Synthesis of novel functionally substituted pyridazines and oxazines

Article abstract of DOI:10.1007/s10593-008-0141-2

Acetone 1,3-di(phenylhydrazone) reacts with arylidenemalononitriles in the presence of piperidine to give the coressponding 3,3′- carbonylbispyridazine derivatives. Under the same reaction conditions dioxime reacts with arylidenemalononitriles to give the corresponding 3,3′-carbonylbis-1,2-oxazines. Dioxime reacts with primary aromatic amines and formalin in a molar ratio of 1:1:2 to give 1-arylidene-3,5-dihydroxyimino- piperidine-4-ones.

Full text of DOI:10.1007/s10593-008-0141-2

Chemistry of Heterocyclic Compounds, Vol. 44, No. 8, 2008
SYNTHESIS OF NOVEL FUNCTIONALLY
SUBSTITUTED PYRIDAZINES AND OXAZINES
M. Hammouda, Z. M. Abou Zeid, M. A. Metwally
Acetone 1,3-di(phenylhydrazone) reacts with arylidenemalononitriles in the presence of piperidine to
give the coressponding 3,3'-carbonylbispyridazine derivatives. Under the same reaction conditions
dioxime reacts with arylidenemalononitriles to give the corresponding 3,3'-carbonylbis-1,2-oxazines.
Dioxime reacts with primary aromatic amines and formalin in a molar ratio of 1:1:2 to give
1-arylidene-3,5-dihydroxyimino- piperidine-4-ones.
Keywords: acetone 1,3-dioxime,acetone 1,3-diphenylhydrazone,1,2-dioximes, pyridazines.
Although β-aminoenones and β-nitroenamines are already established as synthetic intermediates,
particularly, in heterocyclic chemistry [1–5], the utility of phenylhydrazones and oximes, which have closely related
structures to them, is little studied [6–8]. In this paper we describe the reaction of cyanoolefins 1 with
diphenylhydrazone 2 and dioxime 3 as a route to functionally substituted pyridazines and oxazines, respectively.
The reaction of electrophiles such as compound 1 with nucleophiles such as compound 2 is of interest
because it may occur either at the nitrogen atom of the NH group or at the carbon atom of the cyano group. Thus,
condensation of diphenylhydrazone 2 [9] with activated cyanoolefins 1a–c in a molar ratio of 1:2 in refluxing
ethanolic piperidine afforded 3,3'-carbonylbis(6-amino-4-aryl-5-cyano-1-phenylpyridazine) 4a–e (Scheme 1).
The structure of compound 4 was established for the reaction product, and the structure 5 was excluded,
1
based on analytical and spectral data (cf. Experimental). The H NMR spectrum of compound 4c exhibited a four
proton singlet at δ 5.55 (s, 2NH2), a two-proton singlet at δ 4.42 due to H-4 of pyridazine, and eighteen proton
multiplets at δ 7.27-7.62 (Ar).
m/z 273
C6H5
C6H5
O
CN
NC
N
N
N
NH2
N
H2N
Ph
Ph
m/z 301
4a
The mass spectrum of compound 4a showed a molecular ion at m/z 573 [M+–H], m/z 273 [pyridazine], m/z
301 [pyridazine–CO], m/z 196 [pyridazine–C6H5], and m/z 77 base peak [C6H5].
__________________________________________________________________________________________
Department of Chemistry, Faculty of Science, University ofMansoura, Mansoura, Egypt; e-mail:
mamegs@mans.edu.eg Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1223-1229,
August, 2008. Original article submitted May 21, 2007. In revised form March 10, 2008.
0009-3122/08/4408-0985©2008 Springer Science+Business Media, Inc.
985

