A simple method for knoevenagel condensation of α,β-conjugated and aromatic aldehydes with barbituric acid

Article abstract of DOI:10.1002/jhet.5570380318

Several aromatic and α,β-conjugated aromatic aldehydes were condensed with barbituric acid in methanol solution in the absence of acid or base as a catalyst, affording 5-ylidenebarbituric acid derivatives in almost quantitative yields.

Full text of DOI:10.1002/jhet.5570380318

May-Jun 2001
A Simple Method for Knoevenagel Condensation of
α,β-Conjugated and Aromatic Aldehydes with Barbituric Acid
Branko S. Jursic
655
Department of Chemistry, University of New Orleans, New Orleans, Louisiana 70148
Received June 26, 2000
Several aromatic and α,β-conjugated aromatic aldehydes were condensed with barbituric acid in
methanol solution in the absence of acid or base as a catalyst, affording 5-ylidenebarbituric acid derivatives
in almost quantitative yields.
J. Heterocyclic Chem., 38, 655 (2001).
The derivatives of barbituric acid have a special place in
pharmaceutical chemistry. Their biological activities range
from classical applications in medical treatments as hypnotic,
sedative, and anesthetic drugs [1] to the more recent reports
indicating that they have applications in anti-tumor [2], anti-
cancer [3], and anti-osteoporosis [4] treatments.
The α,β-conjugated aromatic aldehydes, such as trans-
cinnamaldehyde and trans-3-(2-furyl)acrolein, produce a
solid precipitate (product) after several minutes. This is
also true for electron rich aromatic aldehydes, such as
4-dimethylaminobenzaldehyde, hydroxybenzaldehyde,
and indole-3-carbaldehyde. In these cases, the reaction is
practically over in several minutes. The product has a very
low solubility in cold methanol. Separation of the product
from traces of both reactants involves a simple filtration of
the reaction mixture followed by washing the crystals with
Barbituric acid is a strong acid, having a pK = 4.01 in
a
water. It is partially soluble in solvents such as water and
methanol in which barbituric acid continue to have strong
acidic properties [5]. Barbituric acid also has an "active"
methylene group and can be involved in condensation
reactions with aldehydes or ketones that do not contain an
α-hydrogen. The general type of this reaction is usually called
the Knoevenagel condensation [6]. The reaction of barbituric
acid with carbonyl compounds was studied as early as 1864.
The isolated products contain mono- as well as di-substituted
condensation products [7]. The target of every synthetic
chemist is to develop a simple procedure that produces the
quantitative formation of one product. To achieve formation
of only one (mono) condensation product between aromatic
aldehydes and barbituric acid, various acid and base catalyzed
reactions were used [8-14]. There are some very interesting
approaches to obtain high yields in this condensation. For
instance, Villemin and Labiad microwaved a mixture of
barbituric acid, aromatic aldehyde, and clay (Montmorillonite
KSF) without solvent [10]. The product was obtained in high
yield after the DMF extraction from the solid reaction
mixture. Another interesting approach also performs
condensation in the solid state with another clay (Tonsil
Actisil FF) and infrared irradiation [15,16].
Table
Knoevenagel Reaction Between Various Aromatic and
Conjugated Aromatic Aldehydes with Barbituric Acid
Here we would like to present an exceptionally simple
procedure for performing the Knoevenagel condensation
between aromatic and α,β-conjugated aromatic aldehydes
with barbituric acid in a methanol solution. Some selected
products of this condensation are presented in the Scheme.
First of all, the reaction is performed without a base or acid
catalyst, excluding the auto-catalyst of the barbituric acid
alone. The procedure involves mixing an aldehyde with a
barbituric acid in a sufficient amount of methanol to
dissolve both of the reactants. Regarding the reactivity of
the applied aldehyde, the reaction mixture is left to stir at
room temperature for few hours or as long as five days.
The completion of the reaction determines the way in
which the product is isolated.
Aldehyde
R
n
Procedure Product Yield (%) [a,b]
1a
1b
1c
1d
1e
1f
3
H
H
0
2
0
2
0
2
B
A
A
A
A
A
B
B
A
A
2a
2b
2c
2d
2e
2f
7
8
9
10
85
95
98
99
95
98
83
81
96
97
p-(CH ) N
p-(CH ) N
3 2
3 2
p-OH
p-OH
4
5
6
1
13
[a] Isolated yields; [b]All products have identical H and C nmr spectra
as authentic samples reported elsewhere [9-16].

