Synthetic studies with 3-Oxo-N-[4-(3-oxo- 3-phenylpropionylamino)-phenyl]- 3-phenylpropionamide

Article abstract of DOI:10.1002/jhet.784

3-Oxo-N-[4-(3-oxo-3-phenylpropionylamino)-phenyl]-3-phenylpropionamide 1 and its derivative 2-benzoyl-N-[4-(2-benzoyl-3-(dimethylamino-acryloylamino)- phenyl]-3-dimethylaminoacrylamide 12 are used for the synthesis of the hitherto not known bis-heterocycl

Full text of DOI:10.1002/jhet.784

March 2012
Synthetic Studies with 3-Oxo-N-[4-(3-oxo-
3-phenylpropionylamino)-phenyl]-3-phenylpropionamide
381
Fathy M. Abdelrazek,a* Nehal A. Sobhy,a Peter Metz,b
and Akram A. Bazbouzc
aChemistry Department, Faculty of Science, Cairo University, Giza, Egypt
bInstitut fur Organische Chemie, TU-Dresden, 01062-Dresden, Germany
cChemistry Department, Faculty of Science, Al-Baath University, Homs, Syria
*E-mail: prof.fmrazek@gmail.com
Received September 3, 2010
DOI 10.1002/jhet.784
Published online 31 December 2011 in Wiley Online Library (wileyonlinelibrary.com).
3-Oxo-N-[4-(3-oxo-3-phenylpropionylamino)-phenyl]-3-phenylpropionamide 1 and its derivative 2-
benzoyl-N-[4-(2-benzoyl-3-(dimethylamino-acryloylamino)-phenyl]-3-dimethylaminoacrylamide 12 are
used for the synthesis of the hitherto not known bis-heterocyclic amine and bis-heterocyclic carboxa-
mide derivatives. Plausible mechanisms are discussed for the formation of the new compounds.
J. Heterocyclic Chem., 49, 381 (2012).
INTRODUCTION
azo/hydrazo compounds are important precursors to pyr-
idazines [14]. The reaction of enaminones with active
methylene reagents [15], amines [16], or hydrazines [17]
represents one of the strategies for the preparation of 2-
1H-pyridones, pyrroles, and pyridazines, respectively.
Over the last two decades, we have been involved in a
program aiming at the synthesis of functionally substi-
tuted heterocyclic compounds from cheap laboratory
available starting materials to be evaluated as biodegrad-
able agrochemicals [18–22]. As a part of this program,
some bis-pyridazine, bis-pyridine, and other bis-hetero-
cyclic carboxamide derivatives were required for biolog-
ical evaluation studies. 3-Oxo-N-[4-(3-oxo-3-phenylpro-
pionylamino)-phenyl]-3-phenylpropionamide 1 and its
derivative 2-benzoyl-N-[4-(2-benzoyl-3-(dimethylamino-
acryloylamino)-phenyl]-3-dimethylaminoacrylamide 12
seemed to be good candidates to fulfill this objective.
Functionalized pyridines, pyrimidines, pyridazines,
and pyrazoles and their fused derivatives have received
much attention due to their diverse biological activities
as immunosuppressant agents and antitumor active
agents [1–9]. Azepines generally also represent an im-
portant class of heterocyclic compounds due to their
psychopharmacological applications and general thera-
peutic activities [10]. The majority of attention has been
so far paid to the development of syntheses of only one
functionally substituted unit of these nuclei [11]. To our
knowledge, there are only few reports describing the
synthesis of bis-compounds containing two benzofuran
units, two thiazepine, two chalcone [12], or two pyrimi-
dine units [13], but those containing two pyridazine or
two diazepine units are hitherto not investigated. The
C
V
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F. M. Abdelrazek, N. A. Sobhy, P. Metz, and A. A. Bazbouz
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Scheme 1. The azo coupling of compound 1 with aryl diazonium salts.
