A novel synthesis of some 1,4-phenylene-bis-heterocyclic carboxamide derivatives

Article abstract of DOI:10.1002/jhet.257

(Chemical Equation Presented) N,N′-(1,4-phenylene)bis(3-oxo-3- phenylpropanamide) 1 reacts with DMFDMA in refluxing toluene to afford N,N′-(1,4-phenylene)bis(2-benzoyl-3-(dimethylamino)acrylamide) 2. Compound 2 reacts with a twofold excess of the active methylene reagents 3a-c to afford the pent-2-enediamide derivatives 7 and 8a,b, respectively. Compounds 7 and 8a could be cyclized to afford the same compound N,N′-(1,4-phenylene) bis(5-cyano-6-oxo-2-phenyl-1,6-dihydropyridine-3-carboxamide) 9a while 8b was cyclized to afford the 6-thioxo analogue 9b. Compound 2 reacts with hydrazine derivatives 10a,b in refluxing ethanol/piperidine to afford the hydrazinylacrylamide derivatives 11a,b, which have been cyclized to the corresponding N,N′-(1,4-phenylene)bis(1H-pyrazole-4-carboxamide) derivatives 12a,b, respectively. Compound 2 reacts also with urea derivatives 13a-c in refluxing ethanol/piperidine to afford the N,N′-(1,4-phenylene) bis(2-benzoyl-3-substituted-acrylamide) derivatives 14a-c, which could be cyclized into N,N′-(1,4-phenylene)bis(6-phenyl-1,2-dihydropyrimidine-5- carboxamide)-2-oxo; 2-thioxo or 2-imino derivatives 15a-c, respectively.

Full text of DOI:10.1002/jhet.257

1380
A Novel Synthesis of Some 1,4-Phenylene-bis-heterocyclic
Carboxamide Derivatives
Vol 46
Fathy M. Abdelrazek,* Nadia H. Metwally, Nazmi A. Kassab,
and Nehal A. Sobhy [1]
Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
*E-mail: prof.fmrazek@gmail.com
Received May 29, 2009
DOI 10.1002/jhet.257
Published online 11 November 2009 in Wiley InterScience (www.interscience.wiley.com).
N,N0-(1,4-phenylene)bis(3-oxo-3-phenylpropanamide) 1 reacts with DMFDMA in refluxing toluene to
afford N,N0-(1,4-phenylene)bis(2-benzoyl-3-(dimethylamino)acrylamide) 2. Compound 2 reacts with a
twofold excess of the active methylene reagents 3a-c to afford the pent-2-enediamide derivatives 7 and
8a,b, respectively. Compounds 7 and 8a could be cyclized to afford the same compound N,N0-(1,4-phe-
nylene)bis(5-cyano-6-oxo-2-phenyl-1,6-dihydropyridine-3-carboxamide) 9a while 8b was cyclized to
afford the 6-thioxo analogue 9b. Compound 2 reacts with hydrazine derivatives 10a,b in refluxing etha-
nol/piperidine to afford the hydrazinylacrylamide derivatives 11a,b, which have been cyclized to the
corresponding N,N0-(1,4-phenylene)bis(1H-pyrazole-4-carboxamide) derivatives 12a,b, respectively.
Compound 2 reacts also with urea derivatives 13a-c in refluxing ethanol/piperidine to afford the N,N0-
(1,4-phenylene)bis(2-benzoyl-3-substituted-acrylamide) derivatives 14a-c, which could be cyclized into
N,N0-(1,4-phenylene)bis(6-phenyl-1,2-dihydropyrimidine-5-carboxamide)-2-oxo; 2-thioxo or 2-imino
derivatives 15a-c, respectively.
