First report of the application of simple molecular complexes as organo-catalysts for Knoevenagel condensation

Article abstract of DOI:10.1039/c5ra09036a

A series of molecular complexes have been designed, synthesized and used as organo-catalysts for the first time for very efficient Knoevenagel condensation. Molecular complexes are thermally stable, easily recyclable, and have a low cost of preparation. T

Full text of DOI:10.1039/c5ra09036a

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DOI: 10.1039/C5RA09036A
First Report of Application of Simple Molecular Complexes as Organoꢀ
Catalyst for Knoevenagel Condensation
Sumit Kumar Panja, Nidhi Dwivedi and Satyen Saha*
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi-221005, India.
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Graphical Abstract
Abstract
10 A series of molecular complex have been designed, synthesized and used as organo-catalyst for the first time for very efficient
Knoevenagel condensation. Molecular complexes are thermally stable, low cost for preparation, easily recyclable. Role of acidic proton
in molecular complexes towards Knoevenagel condensation has been identified as the key factor and helps us to provide useful
information of reaction path way. The acidic proton of catalyst enhances the electrophilicity of the aldehyde and accelerates dehydration
process of reaction at room temperature (RT). Eco-friendly, green synthetic protocol for Knoevenagel condensation is used to synthesize
15 a series of important cyano group containing synthetic precursor for synthesis of biologically active molecules at RT using minimum
amount of catalyst (~5 mol %) without chromatographic separation technique. Detailed mechanistic studies and substituents effect of
aromatic aldehyde on reaction have been investigated. In addition biologically active 2-Amino-4H-Chromene derivatives have also been
synthesized by Knoevenagel condensation of salicylic aldehydes with active methylene compounds, followed by intramolecular
cyclization (via Michael addition) delivering higher yield within shortest reaction time at RT without any need of chromatographic
20 separation.
40 Traditionally, Knoevenagel condensation is carried out under
Introduction
homogeneous conditions in the presence of catalysts such as
organic bases5 solid bases,6 ionic liquids,7 amino acids,8 Lewis
Synthetic organic chemist has focused on converting a difficult
acids,9 organometallic catalysts,10 metal complexes immobilized
synthetic protocol to an easier and greener one with simple
organic synthone to produce entirely new organic molecules.1
25 The useful synthetic techniques is expected to contain one-pot
single step using environmentally benign non-hazardous catalyst
and solvent-free condition.2 Performing an organic reaction in
environmentally suitable mode is still a challenge to the chemist
even today. One of the important objectives in organic synthesis,
30 especially in the synthesis of fine chemical products such as
pharmaceuticals, is the facile synthesis of new carbon-carbon
bonds etc. The Knoevenagel reaction is a well-known carbon-
carbon bond-forming reaction, discovered by E. Knoevenagel in
1896, is also widely used both in the chemical, pharmaceutical
35 and perfume industries.3 The reaction is also well known for the
synthesis of a large variety of intermediates useful in the
manufacture of top selling drugs (such as Atorvastatin,
Pioglitazone, AMG 837, Pregabalin, Lumefantrine, Entacapone)
in the world.4
on a solid support such as oxide and zeolite deteriorates,11 oxides
45 modified by salts,12 and amine-functionalized materials affording
variable yields with different reaction time.13 Recently, synthesis
of 2-Amino-4H-chromenes derivatives has attracted great interest
to their biological and pharmacological activities.14 2-Amino-4H-
chromenes constitute a major class of naturally occurring
50 compounds, and interest in their chemistry continues because of
their utility as biologically active agents.15 They occur widely in
plants, including edible vegetables and fruits.16 Synthetic
chromene analogues have been developed over the years, and
some of them have been employed in pharmaceuticals,17 which
55 includes antifungal18 and antimicrobial agents.19 2-Amino-4H-
chromenes are employed as pigments,20 cosmetics,
agrochemicals21 and are major constituents of biologically active
many natural products (such as HA 14-1, Inhibitor of MK-2,

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DOI: 10.1039/C5RA09036A
IRSP Inhibitor and MX58151) as shown in Fig 1.22
RT (Table 1, entry 2). Further, when the catalyst loading is
40 increased to 0.05 mmol in the same condition, yield of 3aa
(desired product) is increased to 98 % (Table 1, entry 3).
However, no change of yield is observed when higher mole % of
catalyst is used (Table 1, entry 8).
