The Knoevenagel condensation using quinine as an organocatalyst under solvent-free conditions

Article abstract of DOI:10.1039/c8nj04219e

The Knoevenagel condensation between active methylene compounds and aromatic carobonyl compounds has been developed using quinine as an organocatalyst to afford various electrophilic alkenes in excellent yields (up to 90%). In the presence of a catalytic amount of quinine (15 mol%), the reaction proceeded at room temperature (RT) under solvent-free conditions. In this green approach, the organocatalyst was recovered and recycled for up to four cycles without appreciable loss of activity.

Full text of DOI:10.1039/c8nj04219e

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The Knoevenagel condensation using quinine as
an organocatalyst under solvent-free conditions†
Cite this: New J. Chem., 2019,
43, 1299
Kavita Jain,a Saikat Chaudhuri,b Kuntal Palc and Kalpataru Das
*
a
The Knoevenagel condensation between active methylene compounds and aromatic carobonyl compounds
has been developed using quinine as an organocatalyst to afford various electrophilic alkenes in excellent
yields (up to 90%). In the presence of a catalytic amount of quinine (15 mol%), the reaction proceeded at
room temperature (RT) under solvent-free conditions. In this green approach, the organocatalyst was
recovered and recycled for up to four cycles without appreciable loss of activity.
Received 17th August 2018,
Accepted 6th November 2018
DOI: 10.1039/c8nj04219e
rsc.li/njc
Introduction
The Knoevenagel condensation is one of the most powerful
reactions for the synthesis of substituted electrophilic alkenes
via C–C bond formation.1 The electrophilic alkenes are versatile
intermediates in organic synthesis and have widespread appli-
cations for the synthesis of various important organic compounds,
viz polymers, natural products, fine chemicals, fluorescent dyes
etc.2–4 Moreover, substituted alkenes themselves act as inhibitors
of various enzymes5 and they display a range of biological
activities,6–10 including anticancer, antitumor, antioxident, anti-
malarial, and antiviral activities. Additionally, substituted electro-
philic alkenes are valuable building blocks for the synthesis of
important drugs.11–14 Some representative commercially available
drugs are shown in Fig. 1.
Due to the enormous range of applications of electrophilic
alkenes as Knoevenagel condensation products, the development
of new and efficient methods for Knoevenagel condensation is a
topic of significant research interest. A variety of synthetic
Fig. 1 Representative commercially available drugs derived using the
Knoevenagel condensation.
methods have been developed using different kinds of catalysts such as the use of expensive metal complexes, additives, high
such as organocatalysts,15 ionic liquids16 and metal based boiling solvents, high temperatures, limited substrate scopes
catalysts including Lewis acids,17 MOFs,18 and nanocatalysts.19 and long reaction times. Furthermore, some reported methods
However, most of these methods have one or several drawbacks suffer from other serious disadvantages due to the formation of
undesirable side products and waste caused by self-condensation,
polymerization and addition reactions.20
Accordingly, it is desirable to develop novel and efficient
methods for Knoevenagel condensation by following the green
a Department of Chemistry, School of Chemical Sciences and Technology,
Dr Harisingh Gour University, Sagar, Madhya Pradesh 470 003, India.