J. Heterocyclic Chem., 46, 1380 (2009).
INTRODUCTION
nuclei [7,8]. To our knowledge there is only one report
describing the synthesis of compounds containing two
4H-benzopyran units [9], but those containing two pyri-
done units, two pyrazole units or two pyrimidine units,
are hitherto not investigated. The reaction of enami-
nones with active methylene reagents [10], amines [11],
or hydrazines [12] represents one of the strategies for
the preparation of 2-1H-pyridones, pyrroles, and pyrida-
zines, respectively. In the last two decades, we have
been involved in a program aiming at the synthesis of
functionally substituted heterocyclic compounds from
Pyridines and pyridones represent an important class
of organic compounds due to their pharmaceutical appli-
cations [2–4]. Furthermore functionalized pyrazoles
have received much attention due to their diverse bio-
logical activities as immunosuppressant agents, selective
COX-2 inhibitors, and antitumor agents [5]. Pyrimidine
derivatives also exhibit HMG-CoA reductase inhibitory
effect and antitumor activity [6]. The majority of atten-
tion has been so far paid to the development of synthe-
ses of only one functionally substituted unit of these
C
V
2009 HeteroCorporation

November 2009
A Novel Synthesis of Some 1,4-Phenylene-bis-heterocyclic
Carboxamide Derivatives
1381
Scheme 1. Preparation of compounds 2, 7, 8, and 9.
cheap laboratory available starting materials to be tested
as biodegradable agrochemicals [13–15]. Some func-
tional compounds bearing two or more of the aforemen-
tioned units are required for biological activity studies.
1,4-Phenylenediamine seemed a suitable candidate to
fulfill this objective.
RESULTS AND DISCUSSION
1,4-Phenylenediamine smoothly undergoes the con-
densation reaction with twofold excess of ethyl benzoy-
lacetate in refluxing dimethylformamide (DMF) to
afford quantitatively N,N0-(1,4-phenylene)bis(3-oxo-3-
phenylpropanamide) 1.
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DOI 10.1002/jhet

1382
F. M. Abdelrazek, N. H. Metwally, N. A. Kassab, and N. A. Sobhy
Vol 46
Scheme 2. Preparation of compounds 11, 12, 14, 15.
Compound 1 reacts with dimethylformamide dimethy-
tion to the bis-iminopyran derivative 6, which is re
attacked by dimethylamine to afford the isolable product
7. Recently, we could prove via an X-ray crystallo-
graphic study that 3a substitutes NMe2 followed by cy-
clization into iminopyran and ring opening by the attack
of dimethylamine [10].
lacetal (DMFDMA) in refluxing toluene to afford N,N0-
(1,4-phenylene)bis(2-benzoyl-3-(dimethylamino)acryla-
mide) 2 in quantitative yield (cf. Scheme 1).
Compound 2 reacts with a twofold excess of malono-
nitrile 3a to afford a product of molecular mass m/z ¼
642. This molecular mass is applicable to the molecular
formula C36H34N8O4. N,N0-(1,4-phenylene)bis(2-cyano-
4-((dimethylamino)(phenyl)methylene)pent-2-enediamide)
7 (Scheme 1) was assigned to this product based on ana-
lytical and spectral data (cf. Experimental part). In this
reaction it is apparent that malononitrile moieties readily
substitute the dimethylamino groups in 2 with elimina-
tion of dimethylamine to give the intermediate 5 rather
than the initial condensation of 3a with the carbonyl
groups of 2 and cyclization after the claimed hydrolysis
of two cyano groups (one on each side) to amide groups
to give 4 [16,17]. The intermediate 5 undergoes cycliza-
Refluxing compound 7 in ethanol/sodium ethoxide
furnished its cyclization to the desired N,N0-(1,4-phenyl-
ene)bis(5-cyano-6-oxo-2-phenyl-1,6-dihydropyridine-3-
carboxamide) 9a via re-elimination of dimethylamine.
The IR spectrum of this product showed absorption
bands at tmax at 3451–3141 cmꢀ1 for the NH protons,
2213 cmꢀ1 for the CN groups, 1687 and 1659 cmꢀ1 for
the carbonyl groups. The mass spectrum showed the
1
molecular ion peak at m/z ¼ 552 [Mþ]. H NMR spec-
trum showed signals at dH ¼ 7.15–7.68 (m, 14H, Ar-
Hs), 7.70 (s, 2H, 2NH), 7.99 (s, 2H, Pyridone 4-Hs),
10.07 (s, 2H, 2NH). Thus structure 9a was established
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009
A Novel Synthesis of Some 1,4-Phenylene-bis-heterocyclic
Carboxamide Derivatives
1383
for this product on the basis of the spectral and element
analysis data, which are in complete agreement with this
structure.
CONCLUSION
We could obtain some novel p-phenylene-bis-hetero-
cyclic carboxamides from readily available cheap
starting materials that could be useful for biological
evaluation studies.
