method C), indicating that the
oxidation favors the formation of an acyclic intermediate by the
nucleophlic addition of alcohol in the transition state,14a−c
whereas the secondary alcohol is oxidized more rapidly than the
primary alcohol (method D), indicating that the oxidation
favors the intermolecular hydride transfer in the transition state
(eq 8).14d
that becomes involved again in the catalytic cycle (right cycle).
Aldehydes 5 (R2 = H) obtained from primary alcohols 3 are
rapidly oxidized to the corresponding carboxylic acids 4 by
residual oxidants through the formation of their hydrates under
acidic conditions. In method A, the bromonium ion
competitively reacts with alcohols (1 and 3) through an ionic
pathway to produce the corresponding carbonyl compounds
(left cycle). In contrast, the addition of TEMPO in methods C
and D rapidly promotes the formation of oxoammmonium ion
(D) from TEMPO via oxidation by the bromo radical or the
bromonium ion, and the addition of alcohols 3 gives the
corresponding aldehydes 5. In particular, the TEMPO
oxidation preferentially occurs via the formation of an acyclic
intermediate in method C14a−c or the intermolecular hydride
transfer from the α-carbon of alcohol to the oxygen of the
oxoammonium cation in method D.14d Reduced hydroxylamine
(E) is reoxidized by activated bromine species (Br• or Br+) to
promote the catalytic process (bottom cycle).
Finally, the bromide catalyzed oxidation of alcohols (8)
bearing an unsaturated aliphatic carbon, such as alkene or
alkyne, was attempted with alkali metal bromide because it was
difficult to oxidize alcohols 8 by the high reactivity of
unsaturated aliphatic carbon with activated bromine. Indeed,
the bromide-catalyzed oxidation of 8a−c with KBr under both
method A and method B conditions absolutely did not provide
the desired ketone (9a−c), respectively.16 Basifying the
conditions for oxidation of 8 with TEMPO suppressed
undesirable reactions; when alkynyl alcohol 8a, cinnamyl
alcohol 8b, and terminal alkenyl alcohol 8c were treated with
KBr (20 mol %), Oxone (1.0 equiv), TEMPO (20 mol %), and
Na2CO3 (3.0 equiv) in CH2Cl2, the desired ketones 9a−c were
A plausible mechanism for the alkali metal bromide catalyzed
oxidation of alcohols is depicted in Figure 3.
In the first step of all the reaction conditions, the oxidation of
KBr with an oxidant generates hypobromous acid (A) in situ,
the formation of which is promoted by the nucleophilic
substitution to potassium peroxymonosulfate bearing the
monosulfate as the leaving group with bromide ion (method
A) or by hydrogen peroxide activated by Brønsted acid with
bromide ion (method B). In method B, KBr in the presence of
PhSO3H is in equilibrium with HBr and PhSO3K, but the
equilibrium favors KBr and PhSO3H over HBr and PhSO3K
(pKa: 4-Me-C6H4SO3H, 8.0; HBr, 5.5; in MeCN).15 In the
bromide-catalyzed oxidation in the absence of TEMPO,
hypobromous acid (A) is mainly converted into molecular
bromine (Br2), which forms a bromo radical (Br•) that
expeditiously reacts with alcohols (1 and 3) to yield
hypobromite intermediate (B). Subsequent oxidation of B
provides the corresponding carbonyl compounds 2 and 5 via
the trapping of hydrogen atom at the α carbon of an alkoxy
radical intermediate (C) by a bromo radical (Br•). The reduced
bromide is oxidized again by oxidants to form a bromo radical
G
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concentrated under reduced pressure, and the crude product was
purified by silica gel column chromatography (eluent hexane/AcOEt
3/1) to give the desired product 2w (162.1 mg, 99% yield).
obtained in high yields (78 to >99%) without damaging the
unsaturated aliphatic groups (Scheme 6).
General Procedure for Bromide Catalyzed Oxidation of
Alcohols 1 and 3 Using Alkali Metal Bromides and Aqueous
H2O2 (Method B) (Tables 2 and 3). To a solution of 1w (164.7 mg,
0.50 mmol), KBr (11.9 mg, 0.10 mmol), and PhSO3H (7.9 mg, 0.05
mmol) in a mixture of CH2Cl2 (0.9 mL) and H2O (0.1 mL) was added
30% aqueous H2O2 (85.0 μL, 0.75 mmol) at room temperature, and
the mixture was stirred for 24 h. Saturated Na2SO3 aqueous solution
(10 mL) was added to the reaction mixture, and the product was
extracted with AcOEt (15 mL × 3). The combined extracts were
washed with brine (10 mL) and dried over Na2SO4. The organic phase
was concentrated under reduced pressure, and the crude product was
purified by silica gel column chromatography (eluent hexane/AcOEt
3/1) to give the desired product 2w (156.8 mg, 96% yield).
