Oxidation of allylic and benzylic alcohols to aldehydes and carboxylic acids

Article abstract of DOI:10.1039/c4cc01305k

An oxidation of allylic and benzylic alcohols to the corresponding carboxylic acids is effected by merging a Cu-catalyzed oxidation using O ₂ as a terminal oxidant with a subsequent chlorite oxidation (Lindgren oxidation). The protocol was optimized to obtain pure products without chromatography or crystallization. Interception at the aldehyde stage allowed for Z/E-isomerization, thus rendering the oxidation stereoconvergent with respect to the configuration of the starting material.

Full text of DOI:10.1039/c4cc01305k

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Oxidation of allylic and benzylic alcohols to
aldehydes and carboxylic acids†
Cite this: Chem. Commun., 2014,
0, 5014
5
Daniel Konning, Tobias Olbrisch, Fanni D. Sypaseuth, C. Christoph Tzschucke and
¨
Mathias Christmann*
Received 19th February 2014,
Accepted 21st March 2014
DOI: 10.1039/c4cc01305k
www.rsc.org/chemcomm
An oxidation of allylic and benzylic alcohols to the corresponding
carboxylic acids is effected by merging a Cu-catalyzed oxidation
2
using O as a terminal oxidant with a subsequent chlorite oxidation
(
Lindgren oxidation). The protocol was optimized to obtain pure
products without chromatography or crystallization. Interception
at the aldehyde stage allowed for Z/E-isomerization, thus rendering
the oxidation stereoconvergent with respect to the configuration of
the starting material.
The direct oxidation of primary alcohols to their corresponding
carboxylic acids is an important synthetic transformation that consists Scheme 1 Oxidation pathways of alcohols and aldehydes to carboxylic
1
acids.
of two successive steps. While the first step (alcohol to aldehyde) is
usually performed with an electrophilic oxidant, the second oxidation
(
aldehyde to carboxylic acid) often involves a nucleophilic attack of
1
3
We recently investigated the stereoconvergent conversion
the oxidant. Alternatively, it is possible to intercept the aldehyde–
hydrate equilibrium with an electrophilic oxidant (Scheme 1). The
latter strategy requires a significant population of the hydrate, which
of E- and Z-allylic alcohols into E-a,b-unsaturated aldehydes
following in the footsteps of Semmelhack, Sheldon, Mark ´o ,
1
4
15
16
2
1
7
18
Koskinen, and Stahl (Scheme 2). Our studies resulted in
3
is not very favorable in the case of aromatic aldehydes.
I
a protocol using 1 mol% Cu OTf/TEMPO/diMeObpy and DMAP
Alcohol-to-carboxylic-acid oxidations can be conducted either
in a one-pot fashion or as a two-step procedure with isolation of
the intermediate aldehyde. Classical one-pot methods involve
chromium-, tungsten- or ruthenium-based oxidants as well as
hypervalent iodine derivatives such as IBX. The Zhao-modification
(
2 mol%) in acetonitrile as the solvent with oxygen as stoichio-
metric oxidant.
DMAP was shown to play an active role in both the oxidation
4
5
6
1
9
reaction and the isomerization steps. Herein, we report a
two-step one-pot conversion of E- and Z-allylic alcohols into
E-a,b-unsaturated carboxylic acids by joining a further refined
Cu/TEMPO-catalyzed aerobic oxidation protocol
Lindgren’s oxidation.
7
8
9
2
of Anelli’s oxidation (TEMPO, NaClO ) constitutes another alter-
native but also has some drawbacks and, like the other above
mentioned oxidants, may give rise to unwanted side reactions.
An elegant solution to these problems has been provided by using
3
1,32
with
1
0
oxoammonium salts in combination with NaClO
2
.
For sensitive
substrates however, a two-step protocol is often preferred over the one-
11
pot process using a mild oxidant (e.g. Dess–Martin periodinane ) for
12
the initial oxidation to the aldehyde followed by Lindgren oxidation
NaClO as the oxidant) to give the desired carboxylic acid.
(
2
Institute of Chemistry and Biochemistry, Freie Universit a¨ t Berlin, Takustr. 3,
4195 Berlin, Germany. E-mail: m.christmann@fu-berlin.de;
Fax: +49 30 838460182; Tel: +49 30 83860182
Electronic supplementary information (ESI) available: Experimental details and
spectroscopic data for all compounds. See DOI: 10.1039/c4cc01305k
1
†
Scheme 2 Development of Cu-catalyzed aerobic oxidation.
5
014 | Chem. Commun., 2014, 50, 5014--5016
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The goal in the first oxidation step (alcohol to aldehyde) was to Table 1 Oxidation of alcohols to aldehydes
lower the catalyst loading as much as possible in order to minimize
interference with the subsequent steps. Our starting point was built
upon important findings from Sheldon, Koskinen and Stahl. Sheldon
0
found the accelerating effect of 2,2 -bipyridine (bpy) ligands while
17
Koskinen’s careful kinetic studies established optimal ratios within
the catalyst system. Recently, Stahl et al. demonstrated the importance
I
18
of Cu salts supported by mechanistic investigations. As a key result