RESULTS AND DISCUSSION
that the coupling products 3 are present either in the azo
enol forms 3A or in the hydrazo keto forms 3B (Scheme
1). In either case, the nucleophilic attack on the car-
bonyl groups with active methylenes is disfavored by
being either enolized to OH (in 3A) or blocked by the
hydrogen bond (in 3B). A similar behavior has been
previously observed during the trials to condense the
hyrazo derivatives of cyclic b-diketones with 4a [20]. A
detailed study of the azo coupling products confirms this
behavior [23].
It was planned to couple 1 with arene diazonium salts
2a–f to obtain the bis-hydrazo derivatives 3a–f. Condensa-
tion of these hydrazo derivatives with the active methylene
reagents 4a–c was thought to afford the intermediates 5,
which would cyclize to afford our target compounds 6a–d
(from 5a–d) and 7a,b (from 5e,f; X ¼ CN) as shown in
(Scheme 1).
In our hands, compound 1 coupled smoothly with the
diazonium salts 2a–f to afford the nicely colored bis-
hydrazo products 3a–f; however, all trials to perform
the condensation with either of 4a, 4b, or 4c were
unsuccessful under a variety of conditions even on
fusion at above 350ꢀC in the presence of ammonium
acetate, triethylamine, or piperidine, and the hydrazo
derivatives were recovered unchanged. It seemed to us
Therefore, an alternative route featuring a reversal of
events was followed, that is, to perform the condensa-
tion reaction first and then to couple the resulting con-
densation product (compounds 8 in Scheme 2) with the
diazonium salts 2a–d. To this end, the bis-anilinde 1
was allowed to condense with malononitrile 4a and
ethyl cyanoacetate 4b in refluxing acetic acid in
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Synthetic Studies with 3-Oxo-N-[4-(3-oxo-3-phenylpropionylamino)-
phenyl]-3-phenylpropionamide
383
Scheme 2. The condensation of compound 1 with active methylene reagents.
presence of ammonium acetate. These two reactions
were found to afford one and the same yellow crystal-
line product of m.p. >300ꢀC (Scheme 2). The IR spec-
trum of this product shows only one amide carbonyl
absorption band at tmax ¼ 1666 cmꢁ1, a cyano absorp-
tion band at tmax ¼ 2215 cmꢁ1 beside absorption bands
at tmax ¼ 3476, 3314, 3189, and 3089 cmꢁ1, which are
attributed to two NH groups. These IR spectral data are
completely not applicable to 8 or the enol form 9. The
1H NMR spectra of this reaction product did not display
the expected methylene protons signal in 8 d at ꢂ
3 ppm or any signals down 10 ppm that can be attrib-
uted to the OH protons in 9. Based on these data struc-
tures, 8 and 9 were excluded.
via addition of the OH to the cyano group to afford the
bis-iminopyran 10a or via elimination of ethanol to
afford 10b. These latter compounds 10a,b undergo ring
opening and recyclization in a Dimroth-type rearrange-
ment under the effect of ammonia (from ammonium
acetate) to afford the final isolable product 11.
Rearrangement of iminopyrans or pyranones under
the effect of ammonia or amines is well established in
the literature as mentioned above [11,15,25]. It has also
been found that compound 1 condenses with cyanoace-
tamide 4c to afford 11, which is apparently obtained via
the condensation and elimination of water.
The identity of the products was inferred from the
melting points and the spectral data. This last finding
confirms the structure of 11 and approves the suggested
mechanisms for its formation.
A structure, such as the bis-iminopyrans 10a, was
also excluded on the basis of the presence of a carbonyl
absorption band in the IR spectrum at tmax ¼ 1666
cmꢁ1, and the bis-pyranone structure 10b should have
revealed the carbonyl absorption band at much higher
On the other hand, we have previously reported [13]
on the reaction of 12 with malononitrile 4a and cyanoa-
cetamide 4c; however, its reaction with ethyl cyanoace-
tate 4b has not yet been investigated.
