The reaction of ethyl benzoylacetate with malononitrile: A novel synthesis of some pyridazine, pyridazino[2,3-a]quinazoline and pyrrole derivatives

Article abstract of DOI:10.1016/S0040-4020(00)01153-4

Ethyl benzoylacetate undergoes Claisen condensation reaction with malononitrile to afford 2-cyano-5-phenyl-3,5-dioxopentanonitrile which could be cyclized into 2-aminopyran and coupled with diazonium salts to afford azo derivatives. These azo derivatives and those of ethyl benzoylacetate could be cyclized into 4-oxo-, 6-oxo- and 6-iminopyridazines and pyridazino[2,3-a]quinazolines, respectively. The 6-iminopyridazines could be transformed into the 6-oxopyridazines. The imino- and oxopyridazines could be transformed into pyrrole derivatives.

Full text of DOI:10.1016/S0040-4020(00)01153-4

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1813±1817
The reaction of ethyl benzoylacetate with malononitrile: a novel
synthesis of some pyridazine, pyridazino[2,3-a]quinazoline
and pyrrole derivatives
²
Fathy M. Abdelrazek,p Abdellatif M. Salah El-Din and Ahmed E. Mekky
Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
Received 2 October 2000; revised 20 November 2000; accepted 7 December 2000
AbstractÐEthyl benzoylacetate undergoes Claisen condensation reaction with malononitrile to afford 2-cyano-5-phenyl-3,5-dioxopenta-
nonitrile which could be cyclized into 2-aminopyran and coupled with diazonium salts to afford azo derivatives. These azo derivatives and
those of ethyl benzoylacetate could be cyclized into 4-oxo-, 6-oxo- and 6-iminopyridazines and pyridazino[2,3-a]quinazolines, respectively.
The 6-iminopyridazines could be transformed into the 6-oxopyridazines. The imino- and oxopyridazines could be transformed into pyrrole
derivatives. q 2001 Elsevier Science Ltd. All rights reserved.
In the last few years we have been involved in a program
aimed at the synthesis of new heterocyclic systems of
biological interest to be tested as biodegradable agro-
chemicals.1±3 In the context of this program, some new
functionally substituted pyridazine derivatives were
required. Ethyl 4,4-dicyano-3-phenyl-3-butenoate 3 seemed
a good candidate to ful®l this objective via its coupling with
the diazotized aromatic amines 4a±d to afford the azo
derivatives 5a±d, followed by cyclization to the pyridazines
6a±d (Scheme 1) similar to the previously reported work on
related systems.3,4 This prompted us to investigate the
reaction of ethyl benzoylacetate 1 with malononitrile 2
aiming to obtain the Knoevenagel condensation product 3.
To our knowledge this compound has been mentioned twice
as an intermediate which afforded a pyridine derivative on
cyclization in very low yield.5,6
group, but two singlets at d 4.1 (2H) and 4.6 (1H) corre-
sponding to methylene and methyne protons, respectively,
besides an aromatic multiplet at d 7.25±7.8. It is assumed
that the reaction of 1 and 2 took place via a Claisen conden-
sation with elimination of ethanol to afford 7 rather than the
expected Knoevenagel-type condensation to afford 3.
Re¯uxing the pyran derivative 8 in acetic/sulfuric acid
mixture leads to another crystalline product, mp 2568C.
The elemental analysis of this product was consistent with
1
the same formula as that of 8. IR and H NMR spectra
suggested the 4-pyridone structure 9, which was assigned
to this product. The conversion of 2-aminopyrans into func-
tionalized pyridines is well known.8,9 Furthermore, the
synthesis of phenyl substituted pyridines by different
methods has been widely investigated10 and this is one
simple method to 2-phenylpyridine.The formation of pyrans
and pyridines from active methylene compounds and
malononitrile or its derivatives is also well known in the
literature.6,11,12
In our hands ethyl benzoylacetate 1 reacted with malono-
nitrile 2 in re¯uxing ethanol catalyzed by piperidine to
afford a viscous brown oil. Heating of this oil in toluene
led to a crystalline product, mp 2868C. Mass spectrum of
this product showed m/e 212. The IR spectrum showed
The structure of the oily product 7 was further con®rmed
from the following behavior. It undergoes the coupling reac-
tion with the diazonium salts 4a±f to afford the colored
hydrazo products 10a±f, respectively. Elemental analysis
and spectral data are in favor of these proposed hydrazo
structures (see Section 1). Re¯uxing compounds 10a±d in
ethanolic sodium hydroxide (20% water solution) accom-
plished their cyclization to the pyridazine derivatives 11a±
d, while the same treatment of compounds 10e and 10f led
to the pyridazino[2,3-a]quinazoline derivatives 12 and 13,
respectively. The IR spectra of compounds 11a±d, 12 and
13 show absorption bands due to amino, cyano and two
carbonyl groups, except in 13 where an NH and three car-
bonyl absorptions were observed (see Section 1).
