Heterocyclic synthesis via enaminones: Novel synthesis of (1H)-pyridin-2-one, pyrazolo[1,5-a]pyrimidine and isoxazole derivatives incorporating a N-methylphthalimide and their biological evaluation

Article abstract of DOI:10.1002/jhet.5570420222

Novel synthesis of (1H)-pyridin-2-one, pyrazolo[1,5-a]pyrimidine and isoxazole derivatives incorporating N-methylphthalimide moiety are reported. Reaction of enaminone 2 with malononitrile affords 4. Condensation of 2 with cyanothioacetamide or benzoylacetonitrile affords compounds 6 and 7 respectively. Reaction of 2 with hydrazine hydrate afford 2,3- dihydrophthalazine-1,4-dione (10). Condensation of 2 with hydroxylamine and 3-aminopyrazole derivatives affords compounds 12 and 15a,b respectively. Antimicrobial and antifungal activity were determined for representative compounds and most of them showed moderate activity as antimicrobial agents, while compounds 2 and 7 show strong activity against Aspergillus niger. The structure of the newly synthesized compounds was elucidated by elemental analyses and ¹H nmr spectra and some cases by ¹³C nmr investigation.

Full text of DOI:10.1002/jhet.5570420222

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
March 2005
307
Heterocyclic Synthesis via Enaminones: Novel Synthesis of (1H)-
Pyridin-2-one, Pyrazolo[1,5-a]pyrimidine and Isoxazole Derivatives
Incorporating a N-Methylphthalimide and Their Biological Evaluation
Fatima Al-Omran* and Adel A. El-Khair
Department of Chemistry, Kuwait University, P.O. Box 5969,
13060 Safat, Kuwait.
Received April 29, 2004
Novel synthesis of (1H)-pyridin-2-one, pyrazolo[1,5-a]pyrimidine and isoxazole derivatives incorporat-
ing N-methylphthalimide moiety are reported. Reaction of enaminone 2 with malononitrile affords 4.
Condensation of 2 with cyanothioacetamide or benzoylacetonitrile affords compounds 6 and 7 respectively.
Reaction of 2 with hydrazine hydrate afford 2,3-dihydrophthalazine-1,4-dione (10). Condensation of 2 with
hydroxylamine and 3-aminopyrazole derivatives affords compounds 12 and 15a,b respectively.
Antimicrobial and antifungal activity were determined for representative compounds and most of them
showed moderate activity as antimicrobial agents, while compounds 2 and 7 show strong activity against
Aspergillus niger. The structure of the newly synthesized compounds was elucidated by elemental analyses
1
13
and H nmr spectra and some cases by C nmr investigation.
J. Heterocyclic Chem., 42, 307 (2005).
N-alkylphthalimides attracted a great deal of interest due
to their biological properties such as potent acetyl-
cholinesterase (ACHE) inhibitors [1,2], antihypertensive,
CNS depressant activities [3,4] and potent enhancing
activity on TPA-induced TNF-α (tumor necrosis factor
alpha) production [5]. Furthermore, several studies have
also pointed out the value of imide derivatives as interme-
diates in synthesis [6] and in polymer chemistry [7]. In
continuation of our current interest in the synthesis of
functionally substituted heteroaromatic compounds as
potential pharmaceuticals utilizing enaminones [8-12].
We report here on the utility of unreported enaminone (2)
as a building block for the synthesis of (1H)-pyridin-2-one,
(1H)-pyridin-2-thione, isoxazol and pyrazolo[1,5-a]-
pyrimidine derivatives in which an N-alkylphthalimide
ring is incorporated along with the results of their antimi-
crobial antifungal activities.
The reactivity of 2 towards active methylene nitriles was
investigated. Thus, the reaction of compound 2 with mal-
ononitrile in refluxing ethanol along with a catalytic
amount of piperidine gave the substituted 2,4-pentadien-
amide 3. Heating of 2 with malononitrile at 150 °C gave a
single product identified as N-[(3-Cyano(1H)-2-oxopy-
ridin-4-yl)methyl]phthalimide (4). Heating 2,4-pentadien-
amide derivative 3 at 180 °C also affords 4 (the product is
identical in all respects, mp and spectra, with that obtained
previously from reaction of 2 with malononitrile).
