Synthesis of some pyridine, thiopyrimidine, and isoxazoline derivatives based on the pyrrole moiety

Article abstract of DOI:10.1007/s00706-008-0061-y

Condensation of 2-acetylpyrrole with 5-methylfuran-2-carboxyaldehyde and 4-chlorobenzaldehyde in 20% NaOH give the corresponding 2-chalconylpyrroles. Some new 2-alkoxy-3-cyano-4,6-diarylpyridines were synthesized by condensation of chalcones with malononi

Full text of DOI:10.1007/s00706-008-0061-y

Monatsh Chem (2009) 140:229–233
DOI 10.1007/s00706-008-0061-y
ORIGINAL PAPER
Synthesis of some pyridine, thiopyrimidine, and isoxazoline
derivatives based on the pyrrole moiety
Mohamed A. A. Radwan Æ Eman M. H. Abbas
Received: 22 July 2008 / Accepted: 19 August 2008 / Published online: 27 September 2008
Ó Springer-Verlag 2008
Abstract Condensation of 2-acetylpyrrole with 5-meth-
ylfuran-2-carboxyaldehyde and 4-chlorobenzaldehyde in
20% NaOH give the corresponding 2-chalconylpyrroles.
Some new 2-alkoxy-3-cyano-4,6-diarylpyridines were
synthesized by condensation of chalcones with malono-
nitrile, followed by cyclization in sodium alkoxide. The
reactivity of chalcones towards nitrogen nucleophiles such
as thiourea and hydroxylamine hydrochloride to provide
thiopyrimidines and isoxazolines was investigated.
[12]. Also, a large number of substituted pyridines have
been maintained to have several biological activities [13–
17]. Moreover, many biologically active compounds
include thiopyrimidine [18–22] or isoxazoline [23–25] ring
as a structural subunit have been reported. Guided by the
above observations, and in continuation of our previous
work in the direction of the synthesis of bioactive com-
pounds [26–29], we report here a convenient synthesis of
functionalized pyridine, thiopyrimidine and isoxazoline
derivatives incorporating pyrrole moiety as a common
structural subunit.
Keywords Pyrroles ꢀ Pyridines ꢀ Thiopyrimidine ꢀ
Isoxazoline
Results and discussion
Introduction
Chemistry
Pyrrole ring represent a subunit in a large and varied class
of marine natural products possessing interesting and
potentially useful pharmacological activities (e.g., lamel-
larins [1, 2], lukianols [3], ningalins [4], storniamides [5],
arcyriarubins [6], and polycitrins [7]) that exhibit remark-
able biological properties such as hypolipidemic, [8]
antimicrobial, [9] anti-inflammatory [10] and antitumour
activity [11]. Other marine natural products possessing a
3,4-substituted pyrrole ring as a common structural subunit
such as halitulin was found to be cytotoxic against several
tumour cell lines (e.g., P-388, A-549, HT-29 and MEL-28)
Chalcones (1,3-diaryl-2-propen-1-ones) are interesting
precursors and display interesting biological activities,
including cytotoxic and anticancer properties [30–33].
Condensation of the starting compound, 2-acetyl pyrrole
(1) with 5-methylfuran-2-carboxyaldehyde and 4-chloro-
bezaldehyde in the presence of 20% NaOH solution at
60 °C for 6 h afforded the corresponding (E)-3-(5-meth-
ylfuran-2-yl)-1-(1H-pyrrol-2-yl)prop-2-en-1-one (2a) and
(E)-3-(4-chlorophenyl)-1-(1H-pyrrol-2-yl)prop-2-en-1-one
(2b), in a good yields (82 and 86%). The coupling constant
1
(J) in the H NMR spectrum of C2-H and C3-H of the
isolated (2a, 2b) are in the range of 15.8–16 Hz which are
characteristic to (E)-isomer of chalcones (Scheme 1).