Scheme 6. Bromide-Catalyzed Oxidation of Alcohols
Bearing Unsaturated Aliphatic Carbon
Methyl (6-oxoheptyl)(phenylsulfonyl)carbamate (2w). Colorless
oil. 1H NMR (400 MHz, CDCl3): δ 1.31−1.41 (m, 2H), 1.63 (quin, J
= 7.6 Hz, 2H), 1.77 (quin, J = 7.8 Hz, 2H), 2.15 (s, 3H), 2.46 (t, J =
7.6 Hz, 2H), 3.68 (s, 3H), 3.83 (t, J = 7.8 Hz, 2H), 7.53 (t, J = 7.6 Hz,
2H), 7.63 (t, J = 7.6 Hz, 1H), 7.94 (d, J = 7.6 Hz, 2H). 13C NMR (100
MHz, CDCl3): δ 23.1, 26.0, 29.8, 29.9, 43.4, 47.3, 53.7, 128.2 (2C),
128.7 (2C), 133.5, 139.5, 152.8, 208.8. IR (neat): 1732, 1713, 1354,
1275, 1163, 1132 cm−1. MS (ESI) calcd for C15H22NO5S [M + H]+
328.1213, found 328.1210.
a
b
The reaction was carried out in CH2Cl2 (1 mL). The reaction was
carried out at 0 °C.
In conclusion, we have developed an alkali metal bromide
catalyzed oxidation of alcohols, which proceeds under mild
conditions. This bromide catalyzed reaction efficiently
proceeded through an organic-molecule-free oxidation using
Oxone (method A) and a Brønsted-acid-assisted oxidation
using hydrogen peroxide as the oxidant (method B) and by
controlling the transformation into aldehydes by the addition of
a catalytic amount of TEMPO under both oxidation conditions
(methods C and D). The mechanism of the reaction was
proposed from the results of experiments with galvinoxyl free
radical, Hammett plots, the study of the deuterium kinetic
isotope effect, and the competitive reactions of primary and
secondary alcohols. These methods developed herein are
environmentally sustainable strategies for organic synthesis.
We are optimistic that the present catalytic oxidative trans-
formation using alkali metal bromide would be applicable to
fine organic synthesis.
5-Nonanone (2a; Commercially Available). Colorless oil (method
1
A, 70.8 mg, >99%; method B, 68.7 mg, 97%). H NMR (400 MHz,
CDCl3) δ 0.90 (t, J = 7.6 Hz, 6H), 1.31 (sext, J = 7.6 Hz, 4H), 1.55
(quin, J = 7.6 Hz, 4H), 2.39 (t, J = 7.6 Hz, 4H). 13C NMR (100 MHz,
CDCl3): δ 13.8 (2C), 22.3 (2C), 26.0 (2C), 42.5 (2C), 211.7. IR
(neat): 2958, 1712, 1465, 1379, 1133, 1043 cm−1.
4-Methylacetophenone (2b; Commercially Available). Colorless
1
oil (method A, 57.9 mg, 86%; method B, 63.2 mg, 94%). H NMR
(400 MHz, CDCl3): δ 2.41 (s, 3H), 2.58 (s, 3H), 7.26 (d, J = 8.2 Hz,
2H), 7.86 (d, J = 8.2 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 21.6,
26.5, 128.4 (2C), 129.2 (2C), 134.7, 143.8, 197.8. IR (neat): 1679,
1605, 1574, 1265, 1181 cm−1.
4-Chloroacetophenone (2c; Commercially Available). White solid
1
(method A, 73.6 mg, 95%; method B, 75.3 mg, 97%). H NMR (400
MHz, CDCl3): δ 2.59 (s, 3H), 7.44 (d, J = 8.9 Hz, 2H), 7.90 (d, J = 8.9
Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 26.6, 128.9 (2C), 129.7
(2C), 135.4, 139.6, 196.8. IR (neat): 1683, 1587, 1357, 1258, 1092
cm−1.
EXPERIMENTAL SECTION
■
4-Nitroacetophenone (2d; Commercially Available). White solid
1
1
General Procedure. H NMR spectra were measured on a 400
(method A, 82.4 mg, >99%; method B, 82.2 mg, >99%). H NMR
MHz spectrometer. Chemical shifts were recorded as follows: chemical
shift in ppm from internal tetramethylsilane on the δ scale, multiplicity
(s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad),
coupling constant (Hz), integration, and assignment. 13C NMR
spectra were measured on a 100 MHz spectrometer. Chemical shifts
were recorded in ppm from the solvent resonance employed as the
internal standard (deuteriochloroform at 77.0 ppm). 19F NMR spectra
were measured on a 471 MHz spectrometer. High-resolution mass
spectra (HRMS) were obtained by orbitrap mass spectrometers.
