Cobalt-Catalyzed Aerobic Oxidative Cleavage of Alkyl Aldehydes: Synthesis of Ketones, Esters, Amides, and α-Ketoamides

Article abstract of DOI:10.1002/chem.202101035

A widely applicable approach was developed to synthesize ketones, esters, amides via the oxidative C?C bond cleavage of readily available alkyl aldehydes. Green and abundant molecular oxygen (O₂) was used as the oxidant, and base metals (cobalt and copper) were used as the catalysts. This strategy can be extended to the one-pot synthesis of ketones from primary alcohols and α-ketoamides from aldehydes.

Full text of DOI:10.1002/chem.202101035

Accepted Article
Accepted Article
Title: Cobalt-catalyzed Aerobic Oxidative Cleavage of Alkyl Aldehydes:
Synthesis of Ketones, Esters, Amides, and α-Ketoamides
Authors: Gerald Hammond, Tingting Li, and Bo Xu
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.202101035
Link to VoR: https://doi.org/10.1002/chem.202101035
01/2020

10.1002/chem.202101035
Chemistry - A European Journal
Cobalt-catalyzed Aerobic Oxidative Cleavage of Alkyl Aldehydes:
Synthesis of Ketones, Esters, Amides, and α-Ketoamides
Tingting Li,a Gerald B. Hammond,*,b and Bo Xu*,a
Abstract: We have developed
a
widely applicable
C-C cleavage of aldehydes, catalyzed inexpensive and relatively
non-toxic base metals such as cobalt or copper is highly desirable.
approach to synthesize ketones, esters, amides via the oxidative
C-C bond cleavage of readily available alkyl aldehydes. Green
and abundant molecular oxygen (O2) was used as the oxidant,
and base metals (cobalt and copper) were used as the catalysts.
This strategy can be extended to the one-pot synthesis of ketones
from primary alcohols and -ketoamides from aldehydes.
Oxidation is one of the most important transformations in
organic synthesis.[1] Chemical oxidations usually require a
stoichiometric amount of oxidants such as KMnO4 and CrO3,
which lead to a poor atom economy and generate toxic wastes in
many cases.[2] Among commonly used oxidants, molecular
oxygen (O2) is the most abundant, inexpensive, and
environmentally friendly. Also, water is often the only byproduct in
O2-based oxidations.[3] However, molecular oxygen itself is not a
reactive oxidant; much effort has been put into developing
efficient transition metals or non-metals catalyzed aerobic
oxidation systems.[4] Inexpensive and relatively non-toxic base
metals such as cobalt or copper-based catalytic systems are
especially attractive.[5]
The C-C bond cleavage has shown great potential in
synthetic organic chemistry.[6] However, it is also challenging due
to the C-C bonds' inert nature,[7] especially when mild reaction
conditions are required. Because aldehyde is a common
functionality in organic synthesis, oxidative C-C cleavage of an
aldehyde under mild conditions is a very useful tool in the
synthesis of complex molecules.[8] One example is the oxidative
cleavage of aryl acetaldehyde developed by the Plattner group[9]
using the strong oxidant iodosylbenzene/HBF4 (Scheme 1a). Alkyl
aldehydes could be activated by conversion to a more reactive
metal enolate using strong bases enabling O2 use for their
oxidation, but strong bases such as NaH or KH limit the functional
group tolerance of the substrate (Scheme 1b).[10] An aldehyde
could also be activated via enamine catalysis (Scheme 1c)[11] or a
combination of enamine catalysis/photocatalysis (Scheme 1d).[12]
Although many aerobic oxidation systems have been studied,
most of them suffer from drawbacks, such as low product
selectivity, the use of expensive noble metals, or harsh reaction
conditions.[8f, 13] A mild and general strategy for aerobic oxidative
Scheme 1. Aerobic oxidative C-C bond cleavage.
It has been well established that complexes of cobalt (II),[14]
derived from 2,4-dioxo alkanoic acid dialkyl amide complexes,
could activate O2 for oxidative cyclization of 5-hydroxy
pentenes.[5e, 14-15] We report here that these catalysts also show
excellent performance in aerobic oxidative C-C cleavage of
aldehydes. We also used the cobalt catalyst to convert primary
alcohols 3 to ketones 2 directly. Subsequently, we found that the
aldehyde could further react with amines in the presence of
cuprous iodide to form the corresponding -ketoamides 4
(Scheme 1e). Our aerobic oxidative conditions are mild and
general using inexpensive cobalt or copper catalysts.
[
]
a
T. Li, Dr. B. Xu
We selected the oxidative cleavage of aldehyde 1a as our
model reaction (Table 1). First, we tested Co(nmp)2 catalyst in
isopropanol using O2 balloon as the oxygen source, but only a
small conversion was observed (Table 1, entry 1). Pleasingly, we
found that the addition of basic additives improved the conversion
significantly (Table 1, entries 2-3). A good yield of product 2a was
