Reaction of oxime derivatives of β-diketones and β-ketoesters with substituted hydrazides: Novel synthesis of nitroso-N-sulfonyl and nitroso-N-substituted amino pyridones

Article abstract of DOI:10.1081/SCC-120021034

A novel and efficient method for the synthesis of a new variety of nitroso-N-arylsulfonylaminated pyridones and nitroso-N-substitu-tedamino pyridones via the reaction of oxime derivatives of β-diketones and β-ketoesters with N-cyanoacetoarylsulfonylhydraz

Full text of DOI:10.1081/SCC-120021034

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Reaction of Oxime Derivatives of β-Diketones and
β-Ketoesters with Substituted Hydrazides: Novel
Synthesis of Nitroso- N -sulfonyl- and Nitroso- N -
substituted Amino Pyridones
Galal H. Elgemeie a & Ali M. Elzanate b
a Chemistry Department , Faculty of Science , Helwan University , Ain-Helwan, Helwan,
Cairo, Egypt
b Chemistry Department , Faculty of Science , Cairo University (Beni Suef Branch) , Beni
Suef, Egypt
Published online: 17 Aug 2006.
To cite this article: Galal H. Elgemeie & Ali M. Elzanate (2003) Reaction of Oxime Derivatives of β-Diketones and β-Ketoesters
with Substituted Hydrazides: Novel Synthesis of Nitroso- N -sulfonyl- and Nitroso- N -substituted Amino Pyridones, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:12, 2087-2094, DOI:
10.1081/SCC-120021034
To link to this article: http://dx.doi.org/10.1081/SCC-120021034
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 12, pp. 2087–2094, 2003
Reaction of Oxime Derivatives of b-Diketones
and b-Ketoesters with Substituted Hydrazides:
Novel Synthesis of Nitroso-
N-sulfonyl- and Nitroso-N-substituted
Amino Pyridones
2
Galal H. Elgemeie1, and Ali M. Elzanate
*
1Chemistry Department, Faculty of Science, Helwan
University, Ain-Helwan, Helwan, Cairo, Egypt
2Chemistry Department, Faculty of Science, Cairo
University (Beni Suef Branch), Beni Suef, Egypt
ABSTRACT
A novel and efficient method for the synthesis of a new variety
of nitroso-N-arylsulfonylaminated pyridones and nitroso-N-substitu-
tedamino pyridones via the reaction of oxime derivatives of b-
diketones and b-ketoesters with N-cyanoacetoarylsulfonylhydrazides
and substituted cyanoacetohydrazides has been investigated.
The synthetic potential of the method is demonstrated.
*Correspondence: Galal H. Elgemeie, Chemistry Department, Faculty of Science,
Helwan University, Ain-Helwan, Helwan, Cairo, Egypt; E-mail: rughe@
rusys.eg.net.
2087
DOI: 10.1081/SCC-120021034
Copyright & 2003 by Marcel Dekker, Inc.
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2088
Elgemeie and Elzanate
Key Words: N-Amino-pyridones; N-Sulfonylaminated-pyridones;
Substituted hydrazides; Nitroso pyridones; Ketoesters; Diketones.
In recent reports from our laboratory, we described the preparation
of different novel functionalized N-substitutedamino pyridones, which
revealed antagonistic activity.[1–4] These common features, encouraged
us to develop a new straightforward route for the synthesis of these
compounds. The present research deals with a novel synthesis of
nitroso-N-arylsulfonylaminated pyridones and nitroso-N-substituteda-
mino pyridones by the reaction of oxime derivatives of b-diketones and
b-ketoesters with cyanoacetoarylsulfonylhydrazides and substituted cya-
nohydrazides, respectively. Thus, it has been found that cyanoacetoaryl-
sulfonylhydrazides 1 reacted with isonitroso derivatives of b-diketones
3a,b in boiling ethanolic sodium ethoxide to give the corresponding
5-nitroso-N-sulfonylamino-2-pyridones 6. The structures of 6 were estab-
lished on the basis of elemental analysis and spectral data (IR, 1H NMR,
13C NMR and MS). The formation of 6 from the reaction of 1 with 3
is assumed to proceed via Michael addition of active methylene of 1 to
the double bond in 3. The formed Michael adduct then cyclized smoothly
via elimination of two moles of water to give the final pyridones 6.
Similarly it has been found that reaction of compounds 3 with cyanoa-
cetohydrazide 8 in the presence of sodium ethoxide gave the novel
5-nitroso-N-amino-2-pyridones 7, the structures of which were estab-
lished on the basis of elemental analysis and spectral evidence. The
analytical data for 7a revealed a molecular formula C8H8N4O2
1
(Mþ ¼ 192), H NMR spectroscopy was used to confirm this structure
for the product. Thus, 1H NMR revealed two bands at ꢀ 2.46 and
2.68 ppm assignable to two methyl groups and a broad singlet at ꢀ
5.52 ppm assignable for an amino group. The formation of 7 from the
reaction of 3 and cyanoacetohydrazide 8 is assumed to proceed via inter-
mediacy of Michael adduct, which cyclized to yield the final pyridones 7.
Reaction of compound 7 with aryl sulfonyl chlorides in refluxing ethanol
containing catalytic amounts of piperidine gave the corresponding
pyridones 6. In order to investigate the scope of this reaction further
and in order to establish whether the reaction of isonitroso deriva-
tives of b-diketones 3 with activated nitriles could be extended to
provide a general approach to nitrosopyridone derivatives, we studied
the reaction of 3 with other substituted nitriles. Thus, in a typical
experiment, when isonitroso derivatives of b-diketones 3 reacted with
1-cyanoacetyl-4-arylmethylidene-semicarbazide 9 in reluxing ethanolic

