Studies with enamines and azaenamines: A novel efficient route to 6-amino-1,4-dihydropyridazines and their condensed derivatives

Article abstract of DOI:10.1002/jhet.5570440118

(Chemical Equation Presented) 1-Arylhydrazonopyruvaldehydes 1 react with α,β-unsaturated nitriles 2 to yield 6-amino-1,4-dihydropyridazines 4 that are converted into pyridazinones 5 via refluxing in an acetic acid/hydrochloric acid mixture and into the et

Full text of DOI:10.1002/jhet.5570440118

Jan-Feb 2007
105
Studies with Enamines and Azaenamines:
A Novel Efficient Route to 6-Amino-1,4-dihydropyridazines
and their Condensed Derivatives.
Said A. S. Ghozlan*, Ismail A. Abdelhamid, Hamdi M. Hassaneen,
and Mohamed H. Elnagdi*
Department of Chemistry, Faculty of Science, Cairo University, Giza, A. R. Egypt
E-mail: shelmy@access.com.eg, S_ghozlan@yahoo.com,
Received March 20, 2006
O
Ph
X
AcOH / HCl
H C
3
N
O
Ph
N
Ar
5
O
O
X
Ph
CN
X
H C
3
H C
3
+
N
N
NH2
N
NH
Ar
PhNCS
Ar
Condensed Pyridazine
2
1
4
1
-Arylhydrazonopyruvaldehydes 1 react with ꢀ,ꢁ-unsaturated nitriles 2 to yield 6-amino-1,4-
dihydropyridazines 4 that are converted into pyridazinones 5 via refluxing in an acetic acid/hydrochloric
acid mixture and into the ethylidenemalononitrile derivatives 6 on reflux with malononitrile in
ethanolic/piperidine solution.
J. Heterocyclic Chem., 44, 105 (2007).
Enamines are versatile reagents and the nucleophilic
benzoyl-3-phenyl-acrylonitrile 2c adds to 1a to yield 6-
amino-5-benzoyl-pyridazine 4d.
character of C-2 has found extensive applications in
synthetic organic chemistry [1,2]. Aldehyde hydrazones
can also be considered as azaenamines and aldehydic
carbon is also nucleophilic. Although this may be
considered as a way of umpoulung (dipole inversion of
aldehydic carbon) only few synthetic applications of this
phenomenon has so far been reported and are basically
limited to few Mannich alkylations [3-6], Vilsmayer
formylation [7], reactions with aldehydes [4] and quinones
Scheme 1
O
O
Ph
Ph
CN
X
CN
H
3
C
H C
3
N
+
N
X
NH
Ar
NH
Ar
3
1
a, Ar = C H
b, Ar = C H Cl-p
2a
,
X = CN
6
6
5
4
b, X = COOEt
c, X = COPh
[
8]. The recently reported reactivity of pyruvaldehyde-1-
arylhydrazones with quinones [8] prompted us to
investigate the possibility that these pyruvaldehyde-1-
arylhydrazones can also undergo Michael addition to ꢀ-
substituted cinnamonitriles thus affording a novel simple
and efficient approach to 1,4- dihydropyridazines. In
conjunction with our interest in developing synthesis for
biologically interesting pyridazines [9-16] we investigated
this type of Michael addition. Thus it has been found that
refluxing pyruvaldehyde-1-arylhydrazones 1a-c with
benzylidene-malononitrile 2a afford 1:1 adducts. Several
isomeric structures seemed possible. Structures involving
O
Ph
X
H C
3
N
N
NH2
Ar
4a, Ar = C H ;
X = CN
6
6
6
6
5
b, Ar = C H Cl-p; X = CN
4
c, Ar = C H ;
X = COOEt
X = COPh
5
d, Ar = C H ;
5
Formation of 4 is assumed to proceed via initial
addition of hydrazone CH to the activated double bond in
to yield 3 that readily cyclizes into 4. NMR can not
1
2
addition of acyl methyl were readily eliminated as H
however exclude the possible initial addition of hydrazone
NH to activated double bond in 2 yielding 6-H-
pyridazine derivatives, however, X-ray analysis of 4d
confirmed that 4-H-pyridazine 4 are the actual products
NMR revealed methyl signal at ꢂ 2.33 ppm. Acyclic
structure 3 was readily also excluded based on H NMR
1
and IR spectra which revealed amino signals and bands.
