Enamines in heterocyclic synthesis: A novel simple and efficient route to condensed pyridazines

Article abstract of DOI:10.1515/znb-2011-0607

An efficient and easy preparation of enamine derivatives, via active methyl and methylene compounds by in situ-generated 1-(diethoxymethyl)piperidine, produced from the mixture of triethyl orthoformate/piperidine/DMF, are described. Some new pyridazinone

Full text of DOI:10.1515/znb-2011-0607

Enamines in Heterocyclic Synthesis: A Novel Simple and Efficient Route
to Condensed Pyridazines
Elham S. Darwisha, Mahmoud A. Abdelrahmana, and Abdellatif M. Salaheldina,b
a Department of Chemistry, Faculty of Science, Cairo University, Giza-12613, Egypt
b Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University,
P. O. Box 715, Makkah, KSA
Reprint requests to Dr. A. M. Salaheldin. E-mail: amsalaheldin@yahoo.com
Z. Naturforsch. 2011, 66b, 597 – 602; received March 3, 2011
An efficient and easy preparation of enamine derivatives, via active methyl and methylene com-
pounds by in situ-generated 1-(diethoxymethyl)piperidine, produced from the mixture of triethyl
orthoformate/piperidine/DMF, are described. Some new pyridazinone derivatives have been synthe-
sized from the reaction of enamines with hydrazine hydrate and cyanoacid hydrazide.
Key words: Enamines, Pyridazinones, Amidoacetal, Pyridazinylenamine
Introduction
tion of the in situ-generated amidoacetal 1-(dieth-
oxymethyl)piperidine (2). However, in practice only
the acetoxyvinyl pyridazine derivative 4 was obtained
(Scheme 1). Although 4 can also be formulated as 5,
only 4 was formed as 1H NMR revealed the trans
olefinic protons at δ = 5.48, and δ = 8.17 ppm as two
doublets with the coupling constant J = 12.8 Hz.
However, when acetic anhydride was replaced by
DMF, the pyridazinylenamine 3 was formed in good
yield (Scheme 1). The trans structure was inferred
from its 1H NMR spectrum which revealed two singlet
signals for the piperidinyl protons at δ = 1.62 (3-CH2)
and 3.32 (2-CH2) and the trans olefinic protons at δ =
5.47 and δ = 8.16 ppm as two doublets with the cou-
pling constant J = 12.9 Hz.
Enamines are versatile reagents, and the nucleo-
philic character of C-2 has found extensive applica-
tions in synthetic organic chemistry [1, 2]. Recently
we described several efficient approaches to heteroaro-
matics utilizing functionally substituted enamine pre-
cursors [3 – 7]. In conjunction with these studies and
as a part of our new project directed towards devel-
oping efficient routes to pyridazinones and condensed
pyridazinones with potential diuretic [8], antihyperten-
sive [9, 10], anticonvulsant, antispasmodic and mus-
cle relaxant [10, 11] activity. Recently the pyridazinone
unit has proved to be an important pharmacophore in
the search for drugs acting on the cardiovascular sys-
tem [12]. In this work we report a novel synthesis of
condensed pyridazinones.
The approach to generate 2 from triethyl ortho-
formate and piperidine in DMF seems to be a gen-
eral one, as this intermediate could also be condensed
with ethyl cyanoacetate and benzylcyanide [4] to af-
Results and Discussion
One of the main important routes to enamines ford the enamine compounds 6a and 6b, respectively
is condensation of dialkylamine acetals with acti- (Scheme 1).
vated methyl or methylene compounds [13 – 16]. How-
ever, the fact that dimethylformamide-dimethylacetal DMF resulted in the formation of the pyridopyrid-
Replacing piperidine with p-toluidine in refluxing
(DMF-DMA) is a potentially toxic reagent, and expen-
sive, led us to look for alternative routes for the synthe-
sis of enamine derivatives, and to see, if these routes
can constitute a new general approach to enamines.
azine derivative 7. Compound 7 could also be obtained
via reaction of 3 with p-toluidine in refluxing DMF
(Scheme 1).