Compound 2 also reacts with cyanoacetamide 3b in
refluxing ethanol with few drops of piperidine as cata-
lyst to afford the product 8a via substitution of NMe2 in
2 by cyanoacetamide. Refluxing compound 8a in etha-
nol/sodium ethoxide furnished its cyclization to afford
the same product 9a via loss of water. This finding is in
complete agreement with our reported behavior of 3b
with enaminones that had been rationalized in our previ-
ous article [10].
EXPERIMENTAL
Melting points were measured on an Electrothermal (9100)
apparatus and are uncorrected. IR spectra were recorded as
KBr pellets on a Perkin Elmer 1430 spectrophotometer. The
1H NMR and 13C NMR spectra were taken on a Varian Gem-
ini 300 MHz spectrometer in DMSO-d6 using TMS as internal
standard and chemical shifts are expressed in d ppm values.
Mass spectra were taken on a Shimadzu GCMS-GB 1000 PX
(70 ev). Elemental analyses were carried out at the Micro-ana-
lytical Center at Cairo University.
N,N0-(1,4-phenylene)bis(3-oxo-3-phenylpropanamide) 1. A
mixture of p-phenylenediamine (10 mmol) and ethyl benzoyla-
cetate (20 mmol) in DMF (15 mL) was refluxed for 3 h and
then left to cool to room temperature. The reaction mixture
was then poured onto ice-cold water and the precipitated solid
was filtered off and recrystallized from ethanol to afford 1 as
yellow crystalline solid; yield (3.84 g; 96%); mp 237–238ꢁC
(EtOH/DMF). tmax ¼ 3470, 3377, 3271 (NH), 1687(CO),
1641 (amide CO); dH. MS: m/z ¼ 400 (Mþ). dH ¼ 3.54 (s,
4H, 2CH2), 7.29–7.85 (m, 14H, arom. H), 9.95 (s, 2H, 2NH).
Anal. Calcd for C24H20N2O4 (400.43): C, 71.99; H, 5.03; N,
7.00. Found: C, 72.08; H, 5.13; N, 7.28.
N,N0-(1,4-phenylene)bis(2-benzoyl-3-(dimethylamino)acry-
lamide) 2. To compound 1 (4 g; 10 mmol) in 20 mL of dry
toluene was added (2.4 g; 20 mmol) of DMFDMA and the
reaction mixture was refluxed for 4 h, whereby the reactants
dissolve completely to a clear solution and then a precipitate
reappeared. The flask was left to cool to room temperature and
the solid product was collected by filtration and recrystallized
from ethanol to give compound 2 as yellow crystalline solid;
yield (4.85 g; 95%); mp 209–210ꢁC (EtOH/DMF). tmax
3400, 3265, 3131 (NH), 1655(CO), 1642 (amide CO); dH
3.33 (s, 12H, 4CH3), 7.14–8.00 (m, 14H, arom.), 7.44 (s, 2H,
olefinic protons), 10.07 (s, 2H D2O exch., 2NH). MS: m/z ¼
510 (Mþ).
Following the same mechanistic pathway during its
reaction with 3b, compound 2 reacts with cyanothioace-
tamide 3c in refluxing ethanol/piperidine to afford a yel-
low crystalline product, which showed the presence of
sulfur in the element test. The IR spectrum showed car-
bonyl absorption bands at tmax ¼ 1658 & 1680 cmꢀ1
and the mass spectrum showed the molecular ion peak
at m/z ¼ 620 [Mþ]. Based on these data as well as the
1H NMR and elemental analytical data structure 8b was
assigned to this product. Refluxing compound 8b in
ethanol/sodium ethoxide led to its cyclization via loss
of water to afford the N,N0-(1,4-phenylene)bis(5-cyano-
2-phenyl-6-thioxo-1,6-dihydropyridine-3-carboxamide)
compound 9b (cf. Scheme 1 and Experimental part).
Compound 2 reacts also with hydrazine hydrate 10a
and with phenyl hydrazine 10b in refluxing ethanol/pi-
peridine to afford the hydrazinylacrylamide derivatives
11a and 11b, respectively (Scheme 2), in which the
hydrazino moiety (A-NHNHR) of 10a or 10b substitutes
the -NMe2 of 2 on both sides. These could be readily
cyclized in refluxing ethanol/sodium ethoxide to give
N,N0-(1,4-phenylene)bis(5-phenyl-1H-pyrazole-4-carbox-
amide) 12a and N,N0-(1,4-phenylene)bis(1,5-diphenyl-
1H-pyrazole-4-carboxamide) 12b. Analytical and spec-
tral data are in complete agreement with structures
11a,b and 12a,b (cf. experimental).