1
absorption bands at 3400±3300, 2216 and 1650 cm21. H
NMR spectrum revealed a singlet (1H) at d 5.667, a singlet
(2H) at d 7.35 and an aromatic multiplet (5H) at d 7.59±
7.82. On the basis of these data, the pyran-4-one structure 8
was assigned to this product. This result gave us the
impression that the oily product should be 2-cyano-5-
1
phenyl-3,5-dioxopentanonitrile 7. The H NMR spectrum
of this oil did not reveal any signals due to the ester
Keywords: pyridazines; pyridazinoquinazolines; pyrroles.
Corresponding author. E-mail: frazek@chem-sci.cairo.eun.eg
This work is abstracted in part from the M.Sc. thesis of A. E. Mekky.
p
²
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01153-4

1814
F. M. Abdelrazek et al. / Tetrahedron 57 (2001) 1813±1817
Scheme 1.
On the other hand, the initially desired iminopyridazines
6a±d were successfully obtained by fusing the hydrazo
derivatives 14a±d (obtained from coupling of 1 with the
diazonium salt of the appropriate aromatic amine according
to literature methods13,14) with malononitrile 2 in the
presence of ammonium acetate. The IR spectra of 6a±d
showed absorption bands at 3400±3330, 2200±2210 and
1710 cm21 corresponding to NH, CN and ester carbonyl,
respectively. The formation of the pyridazines 6a±d
apparently took place via the intermediacy of 5a±d,
which could not be separated. Compounds 14e,f were
cyclized in the same way to afford the pyridazino[2,3-a]-
quinazoline derivatives 15a and 15b, respectively. The
cyclization took place presumably via an internal addition
of the NH group in the 6-imino pyridazine to the neighbor-
ing CN group in the hypothetical 6e (Arv2-NC±C6H4) to
afford 15a or an internal reaction of the imine with the ester
group in the case of 6f (Arv2-MeO2CC6H4) to afford 15b.
pyridazine derivatives 17a±d were obtained, respectively.
Compounds 6a±d could be quantitatively transformed into
17a±d on re¯ux in ethanolic HCl. The identity of the
compound pairs was inferred from mp and TLC analysis.
In the same way compound 15a was quantitatively trans-
formed into 15b.
Re¯uxing the 6-iminopyridazine derivatives 6a±d in acetic
acid in the presence of zinc dust, they were transformed into
the pyrrole derivatives 18a±d, respectively. The 6-oxo-
pyridazine derivatives 17a±d underwent the same reaction
to afford the dihydropyrrole derivatives 19a±d, respec-
tively. IR, 1H NMR and elemental analyses are in agreement
with the proposed structures. The formation of the pyrrole
derivatives 18a±d and 19a±d from the pyridazines 6a±d
and 17a±d, respectively, is assumed to take place via reduc-
tive cleavage of the N±N bond in the pyridazines followed
by recyclization with loss of ammonia.3,4
When compounds 14a±d were fused with ethyl cyano-
acetate 16 under the same reaction conditions, the 6-oxo-
It should be mentioned that the 4-oxopyridazines 11a±d
undergo the same reaction to afford only one product in

F. M. Abdelrazek et al. / Tetrahedron 57 (2001) 1813±1817
1815
all cases. Structure 20 was assigned to this product and the
identity was inferred from mp, TLC and IR spectra. It is
assumed that compounds 11a±d undergo a reductive
cleavage of the N±N bond followed by recyclization via
the attack of the NH2 on the enamine carbon atom with
elimination of the aromatic amine residue.
diazotized amine (aniline, p-anisidine, p-chloroaniline,
p-toluidine, anthranilonitrile or methyl anthranilate,
10 mmol) while stirring. The addition took about 30 min,
after which stirring was continued for further 1 h. The
colored solid precipitates were collected by ®ltration,
washed with cold water, and recrystallized from ethanol to
afford the title compounds, respectively.