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Oxime Derivatives of b-Diketones and b-Ketoesters
2089
sodium ethoxide, the 5-nitroso-N-arylmethylideneamino-2-oxo-pyridines
13 were obtained in good yields. The structures of 13 were established
and confirmed for reaction products on the basis of their elemental ana-
lysis and spectral data (IR, 1H NMR, 13C NMR and MS). The analytical
data for 13a revealed a molecular formula C15H11N4O2 (Mþ ¼ 280),
1H NMR spectroscopy was used to confirm this structure for the product.
Thus, 1H NMR revealed two bands at ꢀ 2.32 and 2.54 ppm assignable for
two methyl groups, a multiplet at ꢀ 6.98–7.87 ppm assigned for aromatic
protons and a broad singlet at ꢀ 8.67 ppm assigned for yildenic CH. The
formation of 13 from the reaction of 3 and 1-cyanoacetyl-4-arylmethyli-
dene-semicarbazide 9 is assumed to proceed via intermediacy of Michael
adducts, which cyclized to yield the final N-aryl-5-nitroso-2-pyridones 13.
Similarly, the reaction of oxime derivatives of b-ketoesters 14 with acti-
vated nitriles 1 and 9a leads to the corresponding 6-hydroxy-5-nitroso-2-
oxopyridines 15 and 16, respectively. The structures of 15 and 16 were
established on the basis of elemental analysis and spectral data.
In summary, we have achieved a regiospecific synthesis of interesting
nitroso-N-arylsulfonylaminated pyridones and nitroso-N-substituted-
amino pyridones by the reaction of oxime derivatives of b-diketones
and b-ketoesters with cyanoacetoarylsulfonylhydrazides and substi-
tuted cyanohydrazides, respectively. The compounds obtained seems
promising as high potential intermediates for synthesizing antimetabolite
agents.
EXPERIMENTAL
All melting points are uncorrected. The IR spectra were obtained
1
(KBr, disk) on a Perkin Elmer/1650 FT-IR instrument. The H NMR
spectra were measured on a Varian 400 MHz spectrometer for solutions
in (CD3)2SO with SiMe4 as an internal standard. Mass spectra were
recorded on a Varian MAT 112 spectrometer. Analytical data were
obtained from the Microanalytical Data Center at Cairo University.
5-Nitroso-N-phenylsulfonylamino-4-methyl-2-pyridones (6a,b)
General Procedure
A mixture of N-cyanoacetophenylsulfonylhydrazide 1 (0.01 mol) and
oximes of b-diketones 3a,b (0.01 mol) in sodium ethoxide (0.01 mol)
and ethanol (30 mL) was refluxed for 4 h. The reaction mixture was

