Organocatalyzed Aerobic Oxidation of Aldehydes to Acids

Article abstract of DOI:10.1021/acs.orglett.9b00101

The first example organocatalyzed aerobic oxidation of aldehydes to carboxylic acids in both organic solvent and water under mild conditions is developed. As low as 5 mol % N-hydroxyphthalimide was used as the organocatalyst, and molecular O₂ was used as the sole oxidant. No transition metals or hazardous oxidants or cocatalysts were involved. A wide range of carboxylic acids bearing diverse functional groups were obtained from aldehydes, even from alcohols, in high yields.

Full text of DOI:10.1021/acs.orglett.9b00101

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Organocatalyzed Aerobic Oxidation of Aldehydes to Acids
Peng-Fei Dai,† Jian-Ping Qu,*,‡ and Yan-Biao Kang*,†
†Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
‡Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center
for Advanced Materials, Nanjing Tech University, Nanjing 211816, China
S
* Supporting Information
ABSTRACT: The first example organocatalyzed aerobic oxidation of
aldehydes to carboxylic acids in both organic solvent and water under mild
conditions is developed. As low as 5 mol % N-hydroxyphthalimide was
used as the organocatalyst, and molecular O2 was used as the sole oxidant.
No transition metals or hazardous oxidants or cocatalysts were involved. A
wide range of carboxylic acids bearing diverse functional groups were
obtained from aldehydes, even from alcohols, in high yields.
xidation is one of the most fundamental reactions with
are resources for air pollution, contributing to the formation of
Ogreat potential for both academic research and industry. smog and acid rain as well as affecting tropospheric ozone.
Therefore, the development of an efficient, practical, and
inexpensive catalyst system for catalytic oxidation of aldehydes
using molecular oxygen as a terminal oxidant without the
involvement of transition metals or hazardous cocatalysts is
highly desired.
It has long been known that aldehydes are very prone to
oxidation, but transformations of aldehydes to carboxylic acids
under mild and green conditions are still scarce.1,2 They
usually utilize stoichiometric amount of oxidants, such as
KMnO4,3 H5IO6,4 CrO3,5 KHSO5,6 NaClO2,7−9 silver
nitrate,10 copper(II) salt,11 etc., which are normally expensive
and/or hazardous to the environment (Scheme 1). Therefore,
an efficient and environmentally benign transformation of
aldehydes into carboxylic acids is highly desired.
We have reported that an N-hydroxyphthalimide
(NHPI)22−25 could generate benzyl radicals, and it provides
an efficient approach to mono-/diselectivity control in
aromatic nitrile26 or ketone27 synthesis. Recently, we found
that N-hydroxyphthalimide was an efficient organocatalyst for
the aerobic oxidation of aldehydes to carboxylic acids. Utilizing
a catalytic amount of N-hydroxyphthalimide (5 mol %) in the
presence of 1 atm of molecular O2 without any other oxidant
or cocatalyst leads to a wide range of carboxylic acids bearing
diverse functional groups in high yields under mild conditions
(30 °C) in both organic and aqueous conditions (Scheme 1).
The noninvolvement of transition metals and hazardous
reagent-free atmosphere make this method environmentally
benign and useful in pharmaceutical synthesis. Herein, we
report our results in detail.
Scheme 1. Oxidation of Aldehydes to Acids
First, various solvents were investigated using N-hydroxyph-
thalimide (1) as catalysts in the oxidation of aldehyde 2a
(Table 1). Dioxane and toluene afford 53% yields with 16−
30% recovered starting material 2 (entries 1 and 2), while
n
alcohols, such as BuOH and MeOH, do not promote this
oxidation reaction but only starting material 2 was recovered
(entries 3 and 4). CH3CN gives the best yield (entry 5). The
reaction in water also proceeds smoothly and gives 92% yields
(entry 6). The reaction condition in entry 5 was chosen for the
standard reaction conditions where 5 mol % of N-
hydroxyphthalimide was used as catalyst.
