New simple and one-pot synthetic routes to polyfunctionally substituted pyridines; 1,4-dihydropyridazines and 4H-1,2-oxazine

Article abstract of DOI:10.1515/znb-1999-0919

Reactions of arylidenemalononitriles 1a-d with 2-cyano-1,1-diaminoethene (5); arylhydrazones 14a,b and syn-2-pyridinealdoxime 15 afforded the title derivatives 3a-d; 16a,b and 17, respectively. Bipyridyl derivatives 11-13 were also synthesized. Unambiguou

Full text of DOI:10.1515/znb-1999-0919

New Simple and One-Pot Synthetic Routes to Polyfunctionally Substituted
Pyridines; 1,4-Dihydropyridazines and 4H-l,2-Oxazine
M. M. Mashaly3, M. Hammoudab*
Chemistry Department, Faculty of Science at Damietta3 and Mansourab,
Mansoura University, Mansoura, A. R. Egypt
*
Reprint requests to Prof. Dr. M. Hammonda
Z. Naturforsch. 54b, 1205-1209 (1999); received February 15, 1999
Arylidenemalononitriles, 2-Cyano-1,1-diaminoethene, Arylhydrazones,
s_y«-2-Pyridinealdoxime, Pyridines
Reactions of arylidenemalononitriles la-d with 2-cyano-l,l-diaminoethene (5); arylhydra­
zones 14a,b and syn-2-pyridinealdoxime 15 afforded the title derivatives 3a-d; 16a,b and 17,
respectively. Bipyridyl derivatives 11-13 were also synthesized. Unambiguous syntheses and/
or spectral analyses confirmed the suggested structures of 3a-d, 11-13, 16a,b and 17.
In the light of the reported important biological
nation. Ready autoxidation of dihydropyridines
activity of some pyridines [1-7] and in continua­ into pyridines under comparable conditions has
tion of our programme aiming to synthesize poly­ been reported [11,12],
functionally substituted heterocycles of potential
biological activity [8,9], it was interesting to us to tained unambiguously via direct condensation of
study the behaviour of 2-cyano-l,l-diaminoethene
the appropriate aromatic aldehyde 9 and 2 in a
Further confirmation of structure 3 was ob­
towards arylidenemalononitriles as a new syn­ molar ratio of 1 :2, under the same reaction condi­
thetic route to polyfunctionally substituted pyri­ tions (Scheme 1). In this case, one molecule of the
dines. Thus, the reaction of arylidenemalononit­ aldehyde condensed with two molecules of 5 at the
riles la-d with ethyl cyanoiminoacetate (
2
) in a highly nucleophilic site C2, with the elimination of
a water molecule to afford an acyclic intermediate
molar ratio of 1:1, in the presence of ammonium
acetate in refluxing absolute ethanol, afforded 4- 10, which cyclized into 8 via intramolecular elimi­
aryl-2,6-diamino-3,5-dicyanopyridine 3a-d (Sche­ nation of an ammonia molecule, then 8 aromatized
me 1). The structure of 3a-d was established for to 3.
the reaction product based on analytical and
spectral data, while structure of 4 was excluded on to have some pharmaceutical [5,6] or agrochemi­
the same bases (cf. Scheme 1 and Experimental).