1
value (>1700 cmꢁ1[24]). All the data of the IR and H
NMR spectra are completely applicable on the bis-
2(1H)-pyridone structure 11. It can be assumed that the
condensation products 8a,b are enolized under the reac-
tion conditions to give 9a,b, which are directly cyclized
In our hands, this reaction of compound 12 with ethyl
cyanoacetate 4b in refluxing ethanol catalyzed by piperi-
dine afforded a pale yellow crystalline product, which is
formulated as the bis-pyranone-4-carboxamide derivative
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F. M. Abdelrazek, N. A. Sobhy, P. Metz, and A. A. Bazbouz
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(70 ev). Elemental analyses were carried out at the Microana-
lytical Center at Cairo University. A considerable part of the
analyses and spectra has been carried out in the institute of or-
ganic chemistry, Technical University of Dresden, Germany;
during an Alexander von Humboldt fellowship to F. M. Abdel-
razek: July–August 2009.
13 on the basis of elemental analysis and spectral data
(cf. Experimental). Fusion of this compound 13 with
ammonium acetate above their melting points led to the
formation of the bis-2(1H)-pyranone-4-carboxamide 14.
This last compound 14 was previously obtained from
the reaction of 12 with cyanoacetamide 4c [13]. The
identity of the two products was inferred from their
mixed melting point and identical analyses and spectra.
The formation of 13 is assumed to proceed through
substitution of the dimethyl amine moiety on the attack
of the active methylene anion of 4b (CNCHCOOEt)ꢁ,
followed by elimination of ethanol. Compound 13 is
easily attacked by ammonia (from heating ammonium
acetate) to undergo ring opening and recyclization with
loss of water to afford 14. Ring opening of pyranones
and iminopyrans under the effect of ammonia or amines
is well established in the literature [11,15,25]. The struc-
ture of compound 14 was further elucidated by its alter-
native synthesis through the reaction of 12 with cyanoa-
cetamide 4c as previously reported [13].
Compound 12 reacts also with a twofold excess of
the aminopyrazole 15 (Scheme 3) in refluxing ethanol to
afford a yellow crystalline product for which the bis-
pyrazolopyrimidine carboxamide 16 whose structure was
assigned based on analytical and spectral data (cf. Ex-
perimental part). The reaction of 12 with 2-aminobenzi-
midazole 17 and with o-phenylenediamine 19 under the
same reaction conditions followed the same route to
afford the bis-benzimidazolopyrimidine carboxamide 18
and the bis-benzodiazepine 20, respectively. In all these
reactions, it is apparent that amino groups of 15, 17, or
19 readily substitute the dimethylamino groups in 12
followed by elimination of water.
The azo coupling of compound 1 with the aryl diazonium
salts 2a–f. Aryl diazonium salts 2a–f (20 mmol) were freshly
prepared by adding a solution of 20 mmol of sodium nitrite in
5-mL H2O to a cold solution of the respective arylamine
hydrochloride (20 mmol) (aniline, p-chloroaniline, p-toluidine,
p-anisidine, anthranilonitrile, or methyl anthranilate) respec-
tively, in 7-mL conc. HCl with stirring. The resulting solutions
of the aryl diazonium salts were added to a cold solution of 1
(4 g; 10 mmol), in pyridine (30 mL). The reaction mixture
was stirred at room temperature for 2 h in each case, and the
solid products, so formed, were collected by filtration and
recrystallized from pyridine to afford the highly colored prod-
ucts 3a–f, respectively.
N,N0-(1,4-Phenylene)bis(3-oxo-3-phenyl-2-(2-phenylhydra-
zono)-propanamide) 3a. Yellow crystalline product: yield
(5.29 g, 87%); m.p. 302–304ꢀC; tmax ¼ 3209, 3140 (NH),
1640 (w), 1657 (CO) cmꢁ1; dH ¼ 7.15–7.85 (m, 24H, Ar-H),
11.16 (s, 2H, 2CONH), 13.60 (s, 2H, 2 hydrazone H). Anal.
Calcd. for C36H28N6O4 (608.65): C, 71.04; H, 4,64; N, 13.81.
Found: C, 70.99; H, 5.11; N, 13.43.
