Highly efficient synthesis of trioxopyrimidine-based chalconoids under solvent-free conditions

Article abstract of DOI:10.1080/00397911.2013.853801

Straightforward procedures for the fast and efficient synthesis of differently substituted barbituric acid-based chalconoids under solvent-free conditions were developed.

Full text of DOI:10.1080/00397911.2013.853801

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Highly Efficient Synthesis of
Trioxopyrimidine-Based Chalconoids
Under Solvent-Free Conditions
Alexey S. Gorovoy a , David Guyader b & Tore Lejon c
a ARTTsynthesis AS , Tromsø , Norway
b IUT de Lannion , Lannion , France
c Department of Chemistry , University of Tromsø , Tromsø , Norway
Accepted author version posted online: 02 Dec 2013.Published
online: 28 Mar 2014.
To cite this article: Alexey S. Gorovoy , David Guyader & Tore Lejon (2014) Highly Efficient Synthesis
of Trioxopyrimidine-Based Chalconoids Under Solvent-Free Conditions, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:9, 1296-1300, DOI:
10.1080/00397911.2013.853801
To link to this article: http://dx.doi.org/10.1080/00397911.2013.853801
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Synthetic Communications®, 44: 1296–1300, 2014
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2013.853801
HIGHLY EFFICIENT SYNTHESIS OFTRIOXOPYRIMIDINE-
BASED CHALCONOIDS UNDER SOLVENT-FREE
CONDITIONS
Alexey S. Gorovoy,1 David Guyader,2 and Tore Lejon3
1ARTTsynthesis AS, Tromsø, Norway
2IUT de Lannion, Lannion, France
3Department of Chemistry, University of Tromsø, Tromsø, Norway
GRAPHICAL ABSTRACT
Abstract Straightforward procedures for the fast and efficient synthesis of differently
substituted barbituric acid–based chalconoids under solvent-free conditions were developed.
Keywords Barbituric acid; chalconoids; screening; solvent-free reaction
INTRODUCTION
The 2,4,6-(1H,3H,5H)-pyrimidintrione fragment, or barbituric acid, is the
structural basis of many biologically active compounds used in medicine nowadays.
Besides common use as hypnotic, anaesthetic, and anticonvulsive,[1] barbituric acid
derivatives possess anti-inflammatory,[2,3] antiviral,[4] immunosuppressive,[5] and cyto-
static action.[6] Apart from pharmacology, barbituric acid derivatives are, for example,
used in sensor systems, [7] as dyes,[8] and in pesticides.[9] Therefore, the development of
new synthetic methods and the synthesis of libraries of new derivatives of oxopyrimi-
dines is of importance.
The synthesis of trioxopyrimidine-based chalconoids 3 and their derivatives
attracted significant attention in recent decades.[10–14] Reactions used are straightfor-
ward and employ variations of the aldol condensation,[14,15] Zn(L-proline)2-catalyzed
reactions in water,[11] solvent-free reactions of nitrogen-containing aldehydes,[12]
microwave-assisted reactions,[13] and pyridine-catalyzed reactions in ethanol.[16]
Received September 25, 2013.
Address correspondence to Tore Lejon, Department of Chemistry, University of Tromsø, N-9037
Tromsø, Norway. E-mail: tore.lejon@uit.no
1296

