Behaviour of some activated nitriles toward barbituric acid, thiobarbituric acid and 3-methyl-1-phenylpyrazol-5-one

Article abstract of DOI:10.3390/50500746

The effect of some active methylene containing heterocyclic compounds, namely barbituric acid, thiobarbituric acid and 3-methyl-1-phenylpyrazol-5-one on α-cyano-3,4,5-trimethoxycinnamonitrile and ethyl α-cyano-3,4,5- trimethoxycinnamate (1a,b) was investigated. The structure of the new products was substantiated by their IR, ¹H-NMR and mass spectra.

Full text of DOI:10.3390/50500746

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Molecules 2000, 5, 746-755
molecules
ISSN 1420-3049
http://www.mdpi.org
Behaviour of Some Activated Nitriles Toward Barbituric Acid,
Thiobarbituric Acid and 3-Methyl-1-Phenylpyrazol-5-one
H.M.F. Madkour*, M.R. Mahmoud, M.H. Nassar and M.M. Habashy
Synthetic Organic Chemistry Laboratory, Department of Chemistry, Faculty of Science, Ain Shams
University, Abbassiya, Cairo, Egypt
Fax: 00 2024831836, E-mail: hmfmadkour@hotmail.com
*Author to whom correspondence should be addressed.
Received: 6 September 1999; revised form: 15 December 1999 / Accepted: 12 February 2000 / Published: 20 May 2000
Abstract: The effect of some active methylene containing heterocyclic compounds, namely
barbituric acid, thiobarbituric acid and 3-methyl-1-phenylpyrazol-5-one on a -cyano-3,4,5-
trimethoxycinnamonitrile and ethyl a -cyano-3,4,5-trimethoxycinnamate (1a,b) was investi-
1
gated. The structure of the new products was substantiated by their IR, H-NMR and mass
spectra.
Keywords: Barbituric and thiobarbituric acids, pyrazolone, and activated nitriles.
Introduction
Recently, it has been reported that the reaction of chalcones with barbituric or thiobarbituric acid
may afford pyranopyrimidine derivatives in the presence of P O [1] or it may proceed via simple sub-
2
5
stitution with triethanolamine [2] depending on the reaction conditions. Also, the reaction of a -
cyanocinnamonitrile with barbituric acid afforded pyranopyrimidine [3], an arylidene derivative [4] or
simple a substitution product [5]. The present work studies the behaviour of a -cyano-cinnamonitrile
derivatives 1a,b and chalcone 4 toward barbituric or thiobarbituric acid 2a,b. Thus, when compounds
1
a,b or compound 4 were reacted with compounds 2a,b in refluxing pyridine they afforded the aryli-
dine derivatives 3a,b [cf. Scheme 1].
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2000 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.

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Molecules 2000, 5
Results and Discussion
1
The proposed structures of compounds 3a,b were confirmed by H-NMR, molecular weight deter-
1
mination using field desorption mass spectroscopy as well as the chemical evidence. The H-NMR
spectrum of 3 (Y=O,S) in DMSO-d displayed signals from low to high field at d (ppm) 11.5, 11.4
6
(two s, 2H,2NH), 8.4 (s,1H, olefinic proton), 7.9 (br.s, 2H, aromatic protons) and 3.95 (br. s, 9H, 3
OMe) which agree well with the assigned structures.
O
Ph
O
Ph
Ar'
Ar
N
N
N
N
4
Ar' = C H OMe-p
6
4
Me
Y
2 / Py.
Me Ar Me
HN
NH
N
Y
7
O
N
Ar
O
O
Ph
5
HN
NH
CN
2
+
H
EtOH/pip.
Py.
O
O
Z
1
X
O
Ph
N
N
H
Ar
3
Ar = C H (OMe) -3,4,5
6
2
3
NC
a) Z= CN
; Y = O
2
O
/ AcOH
Ar Me
8
b) Z = CO Et ; Y = S
2
5
7
EtOH/pip. Ar
H
a) X = NH ; b) X = OH
2
Scheme 1.
X
X
X
+
-
3CH O
2
HN
NH -Ar
HN
NH C O
HN
NH
O
O
O
O
O
H
m/z=139(0.6%)
m/z=155(100%)
H
Ar
H
Ph
X=O; m/z=306(100%)
X=S; m/z=322(69.6%)
m/z=216(2.6%)
m/z=232(15.6%)
O
-
HN=C=O
H
H
-
NH
+
m/z=68(1.7%)
X
+
C O
+
HN
Ph
C H
6 5
O
m/z=129(10.4%)
m/z=77(9.7%)
Ph
m/z=172(1.6%)
m/z=188(10.4%)
Figure 1.