10a. (2.84 g, 90%), mp 2038C (EtOH); [Found: C, 68.40; H,
3.90; N, 17.80. C18H12N4O2 requires C, 68.35; H, 3.82; N,
17.71; nmax (KBr) 3400±3250 (NH), 2224 and 2210 (2 CN),
1695 and 1680 (2 CvO); dH (200 MHz, DMSO-d6) 4.5 (s,
1H), 7.20±7.80 (m, 10H, arom.), 8.21 (br, s, 1H, NH).
1. Experimental
1.1. General procedure
Melting points were determined on an electrothermal (9100)
apparatus and are uncorrected. The IR spectra were
recorded as KBr pellets on a Perkin Elmer 1430 spectro-
10b. (3.18 g, 92%), mp 1638C (EtOH); [Found: C, 66.00; H,
3.90; N, 16.10. C19H14N4O3 requires C, 65.89; H, 4.07; N,
16.18; nmax (KBr) 3440±3310 (NH), 2245 and 2200 (2 CN),
1705 and 1675 (2 CvO); dH (200 MHz, DMSO-d6) 3.8 (s,
3H, OCH3), 4.45 (s, 1H), 7.25±7.85 (m, 9H, arom.), 8.25
(br, s, 1H, NH).
1
photometer. The H NMR spectra were taken on a Varian
Gemini 200 MHz spectrometer in DMSO-d6 using TMS as
internal standard. Mass spectra were taken on a Shimadzu
GCMS-GB 1000 PX (70 eV). Elemental analyses were
carried out by the Microanalytical Centre at Cairo
University.
10c. (2.8 g, 80%), mp 2028C (EtOH); [Found: C, 61.70; H,
3.30; N, 15.80; Cl, 10.20. C18H11N4O2Cl requires C, 61.64;
H, 3.16; N, 15.97; Cl, 10.11; nmax (KBr) 3410±3350 (NH),
2235 and 2210 (2 CN), 1690 and 1670 (2 CvO); dH
(200 MHz, DMSO-d6) 4.50 (s, 1H), 7.30±7.75 (m, 9H,
arom.), 8.15 (br, s, 1H, NH).
1.1.1. 2-Cyano-5-phenyl-3,5-dioxopentanonitrile 7. To a
mixture of ethyl benzoylacetate 1 (19.2 g, 100 mmol) and
malononitrile 2 (6.6 g, 100 mmol) in 50 mL of absolute
ethanol was added 1 mL of piperidine. The reaction mixture
was re¯uxed for 3 h, then left to cool to room temperature,
then poured on ice cold water and neutralized by HCl. The
water layer was decanted and the remaining oil was washed
several times with cold water and extracted with ether. The
ether layer was dried over anhydrous CaCl2 overnight. The
solvent was removed under vacuum to leave a brown
viscous oil (18 g, 85%). nmax 2250 (CN), 1690 and 1675
(2 CvO); dH (200 MHz, DMSO-d6) 4.1 (s, 2H), 4.6 (s,
1H), 7.25±7.80 (m, 5H, arom.).
10d. (2.48 g, 75%), mp 2388C (EtOH); [Found: C, 68.90; H,
4.20; N, 17.10. C19H14N4O2 requires C, 69.08; H, 4.27; N,
16.98; nmax (KBr) 3420±3310 (NH), 2225 and 2205 (2 CN),
1700 and 1670 (2 CvO); dH (200 MHz, DMSO-d6) 2.35 (s,
3H, CH3), 4.35 (s, 1H), 7.15±7.85 (m, 9H, arom.), 8.30 (br,
s, 1H, NH).
10e. (2.70 g, 79%), mp 1228C (EtOH); [Found: C, 66.80; H,
3.30; N, 20.60. C19H11N5O2 requires C, 66.86; H, 3.25; N,
20.52. nmax (KBr) 3420±3350 (NH), 2235 and 2220 and
2210 (3 CN), 1710 and 1680 (2 CvO); dH (200 MHz,
DMSO-d6) 4.41 (s, 1H), 7.28±7.95 (m, 9H, arom.), 8.15
(br, s, 1H, NH).
1.1.2. 2-Amino-6-phenyl-4-oxo-4H-pyran-3-carbonitrile
8. A solution of the brown oil 7 (4.2 g, 20 mmol) in
30 mL toluene was re¯uxed for 3 h, and left to cool
overnight. The solid precipitate that appeared was ®ltered
off and recrystallized to afford 3.8 g (90%) of 8. Mp 2868C
(toluene); [Found: C, 67.90; H, 3.70; N, 13.20. C12H8N2O2
requires C, 67.92; H, 3.80; N, 13.20; nmax (KBr) 3398±3300
(NH2), 2216 (CN), 1650 (CvO); dH (200 MHz, DMSO-d6)
5.66 (s, 1H, pyran 5-H), 7.35 (s, 2H, NH2), 7.59±7.82 (m,
5H, arom.).