The formation of compound 4 can be explained via initital Michael addition of compound 2 to the ylidene
bond in compound 1 forming an acyclic intermediate which is cyclized by nucleophilic attack of the NH group at the
cyano carbon, followed by tautomerization to the final product 4 (Scheme 1).
Scheme 1
O
CN
2
+
N
N
H
N
Ar
CN
HN
Ph
Ph
1a–c
2
Ethanol
piperidine
Ar
O
Ar
Ar
O
Ar
Ar
O
Ar
NC
O
CN
O
NC
HN
CN
NH
CN
N
NC
..
..
N
N
N
C
H
N
C
H
N
N
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
Ph
Ph
5
Ar
O
Ar
NC
CN
EtOH
piperidine
2 + 2 ArCHO + 2 CH2(CN)2
N
N
H2N
N
NH2
N
Ph
Ph
4
4 a Ar = Ph, b Ar = p-ClC6H4, c Ar = p-BrC6H4, d Ar = p-O2NC6H4,
e Ar = C6H3OCH2O-3,4
The reactivity of compound 2 towards the β-carbon in compound 1 can be accounted for by the contribution
of a resonance structure B analogously to β-nitroenamines [10].
O
O
–
C
–
C
O2N
O2N
C
C
+
N
C
N
+
N
C
N
..
N
..
N
B
B
A
A
Phenylhydrazone
β-Nitroenamine
In view of the previous discussion, it might be expected that dioxime 3 [11] which has a closely related
structure to phenylhydrazone 2, will react with compound 1. Therefore, the authors investigated the reactivity of
compound 3 towards compound 1. Indeed, the treatment of dioxime 3 with activated cyanoolefins 1a–c in a molar
ratio of 1:2 in refluxing 1-propanol in the presence of a catalytic amount of piperidine gave carbonyl bis-oxazine
derivatives 6a–c rather than 7 (Scheme 2).
986