The condensation of 2-(2-phenylhydrazono)-3-oxo-
Initially we thought that reacting the pyridazine butanenitrile (8) with ethyl cyanoacetate in reflux-
derivative 1 [17, 18] with triethyl orthoformate and ing acetic acid yielded a product that may be formu-
piperidine in refluxing Ac2O would afford the cor- lated as the 5-cyano-pyridazine-3-carboxamidederiva-
responding pyridazinylenamine 3 via initial forma- tive 9 or its isomer 6-cyanopyridazine-4-carboxamide
c
0932–0776 / 11 / 0600–0597 $ 06.00 ꢀ 2011 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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E. S. Darwish et al. · Enamines in Heterocyclic Synthesis
Scheme 1.
derivative 10. Structure 9 has been established based where the pyranopyridazine derivative 15 was formed
on the fact that this product could be condensed (Scheme 3).
with triethyl orthoformate and piperidine in refluxing
DMF to yield the pyridopyridazinederivative 11. Com-
pound 11 could be also obtained from the reaction of
the enamine 3 with acetic acid and ammonium acetate,
and was found identical in all details (melting point
and TLC analysis) to the compound obtained from the
other pathway (Scheme 2).
Conclusion
In conclusion we could replace the expensive,
highly volatile, and toxic recommended DMF-DMA
reagent for converting active methyl and methylene
compounds into enamines by in situ-generated, less
In order to explore any further utility of the syn- expensive, and mostly less toxic 1-(diethoxymeth-
thesized enamines, the pyridazinylenamine deriva- yl)piperidine, generated from the mixture of triethyl
tive 3 was reacted with hydrazine hydrate in reflux- orthoformate/piperidine/DMF.
ing ethanol or with cyanoacidhydrazide(2-cyanoaceto-
Although this reagent could not be condensed
hydrazide) in refluxing DMF, where the pyridopyrid- with the methyl function in methyl ketones, activated
azine derivative 12 and the triazolopyridopyridazine methyl and methylene compounds did condense read-
derivative 14 were formed, respectively. Also, the ily. We could also show that enamines synthesized in
pyridazinylenamine derivative 3 underwent acid hy- this way are valuable precursors to condensed hetero-
drolysis in a refluxing mixture of AcOH/H2SO4, aromatics.
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E. S. Darwish et al. · Enamines in Heterocyclic Synthesis
599
Scheme 2.
Scheme 3.
Experimental Section
ses were performed on a LECO CHN-932 by the Microanal-
ysis Unit of Cairo University.
All melting points are uncorrected. IR spectra were
recorded in KBr with a Bruker Vector 22 Germany spec-
trophotometer. The 1H NMR (300 MHz) and 13C NMR
(75.4 MHz) spectra were recorded on a Varian Mercury
300 MHz spectrometer in [D6]DMSO as solvent and TMS
Ethyl 5-cyano-1,6-dihydro-6-oxo-4-(2-(piperidin-1-yl)vin-
yl)-1-p-tolylpyridazine-3-carboxylate (3)
A mixture of triethyl orthoformate (0.2 mol), piperidine
as internal standard; chemical shifts are reported in δ units (0.2 mol) and ethyl 5-cyano-1,6-dihydro-4-methyl-6-oxo-1-
(ppm). Mass spectra were measured at 70 eV using a Shi-
madzu GCMS-QP-1000 EX mass spectrometer. Microanaly- der reflux in dimethylformamide for 24 h, allowed to cool
p-tolylpyridazine-3-carboxylate (1) (0.2 mol) was heated un-
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E. S. Darwish et al. · Enamines in Heterocyclic Synthesis
to r. t. and then poured into cold water. The reaction mix- 1693 (CO), 2900 (aliph.-CH), 2943 (vinyl-CH) cm−1. –
ture was treated with 1 molar aqueous sodium acetate so- 1H NMR (300 MHz, [D6]DMSO, TMS): δ = 1.17 (t, 3H,
lution (100 mL), and the product was collected by filtra- J = 7.4 Hz, CH3), 1.61 – 170 (m, 6H, 3CH2), 3.54 – 3.65 (m,
tion and crystallized from ethanol. The compound ◦was ob- 4H, 2CH2), 4.10 (q, 2H, J = 7.4 Hz, CH2), 7.77 (s, 1H,
tained as red crystals. Yield 65 %; m. p. 150 – 152 C. – IR vinyl-H). – MS (EI, 70 eV): m/z (%) = 208 (67) [M]+. –
(KBr): ν = 2198 (CN); 1720 (CO), 1664 (CO), 2942 (aliph. C11H16N2O2 (208.26): calcd. C 63.44, H 7.74, N 13.45;
1
CH), 3030 (olef.-CH), 3118 (arom. CH) cm−1. – H NMR found C 63.39, H 7.92, N 13.74.