cal [7] applications, it was worthy to apply the
The JH NMR spectrum of 3a showed an accu­ above given reaction as a new synthetic route to
mulated broad singlet at 7.28 ppm for four pro­ 4,2'-; 4,3'- and 4,4'-bipyridyl derivatives, e.g., 11-
tons of the two symmetrical NH groups and a 13. Thus, treatment of 2 with 2-, 3-, or 4-pyridinec-
multiplet signal at <3 7.45-7.60 ppm for the five arboxaldehyde in a molar ratio of 2 :1, in the pres­
As certain bipyridyl derivatives were reported
d
2
aromatic protons and its mass spectrum showed ence of ammonium acetate afforded, under the
the molecular ion, M+, as the base peak at m/e 235. same reaction conditions, derivatives 11-13,
Formation of 3 can be explained via initial
respectively (cf. Experimental). The mass
spectrum of 13 gave its molecular ion, M+, as the
Michael addition of 2-cyano-1,1-diaminoethene
(5) - which was generated from 2 and ammonium
base peak at m/e 236. The 2H NMR spectrum of
acetate [10] - to the ylidenic bond in 1 , leading to
the formation of an acyclic intermediate 6 which
cyclized into the intermediate 7 via a nucleophilic
attack of an NH2 group on a cyano carbon. The
cyclic intermediate 7 underwent tautomerization
into the dihydropyridine intermediate 8, which
aromatized into the final product 3 via dehydroge­
11
12
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1206
M. M. Mashaly and M. Hammouda ■1,4-Dihydropyridazines and 4H-l,2-Oxazine
ArCH=C(CN)2
1
+
a-d
Ar
.CN
CH3C 02NH4
,
CN
I
j f .HCl
EtOH, a
CN
h2n
nh 2
HjN
OEt
1a-d
Ar
N C^L^CN
N=C^=-iL
nh 2
^
n ;
H
H
2
i 7
Ar
NC^A^CN
Ar
NCV J ^ C N
-
NH,
-
H,
“
r V
H
i2n^\
A.nh
H2N
N
NH2
N^
H
2
H2N
tu
H
NH2
H
i
i
H
3
a-d
1
0
CH3C 02NH4
EtOH, A
1
,3,9
Ar
c 6h5
C6H4-Br-p
C6H4-N 02-p
C6H4-CI-p
ArCHO +
a-d
2
2
9
Scheme 1.
1
3 showed a doublet at
protons at C-3' and C-5' and a doublet at
.81 ppm for the two protons at C-2' and C-6 '.
d
7.54 ppm for the two analytical and spectral data (cf. Experimental).
d
The mass spectra of 16a,b showed the moelcular
8
ion, M+, at m/e values of 415 and 493, respectively.
Although enamines are already established as Compounds 16a,b underwent rearrangement in­
synthetic intermediates, particularly in heterocy­ volving the participation of the pyridazine H-4
clic chemistry [10, 13-20], the utility of arylhydra- proton, followed by elimination of tropylium
zones and aldoximes, which have structures closely (C7H7+, m/e = 91, 100%) and bromotropylium
related to them, have been little studied [21-23],
There is no available report on a reaction of an
(C7H6Br+, m/e - 169, 100%) ions as base peaks,
respectively. In parallel to what was suggested for
arylhydrazone, as a binucleophile, with an arylide- 3, formation of 16 could be explained via initial
nemalononitrile for constructing a pyridazine nu­ Michael addition of compound 14 to the ylidenic
cleus. Based on these findings and the reported bond in 1 , forming an acyclic intermediate which
biological activity of some pyridazines [24-26], it was cyclized by the nucleophilic attack of the NH
was interesting to us to introduce a new one-pot
group on a cyano carbon, followed by tautomeri-
synthetic route to polyfunctionally substituted 1,4- zation to the final product 16. Trials to obtain
dihydropyridazines, e.g., 16a,b (Scheme 2).
these pyridazines in either absolute ethanol or n-
propanol were unsuccessful. Their synthesis could
Thus, condensation of 14a with la and 14b with
lb in a molar ratio of 1:1, in presence of triethyla­ be achieved on using the higher boiling point
mine (TEA) in refluxing ethylene glycol (EG), af­ solvent ethylene glycol (EG).
forded the new 1.4-dihydropyridazine derivatives
Similarly, it was convenient to investigate the
1
6a,b respectively (Scheme 2). The structure of 16 first reaction between sy/7-2-pyridinealdoxime (15)
was established for the reaction product based on
and la as a representative example for a new syn-
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M. M. Mashaly and M. Hammouda • 1,4-Dihydropyridazines and 4H-l,2-Oxazine
1207
Ar^^H
fr
Ar
EG.
_ a ^ _
a
^
C u
^
.H EG
T E A ,
TEA, A
N
N
C
NH
c 6h5- s o 2
C(CN)2
n^..
A
o h
14a,b
1
15
thetic route to polyfunctionally substituted 4H-1,2- soura and Cairo Universities. The new compounds
gave satisfactory elemental analysis.
oxazines, e.g., 17 (Scheme 2). Condensation of 15
and la in a molar ratio of 1:1 , in the presence of
TEA in refluxing EG, afforded 6-amino-5-cyano- 1) Synthesis of 4-aryl-2,6-diamino-3,5-dicyano-
pyridines (3a-d)
4-phenyl-3-(pyrid-2'-yl)-4H-l,2-oxazine (17). In
analogy to 16a,b, the mass spectrum of 17 (cf. Ex­
perimental) suggested the participation of the oxa-
zine H-4 in a rearrangement followed by elimina­
tion of a tropylium ion (59.85%).