Scheme 1
Thus, treatment of N-phthalimidoacetone 1 with
dimethylformamide dimethylacetal (DMFDMA) in reflux-
ing xylene for 6 hours was unsatisfactory. However, when
the reaction was refluxed for 20 hours a yellow crystalline
product was obtained that was assigned as the Z-isomer
Compound 4 was also obtained by an independent syn-
thesis. Treatment of N-phthalimidoacetone 1 with mal-
ononitrile in refluxing ethanol in the presence of piperidine
afforded 2-cyano-3-methyl-4-(phthalimido)-2-butenamide
(5). Heating 5 with DMF DMA also afforded 4. On the
other hand, 4 also can be obtained in situ, via the one-step
process of heating 1 with DMF DMA at 150 °C followed
by the treatment of the reaction mixture with malononitrile
or vice versa (Scheme 2). Formation of 4 is assumed to be
formed via initial hydrolysis of malononitrile to cyanoac-
etamide followed by condensation of the active methylene
group with the carbonyl function group of 2 to form 3
which readily undergoes intramolecular cyclisation into
the (1H)-pyridin-2-one derivative 4 via loss of dimethyl-
amine molecule.
1
based on H nmr, which revealed methylene protons as a
singlet at δ 4.44 ppm and two doublets at δ 5.05 and 7.61
H
H
ppm corresponding to vinylic protons with J=10 Hz as
expected for protons in a Z configuration. In addition, two
singlets are observed at δ 2.80 and 3.05 ppm correspond-
H
ing to the two N-methyl groups, thus showing that they are
non-equivalent. Nonequivalence is due to resonance of the
nitrogen atom lone pair of electrons with the α,β-unsatu-
rated carbonyl group which causes partial double bond
character and thus restricted rotation (conformation 2a in
13
Scheme 1). Moreover, the C nmr spectrum revealed the
3
presence of only three sp carbon atoms that resonate at δ
C
46.90, 45.08 and 35.57 ppm for the methylene and two non-
equivalent methyl groups, respectively (Scheme 1).
In a similar manner, compound 2 reacted also with cyan-
othioacetamide or benzoylacetonitrile in refluxing ethanol

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
308
F. Al-Omran and A. A. El-Khair
Vol. 42
to afford the (1H)-pyridine-2-thione and (1H)-pyridin-2-
one derivatives 6 and 7, respectively. The structure of both
compounds 6 and 7 was established on the basis of their
elemental analysis and spectral data (see Section 2).
propyl]phthalimide (11). The latter compound fails to react
with DMF DMA to yield the pyrazolo derivative 9b under a
variety conditions.
Reaction of 2 with hydroxylamine hydrochloride yielded
an isoxazole derivative that was assigned structure 12
On the other hand heating N-phthalimidoacetone 1 with
malononitrile followed by treatment of the reaction mixture
with benzylidinemalononitrile in situ afforded compound 8
in good yield. The ir spectrum of 8 showes absorption
1
13
1
rather than 13 based on both H and C nmr. The H nmr
spectrum showed a resonance at δ = 8.39 ppm corre-
H
sponding to H-3 of isoxazole [14,15]. If the reaction prod-
−1
bands at 3474 and 3338 cm due to NH group in addition
uct is 13, then the H-5 proton should resonate at lower field
2
−1
13
to strong absorption bands at 2204, 1774, 1719 cm which
δ = 9.7 ppm [8]. Moreover, the C nmr spectrum of the
H
are assigned to the nitrile and two phthalimide carbonyl
groups respectively. The H nmr spectrum showed signlets
reaction product revealed three low field signals at δ 167,
C
1
157, 151 ppm. The signal at δ 167 ppm corresponding to
C
at δ 2.24 and δ 4.58 ppm for H-6 and methylene protons,
the two phthalimide carbonyl groups, while the signals at
H
H
respectively. Also revealed broad signals (D O exchange-
δ
157 and 151 ppm corresponding to quaternary carbon
2
C
able) at δ 8.32 ppm due to NH and multiplets at δ 7.23 –
(C-5) and to the (C-3) carbon coupled with a proton. As in
H
2
7.95 ppm corresponding to aromatic protons. Finally, a sig-
the isoxazole system, the carbon resonating at δ 151 ppm
C
nal corresponding to an acetyl group at approximately δ
2.50 ppm was not observed (Scheme 2).
corresponds to C-3 [14,15]. The formation of 12 is
assumed to proceed via 1,4-addition across the α,β-unsatu-
rated ketone moiety with loss of dimethylamine which then
readily undergoes intramolecular cyclisation into the isoxa-
zole derivative via loss of a water molecule (Scheme 3).