E-mail: dkalpataru@gmail.com, kdas@dhsgsu.ac.in; Tel: +91-7582-265265
b Department of Chemistry, Indian Institute of Science Education and Research
(IISER) Bhopal, Bhopal Bypass Road, Bhopal, Madhya Pradesh 462 066, India
c Department of Chemistry, University of Calcutta, 92 APC Road, Kolkata 700 009,
India
chemistry principles, which can reduce the environmental
impact and cost of the chemical processes. In this research
direction, natural and biodegradable catalyst systems have been
attracting more attention in recent years. Calvino-Casilda and
co-workers reported attractive natural biocompatible and less
toxic cholinium-based amino acid ionic liquids [Ch][AA] ILs as a
green catalyst system for Knoevenagel condensation reactions.21
† Electronic supplementary information (ESI) available: The general experi-
mental section and spectroscopic data (copies of 1H, 13C and GC-MS). CCDC
1854216. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c8nj04219e
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Table 1 Optimization of reaction conditionsa
The physicochemical properties of these cholium-based amino
acid ionic liquids (AAILs) have been extensively studied by Tao
et al.22 and AAILs were exploited for designing various chemical
applications such as CO2 absorption and green catalysis.23 Very
recently, using 1,4-diazabicyclo[2,2,2]octane (DABCO), a recycl-
able composite catalyst system [HyEtPy]Cl-H2O-DABCO was
developed by Zhao et al. for the preparation of multifunctional
Knoevenagel condensation products.24 In continuation of our
research study towards the development of green chemical
transformation, and the synthesis of organofluorine compounds,25
we envisioned that a naturally occurring cinchona alkaloid such as
quinine could be a promising organocatalyst for the Knoevenagel
condensation reaction. Although the chirality of quinine has no role
in the Knoevenagel condensation, nevertheless, quinine is easily
available, and it could be a recoverable and recyclable catalyst for
the present reaction. In the past decade, quinine and its derivatives
have been used as efficient organocatalysts in various chemical
transformations.26 Compared to metal catalyzed reactions, organo-
catalytic reactions have attracted great interest in organic synthesis
in terms of their environmental and economical benefit.27 In this
paper, we report an efficient and green method for the syntheses of
a wide range of substituted electrophilic alkenes using quinine as
an organocatalyst at room temperature (RT) under solvent-free
conditions. In this approach, recoverability and recyclability of the
catalyst were also demonstrated.
Entry
Catalyst 3
Mol%
Solvent
Time (min)
Yieldb (%)
c
1
2
3
4
S
6
7
8
None
3a
3a
3a
3b
3b
3c
3d
3e
3f
3g
3h
3a
3a
3a
—
10
15
20
10
15
15
15
15
15
15
15
15
15
15
—
—
—
—
—
—
—
—
—
—
—
—
EtOH
CH2Cl2
Et2O
—
180
30
30
360
90
—
79
97
96
80
91
90
47
44
53
70
80
81
76
69
90
360
360
30
30
30
30
30
30
9
10
11
12
13d
14d
15d
a
Unless otherwise specified, the reaction was carried out with 1a
(1.0 mmol), 2a (1.0 mmol), and catalyst (0.15 mmol) under solvent-
free conditions at r.t. Yield of 4a was determined by 1H NMR analysis.
b
c
d
No reaction. 2.0 mL of solvent was used.
Results and discussion
To demonstrate our hypothesis, we initially tested the efficiency
of quinine 3a as an organocatalyst in the Knoevenagel con-
densation reaction of commercially available ethyl cyanoacetate
1a and benzylaldehyde 2a. It was observed that the reaction
does not proceed in the absence of catalyst at RT under solvent-
free condition (Table 1, entry 1). But, when the reaction was
performed using 10 mol% catalyst 3a at room temperature under
solvent-free conditions, the reaction was very clean and the
desired electrophilic olefin ethyl (E)-2-cyano-3-phenylacrylate 4a
was obtained as the Knoevenagel condensation product (Table 1,
entry 2) without producing any by-product, as observed from the
1H NMR spectrum of the crude reaction mixture.
Fig. 2 Organocatalysts for Knoevenagel condensation.
decreased when 15 mol% cinchonidine 3b was used as catalyst
To optimize the reaction conditions, we performed a series and 91% yield of 4a was obtained after 90 min (Table 1, entry 6).
of reactions by varying reaction time, different cinchonidine A very similar result was obtained when cinchonine 3c was used
based catalysts, organic bases as catalysts (Fig. 2), amount of as the organocatalyst (Table 1, entry 7).
catalyst loading and solvent systems. When the amount of
The lower reactivity of cinchonidine 3b (pKa1 = 8.19) and its
catalyst loading was increased to 15 mol%, to our delight, the isomer cinchonine 3c (pKa1 = 8.54) was due to the lower basicity
reaction was found to be completed within 30 min and the yield as compared to that of quinine 3a (pKa1 = 9.67). We next
of the product improved to 97% (Table 1, entry 3). However, it examined the reaction using N-protected and N,O-protected
was observed that a higher catalyst loading did not improve the cinchonidines 3d and 3e, respectively, as organocatalyst systems.