In the present work, new compounds containing 2-alk-
oxypyridine moieties have been designed for their
biological activity, particularly for antitumor properties. It
was reported that the reaction of chalcones with malono-
nitrile and ethyl cyanoacetate in the presence of ammonium
M. A. A. Radwan (&)
Applied Organic Chemistry Department,
National Research Centre, Dokki, Cairo, Egypt
e-mail: m1radwan@yahoo.com
E. M. H. Abbas
Department of Chemistry of Natural products,
National Research Centre, Dokki, Cairo, Egypt
123

230
M. A. A. Radwan, E. M. H. Abbas
Ar
O
Ar
O
N
Me
a
H 1
*
N
O
H
2a, 2b
CN
Cl
*
CHO
60°C
6 h
EtOH/
20% NaOH
O
CN
b
CHO
Ar
a
b
NC
Cl
Cl
H
N
CN
O
O
3
NaOEt
NaOMe
N
H
O
N
O
Ar
Ar
H
2a
2b
NC
NC
Scheme 1
H
N
H
N
MeO
N
EtO
N
acetate and absolute ethanol afforded cyanopyridines in
low yield [13]. In the same way, the preparation of 2-alk-
oxy cyanopyridines in good yields was reported via
Michael addition of malononitrile to a,b-unsaturated car-
bonyl system [34]. Here in, 2-chalconylpyrroles (2a, 2b)
were condensed with malononitrile in either sodium eth-
oxide/ethanol or sodium methoxide/methanol to yield the
corresponding 2-alkoxycyanopyridines 4a, 4b or 5a, 5b in
a good yield (78 and 80% or 81 and 83%). The reaction
proceeds through Michael addition of a,b-unsaturated
ketones to the malononitrile to afford adduct 3 which
undergoes a nucleophilic attack by alkoxide anion followed
by cyclization and subsequent dehydration of the cyclized
product leads to the 2-alkoxycyanopyridines 4a, 4b or 5a,
5b (Scheme 2). It was observed that the increase in the
carbon number of alkoxyl group caused much prolongation
time of the reaction and relatively low yield. The structure
of the 2-alkoxycyanopyridine compounds was established
on the basis of its elemental analysis and spectral data. For
example, the IR spectrum of compound 4a showed the
presence of an absorption peak at 2,255 cm-1 due to cyano
4a, 4b
5a, 5b
Scheme 2
S
Ar
H
N
S
H2N
NH2
N
H
NH
N
H
O
2a, 2b
Ar
a
b
6a, 6b
Cl
O
Ar
*
*
Scheme 3
spectrum of compound 6a showed the presence of
absorption peaks at 3,250–3,360 cm-1 due to amino groups
and at 1,215 cm-1 due to thione (C=S) group and its H
1
1
stretching frequency and its H NMR spectrum revealed a
NMR spectrum revealed a characteristic two doublets at
d = 5.20 and 7.41 due to thiopyrimidine (H-4 and H-5) and
two singlets at 10.12 and 10.14 ppm due to 2 NH pyrimi-
dine groups. In addition, its mass spectrum revealed a peak
at m/z = 259 corresponding to its molecular ion.
characteristic triplet and quartet signals at d = 1.38 and
4.59 due to methyl and methylene of the ester group, and
singlet at d = 7.76 ppm due to pyridine proton. In addi-
tion, its mass spectrum revealed a peak at m/z = 293
corresponding to its molecular ion.
Also, condensation of 2a, 2b with hydroxylamine
hydrochloride in the presence of anhydrous sodium acetate
in refluxing acetic acid yielded isoxazolines 7a, 7b in a
good yield (69 and 73%) (Scheme 4). The structure of the
isoxazoline derivatives was established on the basis of its
Condensation of 2a, 2b with diamine, namely, thiourea
in refluxing ethanolic potassium hydroxide afforded
2-thiopyrimidine derivatives 6a, 6b, in a good yield (77
and 69%) (Scheme 3). The structure of the 2-thiopyrimi-
dine derivatives was established on the basis of its
elemental analysis and spectral data. For example, the IR
1
elemental analysis and spectral data. For example, the H
NMR spectrum of compound 7a revealed a characteristic
123

Synthesis of some pyridine, thiopyrimidine, and isoxazoline derivatives
231
pyrrole, J = 6.1 Hz), 7.20 (d, 1H, H-a, J = 15.8 Hz), 7.42
(d, 1H, H-b, J = 16 Hz), 11.95 (br s, 1H, NH) ppm; MS
(EI, 70 eV): m/z = 201 (M?, 100), 186 (63), 158 (38), 130
(37), 107 (6), 94 (27), 77 (18).
Ar
NH2OH.H2O
N
N
O
H
N
H
O
2a, 2b
(E)-3-(4-Chlorophenyl)-1-(1H-pyrrol-2-yl)prop-2-en-1-
one (2b)
Ar
7a, 7b
a
b
Cl
In 0.4 g (86%) yield; M.p.: 158–160 °C (ethanol) (Ref.
[35] 154–156 °C).
O
Ar
*
General method for preparation of 2-alkoxy-3-cyano-4,
6-diaryl pyridines
*
Scheme 4
Compound 2a or 2b (2 mmol) were added during stirring
to a freshly prepared sodium alkoxide solution (2 mmol of
sodium in 20 cm3 of each of absolute methanol or ethanol).