The foregoing results prompted us to investigate the behav-
ior of 2 towards some heterocyclic amines as potential precur-
sors for fused heterocyclic system. Thus, treatment of com-
pound 2 with each of 3-amino-5-methyl-1H-pyrazole and
3-amino-5-phenyl-1H-pyrazole in refluxing pyridine furnished
in each case a single product identified as pyrazolo[1,5-a]-
pyrimidine derivatives with possible structures 15 or its isomer
H
The reactivity of enaminone 2 towards some nitrogen
nucleophiles was also investigated. Thus treatment of
compound 2 with hydrazine hydrate in refluxing ethanol in
an attempted to prepare pyrazolo derivative 9a was unsuc-
cessful. The isolated product was identified as 2,3-dihy-
drophthalazine-1,4-dione (10) with mp similar to those
reported in the literature [13].
On the other hand, compound 1 reacted with phenyl-
hydrazine in ethanol at reflux temperature to afford a yellow
product that was identified as N-[(2-phenylhydrazono)-2-
Scheme 2

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
March 2005
Heterocyclic Synthesis via Enaminones
309
Scheme 3
7.97 ppm. Structure 16 was readily ruled out on the basis of
isolated intermediate 14 that was cyclized into 15a on refluxing
pyridine and in the presence of hydrochloric acid [8].
Biological Activity.
The biological activities of some newly synthesized
compounds were screened for their antifungal activity
against Aspergillus niger and Fusarium oxysporiurn while
the antibacterial activity was tested against Eschirichia
coli, Bacillus subtilis and Staphylococcus aureus. Bacteria
and Fungi were maintained on nutrient agar slops (NA)
and sabouraud agar (SA), respectively. When calculated, a
loop full of bacteria was grown on tryplic Saaybroth, while
fungi were subcultured on a yeast nitrogen base supple-
mented with glucose (YNBG). All media used were of
dificagrade. Table 1 shows in vitro bactericidal and fungi-
cidal activities of some newly synthesized compounds.
15-16a:X = Me
b: X = Ph
a: X = NH
b: X = NC H
6
5
EXPERIMENTAL
All melting points are uncorrected. The ir spectra (KBr) were
1
recorded on a Perkin Elmer 2000 FT-IR spectrophotometer. H,
13
C nmr spectra and NOE experiments were recorded on a
Brucker 400 MHz spectrometer with dimethyl-d -sulfoxide
6
(DMSO-d ) or deuteriochloroform (CDCl ) as solvent and
6
3
tetramethylsilane (TMS) as an internal standard; chemical shifts
are reported as δ units (ppm). Microanalyses were performed on
a LECO CHNS 932 analyzer.
N-[2-Oxo-4-(N,N-dimethylamino)-3-butenyl]phthalimide(2).
A solution of 1 (2.03 g, 10 mmol) in xylene (20 mL) was
treated with DMF DMA (1.33 g, 10 mmol) and refluxed for 20
hours. The solvent was evaporated under reduced pressure. The
solid product, so formed, was collected by filtration and recrys-
tallized from ethanol as yellow crystals (2.11 g, 82%); m.p. 155-
158 °C; ir: ν : 1769 and 1715 (phthalimide CO) and 1660
max
−1
cm (conj. CO); δ 2.80 (s, 3H, Me); 3.05 (s, 3H, Me); 4.44 (s,
H
16. The ir spectrum of the reaction product showed the two
2H, CH ); 5.05 (d, 1H, J=10 Hz, H-3); 7.61 (d, 1H, J=10 Hz, H-
2
−1
phthalimide carbonyl absorptions at 1773 and 1710 cm . Also
13
4); 7.84-7.91 ppm (m, 4H, phthalimide-H); C (dimethyl-d -sul-
6
1
the H nmr spectrum revealed three singlet at δ = 2.57, 5.40
H
foxide): δ 187.22 (conj.CO), 168.26 (phthalimide CO); 135.57
C
and 6.57 ppm corresponding to methyl, methylene and pyrazol
proton resonances respectively, in addition to the characteristic
two doublets at 6.94 ppm and 8.33 ppm due to pyrimidine pro-
tons with J=4 Hz and multiplets for aromatic protons at δ 7.27 –
(vinylic C-3), 132.57, 124.29, 124.16, 121.31 (phthalimide car-
bons & vinylic C-4); 46.90 (CH ); 45.08 and 35.57 ppm (NMe).
2
Anal. Calcd. for C H N O : C, 65.12; H, 5.52; N, 10.84.
14 14
2 3
Found: C, 65.09; H, 5.46; N, 10.80.