Similarly, compound 2 reacts with urea 13a, thiourea
13b, and guanidine 13c in refluxing ethanol/piperidine
to afford yellow products with molecular masses 540,
672, and 538, respectively. It is apparent also in this
case that the dimethylamino groups of 2 were substi-
tuted by the ANHCXNH2 of the respective urea deriva-
tive with elimination of dimethylamine to afford com-
pounds 14a, 14b, and 14c, respectively.
Compounds 14a-c could also be cyclized upon their
reflux in ethanol/sodium ethoxide solution to afford
the desired N,N0-(1,4-phenylene)bis(2-oxo-6-phenyl-1,2-
dihydropyrimidine-5-carboxamide) 15a N,N0-(1,4-phe-
nylene)bis(6-phenyl-2-thioxo-1,2-dihydropyrimidine-5-
carboxamide) 15b and N,N0-(1,4-phenylene)bis (2-imino-
6-phenyl-1,2-dihydropyrimidine-5-carboxamide) 15c,
respectively.
¼
¼
Anal. Calcd for C30H30N4O4 (510.58): C, 70.57; H, 5.92; N,
10.97. Found: C, 70.62; H, 5.98; N, 11.17.
N,N0-(1,4-phenylene)bis(2-cyano-4-((dimethylamino)
(phenyl)methylene)pent-2-enediamide)7. To a mixture
of the enaminone 2 (5.1 g; 10 mmol) and malononitrile 3a
(1.32 g; 20 mmol) in ethanol (25 mL) was added few drops of
piperidine as catalyst. The reaction mixture was refluxed for 2
h and then left to cool to room temperature. The solid product
thus precipitated that was collected by filtration and crystal-
lized from acetic acid to afford compound 7 as yellow crystal-
line product: yield (5 g, 78%); mp 246–247ꢁC (AcOH); tmax
¼ 3451, 3333, 3141 (NH & NH2), 2213 (CN), 1687 (CO), and
1659 (CO) cmꢀ1; MS: m/z ¼ 642 [Mþ]; dH ¼ 2.85 (s, 12H, 4
ꢂ CH3), 7.15–7.68 (m, 14H, Ar-Hs), , 6.78 (s, 4H, 2NH2),
7.70 (s, 2H, 2NH), 7.98 (s, 2H, 3-Hs).
Anal. Calcd for C36H34N8O4: (642.71): C, 67.28; H, 5.33;
N, 17.43. Found: C, 67.35; H, 5.38; N, 17.35.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1384
F. M. Abdelrazek, N. H. Metwally, N. A. Kassab, and N. A. Sobhy
Vol 46
drazine 10b (20 mmol) in ethanol (25 mL) was added few
drops of piperidine as catalyst. The reaction mixture was
refluxed for 3 h, where a solid precipitate was formed during
the reflux. The flask was left to cool to room temperature and
the product was collected by filtration in each case and washed
thoroughly with cold ethanol and recrystallized from DMF/
ethanol to afford 11a,b, respectively.
N,N0-(1,4-phenylene)bis(2-benzoyl-3-hydrazinylacrylamide)
11a. Pale yellow crystals, Yield (2.7 g; 56%), mp. 235–236ꢁC
(EtOH/DMF); tmax ¼ 3343, 3235, 2156 (NH & NH2), 1687
and 1655 cmꢀ1 (2CO); MS: m/z ¼ 484 [Mþ]; dH ¼ 4.45 (br.
s, 4H, 2NH2), 7.04–7.68 (m, 14H, Ar.Hs), 7.76 (s, 2H, olefin
Hs), 8.15 (s, 2H, 2NH), 9.55 (br.s., 2H, 2NH).
The reaction of the enaminone 2 with the acetamides
3b,c. To a mixture of the enaminone 2 (5.1 g; 10 mmol) and
cyanoacetamide 3b (1.64 g; 20 mmol) or cyanothioacetamide
3c (2.0 g, 20 mmol) in ethanol (25 mL) was added few drops
of piperidine as catalyst. The reaction mixture was refluxed in
each case for 2 h and then left to cool at room temperature. The
solid products thus precipitated were collected by filtration and
crystallized from acetic acid to afford compound 8a and 8b.
