New one- pot synthesis of pyrazolo[3,4-c]pyridazine and isoxazolo-[5,4-b]pyridine derivatives from potassium cyanoacetahydroxamate

Article abstract of DOI:10.1002/jhet.5570450450

(Chemical Equation Presented) The reaction of potassium cyanoacetohydroxamate 1 with ethyl 2-aryl-hydrazono-3-oxobutyrates 2 gave the unexpected pyrazolo[3,4-c]pyridazines 7 and isoxazolo[5,4-b]pyridines 10 via a one-pot reaction. A mechanistic proof is suggested to account for the products.

Full text of DOI:10.1002/jhet.5570450450

Jul-Aug 2008
1233
New One- Pot Synthesis of Pyrazolo[3,4-c]pyridazine and Isoxazolo-
[5,4-b]pyridine Derivatives from Potassium Cyanoacetahydroxamate
Eman A. El-Rady * and Magda A. Barsy†
Chemistry Department, Faculty of Science, South Valley University, Aswan, Egypt.
emanelradi@hotmail.com
Recevied July 24, 2007
CH3
O
COOH
HN
N
N
N
NNHAr
NH
Ar
OC2H5
H3C
OK
NC
7a- d
O
+
O
O
CH3
O
1
2
NNHAr
O
HN
O
N
10a- d
The reaction of potassium cyanoacetohydroxamate 1 with ethyl 2-aryl-hydrazono-3-oxobutyrates 2 gave
the unexpected pyrazolo[3,4-c]pyridazines 7 and isoxazolo[5,4-b]pyridines 10 via a one-pot reaction. A
mechanistic proof is suggested to account for the products.
J. Heterocyclic Chem., 45, 1233 (2008).
INTRODUCTION
cinnoline, phthalazine and other condensed heterocyclic
derivatives [25-29].
Many new reported synthetic
Pyrazole derivatives have attracted attention because of
their use as a precursor for many drug substances,
covering a broad spectrum of medicinal and pharmacol-
methods for pyrazolo-pyridazine and/or isoxazolo-
pyridine derivatives have been based on using one
functionalized pyrazole (pyridazine/isoxazole) ring to
react with different reagents to construct the second
heterocyclic ring. However, the strategy reported in this
paper is based on the new and facile reaction of potassium
cyanoacetohydroxamate 1 which was not used before in
analogous synthesis with ethyl 2-arylhydrazono-3-
ogical applications [1-6].
Such derivatives have
antibacteriales, antifungicals, anticonvulsants [7],
hypotensives [8], antidepressants [9] and neuroprotective
[10] activities. They are also used as novel ligands for the
estrogen recpetor [11]. Introduction of the azole ring to
other heterocyclic compounds is expected to influence
oxobutyrates
2 to deliver pyrazolo-pyridazine and
their biological activities significantly.
Thus, the
isoxazolo-pyridines analogs via a one-pot synthesis.
The first look on the two reactants led us to expect that
the pyridine ring 4 would be the product via condensation
- elimination reaction in accordance with our previous
results [27, 29] as shown in Scheme 1.
synthesis of pyrazolopyridazine derivatives [12-14] and
their biological activities have attracted interest because
they have shown remarkable effects on the central
nervous system [15], they posses anti-inflammatory
[16,17], anti-HSV-1 [18] activity and they are also used as
selective inhibitors of cyclin-dependent kinases [19],
recently they were investigated as ERK2 inhibitors [20]
and found to be useful as peripheral vasodilators and
evaluated as inhibitors of PDE5 extracted from human
platelets [21]. On the other hand, the isoxazolopyridine
revealed auxin activity [22] and cytotoxic activity against
various human and mouse tumor cells. They also have
potential as antiproliferative [23] and as HMG-CoA
reductase inhibitors [24].
However, potassium cyanoacetohydroxamate
1
reacted with ethyl 2-arylhydrazono-3-oxobutyrates 2a-
d under reflux in a mixture of benzene-acetic acid-
ammonium acetate to give two products and no
pyridine 4 was detected. Red crystals were formed
during reflux, which had melting point > 350 °C, and
lustrous yellow needles that melt at 200 °C were
precipitated at room temperature, careful analysis of
the filtrate showed that no other products were present.
Each of the two products showed the same m/z at 270,
compatible with the expected pyridine compound 4
which would formed via condensation-elimination
reaction through formation of the intermediate 3,
formed via condensation step between the active
RESULTS AND DISCUSSION
Ethyl
2-arylhydrazono-3-oxobutyrates
represent
versatile reagents in organic synthesis. Recently, we
reported their utility to prepare pyridine, pyridazine,