N,N0-(1,4-Phenylene)bis(2-(2-(4-chlorophenyl)hydrazono)-
3-oxo-3-phenylpropanamide) 3b. Yellow flakes: yield (5.75
g, 85%); m.p. 318–320ꢀC; tmax ¼ 3265, 3205, 3132 (NH),
1618 (w), 1657 (CO) cmꢁ1; dH ¼ 7.25–7.90 (m, 22H, Ar-H),
11.05 (s, 2H, 2NH), 13.30 (s, 2H, 2NH). Anal. Calcd. for
C36H26Cl2N6O4 (677.54): C, 63.82; H, 3,87; N, 12.40. Found:
C, 63.61; H, 4.07; N, 12.44.
N,N0-(1,4-Phenylene)bis(3-oxo-3-phenyl-2-(2-(4-tolyl)hydra-
zono)-propanamide) 3c. Dark yellow cotton like product:
yield (4.77 g, 75%); m.p. 295–296ꢀC; tmax ¼ 3205, 3144
(NH), 1632 (w), 1644 (CO) cmꢁ1; dH ¼ 2.3 (s, 6H, 2CH3),
7.18–7.85 (m, 22H, Ar-H), 11.20 (s, 2H, 2NH), 13.80 (s, 2H,
2NH). Anal. Calcd. for C38H32N6O4 (636.70): C, 71.68; H,
5,07; N, 13.20. Found: C, 71.53; H, 5.04; N, 13.15.
N,N0-(1,4-Phenylene)bis(2-(2-(4-methoxyphenyl)hydrazono)-
3-oxo-3-phenylpropanamide) 3d. Canary yellow crystalline
product: yield (5.20 g, 78%); m.p. 240–242ꢀC; tmax ¼ 3218,
3144 (NH), 1643, 1697 (w) (CO) cmꢁ1; MS: m/z ¼ 669
[Mþþ1, 8%]; dH ¼ 3.75 (s, 6H, 2CH3), 6.95–8.00 (m, 22H,
Ar-H), 11.35 (s, 2H, 2NH), 14.00 (s, 2H, 2NH). Anal. Calcd.
for C38H32N6O6 (668.70): C, 68.25; H, 4,82; N, 12.57. Found:
C, 68.23; H, 4.82; N, 12.43.
N,N0-(1,4-Phenylene)bis(2-(2-(2-cyanophenyl)hydrazono)-3-
oxo-3-phenylpropa-namide) 3e. Brick red crystalline product:
yield (4.87 g, 74%); m.p. 305–307ꢀC; tmax ¼ 3352, 3217
(NH), 2221 (CN), 1640 (w), 1658 (CO) cmꢁ1; MS: m/z ¼ 658
[Mþ, 11%]; dH ¼ 7.25–8.10 (m, 22H, Ar-H), 11.00 (s, 2H,
2NH), 14.20 (s, 2H, 2NH). Anal. Calcd. for C38H26N8O4
(658.66): C, 69.29; H, 3.98; N, 17.01. Found: C, 69.32; H,
3.85; N, 17.21.
CONCLUSIONS
We conclude that the 1,4-phenylene-bis-pyridazine-
4-carboxamides such as 6 could not obtained either
through azo coupling followed by condensation with
active methylene reagents or via the reverse of events.
We could also obtain some novel p-phenylene-bis-hetero-
cyclic carboxamides from readily available cheap starting
materials that could be useful for biological evaluation
studies.
EXPERIMENTAL
Melting points were measured on an Electrothermal (9100)
apparatus and 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 Gemini
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
N,N0-(1,4-Phenylene)bis(2-(2-(2-methoxycarbonylphenyl)-
hydrazono)-3-oxo-3-phenylpropa-namide) 3f. Yellow pow-
der product: yield (5.14 g, 71%); m.p. 321–323ꢀC; tmax
3215, 3141 (NH); 1655, 1683 (w), 1713 (CO) cmꢁ1; dH
¼
¼
3.98 (s, 6H, 2CH3), 7.18–8.05 (m, 22H, Ar-H), 11.00 (s, 2H,
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Synthetic Studies with 3-Oxo-N-[4-(3-oxo-3-phenylpropionylamino)-
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385
Scheme 3. The reaction of the bis-enaminone 12 with ethyl cyanoacetate and binucleophiles.