Characteristic peaks in the infrared (IR) spectra are recorded in
wavenumbers (cm−1) using ATR. Melting points are reported as
uncorrected. Thin-layer chromatography (TLC) was performed using
a 0.25 mm silica gel plate (60F-254). The products were purified by
column chromatography on silica gel 60 (63−200 mesh). Visualization
was accomplished by UV light (254 nm), anisaldehyde, KMnO4, and
phosphomolybdic acid.
General Procedure for Bromide Catalyzed Oxidation of
Alcohols 1 and 3 with Metal Bromides (Method A) (Tables 1
and 3). To a solution of 1w (164.7 mg, 0.50 mmol) and KBr (6.0 mg,
0.05 mmol) in a mixture of MeCN (0.9 mL) and H2O (0.1 mL) was
added Oxone (307.4 mg, 0.50 mmol) at room temperature, and the
mixture was stirred for 24 h. Saturated Na2SO3 aqueous solution (10
mL) was added to the reaction mixture, and the product was extracted
with AcOEt (15 mL × 3). The combined extracts were washed with
brine (10 mL) and dried over Na2SO4. The organic phase was
(400 MHz, CDCl3): δ 2.69 (s, 3H), 8.12 (d, J = 8.9 Hz, 2H), 8.32 (d, J
= 8.9 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 27.0, 123.8 (2C),
129.3 (2C), 141.4, 150.3, 196.3. IR (KBr) 3110, 1693, 1608, 1525,
1345, 1261 cm−1.
3-Chloroacetophenone (2e; Commercially Available). Colorless
1
oil (method A, 75.6 mg, 98%; method B, 76.9 mg, >99%). H NMR
(400 MHz, CDCl3): δ 2.60 (s, 3H), 7.41 (t, J = 8.0 Hz, 1H), 7.54
(ddd, J = 8.0, 2.0, 1.2 Hz, 1H), 7.83 (ddd, J = 8.0, 2.0, 1.2 Hz, 1H),
7.93 (t, J = 2.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 26.6, 126.4,
128.4, 129.9, 133.0, 134.9, 138.5, 196.7. IR (neat): 1688, 1572, 1422,
1358, 1251 cm−1.
2-Chloroacetophenone (2f; Commercially Available). White solid
(method A, 76.3 mg, 99%; method B, 76.9 mg, >99%). 1H NMR (400
MHz, CDCl3): δ 2.65 (s, 3H), 7.32 (ddd, J = 7.8, 7.1, 1.8 Hz, 1H),
7.36−7.44 (m, 2H), 7.55 (dd, J = 7.8, 1.8 Hz, 1H). 13C NMR (100
MHz, CDCl3): δ 30.7, 126.9, 129.4, 130.6, 131.3, 132.0, 139.1, 200.5.
IR (neat): 1695, 1432, 1357, 1276, 1240, 1095 cm−1.
Propiophenone (2g; Commercially Available). Colorless oil
1
(method A, 67.0 mg, >99%; method B, 73.7 mg, >99%). H NMR
(400 MHz, CDCl3): δ 1.23 (t, J = 7.3 Hz, 3H), 3.00 (q, J = 7.3 Hz,
2H), 7.45 (t, J = 7.8 Hz, 2H), 7.55 (t, J = 7.8 Hz, 1H), 7.97 (d, J = 7.8
Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 8.2, 31.7, 127.9 (2C), 128.5
(2C), 132.8, 136.8, 200.7. IR (neat): 2979, 1685, 1597, 1448, 1351,
1218 cm−1.
H
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Isobutyrophenone (2h; Commercially Available). Colorless oil
(method A, 70.9 mg, 96%; method B, 69.8 mg, 94%). H NMR (400
2,2-Dimethyl-3-undecanone (2r).17a Colorless oil (method A, 97.5
mg, 98%; method B, 86.2 mg, 87%). H NMR (400 MHz, CDCl3): δ
1
1
MHz, CDCl3): δ 1.22 (d, J = 6.9 Hz, 6H), 3.56 (sept, J = 6.9 Hz, 1H),
7.46 (t, J = 7.3 Hz, 2H), 7.55 (t, J = 7.3 Hz, 1H), 7.96 (d, J = 7.3 Hz,
2H). 13C NMR (100 MHz, CDCl3): δ 19.2 (2C), 35.4, 128.4 (2C),
128.7 (2C), 132.9, 136.3, 204.6. IR (neat): 2972, 1684, 1465, 1383,
1225, 1161 cm−1.