10f. (3.01 g, 81%), mp 2218C (EtOH); [Found: C, 64.20; H,
3.90; N, 14.90. C20H14N4O4 requires C, 64.17; H, 3.77; N,
14.97. nmax (KBr) 3405±3310 (NH), 2216 and 2195 (2 CN),
1720 (CvO ester) 1710 and 1675 (2 CvO); dH (200 MHz,
DMSO-d6) 3.95 (s, 3H, CH3), 4.44 (s, 1H), 7.25±8.1 (m, 9H,
arom.), 8.25 (br, s, 1H, NH).
1.1.3. 2-Hydroxy-6-phenyl-4-oxo-1,4-dihydropyridine-3-
carbonitrile 9. To a solution of the pyran 8 (2.1 g,
10 mmol) in 30 mL of glacial acetic acid was added 1 mL
of concentrated sulfuric acid and the mixture was re¯uxed
for 1 h, then left to cool. The precipitated solid was ®ltered
off and recrystallized to afford (1.8 g, 85%) of 9 mp 2568C
(EtOH); [Found: C, 67.90; H, 3.80; N, 13.30. C12H8N2O2
requires C, 67.92; H, 3.80; N, 13.20; nmax (KBr) 3450±3200
(br, NH and OH), 2210 (CN), 1655 (CvO); dH (200 MHz,
DMSO-d6) 4.2 (br.s, 1H, OH), 5.70 (s, 1H, pyridine 5-H),
7.45 (s, 1H, NH), 7.48±7.60 (m, 5H, arom.).
1.1.5. 6-Amino-1-aryl-3-benzoyl-4-oxo-1,4-dihydropyri-
dazine-5-carbonitriles 11a±d, 6-amino-2-benzoyl-3-oxo-
pyridazino [2,3-a] quinazoline-4-carbonitrile 12 and
2-benzoyl-3,6-dioxo-5,6-dihydropyridazino[2,3-a]quina-
zoline-4-carbonitrile 13 (general procedure). To a solu-
tion of each of 10a±f (10 mmol) in 20 mL ethanol was
added 5 mL of 20% aq. NaOH solution. The reaction
mixture was re¯uxed for 2 h in each case, then left to cool
overnight. The precipitated solid products formed were
®ltered off, washed several times with cold water and
recrystallized from the proper solvent to afford the corre-
sponding cyclized products:
1.1.4. 4-Arylazo/hydrazo-2-cyano-5-phenyl-3,5-dioxo-
pentanonitriles 10a±f (general procedure). To a cold
solution of 7 (2.1 g, 10 mmol) and sodium acetate 1.5 g in
35 mL of ethanol was added dropwise a cold solution of a
11a. (2.81 g, 89%), mp 3008C (EtOH/DMF); [Found: C,

1816
F. M. Abdelrazek et al. / Tetrahedron 57 (2001) 1813±1817
68.30; H, 3.70; N, 17.80. C18H12N4O2 requires C, 68.35; H,
3.82; N, 17.71: nmax (KBr) 3400±3300 (NH2), 2210 (CN),
1710 and 1650 (2 CvO); dH (200 MHz, DMSO-d6) 7.05 (s,
2H, NH2), 7.35±8.10 (m, 10H, arom.).
CH3), 3.7 (s, 3H, CH3), 3.85 (q, Jˆ7 Hz, 2H, CH2), 7.25
(d, 2H), 7.35 (d, 2H), 7.50±8.0 (m, 5H, arom.), 8.20 (br, s,
1H, NH).
6c. (2.64 g, 70%), mp 2248C (EtOH); [Found: C, 63.30; H,
4.10; N, 14.80; Cl, 9.30. C20H15N4O2Cl requires C, 63.41;
H, 3.99; N, 14.79; Cl, 9.37. nmax (KBr) 3390±3320 (NH),
2207 (CN), 1710 (CvO); dH (200 MHz, DMSO-d6) 1.38 (t,
Jˆ7 Hz, 3H, CH3), 3.9 (q, Jˆ7 Hz, 2H, CH2), 7.3±8.10 (m,
9H, arom.), 8.23 (b, s, 1H, NH).