O
NC CN
CN
NH2
EtO
CN
Br
CN
MeO
O
N
NH2
O
NH2
HA14ꢀ1
R2
R2
CHO
Inhibitor of MKꢀ2
OMe
Catalyst
EtOH,RT
+
CN
CN
2
MeO
Br
R1
R1
N
3
1
CN
R1= H (1a), 2-NO2 (1b), 4-CN (1c), 4-NO2 (1d), 4-Cl (1d), 4-Me (1e), 4-OMe (1f)
4-OH (1g), 4-NMe2 (1H), etc.
CN
N
O
NH2
HO
O
NH2
R2 = CN (2a), CO2Et (2b)
MX58151
IRSP Inhibitor
Scheme 1: Synthesis of Knoevenagal Condensation
Figure 1: Example of Biologically Active 2-Amino-4H-Chromene
45 Therefore, the optimized reaction condition is found to be 0.05
mmole (5 mole %) catalyst in ethanol with reaction time of 3 min
at RT. We have also carried the reaction in solvent-free condition
using 0.05 mmole (5 mol %) catalyst at RT. We found that 98 %
of desire product (3aa) is obtained within 3 min in neat condition
50 for making the reaction even more environment friendly. We
have also examined the yield of the reaction in different solvents.
When the reaction is carried out in H2O, 92 % desired product is
obtained using 0.05 mmole (5 mol %) of catalyst, 3 min at RT
(Table 1, entry 5). Slight decrease in yield in DCM (88 %) is
55 observed using 0.05 mmole (5 mol %) of catalyst, 120 min
reaction time at RT (Table 1, entry 6). Similarly, decrease of
yield is also observed when reaction is carried out in an aprotic
polar solvent like acetonitrile (ACN) at RT (Table 1, entry 7).
Recently Li et.al. have used task specific ionic liquid as catalyst
for Knoevenagel condensation at room temperature (RT) with
catalyst loading is as high as 15 mol%.23 Vakili et.al. have
reported L-histidine and L-arginine catalysed Knoevenagel
condensation reaction though the protocol is not superior in terms
of reaction condition, reaction time and yield.24 Further Mase
10 et.al. have also reported eco-friendly organo-catalysed
Knoevenagel condensation but preparation, stability and
recyclability of organo-catalyst are still challenging factors. 25 In
our continuation of work with various kind of molecular
complexes, we are reporting for the first time the use of simple
15 molecular complexes (chart 1) based on weak acid and tertiary
amine as organo-catalyst for the popular Knoevenagel
condensation reaction. The mechanistic aspects of Knoevenagel
condensation using these molecular complexes has been
investigated and presented in our present work. Further our
20 synthetic protocol is used to synthesize a biologically active 2-
amino-4H-chromene derivative.
5
Table 1: Reaction Optimization Conditionsa
Sl.
1
2
3
4
5
6
7
8
Catalyst (mmol)
-
Solvent
EtOH
EtOH
EtOH
Neat
Time (min) Yieldb
c
90
3
3
3
5
120
45
3
-
MP(DNP) (0.02)
MP(DNP) (0.05)
MP(DNP) (0.05)
MP(DNP) (0.05)
MP(DNP) (0.05)
MP(DNP) (0.05)
MP(DNP) (0.1)
MP(DNP) (0.05)
MP(0.05)
85
98
98
92
88
90
98
98
80
H2O
Chart 1: Structural Formula and Abbreviations for the Components of
Molecular Complexes
DCM
ACN
EtOH
Neat
EtOH
EtOH
EtOH
EtOH
EtOH
9
3
10
11
12
13
14
180
360
5
c
DNP(0.05)
-
DNP(0.05)+ MP(0.05)
MP(NP)2 (0.05)
MP(TNP) (0.05)
98
85
84
20
15
60 aReaction condition: benzaldehyde (1 mmol) and malononitrile (1 mmol)
was stirring with different amount of catalyst in ethanol or neat (solvent-
free) condition, bIsolated pure yield. cNo reaction.