1234
E. A. El-Rady and M. A. Barsy
Vol 45
and 13C NMR spectra showed the absence of the
characteristic absorption pattern of ethoxy protons of
ester group. In this light, we assumed that the
precursor of products 7a-d and 10 a-d can be the
Knoevenagel intermediate 3. To account for the
formation of the products, it is plausible that
intermediate 3 undergos intramolecular cycloaddition
of the hydrazo hydrogen to the cyano function yielding
the pyridazine intermediate 5, which is hydrolyzed to
the hydroxamic acid intermediate 6, followed by loss
of water to afford the red pyrazolo[3,4-c]pyridazine 7a-
Scheme 1
NNHAr
OC2H5
NH
H3C
OK
NC
+
O
O
O
1
2
benzene / acetic acid
-H2O
NNHAr
H3C
CO2C2H5
HN OK
1
d, (Scheme 2). The H NMR spectra of 7a-d showed
NC
singlet signals assigned for methyl and NH protons at ꢀ
2.3-2.7 and 12.1-12.5 ppm, respectively. The 13C NMR
of 7a showed signal at ꢀ 15.2 ppm assigned for CH3,
122.2-127.8 (aryl-C), 128.2 (C-6), 132.1 (C-5), 135.6
(C-6a), 140.3 (C-2a), 165.5 (C-7), 170.1 (CO2H), while
revealed the disappearance of any signal at 115-118
ppm of cyano carbon, which would be present in
structure 4.
O
3
-EtOH
-EtOH
- H2O
CH3
CH3
NNHAr
O
O
O
COOH
NNHAr
O
H3C
NC
HN
HN
N
N
OH
N
O
N
N
On the other hand, in the key intermediate 3 the
potassium of hydroxamate moiety may be hydrolyzed to
the hydroxamic acid intermediate 8. The latter readily is
cyclized to the iminoisoxazolone intermediate 9 via an
intramolecular cycloaddition of the hydrogen of
hydroxamic acid to the cyano function. However,
elimination of ethanol from 9 yielded the yellow
isoxazolo[5,4-b]pyridine derivatives 10a-d, (Scheme 3).
The 1H NMR spectrum of 10a revealed two singlet
signals at ꢀ 2.3 and 12.6 ppm due to methyl and hydrazo
protons respectively, beside multiplet at ꢀ 7.1-7.9 ppm for
aromatic and NH of isoxazolone.
Ar
O
10a- d
7a- d
4
methylene of potassium cyanoacetohydroxamate 1 and
the carbonyl oxygen of ester 2, followed by elimination
of ethanol (Scheme 1). However, the IR spectra
showed no absorption band characteristic for the cyano
function, as expected for compound 4, and
consequently formation of compound 4 was ruled out.
On the other hand, the IR spectra revealed bands
1
assigned for carbonyl and NH groups. Meanwhile, H-
Scheme 2
Formation of Pyrazolopyridines
O
NNHAr
CH3
benzene / acetic acid
amm. acetate
NH
OC2H5
+
H3C
CO2C2H5
OK
NC
HN
KO
O
reflux, 4 h.
- H2O
O
O
N
CN
HN
Ar
2
1
3
add.
CH3
CH3
O
CH3
O
O
COOH
hydrolysis
COOH
CO2C2H5
-H2O
HN
OH
HN
HN
N
N
N
N
OK
N
HN
N
HN
N
Ar
Ar
Ar
7a, Ar = C6H5
b, Ar = C6H4-P-Cl
c, Ar = C6H4-P-CH3
6
5
d, Ar = C6H4-P-OCH3