(300 MHz, [D6]DMSO, TMS): δ = 1.27 (t, 3H, J = 7.1 Hz,
CH3), 1.62 (s, 6H, 3CH2, piperidine-H), 2.34 (s, 3H, CH3),
3.32 (s, 4H, 2CH2, piperidine-H), 4.34 (q, 2H, J = 7.1 Hz,
CH2), 5.47 (d, 1H, J = 12.9 Hz, olef.-H), 7.24 (d, 2H, J =
9 Hz, Ar-H), 7.39 (d, 2H, J = 9 Hz, Ar-H), 8.16 (d, 1H,
J = 12.9 Hz, olef.-H). – 13C NMR (75.4 MHz, [D6]DMSO):
δ = 14.46 (CH3), 20.2 (CH3), 23.53 (CH2), 25.62 (2CH2),
52.16 (2CH2), 59.75 (OCH2), 103.90 (C-5), 106.15 (C=CH),
121.59 (CN), 122.93 (C-2ꢀ,6ꢀ), 129.92 (C-3ꢀ,5ꢀ), 134.63 (C-
4ꢀ), 138.68 (C-1ꢀ), 149.39 (C=CH), 152.44 (C-3), 159.94 (C-
4), 166.82 (CO), 168.89 (CO). – MS (EI, 70 eV): m/z (%) =
392 (44) [M]+. – C22H24N4O3 (392.45): calcd. C 67.33,
H 6.16, N 14.28; found C 67.30, H 6.18, N 14.24.
2-Phenyl-3-(piperidin-1-yl)acrylonitrile (6b)
Yield 80 %; m. p. 118 – 120 ◦C (lit.: 115 – 116 ◦C [4]), yel-
lowish needles. – IR (KBr): ν = 2183 (CN), 2931 (vinyl-
CH), 1616 (vinyl C=C) cm−1. – 1H NMR (300 MHz,
[D6]DMSO, TMS): δ = 1.58 (m, 6H, 3CH2), 3.64 (m,
4H, 2CH2), 7,07 (s, 1H, vinyl-H), 7.25 – 7.38 (m, 5H, Ar-
H). – 13C NMR (75.4 MHz, [D6]DMSO): δ = 24.36, 26.41,
51.96, 75.41 (C=CH), 121.59 (CN), 124.48, 125.51, 129.14,
137.27, 149.29 (C=CH). – MS (EI, 70 eV): m/z (%) = 212
(42) [M]+. – C14H16N2 (212.29): calcd. C 79.21, H 7.60,
N 13.20; found C 79.29, H 7.67, N 13.17.
