Study on the Pd/C-catalyzed (retro-)Michael addition reaction of activated methylene compounds to electron-poor styrenes

Article abstract of DOI:10.1002/ejoc.201000961

Palladium on carbon (10 % Pd/C) efficiently catalyzes the (retro-)Michael addition of activated methylene compounds 2a-d, such as malononitrile (2b), to mono- and doubly activated styrenes 1a-h to give the adducts 3a-l. The scope and limitations are described. The Knoevenagel condensation reaction of benzaldehyde and 2b or ethyl cyanoacetate (2c) is also catalyzed by 10 % Pd/C. In these cases the Michael adducts can even be prepared in a three-component reaction. A mechanism, with as first step the oxidative addition of 2a-d to Pd⁰, is proposed. Palladium on carbon (10 % Pd catalyzes the (retro-)Michael addition of activated methylene compounds 2a-d to mono- anddoubly activated styrenes. The scope and limitations of the reaction are described. A mechanism is proposed. Copyright

Full text of DOI:10.1002/ejoc.201000961

FULL PAPER
DOI: 10.1002/ejoc.201000961
Study on the Pd/C-Catalyzed (Retro-)Michael Addition Reaction of Activated
Methylene Compounds to Electron-Poor Styrenes
Nicolai I. Nikishkin,[a] Jurriaan Huskens,[a] and Willem Verboom*[a]
Keywords: Michael addition / Palladium / C-H activation
Palladium on carbon (10% Pd/C) efficiently catalyzes the
(retro-)Michael addition of activated methylene compounds
2a–d, such as malononitrile (2b), to mono- and doubly acti-
vated styrenes 1a–h to give the adducts 3a–l. The scope and
action of benzaldehyde and 2b or ethyl cyanoacetate (2c) is
also catalyzed by 10% Pd/C. In these cases the Michael ad-
ducts can even be prepared in a three-component reaction.
A mechanism, with as first step the oxidative addition of 2a–
limitations are described. The Knoevenagel condensation re- d to Pd0, is proposed.
Introduction
Results and Discussion
Highly substituted propanes containing two pairs of ge-
minal electron-withdrawing groups at the 1,1- and 3,3-posi-
tions are versatile precursors for a large number of hetero-
cyclic compounds, as, for example, 4H-pyranes and 4H-pyr-
idines,[1,2] that are essential parts of biologically important
natural products.[3,4] This type of propanes are usually pre-
pared via a Knoevenagel condensation reaction resulting in
symmetrical compounds with identical electron-with-
drawing groups. However, non-symmetrical 1,1,3,3-tetra-
substituted propanes can be obtained by a Michael addition
of an activated methylene compound to a Knoevenagel ad-
duct. Over the years different studies have appeared to per-
form the Michael addition reaction under mild reaction
conditions, e.g. making use of transition metals. It has been
reported that rhodium, iridium and ruthenium polyhydride
complexes are excellent catalysts for C–H bond activation
of various activated methylene compounds.[5–7] Also tetra-
kis(triphenylphosphane)palladium(0) was reported to give
satisfactory results performing the Michael addition of cya-
noacetates to alkynes bearing electron-withdrawing substit-
uents,[7] However, soluble polyhydride and low-valent tran-
sition metal complexes usually require special reaction con-
ditions, while in addition the catalyst has to be removed
from the crude reaction mixture. In the present work we
report a simple palladium-catalyzed Michael addition of ac-
tivated methylene compounds to mono- and doubly acti-
vated styrenes using catalytic amounts of nontoxic and eas-
ily removable palladium on activated carbon (Pd/C).
First we studied the formation of 1,1,3,3-tetrasubstituted
propanes using a base-catalyzed Michael addition reaction
(Scheme 1). Reaction of benzylidenemalononitrile (1a) with
one equivalent of dimethyl malonate (2a) in the presence of
a catalytic amount of a mild base such as triethylamine or
pyridine in diethyl ether gave an equilibrium mixture con-
taining 76% of the Michael adduct 3a. Slow evaporation of
the solvent induced crystallization of the product and
shifted the equilibrium up to quantitative conversion. When
the reaction was carried out with two equivalents of di-
methyl malonate (2a) the Michael adduct 3a was obtained
in quantitative yield. When a stronger base is being used
such as a hydroxide or alkoxide in-situ intramolecular cycli-
zation of the Michael adduct 3a to the 4H-pyran 4 takes
place as recently described.[1] In our hands reaction of 1a
and 2a in the presence of DBU as a base in diethyl ether
afforded a 1:1 mixture of Michael adduct 3a and 4H-pyran
1
4 according to the H NMR spectrum. At the same time,
base catalysis of a 1:1 mixture of dimethyl benzylidene-
malonate (1b) and 2a or malononitrile (2b) yielded no
Michael adduct (3c or 3a) at all.