Thus structures 4a, b were established. We have extended
our investigation on this type of addition and have found
that ethyl benzylidenecyanoacetate 2b also adds to 1a to
yield ethyl 6-aminopyridazine-5-carboxylate 4c. Also 2-
(
cf figure 1) [17]. X-ray clearly indicates existence of
intramolecular hydrogen bonding between NH2 and
benzoyl carbonyl moiety.

1
06
S. A. S. Ghozlan, I. A. Abdelhamid, H. M. Hassaneen, and M. H. Elnagdi
Vol 44
Reacting 1a with ethoxyethylidenemalononitrile 10
resulted in the formation of a product that may be
1
formulated as 12 or 13. H NMR clearly revealed that the
reaction product is corresponds to 13 as only one methyl
signal is observed. It is possible that 11 is an intermediate.
Formation of 13 is assumed to take place via condensing
1
0 with 1a to yield intermediate 11, which condenses with
malononitrile that results most likely from hydrolysis of
unreacted 10 under these reaction conditions.
In conclusion the addition of hydrozone CH to activated
double bonds is seemingly general reaction that can be
adopted at least for synthesis of functionally substituted
pyridazines.
Scheme 3
NC CN
CH3
CN
Figure 1. X-ray crystal structure of compound 4d.
H C
3
N
N
NH
Compound 4a was readily converted into 5 via
O
CH
3
Ph
refluxing 4a in an acetic acid/hydrochloric acid mixture.
Structure 5 was established based on IR which revealed
absence of NH2 band and also H NMR revealed the
1
NH2
2
H C
OEt
CN
CN
NH
3
1a
H C
3
1
N
NC
NC
N
appearance of two doublets at ꢀ 4.96 (J = 7.2 Hz), and 5.34
ppm (J = 7.2 Hz). In an attempt to synthesis 4a from
reaction of a mixture of benzaldehyde, malononitrile, and
Ph
10
CN
NH
H C
3
1
1
N
N
1
a in ethanolic/piperidine solution only 6 was formed. This
Ph
could be also obtained on reacting 4a with malononitrile.
Typical of the established behaviour of enaminonitriles [18]
compound 4a reacted with phenylisothiocyanate to yield 7.
Also 6 affords 8. Possible isomeric 9 was excluded based
13
EXPERIMENTAL
1
on H NMR that revealed presence of methyl signal at ꢀ
3
.58 ppm and absence of amino signal as required for
Melting points were determined on a Stuart melting point
apparatus and are uncorrected. The ir spectra were recorded as
KBr pellets using a Bruker-vector 22 spectrophotometer FTIR.
structure 8. Finally, the formation of pyrimidines from the
reaction of enamines with isothiocyanates is a well
established behaviour of enaminonitriles [19].
1
13
The H and C nmr spectra were recorded in DMSO-d6 as
solvent at 300 MHz on Varian Gemini NMR spectrometer using
TMS as internal standard. Chemical shifts are reported in ꢀ units
(ppm). Mass spectra were measured on a Shimadzu GMSS -QP-
1000 EX mass spectrometer at 70 eV. The crystal structure was
determined by the X-ray unit at the National Research Center,
Dokki, Cairo. Microwave experiments were conducted in a
DAEWOO, editionII (KOR-8667) at full power. The reactants
were placed in a glass conical container and the oven was placed
in an efficient hood. No special precautions were used as we did
not experience any bumping during our experiments. The
experiments were repeated in CEM Explorer focused microwave
oven. Yields in both cases were almost the same.