2,3,7,8-Tetrahydro-3,8-dioxo-2,7-di-p-tolylpyrido[3,4-c]-
pyridazine-4-carbonitrile (7)
Ethyl 4-(2-acetoxyvinyl)-5-cyano-6-oxo-1-p-tolyl-1,6-di-
hydropyridazine-3-carboxylate (4)
Method A. Compound 7 was obtained by the same
method used for compound 3, except that p-toluidine was
added instead of piperidine, via refluxing the reactants in
DMF for 24 h. The mixture was allowed to cool to r. t., then
poured into cold water. Compound 7 was obtained as a solid
product and crystallized from ethanol.
A mixture of triethyl orthoformate (0.2 mol), piperidine
(0.2 mol) and ethyl 5-cyano-1,6-dihydro-4-methyl-6-oxo-1-
p-tolylpyridazine-3-carboxylate (1) (0.2 mol) was heated un-
der reflux in 30 mL of acetic anhydride for 24 h, allowed
to cool to r. t. and then poured into cold water. The pre-
cipitate was collected by filtration and crystallized from
ethanol. Compound 4 was obtained as a greenish yellow
solid. Yield 75 %; m. p. 175 – 177 ◦C. – IR (KBr): ν = 2233
(CN), 1724, 1715, 1674 (CO), 1624 (C=C vinyl) cm−1. –
1H NMR (300 MHz, [D6]DMSO, TMS): δ = 1.27 (t, 3H, J =
7.4 Hz, CH3), 2.10 (s, 3H, CH3), 2.35 (s, 3H, CH3), 4.33 (q,
2H, J = 7.4 Hz, CH2), 5.48 (d, 1H, J = 12.8 Hz, vinyl-H),
7.27 (d, 2H, J = 9 Hz, Ar-H), 7.37 (d, 2H, J = 9 Hz, Ar-
H), 8.17 (d, 1H, J = 12.8 Hz, vinyl-H). – MS (EI, 70 eV):
m/z (%) = 367 (78) [M]+. – C19H17N3O5 (367.36): calcd.
C 62.12, H 4.66, N 11.44; found C 62.11, H 4.80, N 11.10.
Method B. Compound 3 (0.2 mol) and p-toluidine
(0.2 mol) were kept in refluxing DMF for 24 h, then the mix-
ture was allowed to cool to r. t. and poured into cold water.
The product was then collected by filtration and crystallized
from ethanol to give a black solid. Yield 66 %; m. p. 320 –
323 ◦C. – IR (KBr): ν = 2221 (CN), 1704 (CO), 1669 (CO)
1
cm−1. – H NMR (300 MHz, [D6]DMSO, TMS): δ = 2.38
(s, 6H, 2CH3), 6.18 (d, 1H, J = 6.9 Hz, Ar-H), 7.34 – 7.51 (m,
8H, Ar-H), 7.77 (d, 1H, J = 6.9 Hz, Ar-H). – MS (EI, 70 eV):
m/z (%) = 368 (75) [M]+. – C22H16N4O2 (368.39): calcd.
C 71.73, H 4.38, N 15.21; found C 72.07, H 4.51, N 15.15.
General procedure for the preparation of compounds 6a, b
5-Cyano-1,6-dihydro-4-methyl-6-oxo-1-p-tolylpyridazine-3-
To a mixture of ethyl cyanoacetate or 2-phenylacetonitr-
ile (0.3 mol), triethyl orthoformate (0.32 mol) and piperidine
(0.3 mol) DMF (40 mL) was added, and the solution was
refluxed for 24 h. The reaction mixture was then cooled and
poured onto water. The solid product formed was collected
by filtration and crystallized from ethanol.