During our studies on the further functionalisation of
tetrasubstituted propanes, we attempted the selective re-
duction of the cyano groups in the Michael adduct 3a.
Since the ester moieties had to remain unaffected 10% Pd/
C-catalyzed hydrogenation was chosen.[8] Upon hydrogena-
tion of 3a with 10 bar of H2 the expected amino derivative
could not be detected in the 1H NMR spectrum of the
crude reaction mixture. Instead the 1H NMR spectrum
showed signals at δ = 7.80 and 3.40 ppm, characteristic for
benzylidenemalononitrile (1a) and dimethyl malonate (2a),
respectively. Treatment of a solution of the Michael adduct
3a in methanol with 10% Pd/C in the absence of H2 for
15 h resulted, according to the 1H NMR spectrum, in a
clean mixture of 1a/2a/3a of about 1:1:3. Apparently, a
[a] Laboratory of Molecular Nanofabrication, MESA+ Institute
for Nanotechnology, University of Twente,
P. O. Box 217, 7500 AE Enschede, The Netherlands
E-mail: w.verboom@utwente.nl
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Pd/C-Catalyzed (Retro-)Michael Addition Reaction
Scheme 1. Palladium-catalyzed (retro-)Michael addition of activated methylene compounds to mono- and doubly activated styrenes.
retro-Michael reaction had occurred giving rise to the mix- reaction is much slower. Treatment with dimethyl malonate
ture. Conversely, stirring of a 1:1 mixture of 1a and 2a in (2a) did not give any reaction, even after prolonged heating.
methanol in the presence of 10% Pd/C gave rise to the same The Pd/C-catalyzed reaction with malononitrile (2b) pro-
mixture, proving that equilibrium had been reached.
ceeds very slowly; after three days there is about 30% of
To study the scope of these Pd/C-catalyzed reactions, the the Michael adduct 3a formed which grows to 60% after
behavior of the tetrafunctionalized propanes 3b,d towards six days and upon about seven days equilibrium is reached.
this catalyst was investigated (Scheme 1). In the case of the
To further explore the scope of the Pd/C-catalyzed
propanes 3b and 3d, according to the 1H NMR spectra, Michael addition reaction, a series of experiments was per-
90% conversion was obtained resulting in an equilibrium formed with mono-β-activated styrenes (Scheme 1). Treat-
mixture of 9:9:1 of 1a/2b/3b and 1a/2c/3d, respectively. The ment of 1:1 mixtures of cinnamonitrile (1e) with dimethyl
reverse reaction under identical conditions gave the same malonate (2a) and malononitrile (2b) with 10% Pd/C in re-
ratio.
fluxing methanol for two days did not give rise to any reac-
In case of the retro-reaction of the Michael adducts 3a tion; the formation of the Michael adducts 3f,g could not
and 3d two different alkenes can be formed. In all cases the be detected. The addition of one equiv. of DBU was also
retro-Michael reaction occurred with the exclusive forma- unsuccessful. However, the reaction of trans-chalcone (1f)
tion of the olefin bearing the strongest electron-with- with 2b,c in the presence of 10% Pd/C in methanol at room
drawing functionalities, hence having the highest thermo- temperature gave the corresponding Michael adducts 3h
dynamic stability.
and 3i in quantitative yield. Starting from dimethyl malon-
Upon treatment of 1:1 mixtures of benzylidenemalono- ate (2a) the Michael adduct 3j was only obtained in 35%
nitrile (1a) and acetylacetone (2d) and of benzylidene- yield after stirring for two days. Refluxing the reaction mix-
acetylacetone (1c) and malononitrile (2b) with 10% Pd/C ture gave rise to a complicated mixture of products. The
in methanol overnight the expected product 3e could not described SmI3-catalyzed reaction for the preparation of
be detected. However, a fast tandem intramolecular cycliza- 3h,i gives lower yields and requires chromatographic purifi-
tion of in-situ formed Michael adduct 3e took place to af- cation,[10] underlining the suitability of the Pd/C approach.
ford 4H-pyran 5 in 98% yield (Scheme 1). In addition to
Aliphatic Michael acceptors such as isopropylidene di-
the correct mass, the formation of 4H-pyran 5 could be de- ethyl malonate, acrylonitrile, isopropylidenemalononitrile,
1
duced from characteristic H NMR signals at δ = 4.40 and and neopentylidenemalononitrile failed to react with e.g.