Jul-Aug 2008 New One- Pot Synthesis of Pyrazolo[3,4-c]pyridazine and Isoxazolo[5,4-b]pyridine Derivatives
1235
Scheme 3
Formation of Isoxazolopyridines
NNHAr
benzene / acetic acid
NNHAr
H3C
amm. acetate
NH
OC2H5
+
H3C
CO2C2H5
OK
NC
reflux, 4h.
- H2O
O
O
CN
O
O
HN OK
2
1
3
H+
NNHAr
NNHAr
CO2C2H5
CH3
N
O
HN
H3C
O
H3C
-EtOH
NNHAr
O
CO2C2H5
add.
O
NH
CN
O
HN
O
HN OH
10a, Ar = C6H5
b, Ar = C6H4-P-Cl
c, Ar = C6H4-P-CH3
d, Ar = C6H4-P-OCH3
9
8
Reaction of arylhydrazones (2a-d) with potassium
cyanacetamidehydroxmate (1). mixture of equimolar
Structure of 10 can be ascertained unequivocally as
shown in scheme 4. The hydroxamate 1 was cyclized to
isoxazolone 11 under reflux in methanolic sodium
methoxide according to Khan [30] then allowed to react
with the butyrates 2 using the same reaction conditions.
The same isoxazolo[5,4-b]pyridines 10 were isolated as
the sole products. This may confirm that the intermediate
8 underwent intramolecular cycloaddition forming the
isoxazolone ring before ethanol elimination occurred.
A
amounts (1a) (2.3 g, 0.01 mol), (2a) (1.8 g, 0.01 mol) and
anhydrous ammonium acetate (0.77 g, 0.01mol) in acetic
acid/benzene mixture (50:10 v/v) was heated for 4 hours under
reflux using a Dean-Stark apparatus. The red crystals, which
formed during reflux, were collected by filtration and identified
as compounds (7a-d). The filtrate was cooled to room
temperature and the resulting crystals were collected by
filtration to give compounds (10a-d).
Scheme 4
H3C-CO-C-CO2C2H5
CH3
N
O
NH
O
NH
CH3ONa
NNHAr
2
NNHAr
O
OK
NC
HN
O
O
HN
acetic acid / benzene
amm. acetate / reflux
CH3OH, Reflux
O
1
11
10a, Ar = C6H5
b, Ar = C6H4-P-Cl
c, Ar = C6H4-P-CH3
d, Ar = C6H4-P-OCH3
EXPERIMENTAL
Melting points were determined on
4-Methyl-3-oxo-7-phenyl-2H-pyrazolo[3,4-c]pyridazine-5-
carboxylic acid (7a). mp: >350 °C, Yield: 1g, 38
%
(DMF/H2O). IR: ꢀ 1651-1700 (CO), 3106-3115 (NH), 3469
(OH) cm-1; 1H nmr (DMSO): ꢀ 2.6 (s, 3H, CH3), 7.3-7.9 (m, 5H,
Ar-H), 12.5 (s, 1H, NH), 14.1 (s, 1H, OH); 13C nmr: 15.2 (CH3),
122.2-127.8 (aryl-C), 128.2 (C-6), 132.1 (C-5), 135.6 (C-6a),
140.3 (C-2a), 165.5 (C-7), 170.1 (COOH); MS (70 eV) m/z (%):
270 (M+, 60). Anal. Calcd. For C13H10N4O3 (270.25): C, 57.78;
H, 3.73; N, 20.73. Found: C, 57.88; H, 3.50; N, 20.60.
a
Gallenkamp
electrothermal melting point apparatus and are uncorrected. IR
spectra were recorded as potassium bromide pellets on a Pye
Unicame SP 3-300 and FT IR 8101 PC Shimadzu infrared
spectrophotometer. The 1H NMR, 13C NMR spectra were obtained
in deuterated dimethyl sulfoxide and/or chloroform on a Varian
Gemini 200 NMR spectrometer using tetramethylsilane (TMS) as
an internal reference. Mass spectra were recorded on a GC MS-
QP 1000 EX Shimadzu mass spectrometer at 70 eV. Elemental
analysis was carried out at the Microanalytical Center of Cairo
University, Giza, Egypt. Potassium cyanacetamidehydroxmate 1
was prepared according to a published procedure [30].
4-Methyl-3-oxo-7-(p-chlorophenyl)-2H-pyrazolo[3,4-c]-
pyridazine-5-carboxylic acid (7b). mp: 315-17 °C, Yield: 0.8
g, 27 % (DMF / H2O). IR: ꢀ 1680-1698 (CO), 3185-3190 (NH),
1
3390 (OH) cm-1; H nmr (DMSO): ꢀ 2.7 (s, 3H, CH3), 7.0-7.7
(m, 4H, Ar-H), 12.2 (s, 1H, NH), 14.4 (s, 1H, OH); MS (70 eV)