Table 1
In Vitro Bactericidal and Fungicidal Activity of Newly Synthesized Compounds
Compound
E-coli
B-subtilis
S-aureus
A-niger
F-oxysporium
2
4
7
__
__
__
++
+
+
__
__
++
+++
++
++
__
++++
++
++++
++
+
+
++
__
__
+
__
++
+
+
__
__
8
12
14a
14b
++
__
__
++
__
No effect = -; slight effect = +; Moderate effect = ++; strong effect = +++, ++++

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
310
F. Al-Omran and A. A. El-Khair
Vol. 42
2-Cyano-5-(N,N-dimethylamino)-3-(N-phthalimidomethyl)-2,4-
pentadienamide (3).
172°C; ir: ν : 3446 (NH), 2203 (CN), 1775 and 1717 (phthal-
max
−1
1
imide CO) and 1622 cm (amide CO); H nmr (dimethyl-d -sul-
6
foxide): δ 4.67 (s, 2H, CH ), 6.43 (d, 1H, J=6.8 Hz, H-5), 7.67
H
2
A mixture of enaminone 2 (2.58 g, 10 mmol), malononitrile
(0.66 g, 10 mmol) in ethanol (20 mL) and a few drops of piperi-
dine was refluxed for 6 hours, then left to cool at room tempera-
ture. The solid product, so formed, was collected by filtration
and recrystallized from ethanol as brown crystals (2.78 g, 86%),
m.p. 254-256 °C; ir: ν : 3442, 331 (NH ), 2194 (CN), 1771
(d, 1H, J=6.8 Hz, H-6), 7.76-7.91 (m, 4H, phthalimide-H) and
9.74 ppm (bs, 1H, NH, D O exchangeable).
2
Anal. Calcd. for C H N O : C, 64.51; H, 3.25; N, 15.05.
15
9 3 3
Found: C, 64.75; H, 3.22; N, 15.23.
2-Cyano-3-methyl-4-(N-phthalimido)-2-butenamide (5).
max
2
−1
1
and 1719 (phthalimide CO) and 1668 cm (amide CO); H nmr
(dimethyl-d -sulfoxide): 2.95 (s, 6H, NMe ), 4.79 (s, 2H,
A mixture of 1 (2.03 g, 10 mmol) and malononitrile (0.66 g, 10
mmol) in ethanol (20 mL) and few drops of piperidine was
refluxed for 15 minutes then left to cool at room temperature.
The solid product so formed was collected by filtration and
recrystallized from ethanol as yellow crystals (2.28 g, 85%) m.p.
δ
6
H
2
CH ), 5.45 (d, 1H, J = 10 Hz, vinylic-H), 7.00 (bs, 2H, NH -D O
2
2
2
exchangeable); 7.87-7.90 (m, 4H, phthalimide-H), 8.24 ppm (d,
1H, J = 10 Hz, vinylic-H).
Anal. Calcd. for C H N O : C, 62.95; H, 4.97; N, 17.27.
17 16
4 3
150-152 °C; ir: ν : 3440, 3370 (NH ), 2211 (CN) 1774 and
max
2
Found: C, 62.90; H, 5.05; N, 17.30.
1,2-N-[3-Cyano-(1H)-2-oxopyridin-4-yl)methyl]phthalimide (4).
Method A.
-1
1
1718 (phthalimide CO); 1646 cm (amide CO); H nmr
(dimethyl-d -sulfoxide): δ 2.29 (s, 3H, Me); 5.42 (s, 2H, CH );
6
H
2
7.77-7.94 ppm (m, 6H, phthalimide-H and NH ).
2
Anal. Calcd. for C H N O : C, 62.45; H, 4.12; N, 15.61.
14 11
3 3
A mixture of enaminone 2 (2.58 g, 10 mmol), malononitrile
(0.66 g, 10 mmol) and few drops of piperidine was heated in
an oil bath at 150-160 °C for 10 minutes. The reaction mix-
ture was left to cool at room temperature the solid product was
dissolved in a mixture of ethanol/DMF (10/5 mL) and then
refluxed for 1 hour. The solid product, so formed, was col-
lected by filtration and recrystallized from ethanol as brown
crystals (2.26 g, 75%).
Found: C, 62.28; H, 3.99; N, 15.71.
1,2-N-[3-Cyano-(1H)-2-thioxopyridin-4-yl)methyl]phthalimide
(6).
A mixture of enaminone 2 (2.58 g, 10 mmol) and cyanothioac-
etamide (1.0 g, 10 mmol) in ethanol (20 mL) was refluxed for 2
hours, then left to cool at room temperature. The solid product so
formed was collected by filtration and recrystallized from ethanol
as green crystals (1.94 g, 66%), m.p. 271-272 °C; ir: ν : 3467
max
Method B.
