Enaminones in heterocyclic synthesis: Synthesis and chemical reactivity of 3-anilino-1-substituted-2-propene-1- one

Article abstract of DOI:10.1002/jhet.5570420414

The 3-anilinoenones 3a,b were prepared from the corresponding 3-dimethyl-aminopropenones. The reactivity of 3a,b towards a variety of carbon and nitrogen nucleophiles as well as naphthoquinones is reported.

Full text of DOI:10.1002/jhet.5570420414

Enaminones In Heterocyclic Synthesis: Synthesis and Chemical
Reactivity of 3-Anilino-1-Substituted-2-Propene-1- One
May-Jun 2005
563
Balkis Al-Saleh1*, Morsy Ahmed El-Apasery1, Rasha Safwat Abdel-Aziz2
and Mohamed Hilmy Elnagdi2*
1
Department of Chemistry, Faculty of Science, University of Kuwait, P.O. Box 5969 Safat, 13060 Kuwait
2
Department of Chemistry, Faculty of Science, Cairo University, Giza-Egypt
e-mail: shelmy@access.com.eg . Fax: +202 568 5799
Received October 7, 2004
The 3-anilinoenones 3a,b were prepared from the corresponding 3-dimethyl-aminopropenones. The reac-
tivity of 3a,b towards a variety of carbon and nitrogen nucleophiles as well as naphthoquinones is reported.
J. Heterocyclic Chem., 42, 563 (2005).
In the last few years we have been involved in a program
aimed at exploring-chemistry of enaminones [1-3]. During
this phase of our research a variety of 3-dimethylamino-l-
substituted propen-1-ones 1a-c were prepared in good
yield via refluxing methylketones with dimethylfor-
mamide dimethylacetal (DMFDMA). These enaminones 1
proved to be excellent precursors for heterocycles and pol-
yaroyl benzenes [4-10] (Figure 1).
In conjunction to previous interest in developing syn-
thesis of polyfunctionally substituted heteroaromatics,
we report now on reactivity of 1 and its further utility
in heterocyclic chemistry. Compounds 1a-c reacted
with aniline to yield products of addition and dimethyl-
amine elimination. The formed anilino derivatives
proved to be cis products 3a,b and the trans form 2a,b
were completely excluded since olefinic protons
appeared as a doublet with J = 7 Hz. The predominance
of the cis form is attributed to fixation through hydro-
gen bonding (Figure 1).
meric 5 or cyclic products 6 or 7. Structure 4 was estab-
1
lished through H NMR and 13C NMR. Thus, 13C NMR
revealed the absence of any carbon atoms with sp3
hybridization (Figure 1). Structures 6 and 7 were excluded
based on the presence of olefinic proton doublets at δ 6.05
ppm and 7.98 ppm (J = 7 Hz).
The reaction of compound 3a with ethyl cyanoac-
etate or malononitrile in the presence of piperidine
proved to depend on applied reaction conditions. It is
believed that in acetic acid the formed condensation
product 8 is cyclized into 9 and then hydrolysed to 10.
Finally, compound 10 reacts with piperidine to yield 11
(Figure 2).
Figure 2
On the other hand, in ethanol malononitrile initially
dimerizes to form 1 2, which then condenses with 3a to
yield 13. Compound 13 then looses ammonia and cyclized
to 14, which subsequently reacts with piperidine to yield
final 15 (Figure 3). Under similar conditions compound 3a
failed to condense with ethyl cyanoacetate.
Figure 1
Spectral and analytical data supports the proposed
structure 15 . Thus, in the mass spectrum of 15 a molec-
1
Compound 1a reacted with 1,2- phenylenediamine to
yield product that may be formulated as 4 or stereoiso-
ular ion peak is observed at m/z 406. The H NMR
spectrum revealed a 10 proton multiplet at δ = 1.25-3.72