4.60. The corresponding base-catalyzed reaction gives rise malononitrile (2b) under the 10% Pd/C conditions. Even
to poor yields and requires thorough separation of the after refluxing in methanol overnight, no trace of the
1
crude reaction mixtures containing products due to further Michael adducts could be detected in the H NMR spectra
based-catalyzed reaction of 4H-pyran 5 with 1a,c to give of the crude reaction products; only starting materials were
pyrano[2,3-b]pyridines.[9]
present. Apparently, the presence of the π-accepting phenyl
Both the character of the olefin and the activated methyl- group is a prerequisite for the reaction.
ene compound considerably influence the rate of the reac-
Assuming that Pd/C catalyzes the Michael addition reac-
tion. The Pd/C-catalyzed reaction of benzylidenemalono- tion via C–H bond activation of an activated methylene
nitrile (1a) with dimethyl malonate (2a) takes about 20 h compound, the influence on the Knoevenagel condensation
before equilibrium is reached. In case of the more acidic reaction was investigated. Stirring a solution of benzalde-
malononitrile (2b) the equilibrium is already reached within hyde (6) and dimethyl malonate (2a) or acetylacetone (2d)
3 h. Starting from benzylidene dimethyl malonate (1b), the in the presence and absence of 10% Pd/C in methanol over-
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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N. I. Nikishkin, J. Huskens, W. Verboom
FULL PAPER
night did not give rise to any conversion. However, reaction
of benzaldehyde (6) with ethyl cyanoacetate (2c) in the ab-
sence and presence of 10% Pd/C in methanol for 19 h re-
sulted in the formation of the condensation product 1d in
7% and 80%, respectively. The corresponding reactions
with malononitrile (2b) for 1 h gave benzylidenemalono-
nitrile (1a) in 21 and 90%, respectively (Scheme 2). These
results show that the more acidic the methylene hydrogens
are the faster the Knoevenagel reaction proceeds catalyzed
by Pd/C.
Scheme 4. Proposed catalytic cycle.
To investigate the influence of substituents on the aro-
matic ring of the Michael acceptor on the formation of the
π-complex with palladium (Scheme 4), claimed as the pre-
requisite for this reaction, a series of experiments with 2-(4-
nitrobenzylidene)malononitrile (1g) and 2-(4-methoxy-
benzylidene)malononitrile (1h), as extreme examples of
substrates bearing electron-withdrawing and -donating
groups, respectively, was performed (Scheme 5).
Scheme 2. Palladium-catalyzed Knoevenagel reaction.
This led us to investigate a three-component reaction in
which the Knoevenagel condensation product is formed in-
situ. Reaction of a mixture of benzaldehyde (6) with ma-
lononitrile (2b) and two equivalents of dimethyl malonate
(2a) in the presence of 10% Pd/C gave as expected the
Michael adduct 3a in quantitative yield (Scheme 3).
Scheme 5. Palladium-catalyzed Michael reaction with substituted
benzylidenemalononitriles.
Scheme 3. Palladium-catalyzed three-component reactions.
Upon reaction of 1g with an equimolar amount of 2a in
The same reaction in which 2a was replaced by one the presence of Pd/C (10%) the desired Michael adduct 3k
equivalent of acetylacetone (2d) afforded the 4H-pyran 5 in was formed in 90% yield after stirring overnight. However,
quantitative yield in line with the results described above. a different behavior was observed in case of 1h. Stirring a
The corresponding reaction of a 1:1:1 mixture of benzalde- 1:1 mixture of 1h and 2a in the presence of Pd/C (10%),
hyde, 2b, and ethyl cyanoacetate (2c) gave a 1:1 mixture of the equilibrium was only set after four days; in the reaction
the Knoevenagel adducts 1a,d and traces of the different mixture 43% of the Michael adduct 3l was detected. Appar-
Michael adducts. The latter is explainable by the fact that ently, the reaction rate was considerably decreased by the
the Michael adducts are in equilibrium with the Knoevena- presence of the strongly electron-donating methoxy group.
gel adducts in a 1:9 ratio (vide supra).
The obtained experimental data clearly shows that the
A possible mechanistic rationale that explains this un- presence of a strongly electron-withdrawing group in the
precedented catalytic activity of palladium on carbon in a aromatic ring of the Michael acceptor facilitates its coordi-
Michael addition reaction is shown in Scheme 4. Oxidative nation to the palladium center. This decreases the HOMO–
addition of an activated methylene compound to Pd0 will LUMO gap of Michael donor and Michael acceptor and
furnish a PdII species. Further coordination of an activated hence significantly increases the reaction rate.