656
B. S. Jursic
Vol. 38
cold methanol (Method A). In this case, isolated yields of
the Knoevenagel product of the condensation are close to
quantitative (Table) and the purity is over 99%. All the
products of the condensation with barbituric acid are
thermally sensitive. They all decompose in the course of
melting point determination with decomposition at or over
260 ºC. They are even more thermally sensitive in
solution. Therefore, their purification by hot crystallization
is not advisable.
To obtain 90% conversion for less reactive aromatic
aldehydes, several days stirring of the reaction mixture
at room temperature is required [17]. Even if a solid
precipitates from the reaction mixture, it contains a
mixture of both starting materials. As mentioned above,
crystallization of the product from high temperature
solvent diminishes the isolation yield considerably.
Purification of the product through room temperature
crystallization using solvents such as ethyl acetate or
petroleum ether slightly improves the purity of the
product in regard to the aldehyde, but barbituric acid is
hard to separate in this way. The purification procedure
must be repeated several times, and yields of the
condensation product are modest. The best purification
procedure involves evaporation of methanol at reduced
pressure and room temperature to a solid residue
(Method B). To eliminate barbituric acid, water was
added to the solid residue and after stirring at room
temperature the remaining solid was separated by
filtration. To eliminate the starting aldehyde, the solid
was slurred in ether and the resulting suspension was
stirred at room temperature for several minutes. After
filtration, the crystalline material contains only product
of the Knoevenagel condensation (Table).
Unfortunately, as simple as this reaction is, it is only
applicable to aromatic aldehydes and α,β-conjugated
aromatic aldehydes. Our attempt to use aliphatic
aldehydes, such as hexanal, to obtain the corresponding
barbituric condensation product was not synthetically
successful. Following the reaction by nmr spectroscopy in
methanol-d (CD OD) as a solvent it is possible to
3
4
observe the formation of around 5-10% of the condensa-
tion product [18]. The reaction conversion stays at that
level after several days [19]. If the reaction is carried out
for a long time, a trace of other products, such as products
of an Aldol condensation was formed. This is also the case
when the reaction with ketones was performed. For
instance, when acetophenone was used as a source of
carbonyl compound it was not possible to detect even a
trace of the product in the reaction mixture.
In conclusion, we have described an exceptionally
simple room temperature Knoevenagel condensation
between aromatic and α,β-conjugated aromatic aldehydes
with barbituric acid in methanol without a catalyst. The
yield of the condensation is very high and depends on the
nature of the aldehyde used. Benzaldehydes with extended
conjugation, or with electron-donating substituents will