TRIOXOPYRIMIDINE-BASED CHALCONOIDS
1297
Our interest in synthesis of barbituric acid–based chalconoids started when
investigating similar systems while working on the Knoevenagel condensation of
imines under solvent-free conditions. By employing imines as reactants, it was not
possible to obtain the desired results, and unexpectedly a highly efficient way of syn-
thesizing chalconoids was discovered. This discovery was developed into the conveni-
ent solvent-free procedure presented here.
RESULTS AND DISCUSSION
The synthesis of 5-acetyl-1,3-dimethyl barbituric acid 1 was performed accord-
ing to a well-established procedure.[17]
Chalconoids 3 were synthesized by reaction of 5-acetyl-1,3-dimethyl barbitu-
ric acid with a set of substituted benzaldehydes 2 under solvent-free conditions at
elevated temperature, but unlike in the previously reported reaction where pyrazole
carboxaldehyde was reacted,[12] a catalytic amounts of piperidine was added to the
molten mixture of reactants, providing shorter reaction time. The role of the piperi-
dine has not been investigated; however, one might be speculate that it may either
function as base leading to increased nucleophilicity of the acetyl barbituric acid or it
may increase the electrophilicity of the aldehyde by initial imine formation. In addi-
tion, products 3 with a melting point higher than the operating temperature of the
reaction usually precipitated immediately from the mixture, providing a clear indi-
cation of product formation. Another advantage of the procedure was the simple
workup, as the products were poorly soluble in boiling ethanol, thus facilitating the
removal of by-products and unreacted starting materials.
Because yields varied for different substrates, it was decided to screen the reac-
tion conditions to find out the importance of the individual variables affecting the
outcome of the reaction.
SCREENING
A full factorial design[18,19] of eight experiments was chosen, with each variable
kept at either high level (+) or low level (−), employing p-methoxy benzaldehyde as
model substrate (Table 1).
Results from the analysis show that all variables should be kept at high level,
and these conditions were applied to a set of differently substituted benzaldehydes,
including electron-withdrawing and electron-donating substituents in the para- or
ortho-positions (Table 2).
Scheme 1. Reaction of 5-acetyl-1,3-dimethyl barbituric acid with a range of substituted benzaldehydes.
R=p-MeO, p-N(Me)2, H, p-Cl, p-NO2, o-MeO, o-Cl, o-CN, o-NO2.

1298
A. S. GOROVOY, D. GUYADER, AND T. LEJON
Table 1. Experimental design for screening of reaction conditions for the reaction between
p-methoxy benzaldehyde and 5-acetyl-1,3-dimethyl barbituric acid
Experiment
Variable
Level (−1)
Level (+1)
number
X1
X2
X3
Yield (%)
1
2
3
4
5
6
7
8
−
+
−
+
−
+
−
+
−
−
+
+
−
−
+
+
−
−
−
−
+
+
+
+
31
50
72
75
63
85
75
88
X1 ratioa
1.2
1
2.0
3
X2 time (min)b
X3 temp. (°C)
120
180
aRatio of aldehyde/barbituric acid.
bThe reaction time was measured as the time from addition of piperidine to the time of removal of
the reaction vessel from the oil bath.
As can be seen from the table, electron-donating substituents in the aromatic
ring provide better yields under the chosen conditions than electron-withdrawing
substituents. The fact that yields are higher for para-substituted compounds than for
ortho-substituted compounds is probably due to steric factors. It was therefore of
interest to investigate if better and/or general conditions could be found, and there-
fore screening of reaction variables was undertaken for o-nitro benzaldehyde. Initially
it was believed that the reason for the poor yield was the reaction being slow and
therefore the settings for the screening were set at 1 or 3 eq, 1 or 5 min, and 160 or
200°C. Results revealed that the ratio between aldehyde and acetyl barbituric acid
should be set at the high level, as was the setting for time. On the other hand, the
coefficient for temperature was negative, and consequently yields were higher at lower
temperature. New experiments revealed that the great yields were obtained with 4 eq
of benzaldehyde reacting for 7 min at 120°C, resulting in 52% of product.
Table 2. Yields from reaction of 5-acetyl-1,3-dimethyl barbituric
acid with different aldehydes: R=p-MeO, p-N(Me)2, H, p-Cl, p-NO2,
o-MeO, o-Cl, o-CN, o-NO2
Compound
R
Isolated yield (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
76
84
89
76
31
31
65
66
35
30
p-N(Me)2
p-OMe
p-OH
p-Cl
p-NO2
o-OMe
o-Cl
o-CN
o-NO2
3j