Scheme 2
O
Ph
O
Ph NH
CN
O
Ph
S
3
H C
H
3
C
N
PhNCS
4a
N
N
4
N
N
N
H
4a
AcOH / HCl
Ph
Ph
CN
CN
7
5
4a,b
NC
CN
N
Ph NH
Ph
H
3
C
N
NC
CN
Ph
N
N
H
S
8
PhNCS
CN
CN
General Procedures for Compounds 4a-d. Method A: A
mixture of azaenamine 1 (10 mmol), and benzylidene
Ph
3
H C
6a
+
PhCHO
+
1a,b
NH
2
N
N
NH
2
CN
Ph
S
CN
derivatives 2a-c was refluxed in ethanol (20 ml) in presence of
piperidine (0.5 ml) for 1 h. The solvent was evaporated under
vacuum and the crude product was collected and crystallized
from ethanol.
Methode B: A solution of each of 1a-d (10 mmol) was
treated with the benzylidene 2a-c (10 mmol) in pyridine (2 ml)
was irradiated in a microwave oven for two minutes, then
N
Ph
Ar
CN
NH
6a, Ar = C H ;
X = CN
6
5
b, Ar = C H Cl-p; X = CN
6 4
N
N
2
Ph
9

Jan-Feb 2007
Studies with Enamines and Azaenamines
107
poured onto water and acidified with dilute hydrochloric acid.
The solid product obtained was crystallized from ethanol.
C H N O (317.35): C, 71.91; H, 4.76; N, 13.24. Found: C,
72.11; H, 4.85; N, 13.46.
1
9
15
3
2
6
-Acetyl-3-amino-2,5-diphenyl-2,5-dihydro-pyridazine-4-
carbonitrile (4a). Yield: (78% thermal, 86% microwave), mp:
28-230 °C; ir (KBr): ꢀ 3409 and 3313 (NH ), 2191 (CN), 1678
General procedures for Preparation of compounds 6a,b.
Method A: A mixture of azaenamines 1a, b (10 mmol),
benzaldehyde (10 mmol), and malononitrile (10 mmol) was
refluxed in ethanol (20 ml) in presence of piperidine for 1 h.
The solvent was evaporated under vacuum and the crude product
was collected and crystallized from ethanol/Dioxan.
2
2
-
1 1
(
CO) cm ; H nmr (DMSO-d6): ꢁ = 2.33 (s, 3H, CH -CO), 4.79
s, 1H, CH pyridazine), 6.01 (s, 2H, NH ), 7.21 - 7.52 (m, 10H,
Ph H); C nmr (DMSO-d6): ꢁ = 24.68 (CH ), 36.11 (CH
3
(
2
13
3
pyridazine), 57.05 (C-CN), 120.52 (CN), 125.73, 126.83,
Method B:
A
mixture of pyridazines 1a, b, and
1
1
27.29, 127.91, 128.99, 129.54, 140.16, 142.11 (CH aromatic),
43.99 (C-COCH ), 150.30 (C- NH ), 195.79 (CO); MS (EI):
malononitrile (10 mmol) was refluxed in ethanol (20 ml) in
presence of piperidine (0.5 ml) for 1 h. The solvent was
evaporated under vacuum and the crude product was collected
and crystallized from ethanol/Dioxan.
3
2
+
m/z (%) = 316 (M ). Anal. Calcd. for C H N O ( 316.37): C,
7
19
16
4
2.14; H, 5.10; N, 17.71. Found: C, 72.20; H, 5.31; N, 17.65.
-Acetyl-3-amino-2-(4-chlorophenyl)-5-diphenyl-2,5-dihydro-
6
[1-(6-Amino-5-cyano-1,4-diphenyl-1,4-dihydropyridazine-
3-yl)ethylidene]malononitrile (6a). Yield: (88%), mp: 310°C;
pyridazine-4-carbonitrile (4b). Yield: (82% thermal, 87%
microwave), mp: 198-200 °C; ir (KBr): ꢀ 3405 and 3303 (NH ),
2
-1
1
ir (KBr): ꢀ 3433 and 3328 (NH ), 2198.7 (CN) cm ; H nmr
2
2
-1 1
191 (CN), 1680 (CO) cm ; H nmr (DMSO-d6): ꢁ = 2.33 (s, 3H,
(DMSO-d6): ꢁ = 2.32 (s, 3H, CH ), 4.77 (s, 1H, CH pyridazine),
3
CH -CO), 4.77 (s, 1H, CH pyridazine), 6.15 (s, 2H, NH ), 7.18-
5.99 (s, 2H, NH ), 7.0-8.33 (m, 10H, Ph H); MS (EI): m/z (%) =
3
2
2
13
+
7
.59 (m, 9H, Ar H); C nmr (DMSO-d6): ꢁ = 18.62 (CH ), 24.69
364 (M ). Anal. Calcd. for C H N (364.41): C, 72.51; H, 4.43;
3
22 16
6
(CH pyridazine), 57.17 (C-CN), 120.43 (CN), 126.83, 127.30,
N, 23.06. Found: C, 72.33; H, 4.65; N, 23.41.