May-Jun 2001
A Simple Method for Knoevenagel Condensation
657
-1 1
give the desired product with almost quantitative yields,
while benzaldehydes with electron-withdrawing
substituents will give little or no product at all. All the
reaction manipulations (reaction, separation of the
product, and purification of the product) were performed at
room temperature. In this way, the decomposition of the
thermally sensitive Knoevenagel barbituric acid product is
avoided.
1560-1530 cm ; H nmr: δ 11.35 (s, 1H, NH), 11.26 (s. 1H, NH),
8.45 (d, J = 0.012, 1H, aromatic-H), 8.24 (s, 1H, CH), 8.01
(s, 1H, aromatic-H), 6.90 (d, J = 0.008, aromatic-H); C nmr: δ
159.8, 158.6, 147.7, 146.7, 133.4, 123.0, 111.8, 109.3.
Anal. Calcd. For C H N O : C, 52.44; H, 2.93; N, 13.59.
Found: C, 52.36; H, 3.07; N 13.40
13
9
6 2 4
REFERENCES AND NOTES
[1a] For a historical account of barbituric acids see: M. K. Carter,
J. Chem. Ed., 28, 524 (1951); Vogel's "A Text-Book of Practical Organic
Chemistry", Third Edition, Wiley, New York, 1966; [b] J. T. Bojarski,
J. L. Mokrosz, H. J. Barton, and M. H. Paluchowska, Adv. Heterocycl.
Chem., 38, 229 (1985); [c] W. J. Doran, J. Med. Chem., 4, 1 (1959).
[2] K. S. Gulliya, U.S. Patent 5,869,494; Chem Abstr. (1999).
[3] K. G., U.S. Patent 5,674,870; Chem Abstr. (1997).
[4] K. Sakai and Y. Satoh, International Patent, WO9950252A3;
Chem Abstr (2000).
[5] "The Merck Index", M. Windholz, Editor, 10th edition,
Rahway 1983.
[6a] For a review see G. Jones, Org. React., 15, 204 (1967);
[b] L. F. Tietze, U. Beifuss, in Comprehensive Organic Synthesis,
B. M. Trost, I. Fleming, C. H. Heathcock, Eds. Pergoman press: Oxford,
1919; Vol 2, Ch. 1.11, pp 341-394.
EXPERIMENTAL
Melting points were taken on an Electrothermal IA 9000
Digital Melting Point Apparatus and are uncorrected. The H and
C nmr spectra were run on Varian Unity 400 MHz NMR
1
13
spectrophotometer with DMSO-d as a solvent. The J coupling
6
constants are given in ppm. The mass spectra were recorded on a
Micromass Quattro 2 Triple Quadrapole Mass Spectrometer;
Elementary Analysis was performed by Atlantic Microlab, Inc.,
Norcross, GA.
Preparation of 5-(4-Dimethylaminobenzylidene)barbituric Acid
(1c).
Procedure A.
[7] A. Baeyer, Liebigs Ann. Chem., 130, 129 (1864).
[8] For uncatalyzed Knoevenagel condensation involving
malononitrile see: F. Bigi, M. L. Conforti, R. Maggi, A. Piccinno, G.
Sartori, Green Chemistry, 2 101 (2000).
A mixture of barbituric acid (12.8g; 0.1 mol) and 4-dimethyl-
aminobenzaldehyde (14.9g; 0.1 mol) in methanol (500 mL) were
stirred at room temperature. After a few minutes the solution
became a suspension and the color of crystals changed from
yellow to deep red [20]. The suspension continued to stir at room
temperature overnight. Solid product was separated by filtration
and washed several times with cold methanol (3 x 50 mL). The
isolated yield of the red crystalline product was 35.4 g (98%). An
analytical sample had mp 277ºC with decomposition; lit. mp
275 ºC with decomposition [9]; IR (potassium bromide)
[9] V. D. Vvedenskii, Khim. Geterotski. Soedin., 5, 1092 (1969).
[10] D. Villemin and B. Labiad, Synth. Commun., 20, 3333 (1990).
[11] D. Villemin, Chem. Commun. 1092 (1983).
[12] B. P. Bandgar, S. M. Zirange, and P. P. Wadgaonkar, Synth.
Commun., 27, 1153 (1997).
[13] S. Kim, P. Kwon, and T. Kwon, Synth. Commun., 27, 533
(1997).
[14] F. Jourdain and J. C. Pommelet, Synth. Commun., 27, 483
(1997).
[15] E. Obrador, M. Castro, J. Tamariz, G. Zepeda, R. Miranda,
and F. Delgado, Synth. Commun., 28, 4649 (1998).
-1
1
3095-3080, 1700, 1640, 1500 cm ; H nmr: δ 11.04 (s, 1H, NH),
10.91 (s, 1H, NH); 8.42 (d, J = 0.031, 2H, aromatic-CH), 8.13
(s, 1H, C=CH), 6.78 (d, J = 0.031, 2H, aromatic-CH), 3.11 (s, 6H,
[16] G. Alcerreca, R. Sanabria, R. Miranda, G. Arroyo, J. Tamariz,
and F. Delgado, Synt. Commun., 30, 1295 (2000).
13
N(CH ) ); C nmr: δ 161.2, 159.2, 152.0, 150.7, 146.8, 135.6,
3 2
+
116.5, 107.7, 106.0, and 38.0; ms 259 (M , 5), 215 (100), 172
1
[17] Determined by H-nmr spectroscopy of the reaction mixture
(96), 166 (11), 144 (7), 128 (18), 101 (15).
after evaporation of methanol at reduced pressure and room temperature.
There is a clear difference in chemical shift for NH signals for the
Knoevenagel condensation product (~11.25 and 11.35 ppm) and starting
barbituric acid (~11.11 ppm). The ratio of the integrals for these signals is
used to determine the percentage of the reaction conversion.
[18] For an aliphatic condensation reaction one can follow
formation of the product by monitoring the intensity of the olefinic
(CH=C) proton the NMR spectra.
[19] One can assume that preparation of these compounds can be
facilitated by using different solvents as well as elevated temperatures.
Formed products are exceptionally sensitive to both high temperature and
acidic solvents. With high temperature they tend decompose (form many
hard to identified products with polymeric tar) or with moderate heat and
high acidic media, such as formic acid, one more step of cyclization
occurs with the formation of 1,5-Dihydro-10-oxa-5-deazaflavins
derivatives. These results will be published elsewhere.
[20] Aromatic conjugated products have deep red color which is
due to both extended conjugation by the formation of a double bond
between the barbituric and the aromatic moiety, as well as existence of
the donor-acceptor interactions.
Anal. Calcd. For C
H N O : C, 60.23; H, 5.05; N, 16.21.
13 13 3 3
Found: C, 60.11; H, 5.13; N 16.08.
Preparation of 5-(2-Furfurylidene)barbituric Acid (8).
Procedure B.
Mixture of barbituric acid (1.28 g; 0.01 mol) and 2-furalde-
hyde (0.96 g; 0.01 mol) in methanol (150 ml) was stirred at room
temperature for five days. Methanol was evaporated at room
temperature under reduced pressure. The solid residue was
slurred in water (100 ml) stirred for two hours and solid residue
separated by filtration. Crystalline product was washed with cold
water (3x50 mL) and again slurred in ether. After filtration, the
crystals were washed with ether (3x20 ml) and dried in the air
resulting in a pure yellow crystalline product (1.67g; 81%). An
analytical sample after drying in vacuum had mp 264 ºC with
decomposition; lit. mp 260 ºC with decomposition [8]; IR
(potassium bromide) 3520-3480, 1730, 1690, 1645, 1615-1590,