2NH), 13.33 (s, 2H, 2NH). Anal. Calcd. for C40H32N6O8
(724.72): C, 66.29; H, 4.45; N, 11.60. Found: C, 66.35; H,
4.52; N, 11.67.
6-({4-[(5-Cyano-6-oxo-4-phenyl(2-hyropyridyl)-amino]-
phenyl}-amino)-2-oxo-4-phenylhydro-pyridine-3-carboni-
trile 11. A mixture of compound 1 (4 g; 10 mmol), malononi-
trile 4a (1.32 g, 20 mmol) or ethyl cyanoacetate 4b (2.26 g,
20 mmol) and ammonium acetate (2.31 g, 30 mmol) were
fused together on an oil bath at 270ꢀC for 3 h and then left to
cool overnight. The solid mass, thus, obtained was dissolved
in hot DMF and precipitated with cold acidified water (drops
of HCl), and the solid precipitate was filtered off, washed with
cold water, dried, and recrystallized from pyridine to afford
compound 11 as pale olive green crystalline product; yield
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(3.57 g, 72% from 4a and 3.77 g, 76% from 4b), m.p.>320ꢀC.
The same compound 11 was obtained from the reaction of 1
with cyanoacetamide 4c under the same reaction conditions
(3.70 g, 75%); tmax¼ 3376, 3314, 3198 (NH), 2215 (CN),
1666 (CO) cmꢁ1; MS: m/z ¼ 496 [Mþ, 19%]; dH ¼ 2.94 (s,
2H, 2NH), 5.78 (s, 2H, pyridone 5-H), 7.11–7.57 (m, 14H,
Ar-H), 7.96 (s, 2H, 2NH). dC ¼ 81.12 (d), 95.68 (s), 116.12
(d), 117.15 (s), 126.23 (d), 127.68 (d), 128.37 (d), 134.92 (s),
136.69 (s), 140.73 (s), 163.05 (s), 169.36 (s). Anal. Calcd. for
C30H20N6O2 (496.52): C, 72.57; H, 4,06; N, 16.93. Found: C,
72.65; H, 4.22; N, 17.15.
N,N0-(1,4-Phenylene)bis(5-cyano-6-oxo-2-phenyl-6H-pyran-
3-carboxamide) 13. To a mixture of the enaminone 12 (5.1 g;
10 mmol) and ethyl cyanoacetate 4b (2.26 g; 20 mmol) in
dimethyl formamide (DMF; 25 mL) was added few drops of
sodium ethoxide as catalyst. The reaction mixture was refluxed
for 5 h and then left to cool to room temperature. The reaction
mixture was poured on ice-cold water and neutralized with
conc. HCl. The solid products thus, precipitated was collected
by filtration and crystallized from acetic acid to afford com-
pound 13 as yellow crystalline product: yield (4.21 g, 76%);
m.p. 215–216ꢀC (AcOH); tmax ¼ 3452, 3330, (NH), 2215
(CN), 1718 and 1686 (2CO) cmꢁ1; MS: m/z ¼ 554 [Mþ,
12%]; dH ¼ 7.15–7.72 (m, 14H, Ar-Hs), 8.10 (s, 2H, pyran
H), 10.05 (s, 2H, 2NH). dC ¼ 103.85 (s), 106.67 (s), 116.86
(s), 120.64 (d), 126.24 (d), 127.68 (d), 128.43 (d), 134.93 (s),
133.79 (s), 153.1 (s), 160.85 (d), 161.15 (s), 163.82 (s). Anal.
Calcd. for C32H18N4O6: (554.51): C, 69.31; H, 3.27; N, 10.10.
Found: C, 69.35; H, 3.15; N, 10.38.