1236
E. A. El-Rady and M. A. Barsy
Vol 45
m/z (%): 304 (M+, 50). Anal. Calcd. For C13H9ClN4O3 (304.69):
C, 51.25; H, 2.98; N, 18.39. Found: C, 51.47; H, 2.51; N, 18.60.
4-Methyl-3-oxo-7-(p-methylphenyl)-2H-pyrazolo[3,4-c]-
pyridazine-5-carboxylic acid (7c). mp: 297- 99 °C, Yield: 0.9
g, 32 % (DMF / H2O). IR: ꢀ 1685-1695 (CO), 3184-3190 (NH),
3400 (OH) cm-1; 1H nmr (DMSO): ꢀ 2.3 (s, 3H, CH3), 2.6 (s, 3H,
CH3), 7.0-7.7 (m, 4H, Ar-H), 12.1 (s, 1H, NH), 14.1 (s, 1H,
OH); MS (70 eV) m/z (%): 284 (M+, 50). Anal. Calcd. For
C14H12N4O3 (284.28): C, 59.15; H, 4.25; N, 19.71. Found: C,
59.32; H, 4.55; N, 19.68.
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4-Methyl-3-oxo-7-(p-methoxyphenyl)-2H-pyrazolo[3,4-c]-
pyridazine-5-carboxylic acid (7d). mp: 300 - 2 °C, Yield: 0.9
g, 26 % (DMF / H2O). IR: ꢀ 1695-1702 (CO), 3188-3199 (NH),
3420 (OH) cm-1; 1H nmr (DMSO): ꢀ 2.3 (s, 3H, CH3), 3.7 (s, 3H,
CH3), 7.1-7.6 (m, 4H, Ar-H), 12.2 (s, 1H, NH), 14.2 (s, 1H,
OH); MS (70 eV) m/z (%): 300 (M+, 40). Anal. Calcd. For
C14H12N4O4(300.27): C, 56.00; H, 4.03; N, 18.66. Found: C,
56.16; H, 4.23; N, 18.88.
3,6-Dioxo-4-methyl-5-phenylhydrazo-2H-5,6-dihydroisox-
azolo[5,4-b]pyridine (10a). mp: 200 - 2 °C, Yield: 0.9 g, 34 %
1
(EtOH). IR: ꢀ 1690-1701 (CO), 3194-3200 (NH) cm-1; H nmr
(CDCl3): ꢀ 2.3 (s, 3H, CH3), 7.1-7.9 (m, 6H, Ar-H + NH), 12.6
(s, 1H, NH); 1C nmr: 15.5 (CH3), 127-130 (aryl-C), 132.9 (C-4),
142.2 (C-5),165.9 (C-6), 170.2 (C-3); MS (70 eV) m/z (%): 270
(M+, 70). Anal. Calcd. For C13H10N4O3 (270.25): C, 57.78; H,
3.73; N, 20.73. Found: C, 57.85; H, 3.59; N, 20.65.
3,6-Dioxo-4-methyl-5-(p-chlorophenylhydrazo)-2H-5,6-
dihydro-isoxazolo[5,4-b]pyridine (10b). mp: 210- 12 °C,
Yield: 0.9 g, 30 % (EtOH). IR: ꢀ 1689-1699 (CO), 3189-3190
1
(NH) cm-1; H nmr (CDCl3): ꢀ 2.4 (s, 3H, CH3), 7.0-7.6 (m, 5H,
Ar-H + NH), 12.1 (s, 1H, NH); MS (70 eV) m/z (%): 304 (M+,
60). Anal. Calcd. For C13H9ClN4O3 (304.69): C, 51.25; H, 2.98;
N, 18.39. Found: C, 51.45; H, 2.59; N, 18.65.
3,6-Dioxo-4-methyl-5-(p-methylphenylhydrazo)-2H-5,6-
dihydro-isoxazolo[5,4-b]pyridine (10c). mp: 190 - 92 °C,
Yield: 1 g, 35 % (EtOH). IR: ꢀ 1688-1702 (CO), 3184-3190
(NH) cm-1; 1H nmr (CDCl3): ꢀ 2.4 (s, 3H, CH3), 2.6 (s, 3H, CH3),
7.0-7.7 (m, 5H, Ar-H + NH), 12.3 (s, 1H, NH); MS (70 eV) m/z
(%): 284 (M+, 40). Anal. Calcd. For C14H12N4O3 (284.28): C,
59.15; H, 4.25; N, 19.71. Found: C, 59.35; H, 4.50; N, 19.65.
3,6-Dioxo-4-methyl-5-(p-methoxyphenylhydrazo)-2H-5,6-
dihydro-isoxazolo[5,4-b]pyridine (10d). mp: 195 - 97 °C,
Yield: 1 g, 33 % (EtOH). IR: ꢀ 1698-1702 (CO), 3184-3195
(NH) cm-1; 1H nmr (CDCl3): ꢀ 2.3 (s, 3H, CH3), 3.5 (s, 3H, CH3),
7.0-7.6 (m, 5H, Ar-H + NH), 12.4 (s, 1H, NH); MS (70 eV) m/z
(%): 300 (M+, 40). Anal. Calcd. For C14H12N4O4 (300.27): C,
56.00; H, 4.03; N, 18.66. Found: C, 56.15; H, 4.13; N, 18.85.
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REFERENCES
† The author is indebted to the Royal Society of Chemistry,
Awards and Lectureships International Affairs for funding this research.
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