0.88 (t, J = 7.0 Hz, 3H), 1.13 (s, 9H), 1.20−1.34 (m, 10H), 1.54 (quin,
J = 7.3 Hz, 2H), 2.47 (t, J = 7.3 Hz, 2H). 13C NMR (100 MHz,
CDCl3): δ 14.1, 22.6, 23.9, 26.4 (3C), 29.2, 29.3, 29.5, 31.8, 36.4, 44.1,
216.2. IR (neat): 2925, 1707, 1465, 1365, 1124, 1072 cm−1.
Ethyl Phenylglyoxylate (2s; Commercially Available). Colorless oil
(method A, 83.1 mg, 93%; method B, 88.6 mg, >99%). 1H NMR (400
MHz, CDCl3): δ 1.42 (t, J = 7.3 Hz, 2H), 4.46 (q, J = 7.3 Hz, 2H),
7.51 (t, J = 7.6 Hz, 2H), 7.66 (t, J = 7.6 Hz, 1H), 8.01 (d, J = 7.6 Hz,
2H). 13C NMR (100 MHz, CDCl3): δ 14.0, 62.3, 128.8 (2C), 130.0
(2C), 132.4, 134.8, 163.8, 186.4. IR (neat): 1733, 1686, 1300, 1198,
1175, 1013 cm−1.
Decyl Pyruvate (2t). Colorless oil (method A, 109.5 mg, 96%;
method B, 113.9 mg, >99%). 1H NMR (400 MHz, CDCl3): δ 0.88 (t,
J = 6.9 Hz, 3H), 1.23−1.42 (m, 14H), 1.73 (quin, J = 6.9 Hz, 2H),
2.47 (s, 3H), 4.25 (t, J = 6.9 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ
14.0, 22.6, 25.7, 26.7, 28.3, 29.1, 29.2, 29.40, 29.43, 31.8, 66.6, 160.8,
192.0. IR (neat): 2925, 1756, 1730, 1467, 1299, 1136 cm−1. MS (ESI)
calcd for C13H24NaO3 [M + Na]+ 251.1618, found 251.1617.
3-Acetoxypropiophenone (2u). Colorless oil (method A, 85.3 mg,
89%; method B, 85.7 mg, 89%). 1H NMR (400 MHz, CDCl3): δ 2.04
(s, 3H), 3.33 (t, J = 6.4 Hz, 2H), 4.53 (t, J = 6.4 Hz, 2H), 7.49 (t, J =
7.6 Hz, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.95−7.99 (m, 2H). 13C NMR
(100 MHz, CDCl3): δ 20.9, 37.3, 59.6, 128.0 (2C), 128.6 (2C), 133.4,
136.5, 171.0, 196.9. IR (KBr) 2984, 1731, 1671, 1372, 1255, 1214
cm−1. MS (ESI) calcd for C11H12NaO3 [M + Na]+ 215.0679, found
215.0679.
Pivalophenone (2i; Commercially Available). Colorless oil
1
(method A, 81.0 mg, >99%; method B, 80.7 mg, >99%). H NMR
(400 MHz, CDCl3): δ 1.35 (s, 9H), 7.39 (tt, J = 7.3, 1.6 Hz, 2H), 7.45
(tt, J = 7.3, 1.6 Hz, 1H), 7.68 (dt, J = 7.3, 1.6 Hz, 2H). 13C NMR (100
MHz, CDCl3): δ 27.9 (3C), 44.1, 127.8 (2C), 128.0 (2C), 130.7,
138.5, 209.2. IR (neat): 2969, 1674, 1476, 1366, 1277, 1175 cm−1.
Benzophenone (2j; Commercially Available). White solid (method
1
A, 90.9 mg, >99%; method B, 90.7 mg, >99%). H NMR (400 MHz,
CDCl3): δ 7.49 (t, J = 7.8 Hz, 4H), 7.60 (t, J = 7.8 Hz, 2H), 7.81 (d, J
= 7.8 Hz, 4H). 13C NMR (100 MHz, CDCl3): δ 128.2 (4C), 130.0
(4C), 132.2 (2C), 137.6 (2C), 196.7. IR (KBr) 3055, 1652, 1596,
1319, 1278 cm−1.
α-Tetralone (2k; Commercially Available). Colorless oil (method
A, 64.7 mg, 89%). 1H NMR (400 MHz, CDCl3): δ 2.14 (quin, J = 6.4
Hz, 2H), 2.66 (t, J = 6.4 Hz, 2H), 2.97 (t, J = 6.4 Hz, 2H), 7.25 (d, J =
7.6 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.47 (td, J = 7.6, 1.4 Hz, 1H),
8.03 (dd, J = 8.0, 1.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 23.4,
29.7, 39.1, 126.6, 127.1, 128.7, 132.6, 133.4, 144.4, 198.4. IR (neat):
2944, 1679, 1600, 1324, 1284 cm−1.
2-Octanone (2l; Commercially Available). Colorless oil (method
1
A, 64.0 mg, >99%; method B, 54.3 mg, 85%). H NMR (400 MHz,
CDCl3): δ 0.88 (t, J = 6.9 Hz, 3H), 1.24−1.36 (m, 6H), 1.52−1.62 (m,
2H), 2.13 (s, 3H), 2.42 (t, J = 7.6 Hz, 2H). 13C NMR (100 MHz,
CDCl3): δ 14.0, 22.4, 23.8, 28.8, 29.8, 31.5, 43.7, 209.3. IR (neat):
2928, 1715, 1410, 1359, 1226, 1164 cm−1.
