Aldehydes as Alkylating Agents for Ketones

Article abstract of DOI:10.1002/chem.201904605

Common and non-toxic aldehydes are proposed as reagents for alkylation of ketones instead of carcinogenic alkyl halides. The developed reductive alkylation reaction proceeds in the presence of the commercially available ruthenium catalyst [(cymene)RuCl₂]₂ (as low as 250 ppm) and carbon monoxide as the reducing agent. The reaction works well for a broad substrate scope, including aromatic and aliphatic aldehydes and ketones. It can be carried out without a solvent and often gives nearly quantitative yields of the products. This straightforward and cost-effective method is promising not only for laboratory application but also for industry, which produces carbon monoxide as a large-scale waste product.

Full text of DOI:10.1002/chem.201904605

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Accepted Article
Title: Aldehydes as alkylating agents for ketones
Authors: Sofiya A Runikhina, Oleg I Afanasyev, Klim Biriukov, Dmitry S
Perekalin, Martin Klussmann, and Denis Chusov
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To be cited as: Chem. Eur. J. 10.1002/chem.201904605
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Aldehydes as alkylating agents for ketones
Sofiya A. Runikhina,[a] Oleg I. Afanasyev,[a] Klim Biriukov,[a] Dmitry S. Perekalin,[a],[b] Martin
Klussmann,[c] and Denis Chusov*[a],[b]
Dedication ((optional))
Abstract: Common and non-toxic aldehydes are proposed as
We chose the aldehydes appeared as the alkylating agents as
reagents for alkylation of ketones instead of carcinogenic alkyl halides. they are generally non-toxic and readily available. In contrast to
The developed reductive alkylation reaction proceeds in the presence
of the commercially available ruthenium catalyst [(cymene)RuCl2]2 (as
low as 250 ppm) and a carbon monoxide as the reducing agent. The
reaction works well for a broad substrate scope, including aromatic
and aliphatic aldehydes and ketones. It can be carried out without a
solvent and often gives nearly quantitative yields of the products. This
straightforward and cost-effective method is promising not only for
laboratory application but also for industry, which produce carbon
monoxide as a large scale waste product.
alkyl halides, aldehydes give solid waste products.
The α-alkylation of carbonyl compounds1 is well known and widely
used reaction. Yet, classical approaches that employ alkyl halides
are remarkably ineffective as they require stoichiometric amounts
of base, produce halide wastes and are often complicated by
overalkylation (Scheme 1a). Moreover, many alkyl halides are
Scheme 1. Strategies for the alkylation of ketones.
toxic, mutagenic and carcinogenic. Therefore, there is
a
continued interest in the development of more effective and
benign methods, especially for medicinal chemistry.2 For example,
hydrogen-borrowing strategy has been developed for reductive
alkylation of ketones.3 Another classical approach is
hydrogenation of the corresponding enone, which is accessible
via an aldol condensation (Scheme 2). However, most of these
methods suffer from high catalyst loading, the need of a strong
base, or may lead to non-selective overreduction even under mild
conditions.
Herein, we report the reductive alkylation of ketones with
aldehydes without an external hydrogen source (Scheme 1b).4
We use carbon monoxide as a reducing agent, which helps to
avoid undesired overreduction.4d,5 Moreover, the use of CO is
attractive from environmental point of view. It can be obtained by
gasification of biomass6 and it is already generated by industry on
large scale in processes like steel production.7 Thus the use of
CO as a reductant provides value-added products and at the
same time reduces the amounts of industrial waste.
Scheme 2. New reductive cross-coupling vs. classical reducing approaches for
the alkylation of ketones.
First the model reaction of acetophenone 7a with p-
chlorobenzaldehyde 8a was evaluated under various conditions.
The ketone component was used in three-fold excess to achieve
full conversion of the aldehyde in a short time, although this is not
necessary for preparative purposes. The reactions were stopped
after five hours to enable a direct comparison.