11b. (2.94 g, 85%), mp 3028C (EtOH/DMF); [Found: C,
66.00; H, 4.20; N, 16.20. C19H14N4O3 requires C, 65.89;
H, 4.07; N, 16.18. nmax (KBr) 3410±3320 (NH2), 2215
(CN), 1710 and 1655 (2 CvO); dH (200 MHz, DMSO-d6)
2.85 (s, 3H, OCH3), 6.95 (s, 2H, NH2), 7.25 (d, 2H), 7.35 (d,
2H), 7.55±8.05 (m, 5H, arom.).
6d. (2.83 g, 79%), mp 2338C (EtOH); [Found: C, 70.30; H,
4.90; N, 15.60. C21H18N4O2 requires C, 70.38; H, 5.06; N,
15.63. nmax (KBr) 3385±3300 (NH), 2210 (CN), 1715
(CvO); dH (200 MHz, DMSO-d6) 1.43 (t, Jˆ7 Hz, 3H,
CH3), 2.43 (s, 3H, CH3), 3.80 (q, Jˆ7 Hz, 2H, CH2),
7.25±7.85 (m, 9H, arom.), 8.30 (br,s, 1H, NH).
11c. (2.98 g, 85%), mp.3308C (EtOH/DMF); [Found: C,
61.70; H, 3.20; N, 16.10; Cl, 10.20. C18H11N4O2Cl requires
C, 61.64; H, 3.16; N, 15.97; Cl, 10.11. nmax (KBr) 3390±
3330 (NH2), 2205 (CN), 1705 and 1660 (2 CvO); dH
(200 MHz, DMSO-d6) 6.99 (s, 2H, NH2), 7.15±7.85 (m,
9H, arom.).
15a. (2.93 g, 80%), mp 2428C (EtOH); [Found: C, 68.30; H,
3.90; N, 18.80. C21H15N5O2 requires C, 68.28; H, 4.09; N,
18.96. nmax (KBr) 4090±3300 (NH), 2225 (CN), 1715
(CvO); dH (200 MHz, DMSO-d6) 1.30 (t, Jˆ7 Hz, 3H,
CH3), 3.90 (q, Jˆ7 Hz, 2H, CH2), 7.30±7.90 (m, 9H
arom.), 8.25 (br,s, 1H, NH).
11d. (2.77 g, 84%), mp.3308C (EtOH/DMF); [Found: C,
69.10; H, 4.30; N, 16.90. C19H14N4O2 requires C, 69.08; H,
4.27; N, 16.98. nmax (KBr) 3400±3300 (NH2), 2210 (CN),
1695 and 1650 (2 CvO); dH (200 MHz, DMSO-d6) 2.80 (s,
3H, OCH3), 6.90 (s, 2H, NH2), 7.25±8.15 (m, 9H, arom.).
12. (2.56 g, 75%), mp.3308C (EtOH/DMF); [Found: C,
66.80; H, 3.40; N, 20.60. C19H11N5O2 requires C, 66.86;
H, 3.25; N, 20.52. nmax (KBr) 3340±3320 (NH2),2220
(CN), 1715 and 1650 (2 CvO); dH (200 MHz, DMSO-d6)
7.15±7.79 (m, 9H, arom.), 8.10 (s, 2H, NH2).
15b. (3.03 g, 82%), mp 2238C (EtOH); [Found: C, 68.20; H,
3.70; N, 15.20. C21H14N4O3 requires C, 68.10; H, 3.81; N,
15.13. nmax (KBr) 2223 (CN), 1710 and 1680 (2 CvO); dH
(200 MHz, DMSO-d6) 1.35 (t, Jˆ7 Hz, 3H, CH3), 3.85 (q,
Jˆ7 Hz, 2H, CH2), 7.35±7.90 (m, 9H arom.).
13. (2.46 g, 72%), mp.3308C (EtOH/DMF); [Found: C,
66.80; H, 3.10; N, 16.40. C19H10N4O3 requires C 66.67; H,
2.94; N, 16.37. nmax (KBr) 3410±3350 (NH2), 2215 (CN),
1710 and 1680 and 1650 (3 CvO); dH (200 MHz, DMSO-
d6) 6.80 (s, 1H, NH), 7.15±7.90 (m, 9H, arom.).