4-Chlorobutyrophenone (2v; Commercially Available). Colorless
oil (method A, 91.1 mg, >99%; method B, 82.5 mg, 90%). H NMR
1
(400 MHz, CDCl3): δ 2.23 (quin, J = 6.8 Hz, 2H), 3.18 (t, J = 6.8 Hz,
2H), 3.68 (t, J = 6.8 Hz, 2H), 7.44−7.51 (m, 2H), 7.57 (tt, J = 7.4, 1.4
Hz, 1H), 7.98 (dd, J = 8.3, 1.4 Hz, 2H). 13C NMR (100 MHz,
CDCl3): δ 26.7, 35.2, 44.6, 127.9 (2C), 128.6 (2C), 133.2, 136.6,
198.9. IR (neat): 1683, 1448, 1322, 1225, 742, 688 cm−1.
Cyclododecanone (2m; Commercially Available). White solid
1
(method A, 91.0 mg, >99%; method B, 90.7 mg, >99%). H NMR
(400 MHz, CDCl3): δ 1.22−1.37 (m, 14H), 1.67−1.76 (m, 4H),
2.44−2.49 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 22.3, 22.5 (2C),
24.2 (2C), 24.6 (2C), 24.7 (2C), 40.3 (2C), 212.9. IR (neat): 2927,
1702, 1470, 1362, 1204, 1131 cm−1.
5-Phenyl-2-pentanone (2x).17b White solid (method A, 63.2 mg,
78%; method B, 66.2 mg, 87%). 1H NMR (400 MHz, CDCl3): δ 1.91
(quin, J = 7.5 Hz, 2H), 2.11 (s, 3H), 2.43 (t, J = 7.5 Hz, 2H), 2.62 (t, J
= 7.5 Hz, 2H), 7.14−7.22 (m, 3H), 7.28 (t, J = 7.3 Hz, 2H). 13C NMR
(100 MHz, CDCl3): δ 25.1, 29.9, 34.9, 42.8, 125.9, 128.3 (2C), 128.4
(2C), 141.5, 208.8. IR (neat): 1712, 1496, 1453, 1358, 1159 cm−1.
4-Methylbenzoic Acid (4a; Commercially Available). White solid
4-tert-Butylcyclohexanone (2n; Commercially Available). White
1
solid (method A, 67.1 mg, 87%; method B, 41.3 mg, 54%). H NMR
(400 MHz, CDCl3): δ 0.92 (s, 9H), 1.38−1.55 (m, 3H), 2.03−2.15
(m, 2H), 2.25−2.36 (m, 2H), 2.36−2.45 (m, 2H). 13C NMR (100
MHz, CDCl3): δ 27.4 (5C), 32.4, 41.2 (2C), 46.6, 212.5. IR (neat):
2947, 1722, 1419, 1365, 1222, 1161 cm−1.
1
(method A, 45.8 mg, 67%; method B, 47.2 mg, 69%). H NMR (400
MHz, CDCl3): δ 2.43 (s, 3H), 7.28 (d, J = 8.2 Hz, 2H), 8.01 (d, J = 8.2
Hz, 2H), 12.20 (brs, 1H). 13C NMR (100 MHz, CDCl3): δ 21.8,
126.5, 129.2 (2C), 130.2 (2C), 144.6, 172.4. IR (neat): 2823, 1668,
1610, 1416, 1281, 1181 cm−1.
(−)-Menthone (2o; Commercially Available). Colorless oil
1
(method A, 47.9 mg, 62%). H NMR (400 MHz, CDCl3): δ 0.85
(d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H), 1.01 (d, J = 6.4 Hz, 3H),
1.28−1.45 (m, 2H), 1.78−1.93 (m, 2H), 1.99 (td, J = 12.8, 1.2 Hz,
1H), 2.01−2.09 (m, 2H), 2.09−2.21 (m, 1H), 2.35 (ddd, J = 12.8, 3.9,
2.3 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 18.7, 21.2, 22.3, 25.8,
27.8, 33.9, 35.5, 50.8, 55.9, 212.5. IR (neat): 2955, 1708, 1456, 1366,
1202, 1045 cm−1.
4-Fluorobenzoic Acid (4b; Commercially Available). White solid
1
(method A, 63.7 mg, 91%; method B, 63.7 mg, 91%). H NMR (400
MHz, DMSO-d6): δ 3.34 (brs, 1H), 7.31 (t, J = 9.1 Hz, 2H), 7.99 (dd,
J = 9.1, 5.6 Hz, 2H). 13C NMR (100 MHz, DMSO-d6): δ 115.6 (d, J =
22.0 Hz, 2C), 127.4 (d, J = 2.9 Hz), 132.1 (d, J = 9.6 Hz, 2C), 164.9
(d, J = 252.0 Hz), 166.4. 19F NMR (471 MHz, DMSO-d6) d −106.8.
