Enaminones as building blocks in heterocyclic synthesis: New syntheses of nicotinic acid and thienopyridine derivatives

Article abstract of DOI:10.1002/jhet.5570410321

Reacting 1,3-diphenyl-propan-2-one with equimolecular amount of dimethylformamide dimethylacetal afforded the enaminone 4. This when reacted with another equimolecular amount of dimethylformamide dimethylacetal afforded the dienaminone 5. Compound 4 condenses with cyanothioacetamide and with cyanoacetamide to yield 2-thioxo- and 2-oxo-pyridine-3-carbonitrile derivatives 6a,b respectively. Compound 6a reacted with (x-chloroacetone 8 to yield the thieno[2,3-b]pyridine derivative 10 that cyclized further into 4,7,8-trisubstituted pyrido[2′,3′:2,3] thieno[4,5-d]pyrimidine 12. Compound 4 also afforded 2,5,6-trisubstituted nicotinic acid ethyl ester 13 by reaction with ethyl acetoacetate in acetic acid in the presence of ammonium acetate. The dienaminone 5 reacted with acetic acid, ammonium acetate/acetic acid, phenylhydrazine and 5-amino-3-methylpyrazole yielding 3,5-diphenyl-pyran- 4-one 15a, 3,5-diphenyl-1H-pyridin-4-one 15b and 1,3,5-trisubstituted pyridin-4-ones 16a-b.

Full text of DOI:10.1002/jhet.5570410321

May-Jun 2004
431
Enaminones as Building Blocks in Heterocyclic Synthesis: New
Syntheses of Nicotinic Acid and Thienopyridine Derivatives
Mervat Mohammed Abdelkhalika, Afaf Mohammed Eltoukhya,
Samia Michel Agamya, and Mohammed Hilmy Elnagdi*b
a
Department of Chemistry, Girls College for Arts, Science and Education, Ain Shams University, P. O. Box
11757 Heliopolis, Cairo, A. R. Egypt.
b
Department of Chemistry, Faculty of Science, Cairo University, Giza, A. R. Egypt.
e-mail: Shelmy@access.com.eg
Received December 15, 2003
Reacting 1,3-diphenyl-propan-2-one with equimolecular amount of dimethylformamide dimethylacetal
afforded the enaminone 4. This when reacted with another equimolecular amount of dimethylformamide
dimethylacetal afforded the dienaminone 5. Compound 4 condenses with cyanothioacetamide and with
cyanoacetamide to yield 2-thioxo- and 2-oxo-pyridine-3-carbonitrile derivatives 6a,b respectively.
Compound 6a reacted with α-chloroacetone 8 to yield the thieno[2,3-b]pyridine derivative 10 that cyclized
further into 4,7,8-trisubstituted pyrido[2',3':2,3] thieno[4,5-d]pyrimidine 1 2. Compound 4 also afforded
2,5,6-trisubstituted nicotinic acid ethyl ester 13 by reaction with ethyl acetoacetate in acetic acid in the pres-
ence of ammonium acetate. The dienaminone 5 reacted with acetic acid, ammonium acetate/acetic acid,
phenylhydrazine and 5-amino-3-methylpyrazole yielding 3,5-diphenyl-pyran-4-one 15a, 3,5-diphenyl-1H-
pyridin-4-one 15b and 1,3,5-trisubstituted pyridin-4-ones 16a-b.
J. Heterocyclic Chem., 41, 431 (2004).
Certain functionally substituted pyridines are potent
meric 7 a. The cyclization reaction may proceed by two
possible mechanisms, which differ in their sequential
nucleophilic attack/amine exchange reaction. The H
inhibitors of the human immunodeficiency virus type 1
(HIV-1) reverse transcriptase. For example atevirdine 1
has been selected for further clinical evolution as anti-HIV
agent [1], the dihydropyridines, e.g. adalate, are still the
most widely used calcium channel blockers [2]. Certain
functionally substituted pyridones, e.g. amrinone 2a [3]
and milrinone 2b [4], are used for treatment of congestive
heart failure. Compounds 3 have been proved to be selec-
tive antagonists of P2 receptors for neurotransmitters [5]
(Figure 1).
