Transition-metal-free aerobic oxidation of primary alcohols to carboxylic acids

Article abstract of DOI:10.1039/c3nj00045a

A transition-metal-free aerobic oxidation of primary alcohols to acids was achieved in the presence of a base. This transformation provides an effective protocol towards the synthesis of aryl, alkyl, heterocyclic and vinyl carboxylic acids.

Full text of DOI:10.1039/c3nj00045a

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A transition-metal-free aerobic oxidation of primary alcohols to acids was achieved in the
presence of NaOH or NatOBu. This transformation provides an effective protocol towards the
synthesis of aryl, alkyl, heterocyclic and vinyl carboxylic acids.

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Letter
Transition-Metal-Free Aerobic Oxidation of Primary Alcohols to
Carboxylic Acids†
Jing Wang,a‡ Chao Liu,a‡ Jiwen Yuana and Aiwen Lei*a,b
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A transition-metal-free aerobic oxidation of primary alcohols
to acids was achieved in the presence of base. This
transformation provides a effective protocol towards the
Table 1 Impact of reaction parameters
synthesis of aryl, alkyl, heterocyclic and vinyl carboxylic acids.
10 Alcohol oxidation has been a fundamental research area in both
laboratories and chemical industries during the past decades.[1] It
is one of the most important functional group interconversion
(FGI) in organic synthesis. Especially, for the oxidation of
primary alcohols, most attention has been focused on the
15 selective formation of aldehyde.[2] Actually, overꢀoxidation of
primary alcohols to carboxylic acids is also an important
functional group interconversion. Attentions have also been paid
on this specific area. However, most of the classic
transformations involved stoichiometric highꢀvalent metal salts or
20 organic compounds as the oxidants [3] and recently, direct aerobic
oxidation of primary alcohols to carboxylic acids in the presence
of transition metal catalysts has been developed, representing a
promising protocol for organic synthesis and industrial
applications.[4] However, the use of transition metal catalysts
25 might limit its application in lateꢀstage pharmaceutical synthesis.
Therefore, developing simple transitionꢀmetalꢀfree oxidation of
primary alcohols to carboxylic acids by using O2 as the sole
oxidant would be an appealling approach. To our knowledge,
only one example have been demonstrated on this topic by using
30 a special base (sodium pyrazolide) as the promoter in 1983.[5]
Very recently, a base (NaH) promoted transitionꢀmetalꢀfree
aerobic oxidation of secondary alcohols to ketones has also been
disclosed.[6] Herein, we report a transitionꢀmetal free aerobic
oxidation of primary alcohols to carboxylic acids promoted by
35 the widely available NaOH.
o
Upon optimizing catalyst condition, the condition of 60 C
in air with 2 equivalents of NaOH was applied to investigate the
50 substrate scope as illustrated in Scheme 1. The desired acid was
obtained in 69% isolated yield when benzylic alcohol with strong
electron donating pꢀmethoxyl group was employed (Scheme 1,
2d). Meanwhile, benzylic alcohols with electron withdrawing
groups as well as sterically hindered alcohols gave high yields
55 (Scheme 1, 2b, 2c, 2h). Even for heterocyclic, allylic alcohols ,
the desired acids were also obtained with moderate yields
(Scheme 1, 2g, 2f). It was worthy of noting that aliphatic
alcohols also proceeded well and gave the corresponding acids in
moderate yields (Scheme 1, 2e, 2j, 2k).
We also found that when a stronger base, tBuONa, was used
as the base instead of NaOH, the reaction temperature could be
lowered to room temperature. Full conversion was observed
within a much shorter time. We also tested the substrate scope
under this reaction condition. The results were illustrated in
Initially, the oxidation of benzyl alcohol (1a) in the presence
of NaOH in THF solution under balloon pressure of O2 was
selected as the model reaction. Improved yield was obtained by
o
increasing the reaction temperature from 25 to 60 C (Table 1,
40 Entry 1, 2).Without NaOH, no desired product was obtained
(Table 1, Entry 3). Gas source screening showed that O2 and air
afforded similar results (Table 1, Entry 4). Further improvements
of yield were achieved by increasing the equivalent of NaOH
(Table 1, Entry 5). Quantitative yield was obtained by using 2
45 equivalents of NaOH (Table 1, Entry 6).
60
65 Scheme 2.
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30
Scheme 2 Aerobic oxidation of different alcohols with tBuONa.
Reaction conditions: 0.5 mmol alcohol 1, 1.0 mmol tBuONa, 2.0 mL THF,
air, rt, 1h. The suspended solution was quenched with water, the aqueous
layer was acidified with diluted hydrochloride and extracted with ethyl
35 acetate. b Isolated yield.
a
Scheme 1 Aerobic oxidation of different alcohols with NaOH. a Reaction
conditions: 0.5 mmol alcohol 1, 1.0 mmol NaOH, 2.0 mL THF, air, 60 oC,
12 h. The suspended solution was quenched with water, the aqueous layer
was acidified with diluted hydrochloride and extracted with ethyl acetate.
bIsolated yield.
0.5
PhCOOH
0.4
0.3
5
The above optimized condition could be applied to various
alcohols. Similar results were obtained for strong electron
donating group (Scheme 2, 2d), electron withdrawing groups
10 (Scheme 2, 2b) substituted benzylic alcohols, sterically hindered
alcohols (Scheme 2, 2h) and aliphatic alcohols (Scheme 2, 2j).
To our surprise, when heterocyclic (Scheme 2, 2g), allylic
alcohols (Scheme 2, 2f) were employed, tBuONa as the base gave