carboxamide (9)
A mixture of 2-(2-p-tolylhydrazono)-3-oxobutanenitrile
(8, 0.3 mol), prepared as previously reported [19], ethyl
cyanoacetate (0.3 mol) and ammonium acetate (0.35 mol)
was heated under reflux in glacial acetic acid for 24 h, al-
lowed to cool to r. t. and then poured into cold water. The
solid product formed was collected by filtration and crystal-
lized from glacial acetic acid. This compound was obtained
Ethyl 2-cyano-3-(piperidin-1-yl)acrylate (6a)
This compound was obtained as colorless crystals. as a green solid. Yield 83 %; m. p. 260 – 261 ◦C. – IR (KBr):
◦
Yield 71 %; m. p. 80 – 82 C. – IR (KBr): ν = 2198 (CN), ν = 3376 (NH2), 2239 (CN), 1685, 1655 (CO), cm−1. –
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E. S. Darwish et al. · Enamines in Heterocyclic Synthesis
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1H NMR (300 MHz, [D6]DMSO, TMS): δ = 2.18 (s, 3H, 7.34 – 7.49 (m, 4H, Ar-H). – MS (EI, 70 eV): m/z (%) = 293
CH3), 2.35 (s, 3H, CH3), 7.32 – 7.56 (m, 4H, arom.-H), 7.72 (48) [M]+. – C15H11N5O2 (293.28): calcd. C 61.43, H 3.78,
(s, 1H, NH, D2O-exchangeable), 7.98 (s, 1H, NH, D2O-ex- N 23.88; found C 61.60, H 4.14, N 24.03.
changeable). – MS (EI, 70 eV): m/z (%) = 268 (66) [M]+. –
C14H12N4O2 (268.27): calcd. C 62.68, H 4.51, N 20.88;
found C 62.79, H 4.68, N 20.85.
2-Cyanomethyl-6-ethyl-9-oxo-8-p-tolyl-8,9-dihydro-1,3,3a,
7,8-pentaazacyclopenta [a]naphthalene-6-carboxylate (14)
A mixture of compound 3 (0.1 mol) and 2-cyanoaceto-
hydrazide (0.1 mol) was refluxed in dimethylformamide
for 3 h, allowed to cool to r. t. and then poured into ice-cold
2,3,7,8-Tetrahydro-3,8-dioxo-2-p-tolylpyrido[3,4-c]pyrid-
azine-4-carbonitrile (11)
Method A. A mixture of triethyl orthoformate (0.2 mol), water. The solid product was collected by filtration and crys-
piperidine (0.2 mol) and pyridazine carboxamide 9 (0.2 mol) tallized from ethanol and a few drops of dioxane. This com-
was heated under reflux in dimethylformamide for 24 h, al- pound was obtained as a brown solid. Yield 71 %; m. p. 320 –
lowed to cool to r. t. and poured into cold water. The solid 323 ◦C. – IR (KBr): ν = 2202 (CN), 1724 (CO), 1666 (CO)
product was filtered off and crystallized from glacial acetic cm−1. – 1H NMR (300 MHz, [D6]DMSO, TMS): δ = 1.17 (t,
acid (yield 65 %).
3H, J =7.2 Hz, CH3), 2.14 (s, 3H, CH3), 4.14 (s, 2H, CH2),
4.34 (q, 2H, J = 7.2 Hz, CH2), 7.36 – 7.51 (m, 4H, Ar-H),
8.62 (d, 1H, J = 7.8 Hz, olef.-H), 9.39 (d, 1H, J = 7.8 Hz,
olef.-H). – MS (EI, 70 eV): m/z (%) = 388 (69) [M]+. –
C20H16N6O3 (388.38): calcd. C 61.85, H 4.15, N 21.64;
found C 62.09, H 4.13, N 21.58.
Method B. Compound 3 (0.2 mol) was kept in reflux-
ing glacial acetic acid in the presence of ammonium acetate
(0.21 mol) for 3 h. The mixture was allowed to cool to r. t.
and then poured into cold water. The solid product was col-
lected by filtration and crystallized from glacial acetic acid.