1
NMR spectra for the reaction product showed the pyridine
ring CH as singlet at δ = 7.76 ppm. This may suggest a
favorable reaction product 6a formed via initial addition of
the active methylene moiety in cyanothioacetamide across
the activated double bond in 4 and subsequent cyclization
In conjunction to previous interest in developing synthe-
ses of polyfuctionally substituted heteroaromatics utilizing
readily obtainable and inexpensive starting materials [6-8],
we report here on syntheses of 7-benzyl-4-methyl-8-phenyl-
pyrido[2',3':2,3]thieno[4,5-d]pyrimidine 1 2, 4-unsubstituted
2,5,6-trisubstituted nicotinic acid ethyl ester 13, 3,5-
diphenyl-pyran-4-one 1 5 a, 3,5-diphenyl-1H-pyridin-4-one
15b and of 1,3,5-trisubstituted pyridin-4-ones 16(I)a,b
using compounds 4 and 5 as key intermediates.
Enaminone 4 was readily obtained from the reaction of
an equimolecular amount of 1,3-diphenyl-propan-2-one
with dimethylformamide dimethylacetal for four hours at
120 °C in absence of solvent (Figure 1). This product 4
reacted with another equimolecular molecule of dimethyl-
formamide dimethylacetal (DMFDMA) for ten hours to
yield the dienaminone 5. Compound 5 has been prepared
earlier [9] via reacting dibenzylketone with excess of
DMFDMA at 110° C. In our hands a higher yield was
obtained on refluxing 4 with an equivalent amount of
DMFDMA in toluene solution for 10 hours.
Compound 4 condensed with cyanothioacetamide via
dimethylamine elimination to yield the thioxo-pyridine-
carbonitrile derivative that may be formulated as 6a or iso-
Figure 1

432
M. M. Abdelkhalik, A. M. Eltoukhy, S. M. Agamy, and M. H. Elnagdi
Vol. 41
and aromatization v i a dimethylamine elimination
(Figure 1). The alternative structure 7 which could have
resulted via initial condensation of the active methylene
with the carbonyl function, should display a doublet for
the pyridine ring CH.
ammonium ion in aqueous solution [11] in 40-50% yield
(lit mp. 396 °C) (Figure 3).
Similarly reaction of 4 with cyanoacetamide afforded
the 5,6-disubstituted 2-oxo-pyridine-3-carbonitrile 6b in
good yield.
Reacting 6a with α-chloroacetone 8 afforded the 3-amino-
thieno[2,3-b]pyridine derivative 10 most likely via intermedi-
acy of 9. This when condensed with DMFDMA afforded the
N,N-dimethyl-formamidine derivative 11, which is subse-
quently reacted with acetic acid in the presence of ammonium
acetate to yield 4,7,8-trisubstituted pyrido[2',3':2,3]thieno-
[4, 5-d]pyrimidine derivative 12 (Figure 2).
Figure 3
Compound 5 was similarly treated with phenylhy-
drazine and 3-amino-5-methyl-pyrazole to furnish the rea-
sonance stabilized product 16(I)a,b and 16(II)a,b or their
potential tautomers e.g 17 and 18, which are difficult to
establish with certainty. Possible initial condensation of
the hydrazine and/or amine with the carbonyl group in an
intermediately formed pyranone was excluded based on
the stability of the reaction product at reflux in acetic acid
in the presence of ammonium acetate, a condition that
would lead to conversion of this pyranhydrazone into pyri-
dine. It is thus believed that initially hydrazine and/or
aminopyrazole add to the enaminone double bond and this
addition reaction is then followed by dimethylamine elim-
ination and subsequent cyclization (Figure 3).
Figure 2
EXPERIMENTAL
Compound 4 reacted with ethyl acetoacetate in acetic
acid in the presence of ammonium acetate affording 2,5,6-
trisubstituted nicotinic acid ethyl ester that was confirmed
to be 13 rather than 14 as the NOE difference experiments
indicated proximity of the carboethoxy methyl protons and
nicotine ring CH.
