A Simple and straightforward synthesis of cinnamic acids and ylidene malononitriles via knoevenagel condensation employing dabco as catalyst

Article abstract of DOI:10.14233/ajchem.2017.20575

An efficient method for the synthesis of substituted cinnamic acid and ylidene malanonitriles is developed via Knoevenagel condensation of aromatic aldehydes with malonic acid and malononitrile in the presence of catalytic amounts of DABCO. This method has many advantages, such as mild reaction conditions, excellent yields, short reaction times and no furthur purification required.

Full text of DOI:10.14233/ajchem.2017.20575

Asian Journal of Chemistry; Vol. 29, No. 7 (2017), 1561-1564
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2017.20575
A Simple and Straightforward Synthesis of Cinnamic acids and Ylidene
Malononitriles via Knoevenagel Condensation Employing DABCO as Catalyst
1,*
2
3
4
5
K. NAGALAKSHMI , B.S. DIWAKAR , B. GOVINDH , P. GOPAL REDDY , R. VENU ,
1
1
1
1
I. BHARGAVI , T.J. PRASANNA DEVI , Y.L.N. MURTHY and V. SIDDAIAH
1Department of Organic Chemistry, Organic Research Labs, Andhra University, Visakhapatnam-530 003, India
2Department of Engineering Chemsitry, SRKR Engineering College (A), Bhimavaram-534 204, India
3Department of H&S, Raghu Institute of Technology, Visakhapatnam-531 162, India
4Shilpa Medicare Limited, Raichur-584 135, India
5School of Engineering Science & Technology, University of Hyderabad, Hyderabad-500 046, India
*Corresponding author: E-mail: nagalakshmi3083@gmail.com
Received: 8 February 2017;
Accepted: 20 April 2017;
Published online: 13 May 2017;
AJC-18393
An efficient method for the synthesis of substituted cinnamic acid and ylidene malanonitriles is developed via Knoevenagel condensation
of aromatic aldehydes with malonic acid and malononitrile in the presence of catalytic amounts of DABCO. This method has many
advantages, such as mild reaction conditions, excellent yields, short reaction times and no furthur purification required.
Keywords: DABCO, Aromatic aldehydes, Malonic acid, Malononitrile, Knoevenagel condensation.
promoted reaction it takes more time and products are purified
by flash column chromatograph in which the products are
obtained in less yield.
INTRODUCTION
The α,β-unsaturated compounds such as cinnamic acid
and ylidene malanonitriles are important reagents in organic
synthesis both as intermediates and final products. They have
been used to prepare compounds of biological relevance such
as terahydromyricoid [1] or the antibacterial reutericyclin [2].
They are also present in some natural products, such as the
juice secreted by queen honey bee [3]. They are synthesized
on a commercial scale owing to their applications in food
industry, polymer industry, perfume industry and technical
applications. The ylidene malononitriles (α,β-unsaturated
nitriles) are versatile tools for production of a variety of biolo-
gically active new heterocycles [4]. Knoevenagel condensation
(Doebner modification) is one of the leading methods for the
synthesis of α,β-unsaturated carboxylic acids and nitriles from
aromatic aldehydes possessing active methylene group. The
classic Knoevenagel-Doebner reaction has been carried out
using high amounts of basic solvents like pyridine, NaOH,
Et3N, CH3NH2 and KOH.
However, some of these procedures suffer from one or
more limitations such as use of toxic reagents/solvents, need
drastic conditions, use of expensive chemicals and relatively
low yields strongly indicate the demand to develop convenient
methods for classic Knoevenagel-Doebner reaction. In order
to overcome these disadvantages, we used DABCO as catalyst
for Knoevenagel condensation of aromatic aldehydes posse-
ssing active methylene group.
DABCO is a diazabicyclic molecule with medium-
hindrance and is being widely used in organic synthesis and
can serve as a weak base and ligand. DABCO has received
considerable attention as an inexpensive, eco-friendly, high
reactive, easy to handle and non-toxic base catalyst for various
organic transformations affording the corresponding products
in excellent yields with high selectivity [9].
DABCO and its analogues show high efficiency in Morita-
Baylis-Hillman reactions [10]as well as cyanation of ketones
[11]. It has also been employed as a catalyst for the substitution
of chloropurine with alcohols [12], isothiocynation of amines,
isoxazoline derivatives from activated primary nitro compounds
and tertiary diamines, synthesis of naphthopyrans. Recently
DABCO was used in addition of selenosulfonates to α,β-
unsaturated ketones and in Sonogashira coupling reaction [13].
The excess amounts of these solvents damage the chemicals
employed in the reaction due to their volatile nature and they
are also environmentally hazardous [5]. A range of various
catalysts have been used for this reaction such as ammonia,
primary and secondary amines, Lewis acids, surfactants and
ionic liquids [6]. In case of ultrasound [7] and microwave [8]