This compound was obtained as a yellow solid. Yield 80 %;
m. p. > 320 ◦C. – IR (KBr): ν = 3360 (br. NH), 2221
(CN), 1681 (CO), 1664 (CO) cm−1. – 1H NMR (300 MHz,
[D6]DMSO, TMS): δ = 2.4 (s, 3H, CH3), 6.14 (d, 1H, J =
7.6 Hz, olef.-H), 6.97 (d, 1H, J = 7.6 Hz, olef.-H), 7.46 –
7.53 (m, 4H, Ar-H), 11.74 (s, 1H, NH, D2O-exchangeable). –
13C NMR (75.4 MHz, [D6]DMSO): δ = 22.29 (CH3), 104.24
(C-4), 106.75 (C-5), 117.02 (CN), 121.93 (C-2ꢀ,6ꢀ), 122.44
(C-6), 129.62 (C-3ꢀ,5ꢀ), 136.55 (C- 4ꢀ), 139.62 (C-1ꢀ), 152.14
(C-8a), 152.54 (CO), 162.94 (C-4a), 164.84 (CO). – MS (EI,
70 eV): m/z (%) = 278 (80) [M]+. – C15H10N4O2 (278.27):
calcd. C 64.74, H 3.62, N 20.13; found C 65.11, H 3.87,
N 20.29.
3,8-dihydro-3,8-dioxo-2-p-tolyl-2H-pyrano[3,4-c]pyrid-
azine-4-carboxamide (15)
Compound 3 (0.1 mol) was refluxed in a mixture of glacial
acetic acid (10 mL) and sulfuric acid (5 mL) for 3 h. The
reaction mixture was left to cool, then poured onto ice wa-
ter and neutralized with ammonia solution. The solid prod-
uct was collected by filtration and crystallized from ethanol.
This compound was obtained as a green powder. Yield 75 %;
m. p. 270 – 272 ◦C. – IR (KBr): ν = 3316 (NH2), 1697 (CO),
1656 (CO) cm−1. – 1H NMR (300 MHz, [D6]DMSO, TMS):
δ = 2.37 (s, 3H, CH3), 5.66 (brs. 2H, NH2, D2O-exchange-
able), 7.04 (d, 1H, J = 6.8 Hz, olef.-H), 7.28 – 7.42 (m,
4H, Ar-H), 7.78 (d, 1H, J = 6.8 Hz, olef.-H). – 13C NMR
(75.4 MHz, [D6]DMSO): δ = 23.30 (CH3), 104.95 (C-5),
121.84 (C-2ꢀ,6ꢀ), 125.92 (C-6), 130.12 (C-3ꢀ,5ꢀ), 136.15 (C-
4ꢀ), 140.14 (C-1ꢀ), 142.02 (C-4), 153.14 (C-8a), 158.44 (C-
4a), 159.96 (CO), 163.48 (CO), 168.92 (CO). – MS (EI,
70 eV): m/z (%) = 297 (36) [M]+. – C15H11N3O4 (297.27):
calcd. C 60.61, H 3.73, N 14.14; found C 60.54, H 3.89,
N 14.20.
2,3,7,8-Tetrahydro-7-amino-3,8-dioxo-2-p-tolylpyrido[3,4-
c]pyridazine-4-carbonitrile (12)
A mixture of compound 3 (0.2 mol) and hydrazine hydrate
(0.2 mol) was refluxed in ethanol for 3 h. Then the reaction
mixture was left to cool, and the solid product was collected
by filtration and crystallized from ethanol/DMF (1 : 1). This
compound was obtained as a dark-brown solid. Yield 65 %;
m. p. 320 – 321 ◦C. – IR (KBr): ν = 3400, 3293 (NH2), 2209
(CN), 1669 (CO), cm−1. – 1H NMR (300 MHz, [D6]DMSO,
TMS): δ = 2.39 (s, 3H, CH3), 6.14 (d, 1H, J = 7.4 Hz, olef.-
H), 6.45 (s, 2H, NH2), 7.26 (d, 1H, J = 7.4 Hz, olef.-H),
Acknowledgement
We are grateful to Prof. M. H. Elnagdi for continuous help
and critical comments on research progress.
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