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2090
Elgemeie and Elzanate
cooled and acidified with HCl. The resulting solid product was filtered off
and recrystallized from the appropriate solvent.
6a. Brown crystals, from DMF, 56% yield, m.p. 300ꢀC. IR (cmꢁ1):
1
3294, 3198 (NH); 2216 (CN); 1663 (CO). H NMR (ꢀ ppm): 2.42 (s, 3H,
CH3); 2.51 (s, 3H, CH3); 11.00 (s, 1H, NH). 13C NMR (ꢀ ppm): 16.34
(CH3); 18.00 (CH3); 110.56 (CN); 164.12 (C-2); 126.32 (C-3); 152.69 (C-
4); 138.65 (C-5); 156.11 (C-6). Found: C, 50.8; H, 3.4; N, 17.0%; Calcd.
for C14H12N4O4S (m/z ¼ 332): C, 50.6; H, 3.6; N, 16.9%.
6b. Yellow crystals from EtOH/DMF , 50% yield, m.p. 290ꢀC. IR
1
(cmꢁ1): 3400, 3320 (NH); 2220 (CN); 1670 (CO). H NMR (ꢀ ppm): 2.40
(s, 3H, CH3); 2.58 (s, 3H, CH3); 7.00–7.99 (m, 5H, C6H5), 11.17 (s, 1H,
NH). 13C NMR (ꢀ ppm): 16.00 (CH3); 113.00 (CN); 120.43–127.11
(phenyl carbons), 165.19 (C-2); 128.67 (C-3); 150.43 (C-4); 137.10
(C-5); 157.00 (C-6). Found: C, 57.7; H, 3.5; N, 14.4%; Calcd. for
C19H14N4O4S: C, 57.9; H, 3.6; N, 14.2%.
5-Nitroso-N-phenylsulfonylamino-6-hydroxy-2-
pyridones (15a,b)
General Procedure
A mixture of N-cyanoacetophenylsulfonylhydrazide 1 (0.01 mol) and
oximes of b-ketoesters 14a,b (0.01 mol) in sodium ethoxide (0.01 mol)
and ethanol (30 mL) was refluxed for 4 h. The reaction mixture was
cooled and acidified with HCl. The resulting solid product was filtered
off and recrystallized from the appropriate solvent.
15a. Yellow crystals, from EtOH, 62% yield, m.p. >300ꢀC. IR
1
(cmꢁ1): 3490–3370 (OH, NH); 2230 (CN); 1680 (CO). H NMR (ꢀ ppm):
2.30 (s, 3H, CH3); 11.00 (s, 1H, NH), 12.09 (s, br, 1H, OH). Found: C, 46.9;
H, 3.1; N, 17.0%; Calcd. for C13H10N4O5S: C, 46.7; H, 3.0; N, 16.8%.
15b. Yellow crystals, from DMF-MeOH, 60% yield, m.p. 295ꢀC.
Found: C, 54.4; H, 2.8; N, 14.3%; Calcd. for C18H12N4O5S: C, 54.5;
H, 3.0; N, 14.1%.
5-Nitroso-N-amino-2-pyridones (7a,b)
General Procedure
A mixture of oximes 3a,b (0.01 mol) and cyanoacetohydrazide
8 (0.01 mol) was refluxed in sodium ethoxide solution (0.01 mol) and