Malononitrile (0.2 g, 3 mmol) was then added with con-
tinuous stirring at room temperature until the precipitate
was separated out. The solid separated was collected by
filtration and recrystallized from suitable solvent.
signals at d = 1.65, 1.80 due to methylene and
d = 5.15 ppm due to methine protons of isoxazoline ring.
In addition, its mass spectrum revealed a peak at
m/z = 216 corresponding to its molecular ion.
2-Ethoxy-4-(5-methylfuran-2-yl)-6-(1H-pyrrol-2-yl)
pyridine-3-carbonitrile (4a, C17H15N3O2)
Experimental
In 0.46 g (78%) yield; M.p.: 202 °C (DMF); IR (KBr):
Chemistry
1
m ¼ 3241 (NH), 2,255 (CN) cm-1; H NMR (270 MHz,
ꢀ
DMSO-d6): d = 1.38 (t, 3H, Me, J = 6.7 Hz) 2.37 (s, 3H,
Me), 4.59 (q, 2H, CH2, J = 6.7 Hz), 6.23 (dd, 1H, H-4,
pyrrole, J = 5.9, 5.6 Hz), 6.42 (d, 1H, H-4, furan,
J = 6.8 Hz), 6.95 (d, 1H, H-3, furan, J = 6.8 Hz), 7.10
(d, 1H, H-3, pyrrole, J = 5.6 Hz), 7.4 (d, 1H, H-5, pyrrole,
J = 5.9 Hz), 7.6 (s, 1H, H-5, pyridine), 11.75 (br s, 1H,
NH) ppm; MS (EI, 70 eV): m/z = 293 (M?, 100), 278
(16), 265 (51), 236 (11), 194 (7), 179 (3), 132 (4).
Melting points were determined on a Gallenkamp melting
point apparatus. IR spectra were recorded on Shimadzu FT-
1
IR 8101 PC infrared spectrophotometer. H NMR spectra
were recorded on a Jeol EX-270 MHz spectrometer using
DMSO-d6 or CDCl3 as solvent and TMS as the internal
standard. Mass spectra were recorded on a Finnigan SSQ
7000 GC-MS spectrometer. Microanalyses were performed
at the Microanalytical Center of Cairo University and
results agreed favorably with calculated values.
4-(4-Chlorophenyl)-2-ethoxy-6-(1H-pyrrol-2-yl)pyridine-
3-carbonitrile (4b, C18H14ClN3O)
General procedure for the synthesis
of 2-chalconylpyrroles
In 0.52 g (80%) yield; M.p.: 197 °C; IR (KBr) (DMF/
H2O): m ¼ 3265 (NH), 2,248 (CN), cm
-1
;
1H NMR
ꢀ
(270 MHz, DMSO-d6): d = 1.37 (t, 3H, Me), 4.61 (q,
2H, CH2), 6.26 (dd, 1H, H-4, pyrrole, J = 5.7, 6.1 Hz),
7.11 (d, 1H, H-3, pyrrole, J = 5.7 Hz), 7.45 (d, 1H, H-5,
pyrrole, J = 6.1 Hz), 7.61 (d, 2H, J = 7.8 Hz, Ph), 7.72
(d, 2H, J = 7.8 Hz, Ph), 7.76 (s, 1H, H-5, pyridine), 11.84
(br s, 1H, NH) ppm; MS (EI, 70 eV): m/z = 323 (M?,
100), 294 (24), 278 (14), 243 (41), 229 (17), 217 (10), 194
(6), 131 (15), 113 (12), 91 (4), 77 (7).
A mixture of 0.22 g 2-acetylpyrrole (1) (2 mmol) and
2 mmol of the appropriate aldehyde (2a: 5-methylfuran-2-
carboxyaldehyde, 2b: 4-chlorobenzaldehyde) in 30 cm3
20% ethanolic NaOH was heated at 60 °C for 6 h. The
reaction mixture was left to cool. The obtained solid was
filtered off, air-dried, and crystallized from ethanol to give
the corresponding chalcones 2a, 2b.