1562 Nagalakshmi et al.
EXPERIMENTAL
Asian J. Chem.
RESULTS AND DISCUSSION
All chemicals were purchased from Merck or Sigma-
Aldrich.All compounds were identified by comparison of their
melting points and spectral data with those reported in the
literature. Mp: Buchi-530 capillary apparatus; open capillary
method and are uncorrected. IR spectra: Shimadzu IR-Affinity
In present work, we reported amild and efficient method
for Knoevenagel condensation of aromatic aldehydes with
active methylene compounds catalyzed by DABCO. Using
malonic acid and malononitriles as substrates, the reaction
resulted the formation of substituted trans-cinnamic acids
(Scheme-I) and ylidene malononitriles (Scheme-II), respectively.
1
spectrometer, KBr disks; νmax, cm-1. H NMR & 13C NMR
spectra: Bruker Advance DPX 300 MHz; at 300 (1H) and 75
(13C) spectrometer in CDCl3; DMSO-d6; CD6CO; δ in ppm,
TMS as internal standard, J in Hz. Data reported in coupling
constant(s) in Hertz, integration assignment]. ESI-MS: JEOL
SX 102/DA-6000 mass spectrometer; in m/z.
O
O
CHO
OH
OH
DABCO (2equiv)
OH
R
R
DMF, 100-1100C
60-90 min
O
A
1-14
1a-14a
Scheme-I: DABCO-catalyzed synthesis of cinnamic acids
Preparation of cinnamic acids: To aromatic aldehyde
(500 mg, 1.0 equiv) and malonic acid (981 mg, 2.0 equiv)
was added DABCO (105 mg, 2 equiv) in dimethyl formamide
(5 mL) and the reaction mixture was stirred at 100-110 °C for
60-90 min.After completion of the reaction (TLC monitoring),
reaction mixture was poured in water and then extracted with
ethyl acetate. Crude product was recrystallized from chloro-
form/hexane system to provide cinnamic acids in good yield.
Preparation of ylidene malononitriles: To the aromatic
aldehyde (500 mg, 1.0 equiv) and malononitrile (291 mg, 1.2
equiv) was added DABCO (105 mg, 2 equiv) in DMF (5 mL)
and the reaction mixture was stirred at room temperature for
45-60 min. After completion of the reaction (TLC monitoring)
the reaction mixture was poured in water and then extracted
with ethyl acetate. Crude product was recrystallized from
chloroform/hexane system to provide ylidene malanonitriles
in good yield.
CHO
CN
DABCO (2equiv)
CN
CN
R
R
CN
DMF, rt
45-60 min
15-19
B
15a-19a
Scheme-II: DABCO-catalyzed synthesis of ylidene malanonitriles
Our preliminary studies were focused on the reaction
conditions for the synthesis of trans-cinnamic acids and ylidene
malanonitriles. In case of malonic acid the reaction performed
at room temperature took 22-24 h for the completion of the
reaction. Whereas, at refluxing conditions it took only 60-90
min for the completion of the reaction (Table-1). These results
were monitored by TLC and complete disappearance of starting
material was observed. In case of malononitrile stirring at room
temperature gave the desired products within 45-60 min, which
was also monitored by TLC and complete disappearance of
starting material was observed (Table-2).
TABLE-1
KNOEVENAGEL CONDENSATION OF SUBSTITUTED AROMATIC ALDEHYDES WITH MALONIC ACID PROMOTED BY DABCO
Entry
Substrate
Product
Time (min)
Yield (%)
O
CH O
OH
1
80
95
1
2
3
4
1a
2a
3a
4a
O
O
O
CHO
OH
2
3
4
75
80
80
93
98
97
F
F
CHO
CH O
OH
OH
Cl
Br
Cl
Br
O
CHO
OH
5
70
98
NO
2
NO
2
5
5a