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B. Al-Saleh, M. A. El-Apasery, R. S. Abdel-Aziz and M. H. Elnagdi
Vol. 42
towards actylacetone it reacted with cyanothioacetamide
to yield 22 through intermediacy of 21 (Figure 5). Again
this product proved identical with authentic specimens of
6-phenyl pyridine. Structures 20 and 22 are preferred over
1
possible 4-phenyl pyridine structures based on H NMR,
which revealed pyridyl hydrogen resonances as doublets
with J = 7 Hz. Isomeric 4-phenyl pyridine should show
lower coupling (J = 2-3 Hz) [10].
Figure 3
corresponding to the piperidenyl protons a two protons
doublet at δ = 6.09 and 7.96 (J = 8Hz) for the dihy-
dropyridine protons and a 10 proton aromatic multiplet
at δ = 7.10-7.52 ppm.
The reaction of 3a with naphthoquinone afforded 1 7.
Structure 18 was excluded as 2D NMR indicated that the
carbonyl carbon is not attached to any protons. It is of
value to report that 1a was also reported to afford a naph-
thofuran derivative but the structure has not been unam-
biguously established [11,12]. It is believed that 16 is an
intermediate in this reaction (Figure 4).
Figure 5
EXPERIMENTAL
All melting points are uncorrected. IR spectra were recorded in
1
KBr with a Pye Unicam SP 1100 spectrophotometer. H NMR
13
and C NMR spectra were recorded on a Varian EM-390-400
2
MHz spectrometer in deuteriochloroform or [ H ] DMSO as sol-
6
vent and TMS as internal standard; chemical shifts are reported in
δ (ppm). Mass spectra were measured on MS 30 and MS 9 (AEI),
70 eV. Microanalyses were performed on LECO CHNS-932.
Microwave experiments were conducted in a microwave oven
DAEWOO, edition II (KOR-8667).
General Procedure for Preparation of Compounds (1a,b).
Dimethylformamide dimethylacetal (DMFDMA) (0.01 mol)
was added to methylketones (0.0l mol) in xylen (50 ml). The
reaction mixture was refluxed for 6-9 h. Removal of solvent
under reduced pressure yielded the crude product, which was
crystallized from ethanol. Compounds (1a,b) were obtained as
yellow crystals with physical characteristics identical with those
reported in literature [1].
Figure 4
General Procedure for Preparation of Compounds (3a,b).
Structure 17 was supported by spectral data. Thus, 13C
NMR revealed a carbonyl carbon at δ = 182.4 ppm.
HMQC indicate that this carbon is not attached to any pro-
tons. On the other hand, the low field proton at δ = 8.64
ppm was found to be attached to C-2 at δ = 152.4 ppm.
The reaction of 3a with actylacetone in refluxing acetic
acid and in presence of ammonium acetate yields product
that may formulated as pyridine derivative 20. The same
compound has been previously obtained from reaction of
1a with acetylacetone [10,13]. It is believed that 19 is an
intermediate (Figure 5). Similar to the behavior of 3a
A solution of 1a,b (0.01 mol) in ethanol (30 ml) was treated
with aniline (0.01 mol) and the reaction mixture was then
refluxed for 3 h. Solvent was then evaporated in vacuum. The
resulting products were triturated with H O and acidified with
2
HCl. The solid products, so formed, were collected by filtration
and crystallized from ethanol. Compounds (3a,b) were formed as
yellow crystals.
1-Phenyl-3-(phenylamino)-2-propene-1-one (3a).
This compound was obtained in yield (1.99 g, 89%); mp 123-
-1
125 °C (EtOH); ir (KBr): ν max/cm 3063 (NH), 3093 (NH),
+
1669 (CO); ms: m/z = 223 (M ); H nmr (deuteriochloroform): δ
1