1
1
27.45, 128.99, 129.74, 132.20, 139.10, 141.90 (CH aromatic),
44.32 (C-COCH ), 150.29 (C-NH ), 195.71(CO); MS (EI): m/z
{1-[6-Amino-1-(4-chlorophenyl)-5-cyano-4-phenyl-1,4-
dihydropyridazine-3-yl]ethylidene}malononitrile (6b). Yield:
3
2
+
(%) = 350 (M ). Anal. Calcd. for C H C1N O (350.81): C,
(86%), mp: 320 °C; ir (KBr): ꢀ 3325 and 3324.8 (NH ), 2194.8
19
15
4
2
-
1
+
6
5.05; H, 4.31; N, 15.97. Found: C, 65.16; H, 4.45; N, 16.1.
(CN) cm ; MS (EI): m/z (%) = 398 (M ). Anal. Calcd. for
Ethyl 6-Acetyl-3-amino-2,5-diphenyl-2,5-dihydropyrida-
C H C1N (398.86): C, 66.25; H, 3.79; N, 21.07. Found: C,
2
2
15
6
zine-4-Carboxylate (4c). Yield: (80% thermal, 87% microwave),
66.39; H, 3.86; N, 21.19.
m.p = 126-128 °C; ir (KBr): ꢀ 3417.6 and 3301.9 (NH ), 1658.7
1-(5-Imino-1,4,6-triphenyl-7-thioxo-1,4,5,6,7,8-hexahydro-
pyrimido-[4,5-c]pyridazin-3-yl)-ethanone (7). A mixture of
pyridazine 4a (10 mmol), and phenyl isothiocyanate (10 mmol)