[a]
S. A. Runikhina, Dr. O. I. Afanasyev, K. Biriukov, Prof. Dr. D. S.
Perekalin, Dr. D. Chusov
Nesmeyanov Institute of Organoelement Compounds,
Russian Academy of Sciences,
Moscow 119991, Russia, Vavilova St. 28
E-mail: chusov@ineos.ac.ru
Prof. Dr. D. S. Perekalin, Dr. D. Chusov
G.V. Plekhanov Russian University of Economics,
36 Stremyanny Per., Moscow 117997, Russia
PD Dr. M. Klussmann
[b]
[с]
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1,
45470 Mülheim an der Ruhr, Germany
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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it provided the highest yield, has highest solubility and because it
can be easily purified by recrystallization.
The reaction can be carried out in various solvents such as
methanol or THF, but it also works well in neat conditions
(compare entries 6-8). Both the temperature and CO pressure can
be reduced: for example, at 130°C and under 5 bar of CO a good
yield (78%) of the product 9aa was reached if the reaction time
was extended to 44 hours (entry 9). The reaction can be even
performed under 1 bar pressure of the carbon monoxide, which
allows one to use common glassware instead of autoclaves (see
below for product 9ci and Supporting Information for details).
The reaction rate can be further enhanced by increasing the
temperature to 180°C (entry 10) and the pressure to 50 bar, which
leads to essentially quantitative yield of the product (entry 11).
Under these conditions, a satisfying yield of 65% is also achieved
if both ketone and aldehyde are reacted in equimolar amounts
(entry 12). Most notably, with a very low amount of catalyst (250
ppm), 90% yield of the product can be obtained (entry 13).
Figure 1. Ruthenium complexes evaluated as catalysts.
Table 1. Evaluation of reaction conditions.
Entry
1[a]
2[a]
3[a]
4[a]
5[a]
6[a]
7[b]
8[b]
9[c]
Catalyst
p (bar)
30
30
30
30
30
30
30
30
5
Yield, [%]
6
Solvent
neat
T, °C
1
2
160
neat
neat
neat
neat
neat
MeOH
THF
neat
neat
neat
neat
neat
160
160
160
160
160
160
160
130
180
180
180
180
12
3
26
4
37
5
41
6
56
6
51
6
59
6
78
10
6
30
50
50
50
80
11
6
99
12[d]
13[e]
6
65
6 (250 ppm)
90
Scheme 3. Reaction conditions: 1 (1.2 mmol), 2 (0.4 mmol), 6 (4.0 μmol, 1
mol%). [a] 250 ppm of 6 were used. [b] 2 mol% DIPEA were added. [c] MS 3A
were added. [d] Performed in a closed high-pressure Schlenk tube, filled with 1
bar CO. [e] 500 ppm of 6 were used.
[a] General reaction conditions: 7a (1.2 mmol), 8a (0.4 mmol), 6 (4.0 μmol,
1 mol%). [b] With addition of 200 μl of solvent. [c] Reaction time 44 h. [d] 1.0
equiv. of 7a (0.4 mmol). [e] Reaction time 72 h, 250 ppm of 6.
For further investigation of the substrate scope, we generally
employed 1.0 mol% of the catalyst and >160 °C temperatures in
order to maintain the reaction times relatively short. However, it
should be underlined, that the reaction conditions are flexible and
can easily be adapted to achieve nearly quantitative yields for
most of the products (see the Supporting Information for details).
We tested the six ruthenium complexes (Figure 1) as well as
ruthenium trichloride as catalysts (Table 1; see Supporting
Information for additional details). At 160 °C and under 30 bar
pressure of CO, the catalysts 3–6 gave reasonable yields 26–56%
of the target product 9aa (Table 1, entries 3-6). We chose the
cymene complex 6 as a catalyst for further optimization because
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In many cases, the catalyst loading can be indeed reduced to 250
ppm.