Compound 5 cyclized directly to the pyran-4-one 15 on
boiling in acetic acid. This pyranone has been obtained
earlier [10] via reaction of dibenzyl ketone 4 with ethyl
formate in sodium ethoxide and subsequent cyclization of
the formed formylated product (lit mp 186 °C). A mixture
of products 15a,b was obtained when the reaction of 5 was
conducted in acetic acid in the presence of ammonium
acetate. Product 15b has been found to be identical with an
authentic specimen [10] as obtained from the reaction of
pyranone 15a in acetic acid in the presence of ammonium
acetate (lit mp. 376 °C), or via reaction of 1,5-dihydroxy-
2,4-diphenyl-penta-1,4-dien-3-one di-sodium salt with
All melting points are uncorrected. IR spectra were recorded in
1
KBr with a Pye Unicam SP 1100 spectrophotometer. H NMR
2
spectra were recorded on a Varian EM-390 spectrometer in [ H ]
DMSO as solvent and TMS as internal standard; chemical shifts
are reported in δ units (ppm). Mass spectra were measured on
MS 30 and MS 9 (AEI), 70 eV. Microanalyses were performed
on LECO CHNS-932. Microanalytical data were obtained from
the Microanalytical Data Unit at Cairo University.
6
4-Dimethylamino-1,3-diphenyl-but-3-en-2-one (4).
A mixture of 1,3-diphenyl-propan-2-one (2.10 g, 10 mmol)
and dimethyl-formamide dimethylacetal (1.19 g, 10 mmol) was
heated under reflux for 6 hrs. The solvent was reduced in vacuo
and the oil obtained was purified by flash chromatography on sil-
ica gel using chloroform/n-hexane (3:1) as eluent.
This compound was obtained in yield 2.0 g (76%); ir (KBr): ν
-1
max/cm : 1640 CO); H nmr (dimethyl sulfoxide-d ): δ (ppm) =
1
6
3.02 (s, 3H, NMe), 3.08 (s, 3H, NMe), 4.18 (s, 2H, CH ), 6.95-
2

May-Jun 2004
Enaminones as Building Blocks in Heterocyclic Synthesis
433
7.00 (m, 2H, arom. H), 7.10-7.18 (m, 5H, arom. H), 7.40-7.43 (m,
3H, arom. H), 8.20 (s, 1H, H-4).
3H, COCH ), 4.27 (s, 2H, CH ), 6.81-6.98 (m, 2H, arom. H),
3
7.16-7.23 (m, 5H, arom. H), 7.28-7.32 (m, 2H, NH , D O
2
2
exchangeable) 7.42-7.43 (m, 3H, arom. H), 7.78 (s, 1H, H-4).
Anal. Calcd. for C H N OS (358.38): C, 73.73; H, 5.06; N,
2
1,5-Bis(dimethylamino)-2,4-diphenylpenta-1,4-dien-3-one (5).
22 18
2
7.82; S, 8.92 %. Found: C, 73.59; H, 5.06; N, 7.75, S, 8.75.
A mixture of compound 4 (2.65 g, 10 mmol) and dimethylfor-
mamide dimethylacetal (1.19 g, 10 mmol) was heated under
reflux for 12 hrs in toluene solution (10 ml). The solvent was
reduced in vacuo and left to cool at room temperature to deposit a
solid after 3 days. The solid product so obtained was crystallized
from dilute ethanol. This compound was obtained in yield 2.36 g
N'-(2-Acetyl-6-benzyl-5-phenyl)thieno[2,3-b]pyridine-3-yl-N,N-
dimethylformamidine (11).
A mixture of compound 10 (3.58 g, 10 mmol) and dimethyl-
formamide dimethylacetal (1.19 g, 10 mmol) was heated under
reflux in dioxane (20 ml) for 4 hrs. The solvent was reduced in
vacuo and left to cool at room temperature to deposit a solid that
was crystallized from dioxane. This compound was obtained
-1
(74%). mp 136-138 °C (EtOH); ir (KBr): ν max/cm : 1645
+
(CO); MS: m/z = 320 [M ]; H nmr (dimethyl sulfoxide-d ): δ
1
6
(ppm) = 3.00 (s, 6H, 2NMe), 3.12 (s, 6H, 2NMe), 7.01-7.12 (m,
2H, arom. H), 7.22-7.28 (m, 5H, arom. H), 7.42-7.49 (m, 3H,
arom. H), 8.24 ( s, 2H, vinyl H).