IR (neat): 2828, 1672, 1603, 1425, 1291, 1157 cm−1.
5α-Cholestan-3-one (2p; Commercially Available). White solid
1
(method A, 174.8 mg, 90%; method B, 141.5 mg, 73%). H NMR
(400 MHz, CDCl3): δ 0.68 (s, 3H), 0.67−0.77 (m, 1H), 0.86 (d, J =
6.6 Hz, 3H), 0.87 (d, J = 6.6 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H), 1.01 (s,
3H), 0.93−1.19 (m, 9H), 1.19−1.44 (m, 9H), 1.46−1.62 (m, 4H),
1.69 (dq, J = 13.1, 3.4 Hz, 1H), 1.76−1.89 (m, 1H), 1.95−2.12 (m,
3H), 2.27 (t, J = 14.6 Hz, 2H), 2.27−2.44 (m, 1H). 13C NMR (100
MHz, CDCl3): δ 11.5, 12.0 18.6, 21.4, 22.5, 22.8, 23.8, 24.2, 28.0, 28.2,
28.9, 31.7, 35.4, 35.6, 35.8, 36.1, 38.2, 38.5, 39.5, 39.9, 42.5, 44.7, 46.7,
53.7, 56.21, 56.24, 212.3. IR (neat): 2930, 1712, 1466, 1383, 1229,
1173 cm−1.
4-Chlorobenzoic Acid (4c; Commercially Available). White solid
(method A, 78.1 mg, >99%; method B, 75.4 mg, 96%). 1H NMR (400
MHz, CDCl3): δ 3.35 (brs, 1H), 7.58 (d, J = 8.6 Hz, 2H), 7.94 (d, J =
8.6 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 128.8 (2C), 129.6,
131.2 (2C), 137.8, 166.5. IR (KBr) 2839, 1685, 1592, 1425, 1324,
1092 cm−1.
3-Chlorobenzoic Acid (4d; Commercially Available). White solid
(method A, 78.1 mg, >99%; method B, 75.2 mg, 96%). 1H NMR (400
MHz, CDCl3): δ 7.44 (t, J = 8.0 Hz, 1H), 7.60 (ddd, J = 8.0, 2.0, 1.2
Hz, 1H), 8.01 (dt, J = 8.0, 1.2 Hz, 1H), 8.10 (t, J = 8.0, 2.0 Hz, 1H),
11.20 (brs, 1H). 13C NMR (100 MHz, CDCl3): δ 128.3, 129.9, 130.3,
130.9, 133.9, 134.7, 170.7. IR (neat): 2882, 1682, 1415, 1299, 1260,
1074 cm−1.
(−)-Camphor (2q; Commercially Available). White solid (method
1
A, 59.7 mg, 78%; method B, 66.2 mg, 87%). H NMR (400 MHz,
CDCl3): δ 0.84 (s, 3H), 0.91 (s, 3H), 0.96 (s, 3H), 1.29−1.46 (m,
2H), 1.69 (td, J = 13.2, 3.9 Hz, 1H), 1.85 (d, J = 18.3 Hz, 1H), 1.90−
2.01 (m, 1H), 2.09 (t, J = 4.5 Hz, 1H), 2.35 (dt, J = 18.3, 4.5 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ 9.2, 19.1, 19.8, 27.0, 29.9, 43.0, 43.3,
46.8, 57.7, 219.7. IR (neat): 2958, 1739, 1448, 1390, 1277, 1045 cm−1.
2-Chlorobenzoic Acid (4e; Commercially Available). White solid
1
(method A, 78.1 mg, >99%; method B, 77.9 mg, >99%). H NMR
(400 MHz, CDCl3): δ 7.37 (ddd, J = 7.8, 6.2, 2.5 Hz, 1H), 7.46−7.53
I
dx.doi.org/10.1021/jo5008064 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(m, 2H), 8.04 (dd, J = 7.8, 1.2 Hz, 1H), 10.97 (brs, 1H). 13C NMR
(100 MHz, CDCl3): δ 126.7, 128.3, 131.5, 132.5, 133.6, 134.8, 170.5.
IR (neat): 2816, 1681, 1408, 1311, 1265, 1042 cm−1.
CDCl3): δ 0.88 (t, J = 6.8 Hz, 3H), 1.21−1.39 (m, 8H), 1.63 (quin, J =
7.4 Hz, 2H), 2.42 (td, J = 7.4, 1.8 Hz, 2H), 9.77 (t, J = 1.8 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ 14.0, 22.0, 22.6, 29.0, 29.1, 31.6, 43.9,
203.0. IR (neat): 2926, 1726, 1465, 1379, 1145 cm−1.
Octanoic Acid (4f; Commercially Available). Colorless oil
(method A, 61.7 mg, 85%; method B, 14.7 mg, 20%). 1H NMR
(400 MHz, CDCl3): δ 0.88 (t, J = 7.0 Hz, 3H), 1.21−1.39 (m, 8H),
1.65 (quin, J = 7.5 Hz, 2H), 2.35 (t, J = 7.5 Hz, 2H), 11.5 (brs, 1H).
