Electrochemical Oxidative Decarboxylation of Malonic Acid Derivatives: A Method for the Synthesis of Ketals and Ketones

Article abstract of DOI:10.1021/acs.orglett.5b02084

A novel electrochemical oxidative decarboxylation of disubstituted malonic acids leading to dimethoxy ketals is described. In the presence of NH₃, a wide range of disubstituted malonic acids was transformed into the corresponding ketals in good to excellent yields under electrochemical conditions. When the crude reaction mixture, obtained after electrolysis, was directly treated with 1 M aq HCl, the initially generated ketals were smoothly transformed into the corresponding ketones in a single vessel operation.

Full text of DOI:10.1021/acs.orglett.5b02084

Letter
pubs.acs.org/OrgLett
Electrochemical Oxidative Decarboxylation of Malonic Acid
Derivatives: A Method for the Synthesis of Ketals and Ketones
Xiaofeng Ma, Xiya Luo, Simon Dochain, Charlotte Mathot, and Istvan E. Marko*
́
̀
Laboratory of Organic and Medicinal Chemistry, Universite
Louvain-la-Neuve, Belgium
́
Catholique de Louvain, Place Louis Pasteur 1 bte L4.01.02, 1348
S
* Supporting Information
ABSTRACT: A novel electrochemical oxidative decarboxylation of
disubstituted malonic acids leading to dimethoxy ketals is described.
In the presence of NH3, a wide range of disubstituted malonic acids
was transformed into the corresponding ketals in good to excellent
yields under electrochemical conditions. When the crude reaction
mixture, obtained after electrolysis, was directly treated with 1 M aq HCl, the initially generated ketals were smoothly
transformed into the corresponding ketones in a single vessel operation.
etones are among the most versatile and valuable
selective mono- and dialkylation of malonic esters. These
alkylated products have been subsequently employed for the
preparation of a wide range of substituted acetic acids.6
Condensations of malonic acids form the basis of several well-
known processes, such as the Knoevenagel reaction7 and the
barbituric acid synthesis.8
1
Kfunctional groups in organic synthesis.
Not only are
they extensively found in a wide range of natural products,
man-made compounds, and fine chemicals, but they are also
key chemical partners in numerous important synthetic
transformations such as the aldol reaction.2 Moreover, ketones
can be further converted into a plethora of other useful
functionalities, such as alcohols, amines, amides, alkenes, and
esters, to cite but a few.3
While numerous transformations of disubstituted malonic
acid derivatives have been reported, their conversion into the
corresponding ketones by double-oxidative decarboxylation has
been little investigated so far, and long synthetic sequences are
typically required. For example, Meinwald and co-workers
reported a five-step procedure to prepare trans-bicyclo[3.2.0]-
heptan-3-one from the corresponding malonic acid derivative.9
A major breakthrough was accomplished by Tufariello,10 who
showed that treatment of disubstituted malonic acids 2 with
lead tetraacetate afforded the corresponding 1,1-diacetates in
moderate to good yields. Basic or acidic hydrolysis then
generated the expected ketones 1 (Scheme 1, eq 1). However,
the conditions are quite harsh, and the reaction appears to be
limited to cases in which both substituents are relatively simple.
Moreover, an excess of the fairly toxic Pb(OAc)4 is required for
the double decarboxylation to reach completion.
In 1979, a particularly interesting, though essentially
unnoticed, contribution was reported by the group of
Nokami,11 who disclosed that passing an electric current
through a basic aqueous solution containing a disubstituted
malonic acid salt led to the corresponding ketone 1 (Scheme 1,
eq 2). Unfortunately, only three examples using simple
substrates were reported, the reaction conditions were rather
severe, and moderate yields were obtained.
Despite their synthetic importance, access to ketones,
especially unsymmetrical ones, usually requires multistep
sequences. Most popular among these are (1) the addition of
an organometallic reagent to an aldehyde followed by a
subsequent oxidation, (2) the α-alkylation of a pre-existing
ketone, and (3) the double alkylation of a carbonyl dianion
equivalent, such as a dithiane.4 More recently, the sequential
nucleophilic addition of organolithium or magnesium species to
electrophilic carbonyl equivalents has received sustained
attention.5
In this context, we wish to report on a novel methodology for
the synthesis of symmetrical and unsymmetrical ketones 1 and
ketals 3 from the corresponding malonic acids 2. In our
approach, disubstituted malonic acids 2 are considered as 1,1-
dicationic synthetic equivalents 4 (Figure 1).