was stirred in DMF in the presence of KOH for 5 hrs and then
left over night. The reaction mixture was then poured onto water
and acidified with dilute hydrochloric acid. The solid product
obtained was crystallized from ethanol; Yield: (69%), mp: 248-
250°C; ir (KBr): ꢀ 3440.8 and 3282.2 (2 NH), 1685.7 (CO),
2
-1 1
(
CH CO), 1616.2 (COOEt) cm ; H nmr (DMSO-d6): ꢁ = 1.17 (t,
3
3
H, CH -CH , J = 7.2 Hz), 2.33 (s, 3H, CH -CO), 4.08 (q, 2H,
3 2 3
CH , J = 7.2 Hz), 5.2 (s, 1H, CH pyridazine), 6.88 (s, 2H, NH ),
2
2
13
7
2
.17-7.56 (m, 10H, Ph H); C nmr (DMSO-d6): ꢁ = 14.47,
4.66 (CH ), 33.91 (CH pyridazine), 58.89 (CH ), 75.92 (C
3
2
-
1
COOEt), 125.69, 126.67, 127.09, 127.87, 128.59, 129.64,
40.06, 143.22 (CH aromatic), 147 (C-COCH ), 151.04 (C-
3
-
1 1
NH ), 168.11(COOEt), 196.03 (CO); MS (EI): m/z (%) = 363
1639.4 (C=NH) cm ; H nmr (DMSO-d6): ꢁ = 2.39 (s, 3H, CH -
2
3
+
(
M ). Anal. Calcd. for C H N O (363.42): C, 69.41; H, 5.82; N,
CO), 5.70 (s, 1H, CH pyridazine), 7.08 (br, 1H, NH), 7.11 (br,
21
21
3
3
1
3
1
1.56. Found: C, 69.22; H, 5.91; N, 11.35.
-(6-Amino-5-benzoyl-1,4-diphenyl-1,4-dihydropyridazine-
1H, NH) 7.14-7.64 (m, 15 H, Ph H); C nmr (DMSO-d6): ꢁ =
1
24.89 (CH ), 32.38 (CH pyridazine), 85.22 (C4-pyridazine),
3
3
1
-yl)ethanone (4d). Yield: (82% thermal, 89% microwave), mp:
125.96, 126.89, 127.44, 127.63, 128.45, 128.61, 128.89, 129.11,
130.17, 130.38, 138.77, 140.36 (CH aromatic), 145 (C=NH),
150.74(C-COCH3), 155.24 (C3-pyridazine), 178.4 (C=S),
85-187°C; ir (KBr): ꢀ 3448.5 and 3302 (NH ), 1681.8
2
-1
1
(COCH ), 1612 (COPh) cm ; H nmr (DMSO-d6): ꢁ = 2.39 (s,
3
+
3
H, CH -CO), 5.28 (s, 1H, CH pyridazine), 7.01-7.62 (m, 15H,
195.55 (CO); MS (EI): m/z (%) = 451 (M ). Anal. Calcd. for
3
1
3
Ph H), 8.50 (br, 2H, NH ); C nmr (DMSO-d6): ꢁ = 24.74
C H N OS (451.55): C, 69.16; H, 4.69; N, 15.51. Found: C,
2
26 21
5
(
CH ), 35.41 (CH pyridazine), 85.50 (CH-COPh), 125.61,
68.96; H, 4.83; N, 15.87.
3
1
1
1
26.51, 126.76, 126.92, 128.14, 128.81, 129.22, 129.46, 129.85,
[1-(5-Imino-1,4,6-triphenyl-7-thioxo-1,4,5,6,7,8-hexahydro-
pyrimido[4,5-c]pyridazin-3-yl)ethylidene]malononitrile (8).
A mixture of pyridazine 6a (10 mmol), and phenyl
39.59, 141.24, 142.18 (CH aromatic), 148.45 (C-COCH ),
3
53.47 (C-NH ), 192.55 (COPh), 195.92 (COCH ); MS (EI):
2
3
+
m/z (%) = 395 (M ). Anal. Calcd. for C H N O (395.47): C,
7
isothiocyanate (10 mmol) was stirred in DMF in presence of
KOH for 5 hrs and then left over night at which time the reaction
mixture was poured onto water and acidified with dilute
hydrochloric acid. The solid product obtained was crystallized
from ethanol/ Dioxan. Yield: (61 %), mp: 245-247 °C; ir (KBr):
25
21
3
2
5.93; H, 5.35; N, 10.63. Found: C, 76.11; H, 5.25; N, 10.72.
-Acetyl-3-oxo-2,5-diphenyl-2,3,4,5-tetrahydropyridazine-
-carbonitrile (5). A solution of 4a (0.01 mol) in acetic acid (15
6
4
ml)/hydrochloric acid (2 ml) was refluxed for 2 hrs, and then the
reaction mixture is poured into water. The solid product so
formed was collected by filtration and crystallized from ethanol.
Yield: (72%), mp: 150-152 °C; ir (KBr): ꢀ 2260 (CN), 1650
-
1 1
ꢀ 3406 (NH), 2198.7 (CN), 1701 (C=NH) cm ; H nmr (DMSO-
d6): ꢁ = 2.38 (s, 3H, CH ), 3.56 (s, 1H, CH pyridazine),7.28-
3
7.69 (m, 15H, Ph H), 8.46 (s, 1H, NH), 11.11 (s, 1H, NH). MS
-
1
1
+
(CO), 1693 (COCH ) cm ; H nmr (DMSO-d6): ꢁ = 2.40 (s, 3H,
(EI): m/z (%) = 499 (M ). Anal. Calcd. for C H N S (499.60):
3
29 21
7
CH -CO), 4.96 (d, 1H, CH pyridazine, J = 7.2 Hz), 5.34 (d, 1H,
C, 69.72; H, 4.24; N, 19.63. Found: C, 69.92; H, 4.12; N, 19.73.