N,N0-(1,4-phenylene)bis(2-benzoyl-4-cyanopent-2-enedia-
mide) 8a. Yellow crystalline product: yield (4.47 g, 76%); mp
234–235ꢁC (AcOH); tmax ¼ 3452, 3330, 3142 (NH & NH2),
2215 (CN), 1686 (CO), and 1656 (CO), 1640 (CO) cmꢀ1; MS:
m/z ¼ 588 [Mþ]; dH ¼ 3.34 (d, 2H, 2Hs; j ¼ 12.62 Hz), 7.15–
7.68 (m, 14H, Ar-Hs), 7.72 (s, 2H, 2NH), 7.98 (d, 2H, 3-Hs;
j ¼ 12.62 Hz), 10.05 (s, 4H, 2NH2).
Anal. Calcd for C26H24N6O4: (484.51): C, 64.45; H, 4.99;
N, 17.35. Found: C, 64.48; H, 5.09; N, 17.47.
N,N0-(1,4-phenylene)bis(2-benzoyl-3-(2-phenylhydrazinyl)
acrylamide) 11b. Yellow crystals, Yield (3.8 g; 60%), mp.
243–245ꢁC (EtOH/DMF); tmax ¼ 3344, 3226 (NH), 1685, and
1654 (2CO) cmꢀ1; MS: m/z ¼ 636 [Mþ]; dH ¼ 5.56 (s, 2H,
2NH), 7.14–7.72 (m, 24H, Ar. Hs), 7.74 (s, 2H, olefin Hs),
8.25 (s, 2H, 2NH), 9.77 (br.s., 2H, NH).
Anal. Calcd for C32H24N6O6: (588.57): C, 65.30; H, 4.11;
N, 14.28. Found: C, 65.32; H, 4.15; N, 14.38.
N,N0-(1,4-phenylene)bis(5-amino-2-benzoyl-4-cyano-5-
thioxopent-2-enamide) 8b. Yellow crystalline product: yield
(4.28 g, 69%); mp 213–215ꢁC (AcOH); tmax ¼ 3454, 3332,
3140 (NH & NH2), 2219 (CN), 1679 (CO), and 1656 (CO)
cmꢀ1; MS: m/z ¼ 621 [Mþ þ 1]; dH ¼ 3.32 (d, 2H, 2Hs; j ¼
12.6 Hz), 7.14–7.67 (m, 14H, Ar-Hs), 7.73 (s, 2H, 2NH), 7.92
(d, 2H, 3-Hs; j ¼ 12.6 Hz), 10.04 (s, 4H, 2NH2).
Anal. Calcd for C38H32N6O4: (636.70): C, 71.68; H, 5.07;
N, 13.20. Found: C, 71.75; H, 5.27; N, 13.38.
Cyclization of 11a,b. To a solution of each of compounds
11a and 11b (10 mmol) in 20 mL of ethanol was added few
drops of sodium ethoxide (freshly prepared by dissolving 0.1 g
of sodium metal in 10 mL of absolute ethanol). The reaction
mixture was refluxed for 1 h in each case then left to cool
overnight. The reaction mixture was poured on ice cold water
and neutralized with few drops of HCl. The precipitated solids
were collected by filtration and recrystallized to give 12a,b,
respectively.
N,N0-(1,4-phenylene)bis(5-phenyl-1H-pyrazole-4-carboxamide)
12a. Pale yellow crystals, Yield (2.6 g; 58%), mp. 295–296ꢁC
(EtOH/DMF); tmax ¼ 3343, 3235 (NH), and 1655 cmꢀ1 (CO);
MS: m/z ¼ 448 [Mþ]; dH ¼ 7.06–7.65 (m, 16H, Ar.Hs), 8.15
(s, 2H, 2NH), 9.25 (br.s., 2H, 2NH).
Anal. Calcd for C32H24N6O4S2: (620.70): C, 61.92; H, 3.90;
N, 13.54; S, 10.33. Found: C, 61.98; H, 3.85; N, 13.74; S,
10.50.
Cyclization of 7 and 8a,b. To the solution of each com-
pounds 7, 8a, and 8b (10 mmol) in 20 mL of ethanol was
added few drops of sodium ethoxide (freshly prepared by dis-
solving 0.1 g of sodium metal in 10 mL of absolute ethanol).