Molecular oxygen is a clean and sustainable oxidant for
oxidation reactions, and it possesses a unique advantage over
the other oxidants in that it produces water as the only
byproduct with a high atom economy. Unlike the catalytic
aerobic oxidation of alcohols to carboxylic acids which has
been well developed by using both homogeneous12−18 and
heterogeneous19,20 catalysts, development of a catalytic process
from aldehydes to carboxylic acids with molecular oxygen as a
terminal remains limited,21 despite the fact that the catalytic
aerobic oxidation of aldehydes to carboxylic acids seems to be
easily achieved. However, large quantities of nitrogen oxides
With the standard reaction conditions in hand, the scope of
this method was investigated. Various alkyl aldehydes were
Received: January 9, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00101
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Reaction Conditions
Scheme 2. Aerobic Oxidation of Aldehydes to Acids
b
c
entry
solvent
3a (%)
2a (%)
1
2
3
4
5
6
dioxane
PhMe
nBuOH
MeOH
CH3CN
H2O
53
53
ND
ND
99
16
30
83
82
0
92
0
a
Reaction conditions: 1 (5 mol %), 2a (0.5 mmol), O2 (1 atm),
b
solvent (2 mL). Yield of 3a was determined by 1H NMR (400 MHz)
using CH3NO2 and MeOtBu as internal standards. ND = not
c
1
determined. Recovery yield of 2a was determined by H NMR.
subjected to the standard conditions, and the corresponding
acids were obtained in 72% to quantitative yields (Scheme 2,
2a−w). Substrate 2m with a ketone functional groups affords
the desired product in 91% yield, and halogen and carbamate
can survive under such conditions as well (2o−q). The
oxidation of α- and β-aryl-substituted aldehydes could be
achieved with 82−91% yield (2r−w). The reactivity of
branched alkyl aldehydes with this catalytic system was also
investigated. The oxidation reaction proceeds reasonably well,
and 83−99% yields could be obtained (2h−l and 2n).
Cyclohex-3-ene-1-carbaldehyde 2c, which could interfere
with the catalytic system due to its CC bond, afforded
92% of the corresponding acid.22 The oxidation conditions are
operational for 2-(6-methoxynaphthalen-2-yl)propanal 2v, a
precursor of naproxen which is a nonsteroidal anti-inflamma-
tory drug that relieves fever, pain, stiffness, and swelling. It
afforded the desired product 3v in 91% yield. Substrates
containing an α-quaternary carbon center, for example, 2k and
2w, could also afford the desired carboxylic acids in good
yields. Aryl acids can also be synthesized from aryl aldehydes
under the oxidation conditions (2A−E). The corresponding
aromatic acid products were obtained in 76−96% yields. The
oxidation of aromatic aldehydes is much slower, and elevated
t
temperatures are needed (2A,B). In some cases, BuONO is
a
Conditions: 2 (0.5 mmol), O2 (1 atm), 1 (5 mol %), CH3CN (2
added to accelerate the oxidation (2C−E). The reason is that
the regeneration of PINO via the oxidation of NHPI needs the
acylhydroperoxy intermediate, whereas such acylhydroperoxy
intermediates derived from aromatic acids are not able to
oxidize NHPI to PINO effeciently. The direct oxidation of
alcohol 4a to the corresponding acid afforded the product in
57% yield. The gram-scale (10 mmol) oxidation of 2r produces
1.43 g of 3r in 95% (eq 1).
b
c
d
mL), 3 h. At 80 °C, 12 h. Determined by 1H NMR (400 MHz). 10
e
f
mol % NHPI, 80 °C, 10 h. 10 mol % NHPI, 90 °C, 1.5 d. 10 mol %
t
NHPI, 2.0 equiv BuONO, 2 mL of dry CH3CN, 2 d.
can be separated by a simple extraction with organic solvent in
good to high yield (Scheme 3).
This method was then applied in a sequential aerobic
oxidation sequence of alkenes, in which the alkenes were first
oxidized to aldehyde via anti-Markovnikov Wacker oxidation28
and finally to carboxylic acids using molecular oxygen as the
sole oxidant for both steps (Scheme 4). The corresponding
acid 6a−c could be obtained in 60−87% yields.
To demonstrate the application potential of this method, it
was used in the final stage oxidation for the synthesis of
indomethacin (Scheme 5). For a compatible method, the
Pinnick oxidation conditions, using 3−6 equiv of oxidant and
additives, provided the desired indomethacin 9 in 78% yield.
By this method, indomethacin 9 is achieved in 91% using 10
mol % of N-hydroxyphthalimide as catalyst using molecular
oxygen.
The scope and functional-group compatibility in aqueous
media was then tested with various functionalized aldehydes.
Because of the lower solubility of substrates in water, the
reaction normally takes a longer time than that in CH3CN.