observed using a weak base like triethylamine as the additive
(Table 1, entry 3), along with a small amount of over-oxidation
product 2a'. Without a cobalt catalyst, no product was detected,
College of Chemistry, Chemical Engineering and Biotechnology
Donghua University, Shanghai 201620, China
Email: bo.xu@dhu.edu.cn
[b]
Dr. G. B. Hammond
Department of Chemistry, University of Louisville
Louisville, KY 40292 USA.
E-mail: gb.hammond@louisville.edu
Supporting information for this article is given via a link at the end
of the document. ((Please delete this text if not appropriate))
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10.1002/chem.202101035
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and the starting material was recovered completely (Table 1, entry
4). Screening the solvents (Table 1, entries 5 and 6) revealed that
isopropanol was the optimal solvent, possibly due to its good
affinity with oxygen gas. When this reaction was performed under
air, the yield of 2a was reduced to 30% (Table 1, entry 7). We
further screened a series of Co(II) complexes; the commercially
available CoCl2 and Co(acac)2 gave inferior results (Table 1,
entries 8-9). Catalysts CoIIL12 and CoIIL22 also gave good
conversion of products. However, a small amount of over-
oxidation product 2a" was detected (Table 1, entries 10-11).
Moreover, we found that copper salts such as CuI and CuBr
catalyzed the oxidative cleavage to give a mixture of 2a' and 2a",
but no 2a was obtained (Table 1, entry 12). Aldehyde 1a has an
active benzylic position, which may lead to easy over-oxidation.
When the more stable substrate 1b was employed, both cobalt
and copper catalysts gave good yields of products (Table 1,
entries 13 and 14). Due to the earth's abundance of cobalt,
together with its tunable reactivity via modulation of diketonate
ligands, we selected Co(nmp)2 as the catalyst of choice.
Table 1. Optimization of reaction conditions. [a]
Entry
1
1
Co(II)
base
—
Solvent
iPrOH
iPrOH
iPrOH
iPrOH
CH3CN
MeOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
Yield[b] 2a:2a’:1a
8/0/92
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
Co(nmp)2
Co(nmp)2
Co(nmp)2
—
2
tBuONa
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
58/7/33
80/20/0
0/0/100
20/1/79
38/9/53
30/1/68
2/0/98
3
4
5
Co(nmp)2
Co(nmp)2
Co(nmp)2
CoCl2
6
7[c]
8
9
Co(acac)2
Co(L1)2
Co(L2)2
CuI
49/21/28
72/18/10
70/17/12
0/33/0[d]
2b: 88
[a] Reaction conditions: 1 (0.5 mmol), Co(nmp)2 (5 mol%), TEA (0.5 mmol),
iPrOH (2 mL), O2 balloon, 60 oC, 12 h. [b] Isolated yields. [c] Determined
by GC-MS analysis.
10
11
12
13
14
We proceeded to explore the scope and functional group
tolerance of our oxidative aldehyde cleavage protocol (Figure 1).
Aldehydes with at least one aromatic substituent in the α-position
were smoothly converted to the corresponding ketones in
excellent yields (Figure 1, 2b-k). Substrates with electron-rich or
electron-deficient substituents (Br, OMe, and CF3) at the aromatic
ring had only a small influence on the reaction efficiency; the
electron-deficient substituents generally slowed down the
reactions (Figure 1, 2c-f). The cyclic secondary aldehydes were
also suitable for the C–C bond cleavage reaction with an excellent
chemical yield (Figure 1, 2l). The reaction efficacy was then tested
with varying N-protecting groups. The diverse protecting groups
Co(nmp)2
CuI
2b: 97
[a] Reaction conditions: 1a (0.1 mmol), metal catalyst (5% mmol), additive
(0.1 mmol), solvent (0.5 mL), O2 balloon, 60 C, 12 h. [b] Determined by
GC-MS analysis. [c] Conducted in air. [d] 2a’ (33%) and 2a’’ (67%) were
obtained.
o
Figure 1. Scope of oxidative cleavage of alkyl aldehydes.
[a][b]
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(Boc, Bz, 2-naphthyl, Ts, Bn, and Cbz) were tolerated under the
reaction conditions and afforded the respective products in good
yields (Figure 1, 2m-r). Analogs of 2a, such as 2v and 2w, were
obtained in similar good yields. To our delight, in addition to the
synthesis of ketones, our method also enabled the synthesis of
esters (Figure 1, 2s, and 2t) and amides (Figure 1, 2u) in excellent
yields.
reaction afforded -ketoamide (Figure 3, 4a) in 89% yield.
According to similar oxidation systems using aromatic ketones or
acids as the starting materials,[18] we believed that acetophenone
was a crucial intermediate in the reaction system. Notably, both
cyclic and acyclic secondary amines were suitable substrates and
generated the corresponding products in good yields (Figure 3,
4b, 4c). Besides, aryl methyl ketones containing electron-
donating or electron-withdrawing groups were compatible with
this reaction, and the latter led to excellent yields of products
(Figure 3, 4d, 4e, 4f).