13C NMR (100 MHz, CDCl3): δ 14.0, 22.6, 24.6, 28.9, 29.0, 31.6, 34.1,
General Procedure for Bromide-Catalyzed Oxidation of
Alcohols (8) with Metal Bromides and TEMPO under Basic
Conditions (Scheme 6). To a solution of 8a (87.1 mg, 0.50 mmol),
KBr (11.9 mg, 0.10 mmol), TEMPO (15.6 mg, 0.10 mmol), and
NaHCO3 (126.0 mg, 1.50 mmol) in CH2Cl2 (2 mL) was added Oxone
(307.4 mg, 0.50 mmol) at room temperature, and the mixture was
stirred for 24 h. Saturated Na2SO3 aqueous solution (10 mL) was
added to the reaction mixture, and the product was extracted with
ether (15 mL × 3). The combined extracts were washed with brine
(10 mL) and dried over Na2SO4. The organic phase was concentrated
under reduced pressure, and the crude product was purified by silica
gel column chromatography (eluent hexane/AcOEt 50/1), to give the
desired product 9a (83.1 mg, 97% yield).
180.5. IR (neat): 2925, 1707, 1413, 1276, 1231 cm−1.
General Procedure for Bromide Catalyzed Transformation
of Alcohols 3 into Aldehydes 5 with Metal Bromides and
TEMPO (Method C) (Table 4 and Scheme 3). To a solution of 3c
(71.3 mg, 0.50 mmol), KBr (6.0 mg, 0.05 mmol), and TEMPO (7.8
mg, 0.05 mmol) in AcOEt (1 mL) was added Oxone (307.4 mg, 0.50
mmol) at room temperature, and the mixture was stirred for 24 h.
Saturated Na2SO3 aqueous solution (10 mL) was added to the
reaction mixture, and the product was extracted with ether (15 mL ×
3). The combined extracts were washed with brine (10 mL) and dried
over Na2SO4. The organic phase was concentrated under reduced
pressure, and the crude product was purified by silica gel column
chromatography (eluent hexane/AcOEt 50/1), to give the desired
product 5c (63.8 mg, 91% yield).
General Procedure for Bromide Catalyzed Transformation
of Alcohols 3 into Aldehydes 5 with Metal Bromides and
TEMPO (Method D) (Table 4 and Scheme 3). To a solution of 3c
(71.3 mg, 0.50 mmol), KBr (11.9 mg, 0.10 mmol), PhSO3H (15.8 mg,
0.10 mmol), and TEMPO (7.8 mg, 0.05 mmol) in CH2Cl2 (1 mL) was
added 30% aqueous H2O2 (113.4 mL, 1.00 mmol) at room
temperature, and the mixture was stirred for 24 h. Saturated Na2SO3
aqueous solution (10 mL) was added to the reaction mixture, and the
product was extracted with ether (15 mL × 3). The combined extracts
were washed with brine (10 mL) and dried over Na2SO4. The organic
phase was concentrated under reduced pressure, and the crude
product was purified by silica gel column chromatography (eluent
hexane/AcOEt 50/1), to give the desired product 5c (69.9 mg, >99%
yield).
1-Phenylhex-1-yn-3-one (9a).17c Colorless oil. 1H NMR (400
MHz, CDCl3): δ 1.00 (t, J = 7.6 Hz, 3H), 1.78 (sext, J = 7.6 Hz, 2H),
2.65 (t, J = 7.6 Hz, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.46 (t, J = 7.6 Hz,
1H), 7.58 (d, J = 7.6 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 13.5,
17.7, 47.4, 87.8, 90.5, 120.0, 128.6 (2C), 130.6, 133.0 (2C), 188.2. IR
(neat): 2964, 2200, 1666, 1278, 1124, 1059 cm−1.
(E)-Chalcone (9b; Commercially Available). White solid (103.9
mg, >99%). 1H NMR (400 MHz, CDCl3): δ 7.39−7.45 (m, 3H), 7.50
(t, J = 7.4 Hz, 2H), 7.54 (d, J = 15.8 Hz, 1H), 7.59 (tt, J = 7.4, 1.4 Hz,
1H), 7.61−7.67 (m, 2H), 7.82 (d, J = 15.8 Hz, 1H), 8.03 (d, J = 7.4
Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 122.0, 128.4 (2C), 128.5
(2C), 128.6 (2C), 128.9 (2C), 130.5, 132.7, 134.8, 138.2, 144.8, 190.5.
IR (neat): 1662, 1603, 1335, 1213, 1015, 977 cm−1.