General procedure A:
A solution of 2 (1 g, 0.0067 mol), the arylide-
nemalononitrile la-d (0.0067 mol) and ammonium
acetate (3.2 g) in absolute ethanol (25 ml) was re­
fluxed for 3 h. The solid product deposited, or ob­
tained after concentration and cooling, was fil­
tered off, washed with water (6 x 15 ml) to get rid
of ammonium chloride, dried in air and crystal­
lized from absolute ethanol to afford 3a-d.
Experimental
Melting points were determined on Griffin
Melting Point Apparatus and were uncorrected.
The IR spectra were recorded on an SP-2000 Pye-
Unicam Spectrophotometer as KBr discs (v in cm~
!). !H NMR spectra were obtained on a Varian-
Gemini 200 MHz, using TMS as an internal stan­
General procedure B:
A solution of 2 (1 g, 0.0067 mol), the appropri­
dard and DMSO-d6 as solvent. Chemical shifts ate aldehyde 9a-d (0.0034 mol) and ammonium ac­
were expressed as ppm. Electron impact mass etate (3.2 g), in absolute ethanol (25 ml) was re­
spectra were recorded on a GC-MS QP1000 EX fluxed for 3 h, then proceeded as in the general
d
Schimadzu, or HP Model: MS-5988 Mass Spec­ procedure A to give compounds 3a-d (analytical
trometer, at 70 eV. Elemental analysis were per­ and spectral data).
formed at the Microanalytical Data Unit at Man-
3a: white, yield 75%, m.p. > 300 °C.
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1208
M. M. Mashaly and M. Hammouda • 1,4-Dihydropyridazines and 4H-l,2-Oxazine
lH NMR: (5 7.28 (s, br„ 4H, 2NH2) and 7.45-
.60 (m, 5H, C6H,); MS: M+at m/e = 235 (100%)
and (M+-HCN) at m/e = 208 (15.58%); IR
cm“1): 3476, 3422, 3362 (NH2), 2207 (CN) and
61 and 702 (monosubstituted benzene).
IR(cm_1): 3421, 3391, 3336, 3265 (NH2) and
2209 (CN).
7
C12H8N6 (236.23)
(
7
Calcd C 61.01 H 3.41%,
Found C 60.90 H3.31%.
CnH9N, (235.24)
Calcd C 66.38 H 3.86%,
Found C 66.25 H3.80%.
12: dark brown, yield 75%, m.p. > 300 °C.
IR(cm_1): 3414, 3204 (NH2) and 2208 (CN).
3b: yellow, yield 71%, m.p. > 300 °C.
lH NMR: (37.30 (s, br„ 4H, 2NH2), 7.46 (d, 2H,
C12H8N6 (236.23)
Calcd C 61.01 H 3.41%,
Found C 60.83 H3.20%.
3
7
3
'-H, 5'-H) and 7.77 (d, 2H, 2'-H. 6 '-H); MS(Br =
9): (M + 2)+at m/e = 315 (100%), M+at m/e
13 (66.31%), (M+-HCN) at m/e = 286 (5.82%)
and (M+-Br) at m/e = 234 (7.72%); IR(cm ]):
480, 3424, 3365 (NH2), 2205 (CN) and 826 (p-
=
13: dark brown, yield 72%, m.p. > 300 °C.
‘
H NMR: (37.54 (d, 2H, 3'-H, 5'-H), 7.94 (s, br.,
3
4
H, 2NH2) and 8.81 (d, 2H, 2'-H, 6 '-H); MS: M+
at m/e = 236 (100%) and (M+-HCN) at m/e = 209
17.85%); IR(cm_1): 3479, 3330, 3221 (NH2) and
217 (CN).
disubstituted benzene).
C13H879.9BrN5 (314.13)
(
2
Calcd C 49.71 H2.57%,
Found C 49.70 H 2.53%.
C12H8N6 (236.23)
Calcd C 61.01 H 3.41%,
Found C 60.97 H 3.38%.
3
c: greenish, yield 73%, m.p. > 300 °C.
!
H NMR: (37.40 (s, br., 4H, 2NH2), 7.81 (d, 2H.