May-Jun 2005
Enaminones In Heterocyclic Synthesis
565
(ppm) = 6.05 (d, 1H, J= 7 Hz, olefinic-H), 7.09- 7.95 (m, 10H,
arom-H). 7.97(d, 1H, J= 7 Hz, olefinic-H), 12.15 (br, 1H, NH).
Anal. Calcd. for C H NO (223.27): C, 80.69; H, 5.86; N,
room temperature. The so formed crystals were collected by fil-
tration and crystallized from ethanol. This compound was
obtained in yield (2.41g, 84%); mp 272-274 °C; ir (KBr): ν
max/cm : 1613 (CO); ms: m/z = 288 (M ); H nmr (deuteri-
ochloroform): δ (ppm) = 7.44-8.21 (m, 10H, arom-H), 8.64 (s,
13
1H, furyl-H), 10.24 (br, 1H, OH); C nmr (dimethyl sulfoxide-
d ): δ (ppm) =182.4 (CO), 152.4 (C-2), 150.6, 147.7 (C-OH),
6
133.4, 132.2, 129.5, 128.8, 128.1, 126.5, 125.3, 124.8, 116.3,
114.8, 105.4.
15 13
-1
+
1
6.27%. Found C, 80.45; H, 5.93; N, 6.41.
l-(3-Furyl)-3-(phenylamino)-2-propene-l-one (3b).
This compound was obtained in yield (1.76 g, 83%); mp 140-
-1
142 °C (EtOH); ir (KBr): ν max/cm : 3110 (NH), 1654 (CO);
+
1
ms: m/z = 213 (M ); H nmr (deuteriochloroform): δ (ppm) =
5.94 (d, J= 7Hz olefinic-H), 6.52 (d, J= 8 Hz, furyl H-3), 7.09-
7.52 (m, 7H, arom-H and furyl H), 7.54 (d, J= 7Hz olefinic-H),
11.91 (br, 1H, NH).
Anal. Calcd for C
Found C, 79.12; H, 4.19.
H O (288.30); C, 79.15; H, 4.19%.
19 12 3
l-(2-Methyl-6-phenyl-3-pyridyl)ethan-l-one (20).
Anal. Calcd for C H NO (213.23): C, 73.22; H, 5.19; N,
13 11
6.56%. Found C, 73.17; H, 5.17; N, 6.69.
2
Equimolecular amount of (0.01 mol) of 3a or 1a were dis-
solved in acetic acid (20 ml) then treated with acetylacetone (0.01
mol), then with ammonium acetate (10 ml) then refluxed for 1.5
h. The resulting solution was poured into water then the solid
products formed were collected and crystallized from ethanol.
This compound was obtained in yield (1.68 g, 80%); mp 92 °C; ir
3-[(2-Aminophenyl)amino]-1-phenylprop-2-en-l-one (4).
A solution of 1a (0.01 mol) in DMF (5 ml) was treated with
1,2-phenylenediamine (0.01 mol) and refluxed for 12 h then
poured into water. The solid product, so formed, was collected by
filtration and crystallized from ethanol. This compound was
obtained in yield 1.95g (82%); mp 175-176 °C (EtOH); ir (KBr):
-1
+
1
(KBr): ν max/cm : 1685 (CO); ms: m/z = 211 (M ); H nmr
(deuteriochloroform): δ (ppm) = 2.65 (s, 3H, CH CO), 2.87 (s,
3
3H, CH ), 7.47-7.53 (m, 6H, arom-H and, pyridyl H) 7.67 (d, 1H,
-1
ν max/cm : 3218 and 3155 (2NH), 3093 (NH), 1624 (CO); ms:
+
3
J = 8 Hz pyridyl H-4).
Anal. Calcd for C H NO (211.26); C, 79.59; H, 6.20; N,
1
m/z = 238 (M ); H nmr (deuteriochloroform): δ (ppm) = 6.05 (d,
J = 7Hz, o1efinic CH), 6.08-7.53 (m, 9H, arom-H), 7.98 (d, J=
14 13
6.63%. Found C, 79.33; H, 6.20; N, 6.68.
13
7Hz, o1efinic CH), 12.37 (br, lH, NH); C nmr (dimethyl sul-
foxide-d ): δ (ppm) = 191.31(CO), 147.71 (C-3 olefinic C),
6
6-Phenyl-2-thioxohydropyridine-3-carbonitrile (22).
139.66, 137.58, 131.88, 128.90, 129.83, 127.71, 125.69, 120.36,
118.15, 117.69, 94.25 ( C-2 olefinic C), 147.71 (C-3 olefinic C).
Anal. Calcd. for C H N O (238.82): C, 75.60; H, 5.92; N,
A solution of 3a or 1a was dissolved in acetic acid then treated
with 2-cyano-thioacetamide, and then with ammonium acetate (2
g) and refluxed for 1.5 h. The resulting solution was poured into
water and crystallized from ethanol. This compound was