a superior yield to that of NaOH.
In order to gain a better understanding of the mechanism, the
oxidation of benzyl alcohol was explored in more detail. Gas
chromatograph (GC) was employed to determine the distribution
of organic components. In the case of benzyl alcohol, with NaOH
as base, benzoic acid and benzaldehyde were initially observed
0.2
PhCH2OH
0.1
PhCHO
0.0
0
2
4
6
8
10
12
t (h)
Figure 1 Distribution versus time in the oxidation of benzyl alcohol with
15
2.0 equiv NaOH at 60 oC.
20 along with the consumption of the starting benzyl alcohol. The
monitor of this reaction clearly exhibited that aldehyde was most
likely to be the reaction intermediate, which was first generated
and then subsequently oxidized to benzoic acid (Figure 1). As a
proof, benzaldehyde was subjected as the substrate under the
25 standard condition. A quantitative yield of the corresponding
benzoic acid was obtained (Actually, 1.0 equivalent of NaOH
was enough to afford quantitative amount of benzoic acid, see SI),
which also proved that aldehyde was most likely to be involved
as the reaction intermediate.
40 Scheme 3 Aerobic oxidation of benzaldehyde.
Based on these results, a possible mechanism was proposed
as shown in Scheme 4. First, in the presence of NaOH, alcohol 1
was in equilibrium with its corresponding sodium alkoxide 3. The
alkoxide anion made the oxygen connected αꢀCH of 3 easy to be
45 abstracted by O2 to form a carbonꢀcentered radical 4 and a
hydrogen peroxide radical. The combination of these two radicals
generated intermediate 5. The release of HOONa from 5 afforded
aldehyde 6. Then, aldehyde further reacted with NaOH to
2
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produce intermediate 7, which would then undergo a CꢀH
oxidation by O2 to generate intermediate 8. Further release of
HOONa from 8 would afford the final sodium benzoate 9. The
desired carboxylic acid was obtained through quenching the
reaction system with dilute HCl solution.
downfield of TMS. All 13C NMR spectra were reported in ppm
and were obtained with 1H decoupling.
35 General Procedure for NaOH Promoted Oxidation of
Primary Alcohols
5
A 10 mL Schlenk tube was charged with 1.0 mmol of NaOH.
After the tube was backfilled with air balloon, 0.5 mmol of
primary alcohol and 2 mL of THF were injected. The resulting
40 solution was kept stirring for 12 h at 60 oC and then the
suspended solution was quenched with water, and extracted with
ethyl acetate (3 × 10 mL). The aqueous layer was acidified with
diluted hydrochloride (2.0 mL, 2M) and extracted with ethyl
acetate (3 × 10 mL). The organic layers were combined and dried
45 over sodium sulphate. The pure product was obtained by
removing the organic solvent.
General Procedure for tBuONa Promoted Oxidation of
Primary Alcohols.
A 10 mL Schlenk tube was charged with 1.0 mmol of
50 tBuONa. After the tube was backfilled with air balloon, 0.5 mmol
of primary alcohol and 2 mL of THF were injected. The resulting
solution was kept stirring for 1 h at 25 oC and then the suspended
solution was quenched with water, and extracted with ethyl
acetate (3 × 10 mL). The aqueous layer was acidified with diluted
55 hydrochloride (2.0 mL, 2M) and extracted with ethyl acetate (3 ×
10 mL). The organic layers were combined and dried over
sodium sulphate. The pure product was obtained by removing the
organic solvent.
Scheme 4 Proposed mechanism.
To further explore the validity of the proposed mechanism, a
radicalꢀtrapping experiment was carried out. BHT (2,6ꢀdiꢀtertꢀ
10 butylꢀ4ꢀmethylphenol) was employed under the standard reaction
conditions. The desired reaction did not occur (Scheme 5), thus
indicating that this transformation is likely to involve a radical
process.
Acknowledgements
60 This work was supported by the 973 Program (2012CB725302),
the National Natural Science Foundation of China (21025206 and
21272180), the China Postdoctoral Science Foundation funded
project (2012M521458) and the Program for Changjiang Scholars
and Innovative Research Team in University (IRT1030).
15
Scheme 5 Investigation into the reaction mechanism.
In conclusion, we have developed a transitionꢀmetalꢀfree
aerobic oxidation of primary alcohols to the corresponding
carboxylic acids in the presence of NaOH or NatOBu. Various 65 Author Contributions
benzylic alcohols, aliphatic alchols and also allylic alcohols were
20 converted to carboxylic acids smoothly under current conditions.
Further mechanistic study on the transitionꢀmetalꢀfree O2
activation is currently on going and will be reported in due course.
‡Jing Wang and Chao Liu contributed equally to this work.
Notes and references
a College of Chemistry and Molecular Sciences, Wuhan University, P. R.
Experimental Section
China. Fax: (+86)-27-68754067; Tel: (+86)-27-68754672; E-mail:
All reactions were performed in an air atmosphere with a balloon
25 fitted on a Schlenk tube. All glassware was oven dried at 110 C
o
70 aiwenlei@whu.edu.cn;
b Lanzhou Institute of Chemical Physics Chinese Academy of Sciences,
for hours and cooled down under vacuum. Unless otherwise
noted, materials were obtained from commercial suppliers and
used without further purification. Thin layer chromatography
730000 Lanzhou..
† Electronic Supplementary Information (ESI) available: See DOI:
10.1039/b000000x/
1
75
(TLC) employed glass 0.25 mm silica gel plates. H NMR and
30 13C NMR were recorded on Mercury 300 MHz or 400 MHz. GCꢀ
Ms spectra were recorded on a Varian GCꢀMs 3900ꢀ2100T. All
1H NMR experiments are reported in parts per million (ppm)
1
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