(E)-3-(5-Methylfuran-2-yl)-1-(1H-pyrrol-2-yl)prop-2-en-1-
one (2a, C12H11NO2)
2-Methoxy-4-(5-methylfuran-2-yl)-6-(1H-pyrrol-2-yl)
pyridine-3- carbonitrile (5a, C16H13N3O2)
In 0.33 g (82%) yield; M.p.: 160–162 °C (ethanol); IR
In 0.45 g (81%) yield; M.p.: 212 °C (AcOH); IR (KBr):
1
(KBr): m ¼ 3271 (NH), 1648 (C=O), 1596 (C=C) cm-1; 1H
m ¼ 3265 (NH), 2,242 (CN), cm-1; H NMR (270 MHz,
ꢀ
ꢀ
NMR (270 MHz, DMSO-d6): d = 2.35 (s, 3H, Me), 6.25
(dd, 1H, H-4, pyrrole, J = 6.1, 5.8 Hz), 6.30 (d, 1H, H-4,
furan, J = 6.8 Hz), 6.85 (d, 1H, H-3, furan, J = 6.8 Hz),
7.12 (d, 1H, H-3, pyrrole, J = 5.8 Hz), 7.15 (d, 1H, H-5,
CDCl3): d = 2.41 (s, 3H, Me), 4.05 (s, 3H, OMe), 6.17 (dd,
1H, H-4, pyrrole, J = 5.6, 5.8 Hz), 6.32 (d, 1H, H-4, furan,
J = 6.5 Hz), 6.86 (d, 1H, H-3, furan, J = 5.5 Hz), 6.95 (d,
1H, H-3, pyrrole, J = 5.6 Hz), 7.48 (d, 1H, H-5, pyrrole,
123

232
M. A. A. Radwan, E. M. H. Abbas
J = 5.8 Hz), 7.51 (s, 1H, H-5, pyridine), 9.43 (br s, 1H,
NH) ppm; MS (EI, 70 eV): m/z = 279 (M?, 34), 278
(100), 263 (59), 249 (73), 235 (71), 220 (75), 192 (79), 178
(68), 166 (54), 140 (69), 91 (83), 77 (58).
pyrimidine, exchangeable with D2O) ppm; MS (EI, 70 eV):
m/z = 389 (M?, 17), 357 (13), 345 (31), 310 (24), 280
(16), 217 (37), 114 (27), 91 (15), 77 (38), 56 (100).
General procedure for the synthesis isoxazoline
derivatives
4-(4-Chlorophenyl)-2-methoxy-6-(1H-pyrrol-2-yl)pyridine-
3-carbonitrile (5b, C17H12ClN3O)
In 0.51 g (83%) yield; M.p.: 266 °C (AcOH/H2O); IR
-1
;
1H NMR
A mixture of 1 mmol 2a, 2b, *0.1 g hydroxylamine
hydrochloride (1 mmol), and 0.082 g anhydrous sodium
acetate (1 mmol) in 30 cm3 glacial acetic acid was heated
under reflux for 6 h. The reaction mixture was cooled,
poured into ice, the obtained solid was collected by filtra-
tion, washed with water, air dried, and crystallized from
suitable solvent to give 7a, 7b.
ꢀ
(KBr): m ¼ 3278 (NH), 2,240 (CN), cm
(270 MHz, CDCl3): d = 4.1 (s, 3H, OMe), 6.3 (dd, 1H,
H-4, pyrrole, J = 5.9, 6.2 Hz), 6.83 (d, 1H, H-3, pyrrole,
J = 5.9 Hz), 7.1 (d, 1H, H-5, pyrrole, J = 6.2 Hz), 7.2 (s,
1H, H-5, pyridine), 7.45 (d, 2H, J = 7.8 Hz, Ph), 7.55 (d,
2H, J = 7.8 Hz, Ph), 9.5 (br s, 1H, NH) ppm; MS (EI,
70 eV): m/z = 309 (M?, 100), 293 (19), 278 (41), 243
(25), 220 (13), 217 (17), 114 (22), 91 (13), 77 (32).
4,5-Dihydro-5-(5-methylfuran-2-yl)-3-(1H-pyrrol-2-yl)
isoxazole (7a, C12H12N2O2)
General procedure for the synthesis 2-thiopyrimidine
derivatives
In 0.15 g (69%) yield; M.p.: 213 °C (AcOH); IR (KBr):
1
m ¼ 3332 (NH), 1586 (C=N) cm-1; H NMR (270 MHz,
ꢀ
DMSO-d6): d = 1.65 and 1.80 (m, CH2-isoxazole), 2.41 (s,
3H, Me), 5.15 (m, CH-isoxazole), 6.13 (dd, 1H, H-4,
pyrrole, J = 5.7, 5.9 Hz), 6.24 (d, 1H, H-4, furan,
J = 6.4 Hz), 6.86 (d, 1H, H-3, furan, J = 6.4 Hz), 6.98
(d, 1H, H-3, pyrrole, J = 5.7 Hz), 7.3 (d, 1H, H-5, pyrrole,
J = 5.9 Hz), 9.11 (br s, 1H, NH, exchangeable with D2O)
ppm; MS (EI, 70 eV): m/z = 216 (M?, 14), 185 (61), 170
(49), 109 (23), 98 (45), 83 (62), 71 (91), 56 (100).