The reaction mixture was refluxed for 1 h in each case then
left to cool overnight. The contents of the flask was poured on
ice cold water and acidified with few drops of HCl till just
neutral. The precipitated solids were collected by filtration and
recrystallized to give.
N,N0-(1,4-phenylene)bis(5-cyano-6-oxo-2-phenyl-1,6-di-
hydropyridine-3-carboxamide) 9a. Pale yellow crystals,
yield (3.7 g, 67 % from 7; mp 282–283ꢁC (AcOH) and 3.86 g;
70% from 8a; mp 284–285ꢁC (AcOH); tmax ¼ 3451, 3333,
3141 (NH), 2213 (CN), 1687 (CO), and 1659 (CO) cmꢀ1; MS:
m/z ¼ 552 [Mþ]; dH ¼ 7.15–7.68 (m, 14H, Ar-Hs), 7.70 (s,
2H, 2NH), 7.99 (s, 2H, Pyridone 4-Hs), 10.07 (s, 2H, 2NH).
Anal. Calcd for C32H20N6O4: (552.54): C, 69.56; H, 3.65;
N, 15.21. Found: C, 69.55; H, 3.68; N, 15.28.
Anal. Calcd for C26H20N6O2: (448.48): C, 69.63; H, 4.49;
N, 18.74. Found: C, 69.52; H, 4.58; N, 18.96.
N,N0-(1,4-phenylene)bis(1,5-diphenyl-1H-pyrazole-4-carboxa-
mide) 12b. Yellow crystals, Yield (3.78 g; 63%), mp. 300–
302ꢁC (EtOH/DMF); tmax ¼ 3344, 3226 (NH), and 1657 (CO)
cmꢀ1; MS: m/z ¼ 600 [Mþ]; dH ¼ 7.21–8.34 (m, 26H, Ar.
Hs), 9.77 (br.s., 2H, NH). dC ¼ 118.81 (s), 119.55 (d), 120.67
(d), 127.75 (d), 127.3 (d), 128.55 (d), 129.05 (d), 129.22 (d),
133.08 (s), 136.53 (s), 138.94 (s), 139.52 (d), 140.01 (s),
193.19 (s).
N,N0-(1,4-phenylene)bis(5-cyano-2-phenyl-6-thioxo-1,6-
dihydropyridine-3-carboxamide) 9b. Yellow crystalline
product, yield (4.2 g; 72 %), mp. 291–292ꢁC (AcOH); tmax
¼
Anal. Calcd for C38H28N6O2: (600.67): C, 75.98; H, 4.70;
N, 13.99. Found: C, 76.08; H, 4.76; N, 13.85.
3345, 3228 (NH), 2215 (CN), and 1658 cmꢀ1 (CO); MS: m/z
¼ 585 [Mþ þ 1]; dH ¼ 7.15–7.68 (m, 16H, Ar.), 8.25 (br.s.,
2H, 2NH), 10.12 (br.s., 2H, 2NH). dC ¼ 104.9 (s), 116.2 (s),
118.05 (s), 119.58 (d), 127.34 (d), 127.67 (d), 128.34 (d),
133.14 (s), 136.85 (s), 154.39 (s), 160.17 (d), 166.5 (s), 175,
52 (s).
The reaction of the enaminone 2 with urea derivatives
13a-c. To a mixture of the enaminone 2 (5.1 g; 10 mmol) and
urea 13a, thiourea 13b, or guanidine hydrochloride 13c (20
mmol) in ethanol (25 mL) was added few drops of triethyl-
amine as catalyst in case of 13a,b and two mole equivalents in
case of 13c. The reaction mixture was refluxed in each case
for 3 h and then left to cool overnight. The contents of the
flask was poured on ice-cold water and neutralized by HCl.
The precipitated products were collected by filtration in each
case and recrystallized from DMF/ethanol to afford 14a, 14b,
and 14c, respectively.
Anal. Calcd for C32H20N6O2S2: (584.67): C, 65.74; H, 3.45;
N, 14.37; S, 10.97. Found: C, 65.78; H, 3.55; N, 14.45; S,
10.58.