yield of the product (Table 1, entry 4). Encouraged by these It was interesting to note that the rate of reaction decreased
results, we then examined various cinchonidine based catalysts considerably when N-protected catalyst 3d was used at RT under
3a–e to investigate their role and efficiency in the Knoevenagel solvent-free conditions (Table 1, entry 8). In this case, the tertiary
condensation reaction. At the same time, we determined the pKa amine quinuclidine nitrogen of 3d is protected and thus the
values of different catalysts in dimethyl sulfoxide (see the ESI†) basicity of the catalyst is certainly lower (pKa = 4.58) as compared
to understand their basicities and to compare their efficacy in to that of the unprotected catalyst 3a–c (see the ESI†). Similarly, a
the present reaction. It was noted that the rate of reaction decrease in the rate of condensation reaction was also observed
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Table
2
Substrate scope of the quinine catalyzed Knoevenagel
when the reaction was carried out using N,O-protected catalyst 3e
(Table 1, entry 9). The organic bases such as triethyl amine 3f
condensationa,b
(pKa = 9.0), piperidine 3g (pKa = 10.9), and DABCO 3h (pKa1
=
8.9)28 were also used as organocatalysts under the same reaction
conditions and found to be less efficient catalysts (Table 1,
entries 10, 11, and 12) compared to catalysts 3a–c in the present
reaction. During optimization of the reaction, it was noticeable
that the cinchonidine based organocatalysts 3a–c are much more
effective catalysts compared to the other organocatalysts 3f–h, as
shown in Fig. 2. Because cinchonidine based catalysts act as a
bifunctional catalyst,29 they simultaneously activate both reacting
partners 1a and 2a to provide the Knoevenagel condensation
product 4a faster. Moreover, the results shown in Table 1 indicate
that quinine 3a was the best organocatalyst for the Knoevenagel
condensation. This is presumably due to the higher basicity of
catalyst 3a compared to the other cinchonidine based catalysts
(Fig. 2), as observed from their pKa values (see the ESI†) and
catalyst 3a also acts as a bifunctional catalyst. Further, we screened
different solvents for the Knoevenagel condensation using quinine
3a as the organocatalyst to set the optimum reaction conditions.
When the reaction was carried out in polar protic solvent like
ethanol at RT, a decrease in the yield (81%) of the condensation
product 4a was observed (Table 1, entry 13). A further decrease in
the yield was observed when the reaction was carried out in aprotic
solvents such as dichloromethane and diethyl ether (Table 1, entries
14 and 15). After screening of various reaction conditions, it was
revealed that under solvent-free conditions, 15 mol% quinine 3a is
required to give the best results at ambient temperature. Thus, we
set the optimum reaction conditions for the organocatalytic
Knoevenagel reaction using quinine as the natural organocatalyst.
In order to generalize our methodology, we next examined
the scope and limitations of the organocatalytic Knoevenagel
condensation under the optimized reaction conditions. In the
present study, a series of aromatic aldehydes 2 underwent
organocatalytic Knoevenagel condensation efficiently with ethyl
cyanoacetate and afforded the corresponding products 4 in
good to excellent isolated yields (up to 90%). The aldehyde
containing electron withdrawing groups reacted faster with
respect to aldehyde having electron donating groups under the
a
Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), and catalyst 3a
b
(0.15 mmol) under solvent-free conditions at r.t. Yield of isolated
products by column chromatography. A few drops of diethyl ether
were added to a make slurry.
c
optimized conditions. The results are summarized in Table 2. It respectively. The results are summarized in Table 3. Under the
was noted that various electrophilic olefins (4j–o) were obtained optimized conditions, we also attempted the reaction with hetero-
within a short period of time (10–20 minutes) under the same cyclic aldehydes such as pyrrole-2-carboxaldehyde and indole-3-
reaction conditions (Table 2) when malononitrile was used as an carboxaldehyde to afford the corresponding olefins 4t and 4u,
active methylene compound.