-1
yield 3.4 g (82%); mp 188-190 °C; ir (KBr): ν max/cm : 1628
+
(CO); MS: m/z = 413 [M ]; H nmr (dimethyl sulfoxide-d ): δ
1
6
(ppm) = 2.58 (s, 3H, COCH ), 3.08 (s, 3H, NCH ), 3.12 (s, 3H,
Anal. Calcd. for C H N O (320.42): C, 78.71; H, 7.55; N,
21 24
2
3
3
8.74%. Found: C, 78.70; H, 7.50; N, 8.62.
Preparation of Compounds (6a,b).
General Procedure.
NCH ), 4.24 (s, 2H, CH ), 6.95-6.97 (m, 2H, arom. H), 7.12-7.21
3 2
(m, 5H, arom. H), 7.39-7.41 (m, 3H, arom. H), 7.62 (s, 1H, H-4),
7.80 (s, 1H, amidine H).
Anal. Calcd. for C H N OS (413.46): C, 72.62; H, 5.61; N,
25 23
3
10.16; S, 7.74 %. Found: C, 72.57; H, 5.67; N, 10.15, S, 7.54.
Each of cyanothioacetamide or cyanoacetamide (10 mmol)
was added to a stirred suspension of the enaminone 4 (2.56 g, 10
mmol) in ethanol (20 ml) in the presence of a few drops of tri-
ethyl amine. The reaction mixture was heated under reflux for 2
hrs. The solvent was reduced in vacuo, then the mixture was pour
onto water and neutralized with dil. HCl to deposit a solid, which
was crystallized from the proper solvent.
7-Benzyl-4-methyl-8-phenylpyrido[2',3':2,3]thieno[4,5- d]pyrim-
idine (12).
Compound 11 (4.13 g, 10 mmol) was heated under reflux in a
mixture of ammonium acetate (1 g) acetic acetic acid (10 ml) for
1 hr. The reaction mixture was left to cool at room temperature to
deposit a solid that was crystallized from dioxane.
6-Benzyl-5-phenyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile
(6a).
This compound was obtained in yield 3.3 g (90%); mp 103-
+
105 °C; MS: m/z = 367 [M ]; H nmr (dimethyl sulfoxide-d ): δ
1
6
(ppm) = 2.60 (s, 3H, CH ), 4.23 (s, 2H, CH ), 6.96-7.00 (m, 2H,
3
2
This compound was obtained in yield 2.6 g (86%); mp 190-
-1
191 °C (dioxan); ir (KBr): ν max/cm : 2835 (NH), 2227 (CN);
arom. H), 7.10-7.23 (m, 5H, arom. H), 7.39-7.42 (m, 3H, arom.
H), 7.64 (s, 1H, H-9), 9.26 (s, 1H, H-2).
Anal. Calcd. for C H N S (367.39): C, 75.19; H, 4.66; N,
+
MS: m/z = 302 [M ]; H nmr (dimethyl sulfoxide-d ): δ (ppm) =
1
6
4.15 (s, 2H, CH ), 6.99-7.01 (m, 2H, arom. H), 7.22-7.28 (m, 4H,
23 17
3
2
11.44; S, 8.71 %. Found: C, 75.10; H, 4.71; N, 11.43, S, 8.65.
arom. H), 7.46-7.47 (m, 4H, arom. H), 7.76 (s, 1H, pyridyl H-4),
12.65 (br s, 1H, NH).
Anal. Calcd. for C H N S (302.32): C, 75.48; H, 4.67; N,
6-Benzyl-2-methyl-5-phenylnicotinic Acid Ethyl Ester (13).
19 14
2
To a solution of compound 4 (2.65 g, 10 mmol) and ethyl
acetoacetate (1.30 g, 10 mmol), ammonium acetate (1 g) in
acetic acid (10 ml) was added. The reaction mixture was heated
under reflux for 3 hr. The solvent was evaporated in vacuo, and
the residual solid was crystallized from dioxane. This com-
pound was obtained in yield 2.45 g (74%); mp 66-67 °C
9.27; S, 10.58 %. Found: C, 75.22; H, 4.78; N, 9.33, S, 10.71.
6-Benzyl-2-oxo-5-phenyl-1, 2-dihydropyridine-3-carbonitrile
(6b).