The reaction of acetophenone with various aromatic
aldehydes gave the target alkylated products in good yields. In
particular aldehydes with strong electron-donating groups like
OMe (9ac) and strong electron-withdrawing groups like CF3 (9ag)
reacted similarly well (Scheme 3). When turning to acetone as
ketone component, we used it in a larger excess and obtained the
mono-alkylated products 9cb and 9ci in very good yields. The
compound 9ci was used as a model for reaction without autoclave.
It was found that at 160°C and 1 bar of CO, the target 9ci was
formed in 82% yield after an extended reaction time of 40 hours.
Scheme 5. Synthesis of anti-inflammatory drug Nabumetone.
We have also carried out some experiments to clarify the
mechanism of the reaction (Scheme 6). It was assumed that initial
aldol reaction of a ketone with an aldehyde gives a β-hydroxy-
ketone such as 13, which may undergo further reversible
dehydration, but will eventually be reduced to the product 9 by the
action of the catalyst and CO. In order to probe this theory, we
synthesized potential intermediates and subjected them to the
typical reaction conditions (see the Supporting Information for
further details). The aldol product 13ax indeed formed some
amount of the product 9ax as well as the acetophenone 7a,
apparently as the result of a retro-aldol reaction (Scheme 6b). In
contrast, the product of aldol condensation 14 remained almost
unchanged under the reaction conditions (Scheme 6c). The
reaction of a ketone with an aldehyde in the presence of H2
instead of CO gave mostly the benzyl alcohol 15 as the result of
aldehyde reduction (Scheme 6d). At 160°C, some amount of the
alkylation product 9aa was formed, but the aldehyde reduction still
prevailed and the reaction was much less selective than that
conducted in the presence of CO.
Apart from acetophenone and acetone other aryl and alkyl
ketones could also be employed. For example, we produced the
derivatives of the tetralone (9ba), the natural pregnenolone
acetate (9ea), and 4-phenyl-2-butanone. The latter is noteworthy
as we obtained selectively only terminally alkylated product 9db
without isomers or overalkylation by-products.
Although we focused on aryl aldehydes (in order to avoid by-
product arising from coupling of two aldehydes) the reaction is not
limited to them. In particular, it was shown that 2-phenyl
propionaldehyde reacts with acetone to give the product 9cj in
75% yield (Scheme 3). Besides aldehydes, a ketone and an
epoxide could also be utilized as alkylating agents (Scheme 4).
Thus the reaction between adamantanone (10) and
acetophenone led to the product 11al in 78% yield. The reaction
between styrene oxide (12) and acetone led to the product 11am
in 79% yield.
The water-gas shift reaction (WGSR), which converts CO and
H2O into CO2 and H2, has been previously suggested as a source
of reducing agent in similar reaction systems.5a Water is expected
by-product in our mixture (arising from the aldol condensation)
and it is likely that some hydrogen can be formed via WGSR. To
clarify the possible involvement of this process, we have removed
the water from our system by addition of molecular sieves. For
some substrates yields indeed dropped by 13-34%, but for other
substrates the yields had even improved by 10-15% (see the
Supporting Information). Thus, while we cannot rule out the
WGSR pathway in our case, we consider it rather unlikely. We
also performed an experiment with acetone-d6 (Scheme 6e). The
general amount of deuterium was preserved and a single D-atom
was incorporated at the former carbonyl carbon atom of the
aldehyde. This experiment confirmed that the reagents were
sufficiently dry and scrambling with protons from residual water
did not occur to any significant extent.
Scheme 4. A ketone and an epoxide as alkylation agents. 5 equivalents of
adamantanone were used. The reaction with styrene oxide was provided in
acetone as a solvent.
We have applied the developed method for the synthesis of
Nabumetone, a non-steroidal anti-inflammatory drug.8 It was
obtained from the commercially available 6-methoxy-2-
naphthaldehyde in good yields using only 500 ppm amount of the
catalyst 6 (Scheme 5).