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Molecules 2000, 5
These structures are further supported by mass spectroscopy data. It was observed that their electron
impact (EI) spectra have several common features, the first of which is that the highest recorded peak
represents the corresponding molecular ion peaks (m/z 306 & 322). The second common feature is the
similarity in their EI fragmentation patterns. The common fragmentation pathways are represented in
Figure 1.
Furthermore, the arylidene derivatives 3a,b are identical (lR, TLC, m.p and mixed m.p) with an
authentic sample prepared by stirring 3,4,5-trimethoxybenzaldehyde with barbituric and/or thiobarbitu-
ric acids in refluxing acetic acid. A possible pathway for the formation of the arylidene derivatives
may be as represented in Scheme 2.
Y
Y
HN
NH
B
HN
NH
+
BH
O
O
O
O
H
H
H
2
(Y=O,S)
O
C N
Ar
Ar'
Ar
4
1
Z
Y
Y
HN
NH
O
HN
NH
O
O
O
O
C N
Ar
Ar'
Ar
Z
BH
BH
Y
Y
HN
NH
O
HN
NH
O
O
O
H
H
O
Y
C N
Ar
Ar
Ar'
HN
NH
Z
B
O
B
O
O
Z
CN
Ar'
H
3
Ar
Scheme 2.

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Molecules 2000, 5
The diverse biological activities of fused pyrazoles have stimulated considerable research in this
field [6-11]. It has been reported [12] that the pyrazolone derivative 5 reacted with a -cyano-
cinnamonitrile in the presence of piperidine to yield the 1:1 adduct 6. On the other hand, it has been
also claimed [13] that the above mentioned reaction afforded two products instead of compound 6 [cf.
Scheme 3].
Me
Ph
CN
CN
ref [12]
ref [13]
+
O
N
N
Ph
5
without
base
piperidine
HN
O
Ph
N
N
Ph
Ph
CN H N
O
Ph
2
N
N
NH Me
Me
H
CN
NC
6
N
Ph Me
O
N
Ph
Scheme 3.
Because of the striking biological activity of fused pyrazoles and to extend the present work, equi-
molar amounts of 1a and 5 were refluxed in absolute ethanol in the presence of piperidine as a basic
catalyst. After 15 minutes an insoluble fraction was isolated as colourless crystals (13%) and identified
as the oxinobispyrazole 7. The reaction was then continued for 3h. Removal of most of the solvent and
acidification with dilute acetic acid afforded the 1:1 adducts 8a and 8b as pale yellow crystals in 44%
and 46% yield respectively [cf. Scheme 1]. The structure of 7 was elucidated exclusively from its IR
and mass spectral data beside the correct analytical data and chemical evidence. Thus, the IR spectrum
of 7 lacks nC=O and nCN. The mass spectrum of 7, which is represented in Figure 2, is in accordance
with the proposed structure. Furthermore, the bispyrazole derivative 7 was identical (TLC, IR, m.p.
and mixed m.p) with an authentic sample synthesized by stirring 3,4,5-trimethoxybenzaldehyde with 5
in absolute ethanol in the presence of a catalytic amount of piperidine for 15 minutes [cf. Scheme 1].

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Molecules 2000, 5
B
O
Ph Ph
+
O
Ph
Ph
N
N
N
N
A
H
N
N
N
Retro Diels-Alder
N
Fragmentation
Me
Ar Me
Me Ar Me
7
m/z=352(100%)
m/z=156(0.7%)
m/z=508(not observed)
(
B) -H
(A) H-abs.
-OMe
Ph
N
+
O
Ph
N
m/z=321
Ar C C C O
(
10.2%)
N
N
m/z=219(17%)
Me
Me
m/z=132(8.1%)
m/z=174(54.9%)
-MeCN
-
C H O
4 5
N
+
PhN2
m/z=105(30.9%)
m/z=91(62.4%)
HCN
-
N2
-
+
C6H5
C H
5
4
m/z=77(83.1%)
m/z=64(5.4%)
Figure 2.
The proposed structure of the adduct 8a is based upon:
i) A satisfactory elemental analysis.
-
1
-1
-1
ii) The IR displayed nNH at 3485 , 3373 and 3223 cm , nCN at 2205 cm and nC=N at 1622 cm .
2
1
iii) The H-NMR spectrum (DMSO-d ) exhibits signals at d(ppm) 7.9-7.3 (m, 5H, Ph), 6.8 (s, 2H,
6
arom. protons), 5.0 (s, 1H, CHAr), 3.90-3.75 (two s, 9H ; 3OMe) and 2.3 (s, 3H, Me).
•
iv) EI fragmentation of 8a involves primary loss of CN followed by H-abstraction to give the radi-
cal cation of m/z=393/100%; base peak). There is also a loss of formaldehyde molecule to give the ion
of m/z=363 (84.0%) which is the major daughter ion. Successive losses of two molecules of formalde-
hyde resulted in the radical cation of m/z = 303 (5.1%). The tentative fragmentation pattern of 8a is
represented in Figure 3.