respectively. Further, we investigated the efficiency of our method-
The greater reactivity of malononitrile in the Knoevenagel ology with aromatic ketones. It was noted that under our reaction
condensation was attributed to the comparatively higher acidity conditions, aromatic ketones such as acetophenone and benzo-
(pKa = 11.1 in DMSO) as compared to that of ethyl cyanoacetate phenone reacted with malononitrile, however, with relatively
(pKa = 13.1 in DMSO).28 However, electron rich and highly slower reaction rates, and yielded the corresponding Knoevenagel
substituted 3,4,5-trimethoxy benzaldehyde and 4-hydroxy-3- products 4v and 4w, respectively, as shown in Table 3.
methoxybenzaldehyde took a slightly longer time for completion
On the other hand, under the optimized reaction conditions,
of the reaction with malononitrile to afford the corresponding salicyldehyde reacted with ethyl cyanoacetate and afforded the
products 4p and 4q, respectively. Further, we explored a wider cyclic product ethyl 2-imino-2H-chromene-3-carboxylate 5 via
substrate scope under our optimized conditions, and we the Knoevenagel condensation reaction (Scheme 1).
observed that 2-phenyl acetaldehyde and cinnamaldehyde under-
The structure of 5 was determined and confirmed by IR, 1H and
went the condensation reaction smoothly with ethyl cyanoacetate 13C NMR, DEPT, and mass spectrometric data. All the synthesized
and afforded the electrophilic alkene 4r and conjugated alkene 4s, compounds were fully characterized by IR, 1H and 13C NMR
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Table 3 Wider substrate scope for the Knoevenagel condensation under
optimized reaction conditionsa,b
a simple commercially available and natural organic molecule,
which is recoverable and recyclable.
Next, we studied the recyclability of quinine 3a as the
organocatalyst in the Knoevenagel condensation between ethyl
cyanoacetate and benzaldehyde. After completion of the reaction,
the crude reaction mixture was directly subjected to flash column
chromatographic purification. Initially, the condensation product
4a was isolated as a pure product using ethyl acetate in hexane
(hexane : ethyl acetate = 49 : 1) as the solvent system. After complete
removal of the condensation product, the same column was eluted
successively using ethyl acetate and methanol in ethyl acetate as
eluents. The catalyst 3a was isolated using methanol in ethyl
acetate (ethtyl acetate : methanol = 9 : 1). The solvent was evaporated
and the catalyst was dried under vacuum to recover the pure
organocatalyst 3a. The purity of the catalyst was confirmed by
GC-MS analysis (see the ESI†).
a
Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), and catalyst 3a
b
(0.15 mmol) under solvent-free conditions at r.t. Yield of isolated
products by column chromatography. A few drops of diethyl ether
were added to make a slurry.
c
The reusability of the catalyst was tested by doing the
condensation reaction repeatedly under the optimized reaction
conditions. The catalyst was recovered after each cycle and reused
in the subsequent cycle. The organocatalyst quinine 3a was found
to be very stable under our reaction conditions. We performed up
to four reaction cycles and observed no significant loss of catalytic
efficiency (Fig. 4). Based on the experimental results and literature
reports,29 a plausible mechanism for the quinine catalysed
Scheme 1 Synthesis of coumarin derivatives via Knoevenagel reaction.
spectroscopic data and mass spectrometric data. Further, to con- Knoevenagel condensation reaction is illustrated in Scheme 2.
firm the geometry of the synthesized electrophilic alkenes, the Initially, the deprotonation of 1a by the tertiary amine
product 4a was recrystallized from ethyl acetate in hexane (hexane : quinuclidine nitrogen of the catalyst 3a takes place, leading
ethyl acetate = 19 : 1) as the solvent system. The crystallized to the formation of an ion pair intermediate 6. The reactive
product was then analyzed by single crystal X-ray diffraction and binary complex 6 then reacts with benzaldehyde through inter-
the E-geometry of 4a was unambiguously confirmed, as shown in molecular hydrogen bonding to provide a ternary complex 7.