Thiourea (0.076 g, 1 mmol) was added to 1 mmol of 2a,
2b in 50 cm3 ethanolic potassium hydroxide (1%). The
reaction mixture was refluxed for 4–6 h and then poured
gradually with stirring into cold water. The solid formed
was filtered off, washed with H2O, and crystallized from
suitable solvent to give 6a, 6b.
3,4-Dihydro-4-(5-methylfuran-2-yl)-6-(1H-pyrrol-2-yl)
pyrimidine-2(1H)-thione (6a, C13H13N3OS)
5-(4-Chlorophenyl)-4,5-dihydro-3-(1H-pyrrol-2-yl)
isoxazole (7b, C13H11ClN2O)
In 0.2 g (77%) yield; M.p.: 272 °C (ethanol/DMF); IR
1
(KBr): m ¼ 3; 250ꢁ3; 260 (3NH), 1215 (C=S) cm-1; H
ꢀ
In 0.18 g (73%) yield; M.p.: 231 °C (AcOH); IR (KBr):
NMR (270 MHz, DMSO-d6): d = 2.43 (s, 3H, Me), 5.20
(d, 1H, H-4, pyrimidine, J = 5.4 Hz), 6.11 (dd, 1H, H-4,
pyrrole,, J = 5.7, 6.1 Hz), 6.21 (d, 1H, H-4, furan,
J = 6.8 Hz), 6.85 (d, 1H, H-3, furan, J = 6.8 Hz), 6.97
(d, 1H, H-3, pyrrole, J = 5.7 Hz), 7.35 (d, 1H, H-5,
pyrrole, J = 6.1 Hz), 7.41 (dd, 1H, H-5, pyrimidine,,
J = 5.4 Hz), 9.43 (br s, 1H, NH, exchangeable with D2O),
10.12, 10.14 (br 2s, 2H, 2NH-pyrimidine, exchangeable
with D2O) ppm; MS (EI, 70 eV): m/z = 259 (M?, 11), 239
(31), 211 (19), 187 (9), 109 (29), 98 (58), 83 (53), 71 (93),
56 (100).
1
m ¼ 3311 (NH), 1582 (C=N), cm-1; H NMR (270 MHz,
ꢀ
DMSO-d6): d = 1.6 and 1.83 (m, CH2-isoxazole), 4.9 (m,
CH-isoxazole), 6.14 (dd, 1H, H-4, pyrrole J = 5.6,
5.9 Hz), 7.13 (d, 1H, H-3, pyrrole J = 5.7 Hz), 7.33 (d,
1H, H-5, pyrrole J = 5.9 Hz), 7.37 (d, 2H, J = 7.8 Hz,
Ph), 7.42 (d, 2H, J = 7.8 Hz, Ph), 9.51 (br s, 1H, NH,
exchangeable with D2O) ppm; MS (EI, 70 eV): m/z = 246
(M?, 32), 244 (69), 216 (9), 181 (12), 151 (36), 139 (13),
111 (27), 94 (100), 78 (30), 66 (41).
Acknowledgments We gratefully acknowledge the financial sup-
port of the National Research Centre (NRC), Dokki, Giza, Egypt.
4-(4-Chlorophenyl)-3,4-dihydro-6-(1H-pyrrol-2-yl)
pyrimidine-2(1H)-thione (6b, C14H12ClN3S)
In 0.27 g (69%) yield; M.p.: 251 °C (ethanol/DMF); IR
References
-1
;
1H
ꢀ
(KBr): m ¼ 3249ꢁ3356 (3NH), 1217 (C=S), cm
NMR (270 MHz, DMSO-d6): d = 5.19 (d, 1H, H-4,
pyrimidine, J = 5.2 Hz), 6.14 (dd, 1H, H-4, pyrrole,
J = 5.8, 6.0 Hz), 7.1 (d, 1H, H-3, pyrrole, J = 5.8 Hz),
7.27 (d, 1H, H-5, pyrrole, J = 6.0 Hz), 7.33 (dd, 1H, H-5,
pyrimidine, J = 5.2 Hz), 7.35 (d, 2H, J = 7.8 Hz, Ph),
7.39 (d, 2H, J = 7.8 Hz, Ph), 9.51 (br s, 1H, NH,
exchangeable with D2O), 10.15, 10.21 (br 2s, 2H, 2NH-
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