1-Phenylbut-3-en-1-one (9c).17d Colorless oil (62.1 mg, 85%). H
1
NMR (400 MHz, CDCl3): δ 3.76 (dt, J = 8.2, 1.4 Hz, 2H), 5.18−5.27
(m, 2H), 6.09 (ddt, J = 17.3, 10.4, 6.8 Hz, 1H), 7.47 (t, J = 7.5 Hz,
2H), 7.57 (t, J = 7.5 Hz, 1H), 7.97 (d, J = 7.5 Hz, 2H). 13C NMR (100
MHz, CDCl3): δ 43.4, 118.7, 128.2 (2C), 128.6 (2C), 131.0, 133.1,
136.5, 198.0. IR (neat): 1682, 1448, 1333, 1208, 1004, 920 cm−1. MS
(ESI): calcd for C10H10NaO [M + Na]+ 169.0624, found 169.0621.
4-Chlorobenzaldehyde (5c; Commercially Available). White solid.
1H NMR (400 MHz, CDCl3): δ 7.52 (d, J = 8.6 Hz, 2H), 7.83 (d, J =
8.6 Hz, 2H), 9.99 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 129.4
(2C), 130.9 (2C), 134.7, 140.9, 190.8. IR (neat): 1689, 1587, 1573,
1385, 1209, 1091 cm−1.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Figures giving H and 13C NMR spectra of compounds in the
4-Methylbenzaldehyde (5a; Commercially Available). Colorless
1
alkali metal bromide catalyzed oxidation of alcohols. This
material is available free of charge via the Internet at http://
pubs.acs.org.
oil (method A, 60.0 mg, >99%; method B, 59.8 mg, >99%). H NMR
(400 MHz, CDCl3): δ 2.44 (s, 3H), 7.33 (d, J = 8.0 Hz, 2H), 7.77 (d, J
= 8.0 Hz, 2H), 9.96 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 21.8,
129.7 (2C), 129.8 (2C), 134.2, 145.5, 191.9. IR (neat): 1701, 1686,
1604, 1388, 1208, 1168 cm−1.
AUTHOR INFORMATION
Corresponding Authors
*E-mail for K.M.: moriyama@faculty.chiba-u.jp.
*E-mail for H.T.: togo@faculty.chiba-u.jp.
■
4-Fluorobenzaldehyde (5b; Commercially Available). Colorless
1
oil (method A, 57.5 mg, 93%; method B, 61.7 mg, >99%). H NMR
(400 MHz, CDCl3): δ 7.22 (t, J = 8.9 Hz, 2H), 7.92 (dd, J = 8.9, 5.5
Hz, 2H), 9.98 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 116.3 (d, J =
22.0 Hz, 2C), 132.2 (d, J = 10.5 Hz, 2C), 132.9 (d, J = 2.9 Hz), 116.5
(d, J = 257.7 Hz), 190.5. 19F NMR (471 MHz, CDCl3): δ −102.2. IR
(neat): 1693, 1595, 1505, 1227, 1202, 1148 cm−1.
Notes
The authors declare no competing financial interest.
3-Chlorobenzaldehyde (5d; Commercially Available). Colorless
oil (method A, 70.1 mg, >99%; method B, 69.8 mg, >99%). H NMR
ACKNOWLEDGMENTS
1
■
(400 MHz, CDCl3): δ 7.49 (t, J = 7.9 Hz, 1H), 7.61 (ddd, J = 7.9, 2.0,
1.3 Hz, 1H), 7.77 (td, J = 7.9, 1.3 Hz, 1H), 7.86 (t, J = 2.0 Hz, 1H),
9.98 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 127.9, 129.3, 130.3,
134.4, 135.4, 137.8, 190.8. IR (neat): 1697, 1572, 1385, 1192, 1072
cm−1.
Financial support in the form of a Grant-in Aid for Young
Scientists B (No.24750033) from the Ministy of Education,
Culture, Sports, Science and Technology of Japan (K.M.) and
the Iodine Research Project of Chiba University is gratefully
acknowledged.
2-Chlorobenzaldehyde (5e; Commercially Available). Colorless
1
oil (method A, 54.1 mg, 77%; method B, 68.1 mg, 97%). H NMR
REFERENCES
(400 MHz, CDCl3) δ, 7.40 (td, J = 7.8, 0.7 Hz, 1H), 7.46 (dd, J = 7.8,
0.7 Hz, 1H), 7.51−7.57 (m, 1H), 7.93 (dd, J = 7.8, 1.4 Hz, 1H), 10.49
(s, 1H). 13C NMR (100 MHz, CDCl3): δ 127.3, 129.3, 130.6, 132.4,
135.1, 137.9, 189.8. IR (neat): 1694, 1591, 1442, 1266, 1197, 1052
cm−1.
■
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dx.doi.org/10.1021/jo5008064 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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