a
Entry
1
Alcohol
Aldehyde
t [h]
[%]
2
0
21
in their subsequent mechanistic studies, aliphatic primary
and secondary alcohols showed a clearly different behavior
from allylic and benzylic primary alcohols.
With our substrates limited to allylic and benzylic alcohols,
we considered it necessary to re-evaluate Cu salts together with
symmetrically (1) and newly synthesized unsymmetrically
substituted bpy ligands (2–3). Using 4a as test substrate, we
found that 0.5 mol% CuI or slightly more reactive CuBr and
2
2
3
3
2.5
99
I
2
3
2
3
1.75
92
1
mol% DMAP resulted in a quantitative conversion of the
substrate within 3 h, whereas reactions using Cu(OTf) and CuCl
were not complete within 5 h.
4
25
18
17
98
89
63
97
In order to compare the efficacies of different bpy derivatives, we
further lowered the catalyst loading to 0.4 mol% CuBrꢀligandꢀTEMPO
0
and 0.8 mol% DMAP. The reaction using the parent 2,2 -bipyridine
b,c
4
stopped at 70% conversion after 6 h. Ligand 1 afforded 90%
conversion whereas the unsymmetrically substituted bipyridines 2
and 3 led to a quantitative conversion, with 3 being significantly
faster than 2. Despite these encouraging results, we selected
b,c
5
0
(
.75 mol% CuBrꢀbpyꢀTEMPO and 1.5 mol% DMAP in MeCN
0.75 M) as our standard protocol for practical reasons, since we
consider these reagents to be inexpensive and in stock in most
organic laboratories.
b
6
As shown in Table 1, the oxidation of alcohols relevant to our
synthetic endeavoura proceeded smoothly with TBS (4a), Ac (4b)
and Bn (4c) protecting groups. The difference in the rate of
oxidation is negligible, while the rate of the Z/E-isomerization is
strongly dependent on the substitution of the Michael acceptor
aldehyde. For substrates 4d–4f, the catalyst loading was increased to
c
7
16.5
6
98
55
8
9
1
mol% in order to ensure complete oxidation. In order to accelerate the
24
Z/E-isomerization (entries 4, 5 and 7) 9-azajulolidine, a more nucleo-
philic analogue of 4-DMAP was used. The low yield of volatile aldehyde
1
1
84
96
5e reflects the difficulties associated with its distillative purification. The
oxidation of furfuryl alcohol 4h and the benzyl alcohols 4i–j afforded the
corresponding aldehydes in moderate to excellent yields. With this
protocol in hand, we next turned our attention to the development of a
one-pot oxidation of the alcohols 4a–j to the corresponding carboxylic
10
a
b
c
Isolated yield. 1 mol% catalyst loading. 9-Azajulolidine was used
acids. The Lindgren oxidation of aldehydes to the corresponding instead of DMAP.
carboxylic acids with sodium chlorite is a straightforward reaction.
However, the formation of the stronger oxidant hypochlorite as the by-
product is often a source of side-reactions. As a result, a variety of
As shown in Table 2, after formation of the E-a,b-unsaturated
25
26,27
hypochlorite scavengers such as 2-methyl-2-butene
have been in aldehydes, a Lindgren oxidation was conducted without prior
use. In order to avoid by-products that are soluble in organic solvents isolation of the aldehydes. The corresponding carboxylic acids
and allow for the isolation of the clean carboxylic acids by extraction, we were obtained in high purity and good to excellent yields without
3
0
selected H O as a scavenger that was previously used by Dalcanale and further chromatographic purification. Furfuryl alcohol was the
2
2
28
Montanari. Since oxidation of 4a with NaClO /H O has been carried only problematic substrate in both oxidations. Skipping the
2
2 2
out in acetonitrile as the solvent by Sorensen et al. in their hirsutellone isolation of the intermediate volatile aldehyde 5e resulted in a
29
studies, we were confident of combining both subsequent oxidation clean conversion of 4e into carboxylic acid 6e and a higher yield
steps in a one-pot procedure.
(compared to 5e).
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Table 2 Oxidation of alcohols to carboxylic acids
corresponding aldehydes and carboxylic acids. For the first
time, submol% quantities of a Cu catalyst were sufficient for
I
converting alcohols into the corresponding aldehydes. The
subsequent oxidation to the corresponding carboxylic acids
was performed in the same reaction vessel, thereby avoiding
isolation of the labile aldehydes. The carboxylic acids were
isolated by extraction with sufficient purity without the need
for further chromatographic purification thus rendering this
protocol both cost and time efficient.
a
Entry Alcohol
Carboxylic acid
t
1
[h]
t
2
[h]
[%]
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0 The NMR spectra of the carboxylic acids shown in the ESI† were
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In conclusion, we have developed an inexpensive system for
the aerobic oxidation of allylic and benzylic alcohols to the
5
016 | Chem. Commun., 2014, 50, 5014--5016
This journal is ©The Royal Society of Chemistry 2014