The structure of compounds 6 was established for the reaction products based on analytical and spectral data
(cf. Experimental). The mass spectrum of compound 6c showed a molecular ion at m/z 408 (base peak), m/z 307
[oxazine−CO+2H], 279 [oxazine + 2H], 270 [M+−2C6H4Br], and 121 [oxazine−C6H4Br].
The reactivity of compound 3 towards the β-carbon in compound 1 can be accounted for by the contribution
of a resonance structure B in the oxime, and its behavior as a bidentate (sites a and b) towards nucleophiles.
a
–
C
C
+
O
N
N
..
O
H
H
b
B
A
Scheme2
O
CN
CN
2
+
N
N
OH
Ar
HO
1a–c
3
1-Propanol
piperidine
Ar
O
Ar
Ar
O
O
Ar
O
NC
O
CN
O
CN
N
NC
N
..
O
..
O
N
N
C
C
H
N
N
H
7
Ar
O
O
Ar
O
O
Ar
Ar
NC
NC
HN
CN
CN
NH
N
N
N
N
H2N
NH2
O
O
6
6 a Ar = Ph, b Ar = p-ClC6H4, c Ar = p-BrC6H4
It has been shown [9] that diphenylhydrazone 2 undergoes a double Mannich reaction with primary
aromatic amines and formalin to give piperidone diphenylhydrazone 10.
O
PhNH
N
N NHPh
ArNH2 + 2CH2O
2
N
Ar
10
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In view of this report and in view of the similarity of dioxime 3 with diphenylhydrazone 2, it appeared
of interest to study the behavior of dioxime 3 toward a double Mannich reaction. Thus, the treatment of
compound 3 with primary aromatic amines and formalin in a molar ratio of 1:1:2 in refluxing ethanol afforded
1-aryl-3,5-dioximes of piperidine-3,4,5-triones 11a–c.
O
HO
N
N
OH
EtOH
2CH2O
ArNH2
3
+
+
∆
N
Ar
11
11 a Ar = Ph,b Ar = p-MeOC6H4.c Ar = p-ClC6H4
The structure of compound 11 was established for the reaction product based on analytical and spectral
1
data (cf. Experimental). The H NMR of compound 11c a exhibited a four-proton singlet at δ 2.11 due to CH2
groups, four aromatic protons at δ 7.50-7.92, and a two-proton broad singlet at δ 10.91 due to OH of oxime
groups.
The mass spectrum of compound 11c showed an intense peak at m/z 156 [M+−C6H4Cl] resulting from
cleavage of the N−C6H4Cl bond . The base peak is at m/z 139 [156 − OH], and there is another intense peak at
m/z 111 [base peak−CO].
EXPERIMENTAL
Melting points (uncorrected) were taken on a Fisher electric melting point apparatus. Elemental analyses
were carried out in the Microanalytical Unit, Faculty of Science, Mansoura and Cairo Universities. IR spectra
1
were recorded on a SP-2000 Pye-Unicam Spectrometer (KBr). H NMR spectra were obtained with Varian-
Gemini 200 MHz and Brucker 250 MHz, TMS (an internal standard). Mass spectra were recorded on a GCMS
QP1000EX Schimadzu mass spectrometer at 70 eV. The purity of the synthesized compounds was tested by thin
layer chromatography (TLC), and no by products were noticed in all cases.
3,3'-Carbonylbis(6-amino-4-aryl-5-cyano-1,4-dihydro-1-phenylpyridazines) 4a-e.
A. A mixture of diphenylhydrazone 2 [9] (2.5 mmol) and the appropriate arylidenemalononitriles 1a-e (5
mmol) in absolute ethanol (40 ml) and piperidine (0.1 ml) was refluxed for 8 h. The solid products obtained were
filtered off and crystallized from ethanol to give compounds 4a-e .
B. A mixture of compound 2 [9] (2.5 mmol), the appropriate aldehyde (5 mmol), and malononitrile (5 mmol)
in absolute ethanol (40 ml) and piperidine (0.1 ml) were refluxed for 8 h. The solid products separated was filtered off
and crystallized from ethanol to give compounds 4a-c (mp and mixed mp).
Compound 4a is obtained as yellow crystals. Yield 74%; mp 218-220°C. IR spectrum, ν, cm–1: 3449, 3225
(NH2), 2190 (C≡N), 1634 (CO). Mass spectrum, m/z (Irel, %): 573 [M+–H] (2), 273 [pyridazine] (29), 301
[pyridazine+CO] (4), 196 [pyridazine–C6H5] (6), 77 [C6H5] (a base peak) (100). Found, %: C 73.23; H 4.67; N 19.59.
C35H26N8O. Calculated, %: C 73.16; H 4.56; N 19.50.
Compound 4b is obtained as yellow crystals. Yield 75%; mp 198-201°C. IR spectrum, ν, cm–1: 3433,
3240 (NH2), 2183 (C≡N), 1640 (CO). Found, %: C 65.22; H 3.68; N 17.29. C35H24Cl2N8O. Calculated, %:
C 65.32; H 3.76; N 17.41.
Compound 4cis obtained as red crstals. Yield 71%; mp 282-285°C. IR spectrum, ν, cm–1: 3450, 3300
1
(NH2), 2185 (CN), 1640 (CO). H NMR spectrum (CDCl3), δ, ppm: 4.42 (2H, s, H-4 pyridazine); 5.55 (4H, s,
988