-1
1
(NH), 2233 (CN), 1775 and 1712 cm (phthalimide CO); H nmr
(dimethyl-d -sulfoxde): δ 4.85 (s, 2H, CH ), 6.79 (d, 1H, J = 7
Compound 3 (3.24 g, 10 mmol) was heated at 180 °C for 10
minutes, then allowed to cool at room temperature. The reaction
mixture was dissolved in a mixture of ethanol/DMF (10/5 mL)
and refluxed for 1 hour. The solid product, so formed, was col-
lected by filtration and recrystallized from ethanol as brown
crystals (2.03 g, 70%).
6
H
2
Hz, H-5), 7.86-7.93 (m, 4H, phthalimide-H); 7.98 (d, 1H, J=7Hz,
13
H-6), 14.60 ppm (bs, 1H, NH -D O exchangeable); C nmr
2
2
(dimethyl-d -sulfoxide); δ 179.16 (C-2), 168.78 (phthalimide
6
C
CO); 153.64, 146.01, 135.98, 132.82, 124.81, 121.31 (aromatic
carbons), 118.02 (CN) and 111.19 (C-3) and 44.97 ppm (CH ).
2
Anal. Calcd. for C H N O S: C, 61.02; H, 3.07; N, 14.23.
Found: C, 61.11; H, 3.22; N, 14.42.
15
9 3 2
Method C:
In a similar manner to that described in Method B. A mixture
of compound 5 (3.24 g, 10 mmol) and DMF DMA (1.33 g, 10
mmol) was heated at 150-160°C for 10 minutes gave compound
4 (2.09 g, 71%).
N-[3-Benzoyl-(1H)-2-oxopyridin-4-yl)methyl]phthalimide (7).
A mixture of compound 2 (2.58 g, 10 mmol) and benzoylace-
tonitrile (1.45 g, 10 mmol) in ethanol (20 mL) was refluxed for 2
hours then left to cool at room temperature. The solid product so
formed was collected by filtration and recrystallized from ethanol
Method D.
A mixture of 1 (2.03 g, 10 mmol), DMF-DMA (1.33 g, 10
mmol) (2.09 g, 71%) was heated in oil bath at 150-160 °C for 10
minutes and then allowed to cool at room temperature. The
reaction mixture was treated with malononitrile (0.66 g, 10
mmol) and heated for 10 minutes in oil bath at 150-160 °C. The
reaction product was dissolved in a mixture of ethanol/DMF
(10/5 mL) and refluxed for 1 hour. The solid product, so
formed, was collected by filtration and recrystallized from
ethanol as brown crystals (2.20 g, 73%).
as brown crystals (2.43 g, 68%), m.p. 120-121 °C; ir: ν : 3441
max
(NH), 1771 and 1714 (phthalimide CO), 1685 (keto CO) and
−1
1
1617 cm (amide CO); H nmr (dimethyl-d -sulfoxide): δ 4.60
6
H
(s, 2H, CH ), 6.22 (d, 1H, J=6 Hz, H-5), 7.23-7.95 ppm (m, 11H,
2
Ar-H and NH-D O exchangeable).
2
Anal. Calcd. for C H N O requires: C, 70.38; H, 3.94; N,
21 14
2 4
7.82. Found: C, 70.18; H, 4.09; N, 8.03.
N-[(6-Amino-1,5,5-tricyano-4-phenyl-1,3-cyclohexadien-2-
yl)methyl]phthalimide (8).
Method E.
A mixture of 1 (2.03 g, 10 mmol), malononitrile (0.66 g, 10
mmol), and few drops of piperidine was heated at 180 °C for 10
minutes, then allowed to cool at room temperature. To the reac-
tion mixture benzylidenemalononitrile (1.45 g, 10 mmol) was
added then heated at 160-170 °C for 10 minutes. The fused mix-
ture was allowed to cool at room temperature and dissolved in a
mixture of EtOH/DMF in ratio (2:1) then refluxed for 1 h. The
solid product so formed was collected by filtration and recrystal-
In a similar manner to that described in Method D, a mixture of
compound 1 (2.03 g, 10 mmol), malononitrile (0.66 g, 10 mmol)
and a few drops of piperidine was heated in an oil bath at 150-160
°C for 10 minutes. The reaction mixture was treated with DMF
DMA (1.33 g, 10 mmol) and heated for 15 minutes. The solid
product so formed was collected by filtration and recrystallized
as brown crystal (2.09 g, 73%). Compound 4 has m.p. 170-