3
'-H, 5'-H) and 8.39 (d, 2H, 2'-H, 6 '-H); MS: M+
at m/e = 280 (100%) and (M+-NOz) at m/e = 234
13.08%); IR(cm_1): 3455, 3383, 3347, 3237 (NH2),
213 (CN), 1515, 1352 (NOz) and 855 (p-disubsti-
3
) Synthesis of 6-amino-4-aryl-l-benzenesul-
phonyl-5-cyano-[3-pyrid-4'- (and -2'-)ylJ-l,4-
dihydropyridazines (16a,b)
(
2
tuted benzene).
A solution of 14a,b (0.0021 mol) and the appro­
priate arylidenemalononitrile la,b (0.0021 mol) in
ethylene glycol, EG, (20 ml) and triethylamine,
TEA, (0.2 ml) was refluxed for 4 h, cooled and
poured onto cold water (200 ml). The deposited
solid product was filtered off, dried in air and crys­
C13H8N60 2 (280.24)
Calcd C 55.72 H2.88%,
Found C 55.69 H2.92%.
3d: yellowish, yield 70% m.p. > 300 °C.
IR(cm_1): 3480, 3427, 3369, 3294 (NH2), 2218 tallized from ethanol to afford 16a,b, respectively.
CN) and 835 (p-disubstituted benzene).
(
16a: brown, yield 65%, m.p. > 300 °C.
MS: M+at m/e = 415 (9.02%), C7H7+at m/e
=
C13H8C1N5 (269.68)
9
1 (100%), C6H5+at m/e = 77 (64.95%), C5H4N+
at m/e = 78 (21.08%) and (C5H4N.CN)+at m/e -
04 (34.33%); IR ^m “1): 3445, 3354, 3224 (NH2),
194 (CN) and 1418, 1309 (S02-N).
Calcd C 57.90 H 2.99%,
Found C 57.80 H 2.96%.
1
2
2) Synthesis of 2,6-diamino-3,5-dicyano-4-(pyrid-
’-; 3'- and 4'-yl)pyridines 11-13, respectively
2
C22H17N,O.S (415.47)
Calcd C 63.60 H 4.12%,
Found C 63.20 H4.35%.
General procedure:
A solution of 2 (1 g, 0.0067 mol), 2-; 3-; or 4-
pyridinecarbox-aldehyde (0.0034 mol) and ammo­
nium acetate (3.2 g), in absolute ethanol (25 ml)
was refluxed for 3 h, then proceeded as in the
general procedure 1A to afford compounds 11-
16b: brown, yield 60%, m.p. > 300 °C.
MS: M+at m/e = 493 (49.35%), (M+2)+at m/e
495 (24.74%), C7H6Br+ at m/e = 169 (100%),
(C7H6Br + 2)+ at m/e = 171 (80.13%), (M-
C6H4Br)+at m/e = 338 (26.60%) and C6H4Br+at
=
13, respectively.
11: dark brown, yield 76%, m.p. > 300 °C.
’
H NMR: (37.62 (dd, 1H. 4'-H), 8.08 (d, 1H, 3'- m/e = 155 (18.26%); ^(cm "1): 3444, 3356, 3220
H) and 8.83 (d, 1H, 6 '-H). (NH-.), 2198 (CN) and 1418, 1334 (S02-N).
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M. M. Mashaly and M. Hammouda • 1,4-Dihydropyridazines and 4H-l,2-Oxazine
1209
C22H 16BrN,02S (494.37)
refluxed for 4 h, then proceeded as for 16a,b, to
afford 17.
17: dark brown, yield 50%, m.p. > 300 °C.
MS: HCNO+at m/e = 43 (100%), HCONH7+at
m/e = 45 (99.08), C7H7+at m/e = 91 (59.85%) and
Calcd C 53.45 H 3.26%,
Found C 53.00 H3.20%.
4
) Synthesis o f 6-amino-5-cyano-4-phenyl-3-(pyrid-
'-yl)-4H-l,2-oxazine (17)
(
CsH4N.CN)+at m/e = 104 (26.38%); IR ^ m “1):
2
3404, 3327, 3211 (NH2) and 2207 (CN).
A solution of 15 (0.5 g, 0.0041 mol) and benzyl- C16H 12N40 (276.30)
idenemalononitrile la (0.63 g, 0.0041 mol) in eth­
ylene glycol (20 ml) and triethylamine (0.2 ml) was
Calcd C 69.55 H4.38%,
Found C 69.00 H4.20%.
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