Our interest in this area was piqued during our investiga-
tion of the oxidative cyclization of 1,4-dienes. In the course
of this study, we observed significant amounts of over-
oxidation that gave rise to carboxylic acids as the major
byproducts (Scheme 2).12 This led to studies on the oxidative
4-hydroxybenzaldehyde and p-anisaldehyde (Table 1, entries
12 and 13) provided the formate esters 14 and 15 as the
major products in 62% and 58% yield, respectively (Scheme
3). This is consistent with previous observations for the
Scheme 3
Scheme 2
cleavage of olefins, where although clean conversion to
aldehydes as the immediate oxidation products was observed,
the isolable products were carboxylic acids.11 We have now
pursued the optimization of this aldehyde oxidation to
carboxylic acids and in the process have also discovered a
new route for the direct conversion of aldehydes to esters.
The scope and limitations for these oxidative processes are
presented. The present method is attractive, since as opposed
to most methodologies that utilize Cr, Mn, Ru, or other
transition-metal oxides, the environmentally benign reagent
Oxone mediates these highly efficient oxidations.1,2,13
Initially, oxidation of aryl aldehydes to carboxylic acids
with Oxone in DMF were investigated, the results of which
are summarized in Table 1. In most cases, the desired
oxidation of electron-rich aromatic rings that are presumed
to undergo a Baeyer-Villiger reaction where the phenolic
or Dakin products were obtained (Scheme 3).16 As expected,
meta-substituted electron-donating groups do not yield
substantial amounts of the Dakin product (Table 1, entry 11).
The potential scope of this method was evident when the
protocol was extended to simple aliphatic aldehydes (Table
2, entries 1-7). In most cases, the oxidation proceeds with
high efficiency and yields of greater than 90% were obtained.
While affording clean reactions (as evident by GC analysis),
smaller aliphatic aldehydes (Table 2, entries 3 and 4)
provided low yields due to problematic isolation from DMF.
Olefinic aldehydes such as 24 were also oxidized efficiently
without any observable reactivity at the double bond
functionality. Oxidation of the electron-rich aldehydes 25
and 27 again provided primarily the Dakin products (Table
2, entries 8 and 9). Interestingly, the oxidation of 5-(4-
bromophenyl)furfural 27 leads to the 1,4-dicarbonyl system
29 through a simple oxidative process upon hydrolysis of
the dehydrolactone 28 (>70% combined yield). The γ-keto
carboxylic acid 29 was the sole isolated product (72% yield)
when oxidation of 27 was followed by a basic workup.
A key feature of the oxidation protocol to carboxylic acids
is its inherent simplicity. A mixture of the aldehyde (1 equiv)
and Oxone (1 equiv) in DMF (0.1-1.0 M) is stirred for 3 h
at rt. There is no need for rigorous exclusion of air or
moisture in order to effect a clean oxidation; however, the
reactions continue to work even with these added precautions.
In most cases, a simple pass through a plug of silica is
enough to obtain highly pure products.
Previous reports concerning the oxidation of aldehydes
with Oxone were performed in aqueous acetone or acetoni-
trile. However, we have found that DMF is also effective
for the oxidation and in some cases superior to aqueous
conditions. To test the range of solvents that may promote
this oxidation, a number of cyclic and linear hydrocarbons,
ethers, esters, and amides were screened. Surprisingly, very
few solvents provided the desired carboxylic acid product
even after extended reaction times of up to 36 h. The absence
of reactivity is not attributed to the lack of solubility of
Oxone because a comparable study using a soluble peroxy-
monosulfate (n-Bu4NHSO5) provided similar results.20 In-
terestingly, solvents such as NMP, HMPA, and pyrrolidinone
were also as effective as DMF in the oxidation of benz-
Table 1. Oxone Oxidations of Aromatic Aldehydesa
entry
X
product
yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
4-NO2, 1
4-CN, 2
2-NO2, 3
4-CO2Me, 4
H, 5
4-Me, 6
3-NO2, 7
2-Cl, 8
1a
2a
3a
4a
5a
6a
7a
8a
95
85
90
95
97
97
95
90
97
97
63
19c
31d
4-Cl, 9
9a
3-Br, 10
3-OH, 11
4-OH, 12
4-OMe, 13
10a
11a
12a
13a
a Aldehyde (1 equiv), Oxone (1 equiv), DMF (0.2 M), 3 h, rt. b Isolated
yields. c 62% yield of 14. d 58% yield of 15.
carboxylic acids were obtained in >85% yield. Electron-
withdrawing and electron-neutral benzaldehydes were oxi-
dized efficiently (Table 1, entries 1-7). Halogenated ben-
zaldehydes were also oxidized effortlessly to their corres-
ponding halogenated benzoic acids in good yields (Table 1,
entries 8-10). However, electron-rich substrates such as
1032
Org. Lett., Vol. 5, No. 7, 2003