6.73 (s, 2H, pyrazole H), 7.43–8.07 (m, 24H, Ar-H), 8.63
(s, 2H, Pyrimidine H), 10.22 (s, 2H, 2NH). dC ¼ 103.92 (d),
120.72 (d), 126.65 (s), 127.12 (d), 127.28 (d), 128.55
(d), 128.59 (d), 129.25 (d), 129.32 (d), 134.15 (s), 134.63 (s),
136.57 (s), 137.15 (s), 150.48 (s), 159.82 (d), 165.55 (s),
166.09 (s). Anal. Calcd for C44H30N8O2: (702.76): C, 75.20;
H, 4.30; N, 15.94. Found: C, 75.38; H, 4.50; N, 16.14.
N,N0-(1,4-Phenylene)bis(4-phenylbenzo[4,5]imidazo[1,2-a]-
pyrimidine-3-carboxamide) 18. Dark yellow crystalline prod-
uct: yield (4.62 g, 71%); m.p. 313–315ꢀC (pyridine); tmax
¼
3335, 3142 (NH), 1662 (CO) cmꢁ1; MS: m/z ¼ 650 [Mþ,
11%]; dH ¼ 7.25–8.62 (m, 22H, Ar-H), 8.64 (s, 2H, Pyrimi-
dine H), 10.20 (s, 2H, 2NH). Anal. Calcd for C40H26N8O2:
(650.69): C, 73.83; H, 4.03; N, 17.22. Found: C, 73.89; H,
4.22; N, 17.50.
(2-Phenyl (1H-benzo[b]-1,4-diazepin-3-yl))-N-{4-[(2-phe-
nyl (1H-benzo[b]-1,4-diazepin-3-yl)-carbo-nylamino-]-phenyl}-
carboxamide 20. Dirty brownish yellow crystals: yield (4.08 g,
68%); m.p. >350ꢀC (pyridine); tmax¼ 3315, 3248 (NH), 1656
(CO) cmꢁ1; MS: m/z ¼ 600 [Mþ, 15%]; dH ¼ 5.2 (s, 2H,
2NH), 6.55–7.68 (m, 24H, Ar-H), 8.20 (s, 2H, 2NH). Anal.
Calcd for C38H28N6O2: (600.67): C, 75.98; H, 4.70; N, 13.99.
Found: C, 76.05; H, 4.78; N, 14.19.
Acknowledgments. F. M. Abdelrazek thanks the Alexander von
Humboldt-Foundation (Germany) for granting a research fellow-
ship (July–August 2009) and continual support. The financial
support of this work from the research fund of the Faculty of
Science, Cairo University, is greatly appreciated.
N,N0-(1,4-Phenylene)bis(5-cyano-6-oxo-2-phenyl-1,6-dihydro-
pyridine-3-carboxamide) 14. A mixture of the bis-pyranone 13
(5.54 g; 10 mmol) and ammonium acetate (3.85 g; 50 mmol)
was fused on an oil bath adjusted at 300ꢀC for 4 h and then
left to cool overnight. The resulting mass was triturated with
acetic acid, and the lumps were crushed; then the reaction
mixture was boiled in acetic acid till complete dissolution and
filtered while hot. On leaving to cool to room temperature,
pale yellow crystals precipitated which were filtered off to
give 14; yield (3.97 g, 72%); m.p. 282–284ꢀC (AcOH). Com-
pound 14 was also prepared from 12 and cyanoacetamide 4c
in refluxing ethanol catalyzed by sodium ethoxide as described
previously [13]; Yield (3.86 g, 70%) m.p. 284–285ꢀC (AcOH);
tmax¼ 3451, 3333, 3141 (NH), 2213 (CN), 1687 (CO), and
1659 (CO) cmꢁ1; MS: m/z ¼ 552 [Mþ, 15%]; 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.
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The reaction of 12 with the heteroaromatic amines 15,
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N,N0-(1,4-Phenylene)bis(2,7-diphenylpyrazolo[1,5-a]pyrim-
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