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Molecules 2000, 5
-
1
The IR spectrum of the adduct 8b lacks n
of ester and displayed n (br) centered at 3913 cm ,
OH
CO
at 1620 cm and n
-
1
-1
-1
-1
1
n
2941 cm n
at 2216 cm , n
at 1595 cm . The H-NMR spec-
CH
CN
C=N
C=C
trum of 8b (DMSO-d ) exhibits signals from low to high field at d(ppm) 7.9-7.4 (m, 5H, ph), 6.9 (s,
6
2H, aromatic protons), 5.0 (s, 1H, CHAr), 4.0 - 3.8 (two s, 9H, 3 OMe). and 2.4 (s, 3H, Me). The mass
spectrum of 8b, which is in accord with the assigned structure, is represented in Figure 4.
H N
O
Ph
2
N
N
NC
Ar Me
8
a
m/z=418(not observed)
CN
H-abs.
-
H N
2
O
Ph H N
O
Ph
-H
2
N
N
N
+
-
CH O
2
C H N O
22 3 4
2
2
N
m/z=392(87.4%)
Me
OMe
Ar Me
-
CH O
2
m/z=393(100%)
MeO
+
-
MeCN
H-abs.
C H N O
2
1
20 3 3
m/z=363(84%)
m/z=362(62.9%)
-
2CH O
2
O
NPh
O
H N
H N
2
2
-PhN,H-abs.
Ph
H N
2
O
N
Ar
Ar
N
m/z=263 (7.8%)
m/z=352 (4.8%)
Ph Me
m/z=303(5.1%)
Figure 3.

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Molecules 2000, 5
A
HO
O
Ph
HO
NC
O
Ph
N
N
-CN
N
N
H-abs.
Ar Me
m/z=394(9.0%)
Ar Me
8
b
m/z=419(3.1%)
Retro Diels-Alder
HO
(A)
-
CH =C=O
O
O
2
(C)
O
Ph
N
Ar
H
NC
Ar
H-abs.
H
N
m/z=353(99.1%)
m/z=263(4.3%) m/z=196(3.9%)
+
Ar Me
m/z=352(100%)
-
OH
+
NC C C OH
-CN
m/z=67(2.1%)
-Ar
B
O
O
Ph
N
N
Ar
m/z=220(80.7%)
H-abst.
+
Me
2
m/z=185(34.6%)
-C H
2 2
O
O
+
5
-3CH O
-CHO
2
C H
6
Ph
H
Ar
H
m/z=77(61.3%)
m/z=106(10.1%)
m/z=196(3.9%)
Figure 4.
The formation of the oxino bispyrazole derivative 7 from the reaction of 1a and/or 1b with 3-
methyl-1-phenylpyrazolone 5 probably proceeds via the initial Michael addition to afford an acyclic
Michael adduct which then loses the active methylene moiety, i.e., malononitrile or ethyl cyanoacetate
to give the arylidene pyrazolone which could be attacked by a new molecule of 5 followed by a cy-
clodehydration step to yield the isolated bispyrazole derivative 7 [cf. Scheme 4]. Cyclization of the
acyclic Michael adducts via attack of the ring carbonyl either on the cyano or ester functional group
yielded the products 8a and 8b respectively.

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Molecules 2000, 5
O
H
H
Ph
O
Ph
CN
CN
N
N
B
N
N
+
H
Z
H
Ar
Z
1
Ar Me
Me
acyclic Michael adduct
5
CN
B
a) Z = CN ; b) Z = CO Et
2
Z
HH
O O
O
Ph
N
N
Ph
Ph
-
H O
2
N
N
N
5
7
H
N
B
Ar Me
Me Ar Me
Scheme 4.
Experimental
General
Melting points are not corrected. The IR spectra were recorded in a Pye-Unicam SP 1200 spectro-
1
photometer using the KBr wafer technique. The H-NMR spectra were recorded on a Varian GEMINI
2
00 MHz NMR Spectrophotometer using DMSO-d as solvent and TMS as internal standard. All
6
chemical shifts are in ppm downfield from TMS. The elemental analysis were carried out in the Cen-
tral Lab., Faculty of Science, Ain Shams University, Abbassiya, Cairo, Egypt. Mass spectra were re-
corded on Shimadzu GC-MS-QP 1000 EX instrument. The purity of the synthesised compounds was
monitored by TLC.
Reaction of a-cyano-3,4,5-trimethoxycinnamonitrile (1a) or ethyl a-cyano-3,4,5-trimethoxycinnamate
(
1b) with barbituric acid or thiobarbituric acid; Formation of 5-(3,4,5-trimethoxybenzylidene)barbi-
turic or thiobarbituric acid (3a or 3b)
A mixture of 1a (2.44 g; 0.01 mol) or 1b (2.91 g, 0.01 mol) and barbituric acid (1.28 g, 0.01 mol) or
thiobarbituric acid (1.44 g, 0.01 mol) in pyridine (30 mL) was refluxed for 3h. Most of the solvent was
distilled off and the reaction mixture was cooled and acidified with ice-cold glacial acetic acid. The
solid which deposited was filtered off, washed with cold water, dried and recrystallized from the
proper solvent to give 3a or 3b [cf. Table 1].