6-Amino-3-imino-8-methyl-2-phenyl-2,3-dihydrocinnoline-
4, 7-dicarbonitrle (13). A mixture of azaenamine 1 (10 mmol),
and ethylidene malononitrile derivatives 10 was refluxed in
Dioxan (20 ml) in the presence of piperidine for 1 h. The solvent
was evaporated under vacuum and the crude product was
3
1
3
CH pyridazine, J = 7.2 Hz), 7.24-7.65 (m, 10H, Ph H); C nmr
DMSO-d6): ꢁ = 24.65 (CH ), 39.07 (CH-CN), 39.12 (CH-Ph)
(
3
1
1
1
14.50 (CN), 125.04, 127.80, 127.93, 128.80, 129.04, 129.46,
33.47, 139.94 (CH aromatic), 149.38 (C-COCH ), 159.1 (CO),
3
+
94.55 (COCH ): MS (EI): m/z (%) = 317 (M ). Anal. Calcd. for
3

1
08
S. A. S. Ghozlan, I. A. Abdelhamid, H. M. Hassaneen, and M. H. Elnagdi
Vol 44
collected and crystallized from Dioxan. Yield: (80%), mp: 245-
[6] V. Atlan, H. Bienayme, L. El-Kaim, A. Majee, Chem.
Commmun., 1585 (2000).
2
2
2
7
47 °C; ir (KBr): ꢀ 3440.8 (NH) 3294.2 and 3201.6 (NH ),
2
-
1
1
[7] R. Brehme, H. Nikolajewski, Z. Chem., 8, 226 (1968).
194.8 (CN), 1639.4 (C=NH) cm ; H nmr (DMSO-d6): ꢁ =
.45 (s, 3H, CH ), 6.15 (s, 1H, CH phenyl), 7.51 (br, 2H, NH ),
[
8] H. Buff, U. Kucklander, Tetrahedron, 56, 5137 (2000).
3
2
1
3
[9] H. M. Fahmy, N. M. Abed, R. M. Mohareb, M. H. Elnagdi,
.51-7.60 (m, 5 H, Ph H), 8.46 (s, 1H, NH); C nmr (DMSO-
Synthesis, 490 (1982).
d6): ꢁ = 21.03 (CH ), 78.60 (C-CN), 102.17 (C-CN), 114.86
3
[
10] K. U. Sadek, M. H. Elnagdi, Synthesis, 483 (1988).
(CH phenyl), 116.47 (CN), 117.39, 120.67, 120.72 (CH
[
11] M. H. Elnagdi, N. S. Ibrahim, K. U. Sadek, M. H. Mohamed,
aromatic), 126.88 (C-CH ), 130.2 (CH aromatic), 139.24 (C-
3
Liebgs Ann. Chem., 1009 (1988).
[12] M. H. Elnagdi, A. M. Negm, A. W. Erian, Liebgs Ann.
Chem., 1255 (1989).
NH ), 139.34 (C=N), 152.4 (C aromatic), 165 (C=NH); MS
2
+
(
EI): m/z (%) = 300 (M ). Anal. Calcd. for C H N (300.33): C,
17 12 6
6
7.99; H, 4.03; N, 27.98. Found: C, 67.73; H, 3.85; N, 27.61.
[13] M. H. Elnagdi, A. W. Erian, Liebgs Ann. Chem., 1215
(
1990).
14] H. Al-Awadi, F. Al-Omran, M. H. Elnagdi, L. Infants, C.
Foces-foces, N. Jagerovic, J. Elguero, Tetrahedron, 51, 12745 (1995).
15] F. Al-Omran, M. M. Abdelkhalik, A. A. Elkhair, M. H.
Elnagdi, Synthesis, 91 (1997).
16] H. M. Hassaneen, T. M. Abdelkhalik, H. Hassaneen, J.
[
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CCDC 616675.
[
(
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