1.1.7. Ethyl 1-aryl-5-cyano-6-oxo-4-phenyl-1,6-dihydro-
pyridazine-3-carboxylates 17a±d. A mixture of 10 mmol
of each of the azo derivatives 14a±d, ethyl cyanoacetate 16
(10 mmol) and 1 g of ammonium acetate (15 mmol) was
fused on an oil bath at 2008C for 2 h and treated as
mentioned above to afford:
1.1.6. Ethyl 1-aryl-5-cyano-6-imino-4-phenyl-1,6-di-
hydropyridazine-3-carboxylates 6a±d, ethyl 4-cyano-6-
imino-3-phenyl-6H-pyridazino[2,3-a]quinazoline-2-car-
boxylate 15a and ethyl 4-cyano-6-oxo-3-phenyl-6H-pyri-
dazino[2,3-a]quinazoline-2-carboxylate 15b (general
procedure). A mixture of 10 mmol of each of the azo
derivatives 14a±f (prepared from ethyl benzoyl acetate 1
by coupling with aromatic diazonium salts according to
the literature methods13,14), malononitrile 2 (10 mmol) and
1 g of ammonium acetate (15 mmol) was fused on an oil
bath at 2008C for 2 h. The melt was left to cool to room
temperature and tritrated with ethanol. The solid precipi-
tates were ®ltered off and recrystallized from acetic acid
to afford:
17a. (2.6 g, 75%), mp 1858C (EtOH); [Found: C, 69.60; H,
4.50; N, 12.30. C20H15N3O3 requires C, 69.56; H, 4.38; N,
12.17. nmax (KBr) 2225 (CN), 1710 and 1670 (2 CvO); dH
(200 MHz, DMSO-d6) 1.29 (t, Jˆ7 Hz, 3H, CH3), 4.10 (q,
Jˆ7 Hz, 2H, CH2), 7.30±7.85 (m, 10H, arom.).
17b. (2.96 g, 79%), mp 1308C (EtOH); [Found: C, 67.30; H,
4.60; N, 11.10. C21H17N3O4 requires C, 67.19; H, 4.56; N,
11.19. nmax (KBr) 2220 (CN), 1710 and 1660 (2 CvO); dH
(200 MHz, DMSO-d6) 1.25 (t, Jˆ7 Hz, 3H, CH3), 3.85 (s, 3H,
CH3), 4.14 (q, Jˆ7 Hz, 2H, CH2), 7.15±7.75 (m, 9H, arom.).
17c. (2.6 g, 68%), mp 1488C (EtOH); [Found: C, 63.30; H,
3.70; N, 10.90; Cl, 9.30. C20H14N3O3Cl requires C, 63.25;
H, 3.72; N, 11.06; Cl, 9.33. nmax (KBr) 2210 (CN), 1710 and
1665 (2 CvO); dH (200 MHz, DMSO-d6) 1.29 (t, Jˆ7 Hz,
3H, CH3), 4.10 (q, Jˆ7 Hz, 2H, CH2), 7.30±7.85 (m, 9H,
arom.).
6a. (2.58 g, 75%), mp 2798C (EtOH); [Found: C, 69.60; H,
4.50; N, 16.20. C20H16N4O2 requires C, 69.76; H, 4.68; N,
16.27. nmax (KBr) 3390±3310 (NH), 2207 (CN), 1712
(CvO); dH (200 MHz, DMSO-d6) 1.45 (t, Jˆ7 Hz, 3H,
CH3), 3.8 (q, Jˆ7 Hz, 2H, CH2), 7.3±7.85 (m, 10H,
arom.), 8.25 (b, s, 1H, NH).
17d. (2.7 g, 75%), mp 1768C (EtOH); [Found: C, 70.20; H,
4.70; N, 11.50. C21H17N3O3 requires C, 70.18; H, 4.77; N,
11.69. nmax (KBr) 2215 (CN), 1715 and 1660 (2 CvO); dH
(200 MHz, DMSO-d6) 1.24 (t, Jˆ7 Hz, 3H, CH3), 2.45 (s,
3H, CH3), 4.12 (q, Jˆ7 Hz, 2H, CH2), 7.25±7.78 (m, 9H,
arom.).
6b. (2.84 g, 76%), mp 2658C (EtOH); [Found: C, 67.20; H,
4.90; N, 15.10. C21H18N4O3 requires C, 67.37; H, 4.85; N,
14.96. nmax (KBr) 3400±3300 (NH), 2200 (CN), 1710
(CvO); dH (200 MHz, DMSO-d6) 1.35 (t, Jˆ7 Hz, 3H,

F. M. Abdelrazek et al. / Tetrahedron 57 (2001) 1813±1817
1817
1.1.8. Transformation of 15a into 15b and 6a±d into
17a±d, respectively (general procedure). To a solution
of 15a or each of 6a±d (50 mmol) in 20 mL ethanol was
added 5 mL of concentrated hydrochloric acid and the
mixture was re¯uxed for 1 h. After cooling to room
temperature, the reaction mixture was diluted with cold
water and neutralized with ammonia. The solid precipitates
were collected by ®ltration and recrystallized from acetic
acid to afford products identical in all respect (mp, mixed
mp, TLC) with 15b and 17a±d, respectively.