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Molecules 2000, 5
Table 1. Physical characteristics of the new compounds.
Mol. Formula
Mol.
Yield %
Recryst.
Compd.
M.P (°C)
Colour
*
**
Wt.
Solvent
E.A
C H N O
14 14 2 6
3
3
a
306
322
508
418
419
236-8
196-8
196-8
170-2
204-6
78.6
83.11
13
Yellow
Pink
C H N O S
14 14 2 5
b
M
C H N O
30 28 4 4
CCl
7
4
4
Colourless
Pale yellow
Pale yellow
C H H O
23 22 4 4
CCl
8
8
a
44
C H N O
23 21 3 5
b
46
B/L.p
*
All elemental analysis (C,H,N) are in agreement with the calculated values.
* E.A. = Ethyl acetate , M = Methanol , B = Benzene. , L.p = Light petroleum.
*
Reaction of chalcone 4 with barbituric or thiobarbituric acid, Formation of 3a or 3b
A mixture of chalcone 4 (3.28g; 0.01mol). and barbituric acid (1.28g.; 0.01mol) or thiobarbituric
acid (1.44g , 0.01 mol) in pyridine (30 mL) was refluxed for 3h. The reaction mixture was concen-
trated, cooled, and acidified with ice cold acetic acid. The solid which separated out was filtered off,
washed with water, dried and recrystallized from the suitable solvent to give 3a (26.7% yield) or 3b
(42.4% yield).
Reaction of barbituric or thiobarbituric acid with 3,4,5-trimethoxybenzaldehyde; Formation of an
authentic sample of 3a
A mixture of barbituric acid (1.28g; 0.01mol) or thiobarbituric acid (1.44g; 0.01mol) and 3,4,5-
trimethoxybenzaldehyde (1.96g; 0.01 mol) in glacial acetic acid (30 mL) was heated under reflux for
3
0 minutes. The reaction mixture was concentrated, diluted with ice cold water. The solid deposited
was filtered off, dried and recrystallized from the proper solvent to yield 3a (77.3% yield) or 3b
86.1% yield).
(
Reaction of 1a or 1b with 3-methyl-1-phenylpyrazol-5-one (5); Formation of 4H-3,5-dimethyl-1,7-
diphenyl-4-(3,4,5-trimethoxy-phenyl)oxino[2,3-c:6,5-¢c] bis-pyrazole (7) and 4H-6-amino-5-cyano-3-
methyl-1-phenyl-4-(3,4,5-trimethoxyphenyl)-pyrano[2,3-c]pyrazole (8a) or 4H-5-cyano-6-hydroxy-3-
methyl-1-phenyl-4-(3,4,5-trimethoxyphenyl)pyrano[2,3-c]-pyrazole (8b)
A mixture of the arylidene derivative 1a (2.4g; 0.01mol) or 1b (2.91g; 0.01 mol) and 3-methyl-1-
phenylpyrazol-5-one 5 (1.74g; 0.01 mol) in absolute ethanol (30 ml) was refluxed in the presence of a

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Molecules 2000, 5
catalytic amount of piperidine. After 15 minutes, the colourless insoluble product was filtered off,
dried and recrystallized from the proper solvent to give compound 7. The filtrate was refluxed up to
3h. Most of the solvent was distilled off and the reaction mixture was cooled and acidified with ice
cold acetic acid. The deposited solid was filtered off, dried and recrystallized from the suitable solvent
to give 8a or 8b [cf. Table 1].
Reaction of 5 with 3,4,5-trimethoxybenzaldehyde; Formation of an authentic sample of 7
A mixture of 3,4,5-trimethoxybenzaldehyde (1.96g; 0.01 mol) and 3-methyl-1-phenylpyrazol-5-one
(
5) (1.74g, 0.01mol) in absolute ethanol (30 mL) was refluxed for 15 minutes in the presence of a
catalytic amount of piperidine. The insoluble product was filtered off, dried and recrystallized from the
appropriate solvent to give 7.
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1
2
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Samples Availability: Available from the authors.
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2000 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.