Nevertheless, the reaction yields are comparable to the
oxidations in CH3CN. Various aldehydes were subjected to
the aqueous conditions; the corresponding alkyl acid products
B
DOI: 10.1021/acs.orglett.9b00101
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Aerobic Oxidation of Aldehydes in Water
Scheme 5. Comparison of Pinnick and Current Method in
Synthesis of Pharmaceuticals via Later Stage Oxidation
Scheme 6. Proposed Mechanism
a
Conditions: 2 (0.5 mmol), O2 (1 atm), 1 (5 mol %), H2O (2 mL).
b
c
d
1
10 mol % NHPI, 80 °C. Determined by H NMR. 15 mol %
e
t
NHPI, 80 °C, 2 d. 10 mol % NHPI and 30 mol % of BuONO, 60
°C, 2 d.
Scheme 4. Sequential Aerobic Oxidation of Alkenes to
Carboxylic Acids
In conclusion, an efficient and practical organocatalyzed
aerobic oxidation of aldehydes to carboxylic acids is presented
utilizing a catalytic amount of N-hydroxyphthalimide in the
presence of 1 atm of molecular O2, which serves as the sole
oxidant under mild conditions. A wide range of carboxylic
acids bearing diverse functional groups were obtained from
aldehydes (also alcohols) in high yields. Its operational
simplicity and gram-scale oxidation and the ability to
successively reuse the commercial available and inexpensive
catalyst make this method environmentally benign and cost-
effective. The generality of this methodology gives it the
potential to be used on an industrial scale. This method might
be a valuable alternative to traditional metal-mediated
oxidations. In addition, a direct conversion of alkenes to
their corresponding carboxylic acids is reported, and final-stage
oxidation using this method was also accomplished to
demonstrate the synthetic application.
a
t
Conditions: 5 (0.5 mmol), Pd(PhCN)2Cl2 (7.5 mol %), BuONO
t
(20 mol %), BuOH, O2 (1 atm); then 1 (5 mol %), O2 (1 atm),
CH3CN (2 mL), 3 h.
The reaction mechanism is proposed in Scheme 6. The
abstraction of hydrogen by PINO affords acyl radical A, which
abstracts oxygen to form B. Peroxide C forms with the
regeneration of PINO via oxidation of NHPI by B. The
oxidation of NHPI to PINO by B is supported by the fact that
the oxidation of aromatic aldehydes is much slower than
t
aliphatic aldehydes, where BuONO is normally used as an
additive to promote the regeneration of PINO.23a Peroxide C
added to aldehyde 2 to form the Criegee intermediate D
followed by a rearrangement to afford 2 mol of acid 3. The
initial PINO might be generated from the oxidation of NHPI
by oxygen.22b,23b
C
DOI: 10.1021/acs.orglett.9b00101
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(15) Matsusaki, Y.; Yamaguchi, T.; Tada, N.; Miura, T.; Itoh, A.
Aerobic photooxidative cleavage of vicinal diols to carboxylic acids
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00101.
■
S
(17) Heyns, K. Oxydative Umwandlungen an Kohlenhydraten. I.
Experimental procedures and NMR spectra (PDF)
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AUTHOR INFORMATION
Corresponding Authors
(18) ten Brink, G. J.; Arends, I. W.; Sheldon, R. A. Green, catalytic
oxidation of alcohols in water. Science 2000, 287, 1636−1639.
(19) Mallat, T.; Baiker, A. Oxidation of alcohols with molecular
oxygen on solid catalysts. Chem. Rev. 2004, 104, 3037−3058.
(20) Zhang, Y.; Cheng, Y.; Cai, H.; He, S.; Shan, Q.; Zhao, H.;
Chen, Y.; Wang, Bo. Catalyst-free aerobic oxidation of aldehydes into
acids in water under mild conditions. Green Chem. 2017, 19, 5708−
5713.
■
*E-mail: ias_jpqu@njtech.edu.cn.
*E-mail: ybkang@ustc.edu.cn.
ORCID
Jian-Ping Qu: 0000-0002-5002-5594
Yan-Biao Kang: 0000-0002-7537-4627
Notes
(21) Liu, M.; Wang, H.; Zeng, H.; Li, C.-J. Silver(I) as a widely
applicable, homogeneous catalyst for aerobic oxidation of aldehydes
toward carboxylic acids in water-“silver mirror”: From stoichiometric
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
(21672196, 21602001, 21831007) for financial support.
■
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DOI: 10.1021/acs.orglett.9b00101
Org. Lett. XXXX, XXX, XXX−XXX