2NH2); 7.27-7.62 (18H, m, Ar). Mass spectrum, m/z (Irel, %): 730 [M+–2H] (2), 352 [pyridazine] (33), 380
[pyridazine+CO] (8), 196 [pyridazine–C6H4Br] (4). Found, %: 57.48; H 3.39; N 15.42. C35H24Br2N8O.
Calculated, %: C 57.39; H 3.30; N 15.30.
Compound 4d is obtained as brown crystals. Yield 64%; mp 232–235°C. IR spectrum, ν, cm–1: 3420,
3320 (NH2), 2180 (C≡N), 1640 (CO). Found, %: C 63.33; H 3.72; N 21.35. C35H24N10O5. Calculated, %:
C 63.25; H 3.64; N 21.08.
Compound 4e is obtained as brown crystals. Yield 68%; mp 219-221°C. IR spectrum, ν, cm–1: 3418,
3347 (NH2), 2205 (C≡N), 1640 (CO) .1H NMR spectrum (CDCl3), δ, ppm: 4.38 (2H, s, H-4 pyridazine); 5.05
(4H, s, 2O−CH2−O); 5.92 (4H, s, 2NH2); 7.28–7.65 (16H, m, Ar). Found, %: C 66.94; H 4.12; N 16.94.
C37H26N8O5. Calculated, %:C 67.06; H 3.66; N 16.91.
3,3′-Carbonylbis(6-amino-4-aryl-5-cyano-4H-1,2-oxazine) 6a-c (General Method). A mixture of
dioxime 3 [11] (2.5 mmol) and the appropriate arylidenemalononitriles 1a-c (5 mmol) in 1-propanol (25 ml) and
piperidine (0.1 ml) was refluxed for 8 h. The reaction mixture was cooled, poured into water, and acidified with
diluted HCl (1:1). The precipitated materials were filtered off and crysallized from ethanol to give brown
crystals of 6a-c.
Compound 6a. Yield 79%; mp > 300°C. IR spectrum (KBr), ν, cm–1: 3469, 3315 (NH2), 2185 (C≡N), 1629
(CO) . Found, %: C 65.21; H 3.92; N 19.95. C23H16N6O3. Calculated, %: C 65.09; H 3.80; N 19.80.
Compound 6b. Yield 80%; mp > 300°C. IR spectrum, ν, cm–1: 3453, 3338 (NH2), 2195 (C≡ ), 1630 (CO).
Found, %: C 56.12; H 2.94; N 17.13. C23H14Cl2N6O3. Calculated, %: C 56.01; H 2.86; N 17.04.
Compound 6c. Yield 78%; mp >300°C. IR spectrum, ν, cm–1: 3420, 3332(NH2), 2201 (C≡N), 1630 (CO).
Mass spectrum, m/z (Irel, %): 408 [base peak] (100), 307 [oxazine–CO+2H] (33), 279 [oxazine+2H] (21), 270 [M+–
C6H4Br] (14), 194 [oxazine–C–C6H4Br] (15.3) and 121 [oxazine–C6H4Br] (18). Found, %: C 47.34; H 2.35; N 14.31.
C23H14Br2N6O3. Calculated, %: C 47.44; H 2.42; N 14.44.
1-Aryl-3,5-dioximes of piperidine-3,4,5-triones 11a-c (General Method). A mixture of compound 3
[11] (2.5 mmol), the appropriate aromatic amine (2.5 mmol), and (5 mmol) formalin in ethanol (30 ml) was
refluxed for 6 h. The reaction mixture was cooled, poured into water, and acidified with diluted HCl (1:1). The
precipitated materials were filtered off and crystallized from ethanol to give brown crystals of compounds 11a-c.
Compound 11a. Yield 54%, mp 177-180°C. IR spectrum, ν, cm–1: 3400 (OH), 1730 (CO), 1660 (C≡N).
Found, %: C 56.52; H 4.63; N 18.12. C11H11N3O3. Calculated, %: C 56.65; H 4.76; N 18.02.
Compound 11b. Yield 56%; mp 167-170°C. IR spectrum, ν, cm–1: 3408 (OH), 1730 (CO), 1663 (C≡N).
Found, %: C 54.62; H 4.88; N 15.86. C12H13N3O4. Calculated, %: C 54.75; H 4.98; N 15.97.
Compound 11c. Yield 57%; mp 258-261°C. IR spectrum, ν, cm–1: 3440 (OH), 1735 (CO).1H NMR
(DMSO), δ, ppm: 2.11 (4H, s, 2CH2); 7.50-7.92 (4H, m, Ar); 10.91 (2H, br. s, 2OH oxime). Mass spectrum, m/z
(Irel, %): 156 [M+–C6H4Cl] (8), 139 [156–OH] (base peak) (100), 111 [base peak–CO]. Found, %: C 49.24;
H 3.64; N 15.56. C11H10ClN3O3. Calculated, %: C 49.35; H 3.77; N 15.70.
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