This compound was obtained in yield 2.4 g (84%); mp 235-
237 °C (EtOH); IR ν = 2830 (NH), 2226 (CN), 1658 (CO); MS:
-1
(EtOH); ir (KBr): ν max/cm : 1724 (CO); MS: m/z = 331
+
m/z = 285 [M -1]; H nmr (dimethyl sulfoxide-d ): δ (ppm) =
1
6
4.02 (s, 2H, CH ), 7.09-7.11 (m, 2H, arom. H), 7.28-7.33 (m, 4H,
+
1
[M ]; H nmr (dimethyl sulfoxide-d ): δ (ppm) = 1.39 (t, 3H, J
6
= 8 Hz, OCH CH ), 2.91 (s, 3H, CH ), 4.17 (s, 2H, CH ), 4.38
2
2
(q, 2H, J = 8 Hz, OCH ), 7.00-7.02 (m, 2H, arom. H), 7.14-
3
3
2
arom. H), 7.45-7.50 (m, 4H, arom. H), 7.87 (s, 1H, pyridyl H-4),
12.96 (br s, 1H, NH).
Anal. Calcd. for C H N O (286.32): C, 79.70; H, 4.93; N,
2
7.22 (m, 5H, arom. H), 7.40-7.45 (m, 3H, arom. H), 8.07 (s,
1H, H-4).
Anal. Calcd. for C H NO (331.40): C, 79.73; H, 6.39; N,
19 14
2
9.78%. Found: C, 79.72; H, 4.90; N, 9.71.
22 21
2
1 ( 3 - A m i n o - 6 - b e n z y l - 5 - p h e n y l ) t h i e n o [ 2 , 3 - b] p y r i d i n - 2 y l ) -
ethanone (10).
4.23 %. Found: C, 79.66; H, 6.32; N, 4.10.
Preparation of Compounds (15a,b).
General Procedure.
To a stirred suspension of compound 6a (3.02 g, 10 mmol) and
chloroacetone (1 g, 11 mmol) in DMF (20 ml), potassium
hydroxide (0.06 g) is added. The reaction mixture was heated
under reflux for 2 hrs. The solvent was reduced in vacuo, then the
mixture was pour onto water and neutralized with dil. HCl to
deposit a solid, which was crystallized from ethanol. This com-
Compound 5 (3.20 g, 10 mmol) was treated with acetic acid
(5ml) in the presence of ammonium acetate (1 g). The reaction
mixture was heated under reflux for 1 hr and left to cool at room
temperature then triturated with ethanol to deposit a mixture of
compound 15a,b that was separated by flash chromatography on
silica gel using chloroform/n-hexane (3:1) as eluent (19% for
compound 15a and 60% for compound 15b).
pound was obtained in yield 2.85 g (80%); mp 176-178 °C; ir
-1
(KBr): ν max/cm : 3284 and 3179 (NH ), 1620 (CO); MS: m/z =
2
357 [M -1]; H nmr (dimethyl sulfoxide-d ): δ (ppm) = 2.51 (s,
+
1
6

434
M. M. Abdelkhalik, A. M. Eltoukhy, S. M. Agamy, and M. H. Elnagdi
Vol. 41
3,5-Diphenyl-pyran-4-one (15a).
Anal. Calcd. for C H N O (338.39): C, 81.63; H, 5.36; N,
23 18
8.28 %. Found: C, 81.60; H, 5.40; N, 8.27.
2
Compound 5 (3.2 0g, 10 mmol) was treated with acetic acid (5
ml) The reaction mixture was heated under reflux for 1 hr and left
to cool at room temperature to deposit a solid that was collected
by filtration and crystallized from ethanol (lit. mp 187 C). This
compound was obtained in yield 1.70 g (69%); mp 180-181 °C; ir
1-(5-Methyl-1H-pyrazol-3-yl)-3, 5-diphenyl-1H-pyridin-4-one
(16b).
This compound was obtained in yield 2.45 g (75%); mp 298-
-1
300 °C; ir (KBr): ν max/cm : 3180 (NH), 1640 (CO); MS: m/z =
-1
+
1
(KBr): ν max/cm : 1645 (CO) MS: m/z = 248 [M ]; H nmr
(dimethyl sulfoxide-d ): δ (ppm) = 7.30-7.42 (m, 6H, arom. H),
+
327 [M ]; H nmr (dimethyl sulfoxide-d ): δ (ppm) = 2.29 (s,
1
6
3H, CH ), 6.62 (s, 1H, pyrazolyl 4-H), 7.31-7.41 (m, 6H,
6
7.62-7.69 (m, 4H, arom. H), 7.96 (s, 2H, pyranyl 2-H and 6-H).