Because primary alcohols could also be oxidized to
aldehydes by O2,[16] we attempted to synthesize ketones directly
from alcohols via a tandem process (Figure 2). However, the
Co(nmp)2 /O2 system could not oxidize the relative unreactive
primary alcohol 3. Since methods based on Co(III)-complexes
and N-hydroxyphthalimide (NHPI) have proven to be applicable
in catalyzed aerobic oxidation of alcohols,[17] we hypothesized that
the CoIII/O2 system might catalyze the tandem oxidation/C-C bond
cleavage sequence (Figure 2). The aldehyde product achieved by
oxidation of primary alcohols could act as the intermediate in the
oxidative C-C cleavage of aldehydes. To our satisfaction, β-
aromatic substituted primary alcohols (Figure 2, 3a-c) gave good
yields in this tandem reaction. Because the CoIII/O2/NHPI/mCPBA
conditions are relatively reactive, some substrates could be over-
oxidized to give a relatively complex mixture. For example, when
non-aromatic substituted alcohols such as chroman-2-yl
methanol (Figure 2, 3d) was used as a substrate, only a trace
amount of the desired product was detected; instead, a carboxylic
acid (2t', 73%) was obtained as the primary product along with the
corresponding aldehyde (22% yield).
Figure 3.
Synthesis of -ketoamides from oxidative cleavage of aryl
propionaldehyde. [a][b]
Figure 2. Co(III) catalyzed aerobic oxidation of alcohols.[a][b]
[a] Reaction conditions: 1 (0.5 mmol), amine (1 mmol), CuI (5 mol%),
iPrOH (2 mL), O2 balloon, 60 oC, 12 h. [b] Isolated yields.
We performed some control experiments to probe the
reaction mechanism (Scheme 2). When the reaction was
conducted under Ar, only a trace amount of the desired product
was detected (Scheme 2a). So, the presence of air (or O2) is
essential for the present reaction. Further, the reaction yield
decreased to 30% in the presence of radical scavengers such as
1,1,5,5-tetramethyl pentamethylene nitroxide (TEMPO) (Scheme
2b). This reaction indicated that a radical process might be
involved. It was noteworthy that -trialkyl acetaldehydes such as
2,2-diphenylpropanal and pivalic aldehyde did not work under the
standard conditions. The importance of -hydrogen indicated that
the enol formation is essential for the reaction (Scheme 2c). In
many literature reports, the tertiary aldehyde was easier to
generate acyl radical and alkyl radical (see Scheme below)
compared to secondary aldehydes. Moreover, the generated
radical could react with an electron-deficient alkene or alkyne to
give addition products. It is well-established that an aldehyde
could generate acyl radical and, after decarbonylation, the alkyl
radical without any catalyst. Moreover, the generated radical
could react with an electron-deficient alkene or alkyne to give
addition products.[8e] We added the same electron-deficient
alkenes or alkynes such as acrylic esters to our reaction mixture,
and no radical addition product was detected. This might indicate
an alkyl radical may not be generated in our system.
[a]Reaction conditions: 3 (0.5 mmol), Co(acac)3 (5 mol%), NHPI (20 mol%),
m-CPBA (5 mol%), EtOAc (2 mL), O2 balloon, 60 oC, 6 h. [b]Isolated yields.
[c] Determined by GC-MS analysis.
In
a surprising observation, we noticed that when
triethylamine was replaced by a secondary amine, -ketoamide
was obtained as the major product (Figure 3). Indeed, when 2-
phenylpropionaldehyde was subjected to the oxidation system
that included CuI as the catalyst and piperidine as the base, the
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.
CoII was oxidized by the oxygen to generate the reactive CoIII-O2
19]
radical intermediate,[5g,
which then reacted with enol
intermediate A to give the 1,2-dioxetane intermediate B,[12, 20]
leading to the ketone product 2 via C−C bond cleavage.
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Scheme 3. Proposed mechanism.
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In summary, we have developed a widely applicable
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catalyst. We believe that this oxidation system can be extended
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Keywords: aerobic oxidation, C-C bond cleavage, cobalt, copper
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We have developed a synthesis of
ketones, esters, amides via oxidative
C-C bond cleavage of alkyl
Tingting Li, a Gerald B. Hammond*b and
Bo Xu*a
aldehydes. Green and abundant
molecular oxygen (O2) was used as
the oxidant, and base metals (cobalt
and copper) were used as the
catalysts. In addition, the same
strategy can be extended to the one-
pot synthesis of ketones from primary
alcohols and -ketoamides from
aldehydes.
Page No. – Page No.
Title
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