25 Results and Discussions
Role of individual counter parts of the catalyst (MP(DNP))
towards product formation has been investigated with an aim to
65 understand the detailed reaction mechanism. Therefore, MP and
DNP, two components of this organo-catalyst have been used
separately as a probable catalyst at otherwise optimized reaction
condition. Interestingly, when MP is used as a catalyst at RT,
reaction takes place but with very long time (~3h) with drastically
70 low yield (Table 1, entry 10). On the other hand, no reaction is
observed even after 6h when DNP is used alone (Table 1, entry
11). For finding out the combining effect of MP and DNP in
reaction, same molar ratio MP is added to reaction mixture
containing DNP. Interestingly, reaction is completed within 5
75 minutes of time at RT. It is clearly indicating that DNP
component actively participates to enhance the reaction rate and
A
well-known simple condensation reaction, Knoevenagel
condensation is preferred as model reaction for studies of our
newly synthesised molecular complexes as organo-catalyst. As
depicted in Scheme 1, 1 mmol of benzaldehyde (1a) and 1.01
30 mmol of malononitrile (2a) are taken in different solvent system
and different amount of catalyst loading (range 0.02 to 0.1 mmol)
at RT. Several set of reactions are performed to optimize the
reaction in terms of yield, reaction time, solvent condition, and
amount of catalyst. It was observed that reaction does not proceed
35 in absence of catalyst (molecular complex) either in ethanol or in
neat condition at room temperature (Table 1, entry 1). But when
reaction is carried out using 0.02 mmol of catalyst (MP(DNP)) in
ethanol, yield of the desire product (3aa) is found to be 85 % at

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to complete the reaction in short time (Table 1, entry 4, 12).
Above experimental result indicates that the in-situ generated
molecular complex shows very similar catalytic activity as
externally added molecular complex (MP(DNP)). This fact is
very important considering the reduction of effort of preparing
the molecular complex separately for usage as catalyst. Other
molecular complexes, (such as MP(NP)2 and MP(TNP)) have
also been studied. It is observed that MP(NP)2 and MP(TNP) take
longer reaction time with lower percentage of yield compared to
10 MP(DNP) (Table 1, entry 13, 14). The higher efficiency of DNP
containing molecular complex compared with other two is due to
the relative stability of nitrophenolate ion in molecular complex
and can be explained considering the the pKa values of
nitrophenols. pKa values of NP, DNP and TNP are 7.16, 4.11 and
15 0.38 respectively.26 The intermediate value for DNP suggests that
it can efficiently acts as both proton donor and acceptor
depending on situation. Since, Scheme 3 and 4 indicates that
catalyst should preferably have both proton donor and accepting
efficiencies depending on reaction steps, DNP containing catalyst
20 therefore works best. Further, it is evident that a very weak acid
additive such as nitrophenol derivatives and/or its salts
(molecular complex: tertiary amine) enhances the electrophilicity
of the aldehyde accelerating the dehydration process shown in
Scheme 3. As a result, Knoevenagel condensation reported here
25 is found to take place at much lower temperature with higher
yield than reported till date. Substituent effect on yield is also
investigated. It is found that excellent yield in all most all cases is
observed except the aldehyde with electron donating group at
para position (Table 2, entry 6 and 18).
35 This is due to the increase of electron density at carbonyl centre
and reducing the formation of stable intermediate as depicted in
intermediate 3a′ (Scheme 3). Using the method and optimized
reaction conditions that are described in this report, a large
number of derivatives have been synthesized and are depicted in
40 Table 2. As a further application of the catalyst (MP(DNP)) and
synthone from Knoevenagel condensation, 2-Amino-4H-
Chromene derivatives have been synthesised via Knoevenagel
condensation of salicylic aldehydes with active methylene
compounds, followed by intramolecular cyclization (via Michael
45 addition). Scheme 2 shows the reaction in ethanol at RT. Yield of
desired reaction product, 2-Amino-4H-Chromene (5aa) is quite
high (~97 %) using 0.05 mmol (5 mol %) of MP(DNP) as catalyst
in ethanol which completes within 7 minutes at RT (Table 3,
entry 5aa). The Michael addition becomes faster and thereby
50 favouring the formation of 2-Amino-4H-Chromene at room
temperature (scheme 4).
5
Scheme 2: Synthesis of 2-Amono-4H-Chromene derivatives.
Based on the experimental results, a conceivable mechanism for
55 Knoevenagel condensation is proposed in Scheme 3. Initially
tertiary amine component (MP, BN,) of the catalyst acts as a
Lewis base and makes 2a′ as the nucleophile from substrate 2a
(pKa ~ 11.1). The 2a′ further takes part in the condensation
reaction with substrate 1a to provide intermediate 3a′. The
60 intermediate 3a′ is then dehydrated in presence of acidic part
(HA, DNP) of the catalyst to give us the desire product (3a).