19b. (2.1 g, 58%), mp 2178C (AcOH); [Found: C, 69.80; H,
4.90; N, 7.60. C21H18N2O4 requires C, 69.60; H, 5.01; N,
7.73. nmax (KBr) 2222 (CN), 1738 and 1690 (2CvO); dH
(200 MHz, DMSO-d6) 1.12 (t, Jˆ7 Hz, 3H, CH3), 3.82 (s,
3H, OCH3), 4.06 (q, Jˆ7 Hz, 2H, CH2), 5.56 (s, 1H,
Pyrrole-H), 7.05 (d, 2H), 7.25 (d, 2H), 7.35±7.65 (m, 5H,
arom.).
19c. (1.9 g, 52%), mp 2348C (AcOH); [Found: C, 65.60; H,
4.20; N, 7.60; Cl, 9.70. C20H15N2O3Cl requires C, 65.49; H,
4.12; N, 7.64; Cl, 9.67. nmax (KBr) 2215 (CN), 1732 and
1693 (2CvO); dH (200 MHz, DMSO-d6) 1.11 (t, Jˆ7 Hz,
3H, CH3), 3.98 (q, Jˆ7 Hz, 2H, CH2), 5.59 (s, 1H, Pyrrole-
H), 7.05±7.55 (m, 9H, arom.).
1.1.9. Ethyl 1-aryl-5-acetylamino-4-cyano-3-phenylpyr-
role-2-carboxylates 18a±d, ethyl 1-aryl-4-cyano-5-oxo-
3-phenyl-2,5-dihydropyrrole-2-carboxylates 19a±d and
2-acetylamino-5-benzoyl-4-hydroxy-1H-pyrrole-3-carbo-
nitrile 20 (general procedure). To a solution of 6a±d,
11a±d or 17a±d (10 mmol) in 25 mL glacial acetic acid
was added 2 g of Zn dust. The reaction mixture was re¯uxed
for 2 h during which time the color turns to pale yellowish
green. The reaction mixture was ®ltered in each case while
hot and left to cool to room temperature. The precipitated
solids were collected by ®ltration and recrystallized to
afford:
19d. (1.73 g, 50%), mp 2438C (AcOH); [Found: C, 72.80;
H, 5.30; N, 7.90. C21H18N2O3 requires C, 72.82; H, 5.24; N,
8.09. nmax (KBr) 2226 (CN), 1735 and 1684 (2CvO); dH
(200 MHz, DMSO-d6) 1.14 (t, Jˆ7 Hz, 3H, CH3), 2.24 (s,
3H, CH3), 3.95 (q, Jˆ7 Hz, 2H, CH2), 5.49 (s, 1H, Pyrrole-
H), 7.0±7.68 (m, 9H, arom.).
20. (1.45 g, 54%), mp 2538C (AcOH); [Found: C, 62.50; H,
4.10; N, 15.40. C14H11N3O3 requires C, 62.45; H, 4.12; N,
15.61. nmax (KBr) 3410±3300 (br, OH and NH) 2222 (CN),
1700 and 1680 (2CvO); dH (200 MHz, DMSO-d6) 2.30 (s,
3H, CH3), 4.21 (s, 1H, OH), 6.85±7.42 (m, 5H, arom.), 7.62
(s, 1H, NH), 8.5 (s, 1H, pyrrole-NH).
18a. (2.42 g, 65%), mp 2458C (AcOH); [Found: C, 70.70;
H, 5.20; N, 11.30. C22H19N3O3 requires C, 70.76; H, 5.13;
N, 11.25. nmax (KBr) 3420±3340 (NH), 2225 (CN), 1715
and 1680 (2CvO); dH (200 MHz, DMSO-d6) 1.21 (t,
Jˆ7 Hz, 3H, CH3), 2.21 (s, 3H, CH3), 3.94 (q, Jˆ7 Hz,
2H, CH2), 7.10 (s, 1H, NH), 7.25±7.85 (m, 10H, arom.).