The reaction of the enaminone 2 with hydrazine hydrate
and phenyl hydrazine 10a,b. To a mixture of the enaminone
2 (5.1 g; 10 mmol) and hydrazine hydrate 10a or phenyl hy-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009
A Novel Synthesis of Some 1,4-Phenylene-bis-heterocyclic
Carboxamide Derivatives
1385
N,N0-(1,4-phenylene)bis(2-benzoyl-3-ureidoacrylamide)
14a. Yellow crystals, Yield (3.51 g; 65%), mp. 213–215ꢁC
(EtOH/DMF); tmax ¼ 3342, 3226, 3167 (NH & NH2), 1678,
dH ¼ 6.45 (s, 2H, 2NH), 7.14–7.88 (m, 16H, Ar), 7.94 (s, 2H,
2NH), 10.17 (s, 2H, 2NH).
Anal. Calcd. for C28H22N8O2: (502.53): C, 66.92; H, 4.41;
N, 22.30. Found: C, 67.12; H, 4.47; N, 22.50.
1662, and 1658 (3CO) cmꢀ1; MS: m/z ¼ 540 [Mþ]; dH
¼
5.51 (s, 4H, 2NH2), 7.08–7.65 (m, 14H, Ar. Hs), 7.92 (s, 2H,
2NH), 8.45 (s, 2H, olefin Hs), 10.17 (s, 2H, 2NH).
Anal. Calcd. for C28H24N6O6: (540.53): C, 62.22; H, 4.48;
N, 15.55. Found: C, 62.28; H, 4.56; N, 15.75.
N,N0-(1,4-phenylene)bis(2-benzoyl-3-thioureidoacrylamide)
14b. Yellow crystalline product, Yield (3.8 g; 67%), mp. 219–
220ꢁC (EtOH/DMF); tmax ¼ 3340, 3225, 3165 (NH & NH2),
1676, 1660, and 1655 (3CO) cmꢀ1; MS: m/z ¼ 572 [Mþ]; dH
¼ 5.52 (s, 4H, 2NH2), 7.08–7.66 (m, 14H, Ar. Hs), 7.75 (s,
2H, olefin Hs), 7.93 (s, 2H, 2NH), 10.15 (s, 2H, 2NH).
Anal. Calcd. for C28H24N6O4S2: (572.66): C, 58.73; H,
4.22; N, 14.68; S, 11.20. Found: C, 58.78; H, 4.26; N, 14.78;
S, 11.00.
Acknowledgments. F. M. Abdelrazek thanks the Alexander von
Humboldt- Foundation (Germany) for granting a research fellow-
ship (Jul-Aug. 2009); and Professor Peter Metz, Institute of
Organic Chemistry, Technical University of Dresden for his kind
hospitality.
REFERENCES AND NOTES
[1] This work is abstracted in part from the Ph.D. thesis of
Mrs. Nehal A. Sobhy.
N,N0-(1,4-phenylene)bis(2-benzoyl-3-guanidinoacrylamide)
14c. Yellow powder, Yield (3.6 g; 68%), mp. 222–224ꢁC
(EtOH/DMF); tmax ¼ 3338, 3222, 3170 (NH & NH2), 1678,
and 1658 (2CO) cmꢀ1; MS: m/z ¼ 538 [Mþ]; dH ¼ 5.51 (s,
4H, 2NH2), 7.05–7.68 (m, 16H, Ar. þ olefin Hs), 7.92 (s, 2H,
2NH), 8.15 (s, 2H, 2NH), 10.17 (s, 2H, 2NH).
[2] Meyer, H.; Sitt, R.; Thomas, G.; KaurseH.; Ger. Offen.
3015 219; Chem Abstr 1982, 96, 6604d.
[3] Deshang, P.; Cipolina, J. A.; Lowmoster, N. K. J Org Chem
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[4] Worbel, J.; Li, Z.; Dietrich, A.; McCaleb, M.; Mihan, B.;
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[5] (a) Wang, A. X.; Qinghua, X.; Lane, B.; Mollison, K. W.;
Hsieh, G. C.; Marsh, K.; Sheets, M. P.; Luly, J. R.; Coghlan, M. J.
Bioorg Med Chem Lett 1998, 8, 2787; (b) Kim, H. H.; Park, T. G.;
Moon, T. C.; Chang, H. W.; Jahng, Y. Arch Pharm Res 1999, 22, 372;
(c) Park, H.-J.; Lee, K.; Park, S.-J.; Ahn, B.; Lee, J.-C.; Yeong, H.;
Lee, C. K.-I. Bioorg Med Chem Lett 2005, 15, 3307.
[6] (a) Watanabe, M.; Koike, H.; Ishiba, T.; Okada, T.; Hirai,
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castre, A.; Solano, J. D. J Pharm Pharmaceut Sci 1999, 2, 108.