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Oxime Derivatives of b-Diketones and b-Ketoesters
2091
ethanol (30 mL) for 5 h. The reaction mixture was cooled, poured over
ice/water mixture and neutralized with dil. HCl. The precipitated product
was collected by filtration and recrystallized from ethanol.
7a. Brown crystals, 50% yield, m.p. >300ꢀC. IR (cmꢁ1): 3420, 3250
(NH2, NH); 2210 (CN); 1680 (CO). 1H NMR (ꢀ ppm): 2.46 (s, 3H, CH3);
2.68 (s, 3H, CH3); 5.52 (s, br, 2H, NH2). Found: C, 50.1; H, 4.4; N,
29.0%; Calcd. for C8H8NO2 (m/z ¼ 192): C, 50.0; H, 4.2; N, 29.2%.
7b. Yellow crystals, 55% yield, m.p. 285ꢀC. Found: C, 61.6; H, 4.1;
N, 22.1%; Calcd. for C13H10N4O2: C, 61.4; H, 3.9; N, 22.0%.
5-Nitroso-N-arylmethylideneamino-4-methyl-2-
pyridones (13a–f )
General Procedure
To a mixture of 1-cyanoacetyl-4-arylmethylidenesemicarbazide 9 and
oximes of b-diketones 3a,b (0.01 mol), sodium ethoxide (0.01 mol) in
ethanol (30 mL) was added. The reaction mixture was heated under
reflux for 4 h. The resultant product was acidified with HCl. The preci-
pitate formed was collected by filtration, dried and then recrystallized
from ethanol.
13a. Yellow crystals, 40% yield, m.p. 300ꢀC. IR (cmꢁ1): 2216
(CN); 1663 (CO). 1H NMR (ꢀ ppm): 2.32 (s, 3H, CH3); 2.54 (s, 3H,
CH3); 6.98–7.87 (m, 5H, C6H5), 8.67 (s, 1H, CH). Found: C, 64.5; H,
4.1; N, 19.8%; Calcd. for C15H12N4O2 (m/z ¼ 280): C, 64.3; H, 4.3;
N, 20.0%.
13b. Brown crystals, 50% yield, m.p. 290ꢀC. IR (cmꢁ1): 2220 (CN);
1670 (CO). 1H NMR (ꢀ ppm): 2.37 (s, 3H, CH3); 2.54 (s, 3H, CH3);
7.11–8.00 (m, 5H, C6H4), 9.05 (s, 1H, CH). Found: C, 57.3; H, 3.6; N,
17.5%; Calcd. for C15H11N4O2: C, 57.2; H, 3.5; N, 17.8%.
13c. Brown crystals, 60% yield, m.p. >300ꢀC. Found: C, 65.4; H,
4.6; N, 19.2%; Calcd. for C16H14N4O2: C, 65.3; H, 4.8; N, 19.0%.
13d. Brown crystals, 48% yield, m.p. 279ꢀC. Found: C, 61.7; H, 4.4;
N, 18.3%; Calcd. for C16H14N4O3: C, 61.9; H, 4.5; N, 18.1%.
13e. Yellow crystals, 40% yield, m.p. >300ꢀC. Found: C, 70.9; H,
4.3; N, 15.9%; Calcd. for C21H16N4O2: C, 70.8; H, 4.5; N, 15.7%.
13f. Brown crystals, 60% yield, m.p. >300ꢀC. IR (cmꢁ1): 2220
(CN); 1690 (CO). 1H NMR (ꢀ ppm): 2.44 (s, 3H, CH3); 3.99 (s, 3H,
OCH3); 6.90–8.23 (m, 9H, C6H5, C6H4), 8.90 (s, 1H, CH). Found: C,
67.9; H, 4.2; N, 14.9%; Calcd. for C21H16N4O3: C, 67.7; H, 4.3;
N, 15.1%.

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2092
Elgemeie and Elzanate
Chart 1.

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Oxime Derivatives of b-Diketones and b-Ketoesters
2093
Chart 2.
6-Hydroxy-4-methyl-5-nitroso-N-phenylmethylideneamino-2-
pyridone (16)
General Procedure
To a mixture of 1-cyanoacetyl-4-phenylmethylidenesemicarbazide 9a
and oxime 14 (0.01 mol), sodium ethoxide (0.01 mol) in ethanol (30 mL)
was added. The reaction mixture was heated under reflux for 4 h. The

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2094
Elgemeie and Elzanate
Chart 3.
resultant product was acidified with HCl. The precipitate formed was
collected by filtration, dried and then recrystallized from ethanol.
16. Yellow crystals, 50% yield, m. p. 295ꢀC. 3490, 3400 (OH), 2210
(CN); 1675 (CO). 1H NMR (ꢀ ppm): 2.30 (s, 3H, CH3); 7.09–8.11 (m, 5H,
C6H5), 8.88 (s, 1H, CH), 11.98 (s, br, 1H, OH). Found: C, 60.7; H, 4.3;
N, 18.8%; Calcd. for: C15H12N4O3: C, 60.8; H, 4.1; N, 18.9%.
REFERENCES
1. Elgemeie, G.H.; Elghandour, A.H.; Elzanate, A.M.; Masoud, W.A.
Novel N-substituted amino-4-methylsulfanyl-2-pyridones and deaza-
purine analogues from ketene dithioacetals. J. Chem. Research (S)
1998, 164–165.
2. Elgemeie, G.H.; Elghandour, A.H.; Ali, H.A.; Abdel-Azzez, H.M. A
novel and efficient method for the synthesis of N-arylsulfonylamino-
2-pyridones. J. Chem. Res. (S) 1999, 6–7.
3. Elgemeie, G.H.; Elghandour, A.H.; Elzanate, A.M.; Masoud, W.A.
Design and synthesis of a new class of N-arylsulfonylaminated
pyridones. Phosphurs, Sulfur and Silicon 2000, 163, 91–97.
4. Elgemeie, G.H.; Ali, H.A.; Elghandour, A.H.; Abd-Elaziz, G.W.
Synthesis of novel derivatives of 4-methylthio-N-aryl-2-pyridone and
deazapurine analogues: the reaction of ketene dithioacetals with sub-
stituted acetanilides. Phosphurs, Sulfur and Silicon 2000, 164, 189–197.
Received in the USA September 16, 2002