Malonic acid derivatives have been used extensively in
organic synthesis, and conditions have been developed for the
Nevertheless, despite its shortcomings, this seminal con-
tribution attracted our interest, and we decided to revisit it in
order to delineate its scope and limitations. In this paper, we
report some of our results concerning the establishment of an
Received: July 21, 2015
Figure 1. Malonic acids as ketones and ketals equivalents.
© XXXX American Chemical Society
A
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Letter
amount of NaOMe by half significantly improved the yield
(Table 1, entry 2). Finally, when 0.1 equiv of sodium
methoxide was used, the desired product could be isolated in
71% yield (Table 1, entry 3). While this protocol gave us ketal
6a in good yield, alternative conditions employing milder bases,
and hence more tolerant toward other functionalities and
protecting groups, were also investigated.
Scheme 1. Decarboxylation of disubstituted malonic acid
derivatives
Thus, the oxidative decarboxylation of 5a was carried out in
the presence of excess ammonia (7.0 M in MeOH) under
otherwise similar conditions. Much to our delight, the desired
ketal 6a could be obtained in 60% yield after 4.5 h (Table 1,
entry 4) and up to 77% yield after 7 h (Table 1, entry 5).
Increasing the current density from 30 to 90 mA reduced
significantly the reaction time without affecting the yield (Table
1, entries 6 and 7). Though these results looked promising,
complete consumption of the starting material was never
observed.
In order to better understand the influence of ammonia in
this process, the corresponding bis-ammonium salt 5a′
(Scheme 2) was independently prepared14 and submitted to
efficient and chemoselective electrochemical oxidative method-
ology for the conversion of malonic acids 2 into ketals 3 and
ketones 1 under mild conditions and in good to excellent yields
(Scheme 1, eq 3).
Scheme 2. Proposed Reaction Mechanism
Our investigation began with the study of the electrochemical
oxidative decarboxylation of the disubstituted malonic acid 5a.
Compound 5a can be easily prepared by the double alkylation
of di-tert-butyl malonate with 1-iodo-4-acetoxybutane followed
by the removal of the two tert-butyl groups in the presence of
TFA. With compound 5a in hand, various reaction conditions
were screened. Some salient results are compiled in Table 1.
a
Table 1. Optimization of the Reaction Conditions
the electrochemical oxidation in pure MeOH. Gratifyingly,
complete conversion ensued and the ketal product 6a could be
isolated in 69% yield (Table 1, entry 8). This result strongly
suggested that a large excess of ammonia had a negative impact
on the reaction. In order to simplify the protocol and avoid the
independent generation of the malonate bis-ammonium salt,
the electrolysis was repeated after addition of malonic acid 5a
to 2.1 equiv of NH3 in MeOH. Using a current density of 10
mA/cm2, substrate 5a disappeared within 8 h and the ketal
product 6a was obtained in 76% yield (Table 1, entry 9).
Increasing the current density to 20 mA/cm2 led to complete
conversion of 6a within 4.5 h, and ketal 6a could be isolated in
80% yield (Table 1, entry 10). Finally, attempts to use catalytic
amounts of ammonia proved to be unsuccessful as no
conversion was observed (Table 1, entry 11).15
Careful optimization thus provided us with two sets of
conditions appropriate for the transformation of malonic acid
5a into the corresponding ketal 6a in good to excellent yield
(Table 1, entries 3 and 10). In order to evaluate the scope and
limitations of this oxidative process, we selected the most
convenient reaction conditions, i.e., 2.1 equiv of NH3 in
MeOH, MeOH as the solvent, and 20 mA/cm2 current density,
at room temperature, for 4.5 to 5 h (Faradaic efficiency = 5.03).
Some of our results are summarized in Table 2. As can be
seen, various symmetrical and unsymmetrical alkyl-substituted
ketals could be obtained in good yields by the electrochemical
oxidative decarboxylation of the corresponding disubstituted
b
entry current (mA)
base (equiv)
time (h) yield (%)
1
2
3
4
5
6
7
8
9
30
30
30
30
30
60
90
30
30
60
30
NaOMe in MeOH (2.2)
NaOMe in MeOH (1.1)
NaOMe in MeOH (0.1)
NH3 in MeOH (42)
NH3 in MeOH (42)
NH3 in MeOH (42)
NH3 in MeOH (42)
none (0)
6.0
4.0
5.5
4.5
7.0
3.0
3.0
6.5
8.0
4.5
8.0
31
74
71
60
77
69
72
69
76
80
0
c
NH3 in MeOH (2.1)
NH3 in MeOH (2.1)
NH3 in MeOH (0.2)
10
11
a
All reactions were carried out using 0.5 mmol of disubstituted
malonic acid 5a as starting material. The surface of the electrodes was
b
c
always 3 cm2. Isolated yield. The corresponding amnonium salt was
used.