obtained in yield (1.50 g, 71%); mp 245-247 °C; ir (KBr): ν
15 14
2
11.75%. Found C, 75.35; H, 5.80; N, 11.75.
l,4-Diphenyl-3(piperidylcarbonyl)hydropyridine-2-one (11).
-1
+
1
max/cm : 3093 (NH), 2211(CN); ms: m/z = 212 (M ); H nmr
(dimethyl sulfoxide-d ): δ (ppm) = 7.11 (d, 1H, J= 7Hz, pyridyl
13
A mixture of 3a (0.1 mol), ethyl cyanoacetate (0.1 mol),
glacial acetic acid (2 ml) and piperidine (0.1 mol) was heated in a
microwave oven for 2 min. then triturated with ethanol. Solid
product formed, was collected by filtration and crystallized from
dioxane. This compound was obtained in yield (2.43 g, 68%); mp
6
H-4), 7.53-7.7 (m, 5H, arom-H), 14.21 (br, 1H, NH). C nmr
(dimethyl sulfoxide-d ): δ (ppm) = 179.54 (CS). 154.52, 145.75,
6
132.31, 132.05, 129.59, 129.34, 129.06, 117,98, 116.00, 112.73
(arom. carbons).
Anal. Calcd for C H N S (212.27); C, 67.89; H, 3.79; N,
-1
290-292 °C; ir (KBr): ν max/cm : 1654 (CO); ms: m/z = 358
+
1
12
8 2
(M ); H nmr (deuteriochloroform): δ (ppm) = 1.34-4.19 (m, 10
H, piperidyl-H), 6.43 (d, 1H, pyridyl-H), 7.97 (d, 1H, pyridyl-H),
6.46-7.87 (m, 10H, arom-H).
13.19; S, 15.10 %. Found C, 67.55; H, 3.83; N, 13.32; S, 15.07.
Acknowledgement.
Anal. Calcd for C H N O (358.44): C, 77.07; H, 6.18; N,
23 22 2 2
7.81%. Found C, 77.16; H, 6.21; N, 7.73.
The authors are grateful to University of Kuwait, Research
Administration for financial support through project SC 02/02.
Analytical facilities provided by SAF are highly appreciated.
2-(1-Cyano-2-oxo-2-piperidylethylidene)-1,4-diphenyl-1,2-dihy-
dropyridine-3-carbonitrile (15).
A mixture of 3a (0.01 mol) and malononitrile in ethanol (10
ml) was refluxed for 3 h. The resulting solution was poured into
water and the resulting reaction product was collected by filtra-
tion and crystallized from acetic acid. This compound was
obtained in yield (2.92 g, 72%); mp 226-228 °C; ir (KBr): ν
max/cm :2187 (CN), 1654 (CO); ms: m/z = 406 (M ); H nmr
(deuteriochloroform): δ (ppm) = 1.25-3.72 (m, 10 H, piperidyl-
H), 6.09 (d, 1H, pyridyl-H), 7.96 (d, 1H, pyridyl-H), 7.10-7.52
(m, 10H, arom-H).
REFERENCES AND NOTES
[1] F. M. A. A. El-Taweel and M. H. Elnagdi, J. Heterocyclic
Chem., 38, 981 (2001).
[2] K. M. Al-Zaydi, E. A. Hafez and M. H. Elnagdi, J. Chem.
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[3] S. M. Al- Mousawi, M. A. Mohammad and M. H. Elnagdi, J.
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[4] A. El-Enzy, B. Al-Saleh and M. H. Elnagdi, J. Chem. Res. (S),
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[5] F. Al-Omran, N. Al- Awadi, M. M. Abdel - Khalik, K. Kaul,
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[6] F. Al-Omran, M. M. Abdel - khalik, A.A. Elkhair and M. H.
Elnagdi, Synthesis, 91(1997).
-1
+
1
Anal. Calcd for C H N O (406.48): C, 76.82; H. 5.45; N,
26 22
13.78%. Found C, 75.72; H, 5.66; N, 13.39.
4
(5-Hydroxynaphtho[1,2-b]furan-3-yl)-phenylmethanone (17).
A mixture of (3a) and naphthoquinone (0.01mol) were dis-
solved in glacial acetic acid (10ml) then stirred over night at
[7] S. Al- Mousawi, K. Kaul. M. A. Mohamad and M. H. Elnagdi,

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Vol. 42
J. Chem. Res. (S), 318; Ibid., (M), 2026 (1997).
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[10] B. Al-Saleh, M.M. Abdel- Khalik, A. M. Eitoukhy and M. H.