References
18b. (2.26 g, 56%), mp 2388C (AcOH); [Found: C, 68.60;
H, 5.20; N, 10.30. C23H21N3O4 requires C, 68.47; H, 5.25;
N, 10.42. nmax (KBr) 3400±3310 (NH), 2215 (CN), 1725
and 1685 (2CvO); dH (200 MHz, DMSO-d6) 1.15 (t,
Jˆ7 Hz, 3H, CH3), 2.24 (s, 3H, CH3), 3.79 (s, 3H, OCH3),
3.98 (q, Jˆ7 Hz, 2H, CH2), 7.04 (s, 1H, NH), 7.24 (d, 2H),
7.35 (d, 2H), 7.45±7.80 (m, 5H, arom.).
1. Metwally, N. H.; Abdelrazek, F. M. J. Prakt. Chem. Chem-
Zeitung 1998, 340, 676±678.
2 Abdelrazek, F. M. Heteroatomchemistry 1995, 6, 211±214.
3. Abdelrazek, F. M.; Salah, A. M. Bull. Chem. Soc. Jpn 1993,
66, 1722±1726.
4. Gewald, K.; Hain, U. Synth. Commun. 1984, 62±63.
5. Gudriniece, E.; Rigerte, B. Latv. Psrzinat. Akad. Vestis, Khim.
Ser. 1974, 2, 239±240 (Russian) Chem. Abstr. 1974, 81,
37490h.
18c. (2.44 g, 60%), mp 2418C (AcOH); [Found: C, 64.90; H,
4.40; N, 10.20; Cl, 8.80. C22H18N3O3Cl requires C, 64.79;
H, 4.45; N, 10.30; Cl, 8.69. nmax (KBr) 3415±3310 (NH),
2210 (CN), 1710 and 1690 (2CvO); dH (200 MHz, DMSO-
d6) 1.14 (t, Jˆ7 Hz, 3H, CH3), 2.18 (s, 3H, CH3), 3.90 (q,
Jˆ7 Hz, 2H, CH2), 6.98 (s, 1H, NH), 7.16±7.82(m, 9H,
arom.).
6. Soto, J. L.; Seoane, C.; Valades, J. A.; Martina, N.; Quinteiro,
M. An. Quim. 1979, 75, 152±155 (Spanish). Chem. Abstr.
1979, 91, 74425t.
7. This chemical shift value matches with that reported for 5-H
of pyran-4-one. Brown, N. M. D.; Bladon, P. Spectrochim.
Acta 1965, 21 (7), 1277±1285.
8. Marugan, M. M.; Martin, N.; Seoane, C.; Soto, J. L. Liebigs
Ann.. Chem. 1989 (2), 145±149.
18d. (2.4 g, 62%), mp 2448C (AcOH); [Found: C, 71.40; H,
5.50; N, 10.50. C23H21N3O3 requires C, 71.30; H, 5.46; N,
10.39. nmax (KBr) 3405±3310 (NH), 2220 (CN), 1715 and
1685 (2CvO); dH (200 MHz, DMSO-d6) 1.12 (t, Jˆ7 Hz,
3H, CH3), 2.16 (s, 3H, CH3), 2.30 (s, 3H, p-CH3), 3.94 (q,
Jˆ7 Hz, 2H, CH2), 7.00 (s, 1H, NH), 7.20±7.80 (m, 9H,
arom.).
9. Srivastava, S.; Batra, S.; Bhaduri, A. P. Indian J. Chem. Sec. B
1996, 35B (6), 602±604.
10. Jones, G. In Comprehensive Heterocyclic Chemistry,
Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford,
1984; 2, pp 395±482.
11. Etman, H. A. Bull. Chim. Farm. 1994, 133 (9), 597±598.
12. Kambe, S.; Saito, K.; Midorikawa, H. Synthesis 1980, 366±
368.
19a. (1.8 g, 55%), mp 2398C (AcOH); [Found: C, 72.40; H,
4.90; N, 8.50. C20H16N2O3 requires C, 72.28; H, 4.85; N,
8.43. nmax (KBr) 2225 (CN), 1735 and 1685 (2CvO); dH
(200 MHz, DMSO-d6) 1.15 (t, Jˆ7 Hz, 3H, CH3), 3.94 (q,
Jˆ7 Hz, 2H, CH2), 5.68 (s, 1H, Pyrrole-H), 7.15±7.85 (m,
10H, arom.).
13. Mitchell, A. D.; Nonhebel, D. C. Tetrahedron Lett. 1975,
3859±3861.
14. Garg, H. G.; Joshi, S. S. J. Ind. Chem. Soc. 1960, 37, 626±631.