Based upon our previous experience on the Kolbe-type
reactions of monocarboxylic acids,12 the electrolysis of malonic
acid 5a was initially performed in the presence of sodium
methoxide (2.2 equiv) in MeOH. Since a double Hofer−-
Moest13 process was to take place, carbon graphite (Cgr)
electrodes were thought to be the most appropriate (Table 1,
entry 1). Disappointingly, despite full conversion of 5a, only
poor yields of the desired ketal 6a were obtained. Lowering the
B
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Letter
a
is the preparation of β-keto ester 7e (Table 2, entry 6), which
offers an alternative synthetic route toward these useful building
blocks.
Table 2. Scope of the Reaction
Based upon our previous work on radical generation under
electrolytic conditions,17 a plausible reaction mechanism can be
proposed (Scheme 2). At the onset, NH3 reacts with the
malonic acid 5 to form the corresponding ammonium
carboxylate 5′. Loss of an electron from 5′ then produces the
unstable radical intermediate A. Elimination of CO2 ensues,
leading to the carboxy-stabilized radical B. This electron-
deficient species is oxidized further, in what is most probably
the rate-determining step of the sequence, generating as a
transient intermediate the zwitterionic species C,18 which can
be captured in an intramolecular manner by the proximal
carboxylate function, leading to the α-lactone D. Reversible ring
opening of lactone D in the presence of MeOH delivers the α-
methoxy-substituted carboxylic acid derivative E.
Carboxylic acids bearing an electron-donating substituent at
the α-position are particularly prone to undergo Hofer−Moest
reactions.19 It is therefore not surprising that E experienced
swift loss of an electron, followed by the release of CO2,
generating radical F, which is rapidly oxidized to the
corresponding oxonium cation G. Addition of MeOH to G
ultimately delivers the desired ketal product 6.
In summary, we have developed a simple, efficient, and
convenient methodology for the synthesis of ketals and ketones
by the electrochemical oxidative decarboxylation of disubsti-
tuted malonic acid ammonium salts. Advantages of our
approach include the use of simple, cheap, and readily available
malonic acid derivatives as substrates, environmentally friendly
electro-organic conditions, mild reaction protocol, and excellent
tolerance toward a large range of functional groups. We believe
that our approach might open new vistas for the construction of
a wide variety of symmetrical and unsymmetrical ketals and
ketones bearing various substitution patterns. The application
of our method to the synthesis of more complex molecules,
including the total synthesis of natural products, is currently
under investigation in our laboratories, and the results will be
reported in due course.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02084.
a
All reactions were carried out using 0.5 mmol of starting material
with 2.1 equiv of NH3 (7.0 M in MeOH) in MeOH at room
b
temperature for 4−4.5 h. Isolated yield (Faradaic efficiency = 5.03).
Experimental procedures and characterization data for all
new compounds (PDF)
malonic acids.16 The functional group tolerance of this method
proved to be quite broad. Indeed, the electrolysis can be
successfully accomplished in the presence of esters (Table 2,
entries 1−3, 6, 7, and 10), alkenes (Table 2, entries 9 and 11),
conjugate alkenes (Table 2, entry 7), vinylsilanes (Table 2,
entry 8), alkynes (Table 2, entry 4), and aromatic group (Table
2, entry 5). In all these cases, the corresponding ketal products
could be obtained in good to excellent yields. It is noteworthy
that the electron-rich vinylsilane 5g, relatively prone toward
oxidation, underwent side reactions resulting in lower yields of
6g. Interestingly, if the crude electrolysis mixture was directly
treated, in the same reaction vessel, with 1 M aq HCl, the
corresponding ketones 7 could be isolated in good yields
(Table 2, entries 2, 5, 6, 10, and 11). Noteworthy among these
AUTHOR INFORMATION
■
Corresponding Author
* E-mail: istvan.marko@uclouvain.be.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this work by the Fonds National pour la
Recherche Scientifique (FNRS - ERA No. R 50.02.11F) is
gratefully acknowledged.
C
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single electron of radical B might be assisted by the neighboring
carboxylate function, and a direct collapse of B to the α-lactone D is a
possible pathway. Ring opening of D to C then ensues.
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Supporting Information).
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D
DOI: 10.1021/acs.orglett.5b02084
Org. Lett. XXXX, XXX, XXX−XXX