3
arom.H), 7.65-7.70 (m, 4H, arom.H), 8.27 (s, 2H, pyridyl 2-H
and 6-H), 12.74 (s, 1H, NH).
Anal. Calcd. for C H N O (327.37): C, 77.04; H, 5.23; N,
Anal. Calcd for C H O (248.27): C, 82.24; H, 4.87 %.
17 12 2
Found: C, 82.22; H, 4.88.
21 17
3
3,5-Diphenyl-1H-pyridin-4-one (15b).
12.84 %. Found: C, 77.01; H, 5.17; N, 12.85.
This compound was obtained in yield 1.48 g (60%); mp > 300
-1
°C (EtOH); ir (KBr): ν max/cm : 3190 (NH), 1635 (CO); MS:
REFERENCES AND NOTES
+
m/z = 248 [M +1]; H nmr (dimethyl sulfoxide-d ): δ (ppm) =
1
6
7.30-7.43 (m, 6H, arom. H), 7.60-7.65 (m, 4H, arom. H), 7.84 (s,
2H, pyridyl 2-H and 6-H), 12.42 (br s, 1H, NH).
A n a l. Calcd. for C H NO (247.28): C, 82.57; H, 5.30; N,
5.66 %. Found: C, 82.56; H, 5.42; N, 5.69.
Preparation of Compounds (16a,b).
General Procedure.
[1] R. Troschütz and A. Karger, J. Heterocyclic Chem. , 34,
1147 (1997).
[2] R. M. Robertson, D. Robertson, The Pharmacological
Basis of Therapeutic, Goodman and Gillman's, p 759, 9th ed, A. G.
Gilman, consulting edd., Mc Graw-Hill Health Professions Divisions,
New York, (1996).
[3] A. E. Farah and A. A. Alousi, Life Sci., 22, 543 (1978).
[4] J. Svetlik, N. Pronayova and V. Hanas, J. Heterocyclic
Chem., 37, 395(2000).
[5] D. H. Bremner, A. D. Dunn, K. A. Wilson, K. R. Sturrock
and G. Wishart, Synthesis, 949 (1997).
[6] S. M. Agamy, M. M. Abdel-Khalik, M. H. Elnagdi, M. H.
Mohamed and Z. Naturforsch, 56b, 1074 (2001).
[7] F. M. A. A. El-Taweel and M. H. Elnagdi, J. Heterocyclic
Chem. 38, 981 (2001).
[8] N. Al-Awadi, M. H. Elnagdi, Y. A. Ibrahim, K. Kaul and A.
Kamar, Tetrahedron, 57, 1609 (2001).
17 13
Compound 5 (3.20 g, 10 mmol) was treated with each of
phenylhydrazine and 3-amino-5-methyl-pyrazole (10 mmol) in
acetic acid (5 ml) in the presence of ammonium acetate (1 g). The
reaction mixture was heated under reflux for 1 hr and left to cool
at room temperature to deposit a solid that was collected by fil-
tration and crystallized from ethanol.
3,5-Diphenyl-1-phenylamino-1H-pyridin-4-one (16a).
This compound was obtained in yield 2.45 g (73%); mp 232-
-1
233 °C; ir (KBr): ν max/cm : 3185 (NH), 1635 (CO); MS: m/z =
[9] J. M. Hook and L. N. Mander, J. Org. Chem., 45, 1724
(1980).
+
338 [M ]; H nmr (dimethyl s.ulfoxide-d ): δ (ppm) = 6.72-6.75
1
6
(m, 2H, arom. H), 6,91-6.96 (m, 1H, arom. H), 7.27-7.41 (m, 8H,
arom. H), 7.63-7.67 (m, 4H, arom. H), 7.91 (s, 2H, pyridyl 2-H
and 6-H), 9.65 (s, 1H, NH).
[10] B. Bitter, Ber., 61, 1059 (1928).
[11] I. E. El-Kholy, M. M. Mishrikey and R. F. Atmeh, J.
Heterocyclic Chem., 10, 665 (1973).