alkene followed by a migratory insertion of the deproton-
To further support the proposed mechanism the palla-
ated Michael-donor into a double bond and subsequent re- dium-catalyzed reaction of methylene-deuterated dimethyl
ductive elimination will afford the Michael adduct and re- malonate (2a-D2) with benzylidenemalononitrile (1a) in
cover the active catalyst. The same type of oxidative ad- THF as an aprotic solvent was carried out and the deuter-
dition of C–H acids to Pd0 was also proposed as the key ated Michael adduct 3a-D2 was obtained (Scheme 6). In the
step in catalytic additions to allenes,[11,12] or methylenecy- 1H NMR spectrum the expected positions of the deuterium
clopropanes.[13]
atoms in adduct 3a-D2 were confirmed by the absence of
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Pd/C-Catalyzed (Retro-)Michael Addition Reaction
General Procedure for the Palladium-Catalyzed Three-Component
Reactions: A mixture of an aromatic aldehyde (1 mmol), two corre-
sponding activated methylene compounds (1 mmol of each), and
10% Pd/C (0.106 g) in methanol (10 mL) was stirred overnight. The
catalyst was filtered off from the resulting mixture and the solvent
removed in vacuo. The residue was analyzed by 1H NMR spec-
troscopy. The spectra correspond with those reported for the dif-
ferent compounds in literature.
two doublets at δ = 4.90 and δ = 4.14 (in 3a) and the pres-
ence of a singlet at δ = 3.95 for the benzylic hydrogen atom.
The formation of 3a-D2 indicates that oxidative insertion of
Pd0 into one of the C–D bonds of 2a-D2 has taken place.
Upon carbopalladation of 1a with the PdII species, in the
resulting complex reductive coupling takes place in which
the D is transferred to the “malononitrile” carbon atom.
The role of Pd0 in the first step was also proven in an ex-
change experiment using a solution of 2a in CD3OD in
which the presence of Pd0 is prerequisite for H–D exchange.
Dimethyl
1,1-Dicyano-1,3-dideuterio-2-phenylpropane-3,3-dicarb-
oxylate (3a-D2): A mixture of methylene-deuterated dimethyl ma-
[21]
lonate 2a-D2
(0.134 g, 1 mmol), benzylidenemalononitrile (1a)
(0.154 g, 1 mmol), and 10%-Pd/C (0.106 g) in dry THF (10 mL)
was stirred for 20 h and then filtered. After removal of the solvent
the 1H NMR spectrum of the residue showed the formation of 76%
1
of 3a-D2. H NMR: δ = 7.40 (m, 5 H), 3.95 (s, 1 H), 3.86 (s, 3 H),
3.50 (s, 3 H) ppm. 13C NMR: δ = 168.0, 166.6, 134.9, 133.7, 131.0,
129.9, 129.5, 128.6, 111.6, 111.5, 53.8, 53.4, 53.3, 52.8, 45.0, 44.9,
44.8, 27.9 ppm.
Scheme 6. Deuterium-labeled Michael addition reaction.
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Conclusions
In conclusion, we have demonstrated an efficient and
very simple palladium-on-carbon-catalyzed (retro-)Michael
addition reaction of activated methylene compounds to
doubly and mono-activated styrenes that in some cases is
superior to base catalysis. The catalyst is very robust, not
air-sensitive, and can easily be removed.
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Experimental Section
General Remarks: The solvents and all reagents were obtained from
commercial sources and used without further purification. 1H
NMR and 13C NMR spectra were recorded on a Varian Unity
INOVA (300 MHz) spectrometer. 1H NMR chemical shift values
(300 MHz) are reported as δ using the residual solvent signal as an
internal standard (CDCl3, δ = 7.257). 13C NMR chemical shift val-
ues (75 MHz) are reported as δ using the residual solvent signal as
an internal standard (CDCl3, δ = 77.0 ppm). Electrospray ioniza-
tion (positive mode) mass spectra were recorded on a WATERS
LCT mass spectrometer. The styrene derivatives 1b,[14] 1c,[15] 1g,[16]
and 1h[15] and the Michael adducts 3a,[17] 3c,[18] 3h,[10] 3i,[10] 3j,[19]
3k,[20] and 3l[19] were prepared according to literature procedures.
General Procedure for the Palladium-Catalyzed (Retro-)Michael Re-
actions: A mixture of a Michael donor (1 mmol), a Michael ac-
ceptor (1 mmol), and 10%-Pd/C (0.106 g) in methanol (10 mL) was
stirred overnight (unless specified). (In case of the retro-reaction
1 mmol of the Michael adduct was used under the same condi-
tions.) Thereafter the catalyst was filtered off and the solvent re-
moved in vacuo. The residue was analyzed by 1H NMR spec-
troscopy. The spectra correspond with those reported for the dif-
ferent compounds in literature. For the 4H-pyranes 4 and 5 see
ref.[1,9]
[20] T. Lemek, H. Mayr, J. Org. Chem. 2003, 68, 6880.
[21] D. J. Hupe, E. R. Pohl, J. Am. Chem. Soc. 1984, 106, 5634.
Received: July 8, 2010
Published Online: October 22, 2010
Eur. J. Org. Chem. 2010, 6820–6823
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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