Vol. 29, No. 7 (2017)
Entry
Synthesis of Cinnamic acids and Ylidene Malononitriles via Knoevenagel Condensation 1563
Substrate
Product
Time (min)
Yield (%)
O
CHO
OH
6
75
95
H C
3
H3C
6
6a
O
CHO
OH
7
8
90
70
85
96
HO
HO
7
8
7a
8a
O
CHO
OH
H
CO
3
H3CO
O
CHO
OH
H CO
9
75
78
80
96
91
92
3
H3 CO
OCH
3
OCH3
9
9a
OCH
3
OCH3
O
CHO
OH
O
10
11
OCH3
OCH
3
10a
10
CHO
OCH
OH
H CO
3
3
H CO
OCH
3
3
OCH
3
OCH
3
11
11a
OCH
3
OCH3
O
CHO
OCH
OH
12
78
92
H3CO
OCH3
OCH3
H CO
3
3
OCH
3
12a
12
NO
2
NO2
O
CHO
OH
13
14
82
76
94
96
H CO
H3CO
3
OCH3
OCH
3
13a
13
OH
CHO
O
O
O
14
14a
To choose the appropriate solvent for the reaction, we exa-
mined the condensation of benzaldehyde (entry 1) with malonic
acid (A) or malononitrile (B) in the presence of DABCO in
different solvents such as dioxane, tetrahydrofuran, acetonitrile
and DMF. It was observed that the high yield of products was
obtained at lower reaction times in DMF solvent than in other
solvents. On the basis of these results we confirm that DMF
solvent is the best solvent for the Knoevenagel-Doebner reaction
catalyzed by DABCO. These results are presented in Table-3.
Conclusion
We have demonstrated a practical application of DABCO
catalyzed Knoevenagel condensation reactions, in which even
hydroxy aldehydes can undergo the desired condensation with
nearly quantitative yield. In addition, the notable advantages
of this procedure are: (a) no need of neutralization; (b) no
need of further purification. The reactions are conducted under
mild conditions to afford substituted cinnamic acids and
ylidene malanonitriles in good to excellent yields.

1564 Nagalakshmi et al.
Asian J. Chem.
TABLE-2
KNOEVENAGEL CONDENSATION OF SUBSTITUTED AROMATIC ALDEHYDES WITH MALONONITRILES PROMOTED BY DABCO
Entry
Substrate
Product
Time (min)
Yield (%)
CH O
CN
CN
CN
CN
1
60
96
F
F
15a
15
16
CN
CN
CHO
CHO
2
3
4
46
55
50
45
95
96
86
96
Cl
Br
Cl
Br
16a
17a
18
17a
CHO
CHO
CN
CN
HO
HO
18a
19a
CN
CN
5
H3CO
H3CO
19
aisolated product
2. U. Marquardt, D. Schmid and G. Jung, Synlett, 8, 1131 (2000);
https://doi.org/10.1055/s-002-411.
3. R.K. Callow and N.C. Johnston, Bee World, 41, 152 (1960);
https://doi.org/10.1080/0005772X.1960.11096785.
4. T. Sasaki, K. Minamoto, T. Suzuki and S. Yamashita, Tetrahedron, 36,
865 (1980);
https://doi.org/10.1016/0040-4020(80)80036-6.
5. Y. Peng and G. Song, Green Chem., 5, 704 (2003);
https://doi.org/10.1039/B310388A.
6. E. knovenagel, Ber., 31, 2596 and 2619 (1898).
https://doi.org/10.1002/cber.18980310308.
7. J. Mc Nulty, J.A. Steere and S. Wolf, Tetrahedron Lett., 39, 8013 (1998);
https://doi.org/10.1016/S0040-4039(98)01789-4.
8. P.S. Kwon, Y.M. Kim, C.J. Kang, T.W. Kwon, S.-K. Chung and Y.-T.
Chang, Synth. Commun., 27, 4091 (1997);
https://doi.org/10.1080/00397919708005456.
9. Y. Peng and G. Song, Green Chem., 5, 704 (2003);
https://doi.org/10.1039/B310388A.
TABLE-3
SOLVENT EFFECTS ON KNOEVENAGEL CONDENSATION
OF AROMATIC ALDEHYDES WITH ACTIVE METHYLENE
COMPOUNDS CATALYZED BY DABCO
trans-Cinnamic acids Ylidene malononitriles
Entry
Solvent
Time (h) Yield (%) Time (h) Yield (%)
1
2
3
4
Dioxane
THF
CH3CN
DMF
3.00
3.00
3.00
1.33
92
89
86
97
1.00
1.20
1.00
0.45
90
85
90
92
ACKNOWLEDGEMENTS
The authors are thankful to Council of Scientific & Industrial
Research (02 (0197)/14/EMR-II), New Delhi, India for its financial
support. The authors also like to acknowledge DST (Department
of Science and Technology), India in the form of INSPIRE
Faculty award, (IFA13-ENG-70) and India-Korea joint project
(INT/Korea/P-27).
10. S.-K. Tian, R. Hong and L. Deng, J. Am. Chem. Soc., 125, 9900 (2003);
https://doi.org/10.1021/ja036222p.
11. D. Basavaiah,A.J. Rao andT. Satyanarayana, Chem. Rev., 103, 811 (2003);
https://doi.org/10.1021/cr010043d.
12. S.K. Tian, R. Hong and L. Deng, J. Am. Chem. Soc., 125, 9900 (2003);
https://doi.org/10.1021/ja036222p.
13. J.A. Linn, E.W. McLean and J.L. Kelley, J. Chem. Soc. Chem. Commun.,
913 (1994);
REFERENCES
1. J. Song and M. Hesse, Tetrahedron, 49, 6797 (1993);
https://doi.org/10.1039/C39940000913.
https://doi.org/10.1016/S0040-4020(01)80423-3.