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Scheme 7. Proposed mechanism for reductive alkylation reaction. Red
numbers in italics correspond to the calculated Gibbs free energies relative to
the starting reagents at PBE/TZVP level with SMD correction for acetone
solvation (in kcal mol–1, at 298 K).
Scheme 6. Mechanistic investigations.
We propose a possible mechanism for the reductive alkylation
(Scheme 7) and assessed its feasibility by DFT calculations at the
PBE/TZVP level. We assume that initially a ketone reacts with an
aldehyde to give an aldol product (model compound M1), while
RuCl3 reacts with CO to give the well-known Ru(CO)3Cl2 species.9
Next Ru(CO)3Cl2 can coordinate the aldol M1 to produce the
chelate complex M2. Enolization of M2 into M3 opens the
opportunity for the cleavage of the now allylic C–OH bond to give
the hydroxo-complex M4. The Gibbs free energy of the transition
state TS1 of this process is 29.2 kcal mol–1. This step is similar to
elimination of water in the classical aldol condensation.
In summary, we have developed a new general method for
reductive alkylation of ketones by using aldehydes as alkylation
agents and carbon monoxide as a reductant. The substrate scope
includes aryl and alkyl aldehydes and ketones. In addition, a
ketone and an epoxide were successfully employed as alkylation
agents. The reaction employs a commercially available ruthenium
catalyst [(cymene)RuCl2]2, which can be used at a very low
loading of 250 ppm. The reaction can be run without a solvent and
also in simple glassware without autoclaves. The abundance of
CO as industrial waste product can make this method useful for
large-scale applications.
Then the OH group in M4 migrates to the CO ligand to form
the carboxyl complex M5. The free energy of the transition state
TS2 here is 30.8 kcal mol–1. Proton transfer from COOH to the
coordinated ketone results in decarboxylation and formation of
the metallacycle M7. The overall transformation of M4 into M7
resembles the classical ruthenium catalyzed water-gas shift
reaction, which has been recently studied in detail by both
theoretical and experimental methods.10 Finally, protonolysis of
the Ru–C bond in M7 by HCl and addition of a new CO ligand
gives the target product M9 and regenerates the active species
Ru(CO)3Cl2. It should be noted that the mixture of RuCl3 and CO
is known to produce a number of catalytically active species,10 so
the calculated mechanism represents just one of several possible
pathways.
Experimental Section
General procedure: A 10 mL titanium autoclave was charged with
prescribed quantity of the catalysts, a carbonyl compound, an epoxide, or
a ketone and 0.2 mL of the corresponding solvent if mentioned. The
autoclave was sealed, flushed three times with 10 bar of CO, and then
charged with the indicated pressure of CO. The reactor was placed into a
preheated oil bath. After the indicated time, the reactor was cooled to room
temperature and depressurized. Yields were determined by NMR,
mesitylene was added as internal standard or by GC. Detailed
experimental data including characterization data are provided in
supporting information.
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Acknowledgements
The work was financially supported by the Russian Science
Foundation (grant # 16-13-10393). NMR studies were performed
with the financial support from Ministry of Science and Higher
Education of the Russian Federation using the equipment of
Center for molecular composition studies of INEOS RAS.
Financial support from the DFG (Heisenberg scholarship to M.K.,
KL 2221/4-1) is gratefully acknowledged.
[4]
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Keywords: aldehydes, alpha-alkylation, ketones, reductive
coupling, ruthenium
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Entry for the Table of Contents (Please choose one layout)
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S. Runikhina, O.I. Afanasyev, K.
Biriukov, D.S. Perekalin, M. Klussmann,
D. Chusov*
Page No. – Page No.
Aldehydes as alkylating agents for
ketones
Alpha-alkylation by aldehydes! There are enough hydrogen atoms in substrates
for reductive alkylation of ketones by aldehydes, a ketone and even an epoxide.
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