30 Table 2: Synthesized Knoevenagel Condensation products at optimized
reaction condition in terms of time taken (min) and yield (%).
Table 3: Synthesized 2-Amino-4H-Chromene Derivatives
65
3

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H
BN+H
CN
CN
O
-O
H
CN
CN
BN
R1
1a
BN+H
H
R1
CN
CN
2a'
BN
H
2a
A
H
H
O+
H
O
BN+H + A-
H
BNHA
H
H
CN
CN
H
CN
H
BN+H
CN
R1
A-
R1
3a'
BN
H
CN
CN
H2O
Figure 2: Recyclability chart (recyclability of the catalyst was tested on
R1
3a
the reaction at standard reaction condition)
Scheme 3: Plausible reaction mechanism of Knoevenagel Condensation.
Here, BN represents proton acceptor (i.e., MP) and HA represents proton
donor (i.e., NP, DNP and TNP).
5
Formation of 2a′, enhancement electrophilicity of the aldehyde
and dehydration process lead the reaction faster. Further, creation
of 2a′ is controlled by base (MP), enhancement electrophilicity of
the aldehyde whereas the dehydration process is controlled by
acidic proton of catalyst. The synergetic effect is found to be the
35 Figure 3: ORTEP diagram of Catalyst (MP(DNP)) (50 % ellipsoid
probability) (CCDC No.: 873550)
10 key factor faster reaction rate.
Separation of desired product and recovery of catalyst from
reaction mixture are also important part of any catalysed reaction.
In this case, the crude reaction mixture is filtered and washed
several times with ethanol (3x10 mL each time) until the catalyst
15 is completely removed. The solid residue is then collected and
dried under vacuum. It is found to provide pure desired product.
Therefore, no column chromatographic separation is necessary.
The collected ethanol is evaporated to obtain pure catalyst back.
Finally, the product is crystallized from ethanol. Reusability of
20 the catalyst is tested by carrying out repeated runs of the reaction
at standard reaction condition. After each cycle of usage, the
catalyst is collected in ethanol and evaporated the solvent. It was
then washed with diethyl ether several times (at least three times)
to get pure catalyst for another set of reaction. We have tested for
25 five times to recycle and observed that there is no loss of its
Figure 4: ORTEP diagram of 2-(naphthalen-1-ylmethylene)malononitrile
(3aj) (CCDC No. 937875)
40
activity and selectivity (Figure 2).
CN
Figure 5: ORTEP diagram of ethyl 2-amino-4-(1-cyano-2-ethoxy-2-
oxoethyl)-4H-chromene-3-carboxylate (5ba) (CCDC No 946632)
CN
NH
O
R1
The structure of catalyst is mainly confirmed beyond doubt by
measuring the single crystal X-ray diffraction (SCXRD) as
45 depicted in Figure 3. In case of condensation products, the
confirmations are made by the detailed analysis of 1H, 13C-NMR,
FT-IR and ESI-MS. In some cases, the desired products (as in 3aj
or 5ba) are further confirmed by SCXRD measurements. The
ORTEP diagram obtained from these SCXRD measurements are
50 presented in Figure 4 and 5. Further hexahydroquinolines
synthetic protocol has been chosen to test the wider applicability
of our molecular complex as efficient catalyst.27 We have
successfully obtained the desired product (Table 2, entry 4N-
HHQ) with this molecular complexes at high yield (80%) within
55 15 mins at room temperature (ESI)
H+A-
N
O
H
R1
+HA-
BN
HA
BN
CN
NC
+HA-
BN
HA
CN
BN
BN+
H
NC
N +
B
NC
CN
CN
NH
BN+
H
CN
NC
NC
CN
CN
NH
CN
NH2
O
R1
O
R1
BN+
H
O
R1
Scheme 4: Probable reaction mechanism of 2-Amino-4H-Chromene.
Here, BN represents proton acceptor (i.e., MP) and HA represents proton
30 donor (i.e., NP, DNP and TNP).
Conclusion
In conclusion, we have reported here some simple molecular
complex which can be used as remarkable organo-catalyst for

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Knoevenagel condensation and Michael addition reactions. Even 55 General Procedure for Synthesis of hexahydroquinolines
the insitu generation of these molecular complexes works as
efficiently as in case of separately preparing and adding in the
condensation step. Among all the catalysts, MP(DNP) is found to
be the most efficient catalyst. Moderate and easily available of
The mixture of the aldehydes (1 mmol), dimedone (1 mmol), ethyl
acetoacetate (1 mmol), ammonium acetate (2.5 mmol) and MP(DNP)
containing (5 mol%) as catalyst were stirred at room temperature for the
15 minute in ethanol. After completion of the reaction (monitored by
5
acidic proton of molecular complexes is the key for highly 60 TLC), the ethanol is evaporated and 3 mL of water was added to the
efficient and remarkable catalytic activity in Knoevenegal
condensation. Further, detailed mechanistic studies reveal that the
electrophilicity of the aldehyde and dehydration process are
mixture. Solid product is obtained and washed several times with water
(at least four times). For recycling the catalysts, after washing the solid
products with water completely, the water containing the molecular
complex (MP(DNP) was evaporated under reduced pressure and
10 enhanced in presence of acidic proton of catalyst to make the
reaction feasible at RT. Therefore, a eco-friendly, green (in 65 molecular complex (catalyst, MP(DNP)) was recovered and reused after
addition to low cost) synthetic protocol has been developed for
synthesizing important organic precursors via the Knoevenagal
condensation suing this highly stable catalyst having higher yield
15 and shortest reaction time at room temperature using minimum
washing with diethylether (~three times). The solid product was purified
by recrystallization from ethanol.
Acknowledgements
amount of catalyst (~
5 mol%) without the need of
We thank CSIR (01(2792)/14/EMR-11), New Delhi and HEMRL-DRDO
70 (Pune), Govt. of India, India for research grants and fellowship to SKP.
Department of Chemistry, BHU is also gratefully acknowledged for
providing instrumentations (including SCXRD) and infrastructure
facilities
chromatographic separation. The catalytic activity is not
significantly lost significantly after use of several times. Further
application purpose of above procedure, 2-Amino-4H-Chromene
20 derivatives have been synthesized by Knoevenagel condensation
of salicylic aldehydes with active methylene compounds,
followed by intramolecular cyclization (via Michael addition)
delivering higher yield within shortest reaction time at RT
without any need of chromatographic separation.
75 Notes and References
Department of Chemistry, Faculty of Science, Banaras Hindu University,
Varanasi-221005, India. E-mail: satyen.saha@gmail.com. Fax: +91-542-
2368127; Tel: +91-9935913355
25 Synthesis and Characterization of Catalyst
† Electronic Supplementary Information (ESI) available: Electronic
N-methylpiperidine (1.01 mmol) was taken in 50 ml round bottom flask 80 Supplementary Information (ESI) available: Detailed experimental
containing 5 ml CHCl3 and nitrophenol derivative (1 mmole) was added.
Immediate yellowish coloured liquid was obtained. Resulting yellowish
solution was stirred for 1-3 h at room temperature and was kept in
30 refrigerator. Finally yellow colour crystal was separated out from
solvent.28 (ESI)
procedure, separation techniques, electronic spectra, NMR spectra of all
compounds.
‡
Crystallographic data in CIF and CCDC reference number: 871913
(3aj), and 946632(5ba).
1
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General Procedure for Synthesis of Knoevenegal Product
Substituted aromatic aldehyde 1 (1 mmol) and active methelene 2 (1.01
mmol), 0.05 mmol, of catalyst (MP(DNP)) were taken in a round bottom
35 flask stirred at room temperature for the stipulated period of time (Table
2) till the completion of the reaction (monitored by TLC). After
completion of the reaction, solid precipitated separated out, filtered and
washed with water (3x10 mL) followed by ethanol (3x10 mL), dried in
high vacuum to afford NMR pure product.
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General Procedure for Synthesis of 2ꢀAminoꢀ4HꢀChromene
derivative
Substituted salisaldehyde (1 mmol, 4), malononitrile (2.01 mmol, 2) and
0.05 mmol of catalyst (MP(DNP)) were taken in ethanol solvent at room
45 temperature for stipulated period of time (Table 3) till the completion of
the reaction (monitored by TLC). After completion of the reaction solid
precipitated was separated out which was filtered and washed with water
(3 x 10 mL) followed by ethanol (3 x 10 mL) and dried in high vacuum to
afford NMR pure product.
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50 Note: In case the final product does not separate from the reaction
mixture, cold water need to be added after the completion of the reaction
with vigorous shaking. Solid precipitated then filtered and washed with
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dried in high vacuum to afford NMR pure product.
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