Fig. 3. The details of the crystallographic analysis are given in the The formation of complex 7 via a bifunctional mode of catalysis
ESI.† When we attempted to perform the condensation reaction of 3a enhances the electrophilicity of benzaldehyde and thus
between diethyl malonate and benzaldehyde, the reaction did not facilitates the generation of intermediate 8 through C–C bond
proceed under the optimized conditions. The low reactivity is formation. The intermediate 8 subsequently undergoes proton
probably due to the low acidity (pKa = 16.4) of diethyl malonate exchange, deprotonation and dehydration, affording the con-
compared to malononitrile and ethyl cyanoacetate.28 However, densation product 4a and regenerating the active catalyst quinine
under our optimized reaction conditions, a variety of aldehydes 3a. The relatively very slow reaction rate observed in the case of
and ketones underwent Knoevenagel condensation with ethyl N-protected and N,O-protected catalysts 3d and 3e, respectively,
cyanoacetate and malononitrile to afford a range of electrophilic was because of the low basicities of these N-protected catalysts and
olefins (Tables 2 and 3).
no such bifunctional catalysis operating with catalyst 3e.
Compared to reported methods under organocatalytic
Finally, the synthetic significance of this methodology was
conditions,15c–f our method has several advantages such as demonstrated by synthesizing a valuable intermediate 11, which
the reaction proceeding at RT within a short period of time has been used as a precursor for the synthesis of trimethoprim,
and without the need of solvent, any additives, promoter or an antibiotic. The Knoevenagel condensation product 4i was
activators. Moreover, the catalyst used in the present reaction is easily converted to 11 by chemoselective reduction with NaBH4,
Fig. 3 Crystal structure of compound 4a (CCDC 1854216†).
Fig. 4 Recyclability of catalyst 3a.
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bottom flask equipped with a magnetic stirrer bar. Then,
quinine 3a (0.15 mmol) was added and the reaction mixture
was stirred at room temperature under solvent-free conditions
until the complete consumption of the substrates, as indicated
by TLC. The crude product was directly purified by flash
column chromatography over silica gel (230–400 mesh) using
ethyl acetate in hexane (hexane : ethyl acetate = 49 : 1) as the
eluent to afford the pure product 4a in 90% yield (181 mg) as a
white solid. Spectral data for ethyl (E)-2-cyano-3-phenylacrylate
(4a): IR nmax (KBr, cmÀ1): 2980, 2223, 1726, 1608, 1445, 1262,
1205, 1095, 768; 1H NMR (500 MHz, CDCl3): d 8.25 (s, 1H), 7.99
(d, J = 7.0 Hz, 2H), 7.57–7.49 (m, 3H), 4.39 (q, J = 7.0 Hz, 2H),
1.40 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3): d 162.6,
155.2, 133.4, 131.6, 131.2, 129.4, 115.6, 103.2, 62.9, 14.3; HRMS
(EI+): m/z calcd. for C12H11NO2 (M+): 201.0790; found: 201.0698.
Note: all reactions of Tables 2 and 3 were performed according
to this general experimental procedure.
Scheme 2 Plausible mechanism for the quinine catalyzed Knoevenagel
condensation.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
KD and KP are grateful to the Science and Engineering Research
Board (SERB), Govt. of India for a research grants EMR/2017/000234
and YSS/2015/000365, respectively. We thank the Department of
Chemistry, Sophisticated Instrumentation Center, Dr Harisingh
Gour University, Sagar, IISER Bhopal and IIT Kanpur for recording
spectral data and HRMS of our compounds. We are thankful to
SAIF, IIEST Shibpur for recording the crystal data. KJ is thankful to
UGC for the award of a MANF research fellowship.
Scheme 3 Synthetic application of a Knoevenagel condensation product.
as shown in Scheme 3. Compared to earlier methods, this
method offers a very simple and convenient procedure for the
synthesis of compound 11.12b,c
Conclusions
In conclusion, we have demonstrated, for the first time, quinine
as an efficient organocatalyst for the synthesis of a wide range of
electrophilic alkenes in high yields by Knoevenagel condensation.
The described procedure has several advantages, such as mild
reaction conditions, short reaction time, proceeding at room tem-
perature and under solvent-free conditions with excellent conversion.
Moreover, the organocatalyst used in this procedure is commercially
available and is recoverable and recyclable. All of these features make
this methodology attractive and useful for the synthesis of electro-
philic alkenes. A plausible mechanism of the Knoevenagel conden-
sation catalyzed by quinine is provided. In addition, a synthesized
olefin was utilized for the preparation of a valuable precursor
required for the synthesis of an antibiotic, trimethoprim. Further
applications of electrophilic olefins and the development of one-pot
sequential reactions are in progress in our laboratory.
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