TRIOXOPYRIMIDINE-BASED CHALCONOIDS
1299
CONCLUSIONS
A new synthetic procedure for synthesis of α,β-unsaturated compounds was
developed, revealing that to achieve optimum yields, reaction conditions have to be
screened for each substrate.[20]
EXPERIMENTAL
(E)-5-(3-(4-Methoxyphenyl)acryloyl)-1,3-dimethylpyrimidine-
2,4,6(1H,3H,5H)-trione (3c)
In a typical example, 5-acetyl-1,3-dimethybarbituric acid 1 (4 g, 20mmol) was
mixed with p-methoxybenzaldehyde (5.49 g, 40mmol). The mixture was melted at
180°C and 2–3 drops of piperidine were stirred into the mixture. Immediate change
of the color of the reaction mixture was observed. After 2 min, the mixture solidified,
providing yellow powder, which was allowed to cool to room temperature. The solid
residue was boiled in ethanol (20mL) for a few minutes and the precipitate was fil-
tered off, rinsed with 20ml of hot ethanol, and dried at room temperature, providing
5.6 g (89% yield) of 3c as a bright yellow solid.
1
Mp 190–192°C. H NMR (400MHz, CDCl3) δ: 16.95 (d, J=1.4Hz, 1H), 8.46
(dd, J=15.7, 1.4Hz, 1H), 7.99 (d, J=15.8Hz, 1H), 7.65 (d, J=8.7Hz, 2H), 6.93 (d,
J=8.8Hz, 2H), 3.86 (s, 3H), 3.38 (6H). 13C NMR (101MHz, CDCl3) δ: 184.11, 170.02,
162.65, 161.68, 147.05, 131.41, 127.76, 117.99, 114.71, 93.97, 77.16, 55.64, 28.30, 28.09.
IR (νmax): 3108, 2955, 2845, 1711, 1654, 1622, 1598, 1506, 1481, 1418, 1257, 1168, 1017,
976, 824, 758 cm−1. HRMS: calcd. for C16H15O5 N2 [M−] 315.0980, obs. 315.0986.
(E)-5-(3-(2-Nitrophenyl)acryloyl)-1,3-dimethylpyrimidine-
2,4,6(1H,3H,5H)-trione (3j)
5-Acetyl-1,3-dimethybarbituric acid 1 (0.144g, 0.73mmol) was mixed with
o-nitrobenzaldehyde (0.437 g, 2.9mmol). The mixture was melted at 120°C and 1
drop of piperidine was stirred into the mixture. After 7 min, heating was discontinued,
and the mixture was allowed to cool to room temperature. The residue was boiled in
ethanol (2mL) for a few minutes, and the precipitate was filtered off, rinsed with 2ml
of hot ethanol, and dried at room temperature, providing 0.13g (52%) of 3j as a pale
yellow solid.
Mp 215–216 °C. 1HNMR (400MHz, CDCl3) δ: 17.08 (s, 1H), 8.50 (d,
J=15.7Hz, 1H), 8.40 (d, J=15.7Hz, 1H), 8.05 (dd, J=8.1, 1.2Hz, 1H), 7.86 (dd,
J=7.8, 1.1Hz, 1H), 7.68 (m, J=7.8, 1.2, 0.7Hz, 1H), 7.57 (td, J=8.1, 1.4Hz, 1H),
3.38 (m, 6H). 13C NMR (101MHz, CDCl3) δ: 183.01, 169.96, 161.42, 150.41, 148.86,
141.00, 133.69, 130.97, 130.87, 129.73, 125.38, 125.14, 95.29, 28.38, 28.21. IR (νmax):
3105, 3079, 2963, 1721, 1672, 1623, 1571, 1514, 1473, 1421, 1353, 1339, 1298, 1212,
1016, 974, 925, 791, 752, 745cm−1.
HRMS: calcd. for C15H13O6 N3Na [M+Na]+ 354.0697, obs. 354.0698.

1300
A. S. GOROVOY, D. GUYADER, AND T. LEJON
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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