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1757.
Anal. Calcd. for C28H26N8O4: (538.56): C, 62.44; H, 4.87;
N, 20.81. Found: C, 62.32; H, 4.58; N, 20.70.
Cyclization of compounds 14a-c. To a solution of each of
compounds 14a, 14b, or 14c (10 mmol) in 20 mL of ethanol
was added few drops of sodium ethoxide and the reaction mix-
ture was refluxed for 1 h in each case then left to stand over-
night. The reaction mixture was poured on ice cold water and
neutralized with few drops of HCl. The precipitated solids
were collected by filtration and recrystallized to give 15a-c,
respectively.
N,N0-(1,4-phenylene)bis(2-oxo-6-phenyl-1,2-dihydropyr-
imidine-5-carboxamide) 15a. Yellow crystals, Yield (3.27 g;
65%), mp. 286–287ꢁC (EtOH/DMF); tmax ¼ 3342, 3226
(NH), 1662, and 1658 (2CO) cmꢀ1; MS: m/z ¼ 504 [Mþ]; dH
¼ 7.12–7.85 (m, 16H, Ar. Hs), 7.92 (s, 2H, 2NH), 10.17 (s,
2H, 2NH).
[8] Yermolayev, S. A.; Gorobets, N. Yu.; Lukinova, E. V.;
Shishkin, O. V.; Shishkina, S. V.; Desenko, S. M. Tetrahedron 2008,
64, 4649.
[9] Fing, Y.-J.; Miao, C.-B.; Gao, Y.; Tu, S.-J.; Fang, F.; Shi,
D.-Q. Chin J Chem 2004, 22, 622.
[10] Abdelrazek, F. M.; Elsayed, A. N. J Heterocycl Chem,
2009, 46, 949.
Anal. Calcd. for C28H20N6O4: (504.50): C, 66.66; H, 4.00;
N, 16.66. Found: C, 66.70; H, 4.05; N, 16.48.
[11] Abdelrazek, F. M.; Metwally, N. H. Synth Commun, to
appear.
N,N0-(1,4-phenylene)bis(6-phenyl-2-thioxo-1,2-dihydropyr-
imidine-5-carboxamide) 15b. Yellow crystals, Yield (3.59 g;
67%), mp. 290–291ꢁC (EtOH/DMF); tmax ¼ 3345, 3228
[12] Abdelrazek, F. M.; Elsayed, A.N. Afinidad, to appear.
[13] Abdelrazek, F. M.; Metz, P.; Metwally, N. H.; El-Mah-
rouky, S. F. Arch Pharm Chem Life Sci (Weinheim) 2006, 339, 456.
[14] Abdelrazek, F. M.; Metz, P.; Kataeva, O.; Jaeger, A.;
El-Mahrouky, S. F. Arch Pharm Chem Life Sci (Weinheim) 2007,
340, 543.
(NH), and 1655 (CO) cmꢀ1; MS: m/z ¼ 535 [Mþ ꢀ 1]; dH
¼
7.14–7.88 (m, 16H, Ar. Hs), 7.90 (s, 2H, 2NH), 10.17 (s, 2H,
2NH).
Anal. Calcd. for C28H20N6O2S2: (536.63): C, 62.67; H,
3.76; N, 15.66; S, 11.95. Found: C, 62.80; H, 3.72; N, 15.45;
S, 12.25.
[15] Abdallah, T. A.; Metwally, N. H.; Abdelrazek, F. M. Afini-
dad 2008, 65, 393.
[16] Al-Omran, F.; Al-Awadhi, N.; Abdelkhalik, M. M.; Kaul,
K.; Abu El-Khair, A.; ElnagdiM. H. J Chem Res (S) 1997, 84; (M)
1997, 601
N,N0-(1,4-phenylene)bis(2-imino-6-phenyl-1,2-dihydropyr-
imidine-5-carboxamide) 15c. Yellowish orange crystals,
Yield (3.16 g; 63%), mp. 280–282ꢁC (EtOH/DMF); tmax
¼
[17] Al-Omran, F.; Abu El-Khair, A.; Elnagdi, M. H. J Chem
Res (S) 1998, 798.
3343, 3232 (NH), and 1656 (CO) cmꢀ1; MS: m/z ¼ 502 [Mþ];
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet