Studies with enaminones: Synthesis of new coumarin-3-yl azoles, coumarin-3-yl azines, coumarin-3-yl azoloazines, coumarin-3-yl pyrone and coumarin-2-yl benzo[b]furans

Article abstract of DOI:10.1002/jhet.5570380428

3-Acetylcoumarine was condensed with dimethylformamide dimethylacetal (DMFDMA) to yield the enaminone, which reacts readily with hydroxylamine and with hydrazines to yield coumarin-3-ylisoxazoles and coumarin-3-ylpyrazoles respectively. Reaction of the enaminone with benzamidine hydrochloride and 3-amino-1,2,4-1H-triazole affords the pyrimidine and triazolo[3,4-b]pyrimidine. The enaminone reacts with hippuric acid and with the dithiocarboxylic acid to yield pyranones. The reaction of the enaminone with 3-amino-1H-1,2,4-triazole gives the triazolo[3,4-b]pyrimidine. The enaminone underwent self dimerization on reflux in acetic acid ammonium acetate to yield the coumarinyl pyridines and reacted with ketone under the same conditions to yield the pyridine. The reaction of the enaminone with 1,4-benzoquinone and 1,4-naphthoquinone gives benzofuryl coumarine derivatives.

Full text of DOI:10.1002/jhet.5570380428

Jul-Aug 2001
Studies With Enaminones: Synthesis of New Coumarin-3-yl
Azoles, Coumarin-3-yl Azines, Coumarin-3-yl Azoloazines,
Coumarin-3-yl Pyrone and Coumarin-2-yl Benzo[b]Furans
Fathy Mohamed Abel Aziz El-Taweel* [a] and Mohamed Hilmy Elnagdi [b]
981
[a] Department of Chemistry ; Faculty of Science ; New Damietta, University of Mansoura, A. R. Egypt
[b] Department of Chemistry; Faculty of Science; Cairo University, Giza- A. R. Egypt
Received February 6, 2001
3-Acetylcoumarine was condensed with dimethylformamide dimethylacetal (DMFDMA) to yield the
enaminone, which reacts readily with hydroxylamine and with hydrazines to yield coumarin-3-ylisoxazoles
and coumarin-3-ylpyrazoles respectively. Reaction of the enaminone with benzamidine hydrochloride and
3-amino-1,2,4-1H-triazole affords the pyrimidine and triazolo[3,4-b]pyrimidine. The enaminone reacts with
hippuric acid and with the dithiocarboxylic acid to yield pyranones. The reaction of the enaminone with
3-amino-1H-1,2,4-triazole gives the triazolo[3,4-b]pyrimidine. The enaminone underwent self dimerization
on reflux in acetic acid ammonium acetate to yield the coumarinyl pyridines and reacted with ketone under
the same conditions to yield the pyridine. The reaction of the enaminone with 1,4-benzoquinone and
1,4-naphthoquinone gives benzofuryl coumarine derivatives.
J. Heterocyclic Chem., 38, 981 (2001).
Enaminones are versatile reagents and their utility in
Similarly, compound 2 reacted with hydrazine
hydrate and with phenylhydrazine to yield the pyrazole
derivatives 6. Attempts to obtain the pyrazole 7 from
the reaction of the hydrazone 8 with DMFDMA failed.
The enaminone 2 also reacted with benzamidine
hydrochloride 9 to yield the 4-coumarinoyl pyrimidine
10 (Figure 2).
heterocyclic synthesis has recently received a considerable
attention [1-4]. In conjunction with our interest in synthesis of
3-heteroarylcoumarine derivatives as potential laser dyes [5],
pharmaceuticals [6] and agrochemicals [7]; we report here an
efficient synthesis of a variety of target molecules utilizing the
readily obtainable 3-acetylcoumarine 1 as starting material.
Thus, 3-acetylcoumarine 1 reacted with dimethylformamide
dimethylacetal (DMFDMA) in refluxing xylene to yield the
1
enaminone 2. The H-NMR spectrum of 2 shows that the
trans isomer is formed exclusively based on coupled olefinic
protons at δ 5.95 and δ = 8.5 ppm with J = 15 Hz (AB
system). The enaminone 2 reacted with hydroxylamine
hydrochloride in the presence sodium acetate in EtOH to
yield a product that may be formulated as the isoxazolyl-
coumarine 3 or 4. Structure 3 was established as the product
because it is identical with product obtained from the reaction
of oxime 5 with DMFDMA in refluxing xylene. It is thus
assumed that compound 3 is formed via initial addition of the
hydroxylamine nitrogen with the carbonyl group in system 2
and the resulting product then cyclizes into the final isoxazole
derivatives 3 (Figure 1).
3-Amino-1H-1,2,4-triazole 11 reacted with 2 to yield a
1,2,4-triazolopyrimidine derivative that may be formulated
as 12 or isomeric 13. Structure 12 was established as the
1
reaction product based on the H-NMR spectrum, where
the triazole proton is observed at δ 8.8 ppm, which is

982
F. M. A. A. El-Taweel and M. H. Elnagdi
Vol. 38
of 2 yielding 16 followed by further rearrange to give
17. This is similar to the well known Kepe [8] pyranone
synthesis that has recently been adopted by Elnagdi et
al. [6] to enable synthesis of pyranones from reaction of
the enaminone 2 with hippuric acid. Compound 2 also
reacted with the dithiocarboxylic acid 18 to yield a
product that may formulated as 20 and 21. Formation of
this product may be assumed to proceed via initial
cyclization of the dithiocarboxylic acid derivatives into
the thiazolone 19. This then condensed with 2 via
dimethylamine elimination to yield 20 that rearranges
into a pyranone derivative 21 in a manner similar to that
suggested to account for formation of pyranones from
reaction of hippuric acid with 2 (Figure 3).
Refluxing of 2 in acetic acid/ammonium acetate
afforded the pyridine derivative 23 (Figure 4). Compound
2 also reacted with 1 in acetic acid/ammonium acetate to
yield the pyridine derivative 24. Compound 2 reacted with
1,4-benzoquinone 25 and 1,4-naphthoquinonone 27
yielding the benzofuran 26 and naphthofuran 28,
espectively. It is believed that 2 first add the quinone to
yield intermediate phenolic adduct that cyclizes via loss
of dimethylamine to yield final isolable products. Similar
reaction sequence has been recently proposed to account
for formation of benzofuran from reaction of enaminones
with quinones [4] (Figure 4).
shifted from the expected value for the triazole proton of
isomeric 13 by 1.0 ppm. This effect results from Van der
Waals deshielding of the coumarinyl H-4 ,which in turn is
deshielded and appears as singlet at δ 8.0 ppm.
EXPERIMENTAL
All melting points are uncorrected. IR spectra were recorded
for KBr disks on a Shimadzu IR-740 spectrometer. H NMR
1
Reacting 2 with hippuric acid 14 in acetic anhydride
afforded the 3-pyranylcoumarine derivative 17. These
are assumed to be formed via initial cyclization of
hippuric acid into the oxazolone 15 which then adds to
the activated double bond system of another molecule
spectra were obtained on a Bruker AC-80 spectrometer with
DMSO-d as solvent and TMS as internal standards and chemical
6
shifts expressed δ ppm. Mass spectra were measured on GC-MS
INCOS XL Finnigan MAT. Elemental analyses were performed
on LECO CHNS-932.

Jul-Aug 2001
Studies With Enaminones: Synthesis of New Coumarin-3-yl Azoles
983
1-(3-Coumarinyl)-3-dimethylamino-2-propen-1-one (2).
and recrystallized from ethanol. Compound 10 was obtained as
buff crystals, yield 70%, mp 185 °C; ir (potassium bromide): ν
Dimethylformamide dimethylacetal (1.19 g, 10 mmol) was
added to 3-acetylcoumarin 1 (10 mmol) in xylene (50 ml), and
the reaction mixture was refluxed for 6 hours. The removal of
solvent under reduced pressure yielded the crude product which
was crystallized from ethanol. Compound 2 was obtained as
yellow crystals (75%), mp 165 °C; ir (potassium bromide): ν
-1
1
1732 (ring CO), 1606 (C=N) cm ; H-NMR (dimethyl-d
6
sulfoxide): δ 7.39-7.90 (m, 9H, Ar-H), 8.20 (s, 1H, coumarin
H-4), 8.96 (d, J = 3Hz, 1H, pyridine H-6), 9.03 (d, J = 3Hz, 1H,
+
pyrdine H-5); ms: 300 (M ).
Anal. Calcd. for C H N O : C, 75.99; H, 4.03; N, 9.33.
19 12
2 2
Found: C, 75.5; H, 4.60; N, 9.41.
-1
1
1720 (ring CO) cm ; H NMR (dimethyl-d sulfoxide): δ 2.90
6
(s, 3H, NCH ), 3.15 (s, 3H, CH ), 5.95 (d, J = 15 Hz, olefinic-H),
4-(Coumarin-3'-yl)-1,2,4-triazolo[4,3-a]pyrimidine (12).
3
3
7.35-7.90 (m, 5H, arom-H), 8.50 (d, J = 15 Hz, olefinic-H); ms :
243 (M ).
A solution of 2 (2.43 g, 10 mmol) and (0.84 g, 10 mmol) of
3-amino-1H-1,2,4-triazole in (30 ml) ethanol/acetic acid (1:1),
was refluxed for 6 hours. The solvent was removed by distillation
under reduced pressure and the resulting solution was left to cool.
The solid precipitate was collected by filtration and recrystallized
from ethanol. Compound 12 was obtained as canary yellow
crystals, yield 70%, mp 250 °C; ir (potassium bromide): ν 1729
+
Anal. Calcd. for C
H NO : C, 69.13; H, 5.39; N, 5.76.
14 13 3
Found: C, 69.22; H, 5.34; N, 5.66.
3-(Coumarin-3'-yl)isoxazole (3).
A mixture of the enaminone 2 (2.43 g, 10 mmol) and hydroxy-
lamine hydrochloride (10 mmol) in ethanol (50 ml), sodium
acetate anhydrous (0.82g, 10 mmol) was refluxed for 6 hours,
then left to cool. The formed precipitate was collected by filtra-
tion and crystallized from ethanol. Compound 3 was obtained as
colorless crystals (65%), mp 195 °C; ir (potassium bromide): ν
-1 1
(ring CO), 1653 (C=N) cm ; H NMR (dimethyl-d sulfoxide): δ
6
7.35-7.50 (m, 2H, arom-H), 7.60-7.73 (m, 2H, arom-H), 7.8-7.9
(d, J = Hz, pyrimidine H-5), 8.5 (s, 1H, coumarinyl H-4), 8.8
+
(s, 1H, triazole H-3), 9.1 (s, 1H, pyrimidine H-6); ms: 264 (M ).
Anal. Calcd. for C H N O : C, 63.64; H, 3.05; N, 21.20.
14
8 4 2
-1
1
1726 (ring CO) cm ; H-NMR (dimethyl-d -sulfoxide): δ 7.25
6
Found: C, 63.41; H, 4.60; N, 21.35.
(d, J = 3Hz, 1H, isoxazoleH-4), 8.75 (d, J = 3Hz, 1H, isoxazole
General Procedure for the Preparation of 3-Substituted-6-
(coumarin-3'-yl)pyran-2-one 17 and 21.
H-5) 7.41-8.0 (m, 4H, Ar-H), 8.9 (s, 1H, coumarin H-4); ms: 213
(M ).
+
Anal. Calcd. for C H NO : C, 67.61; H, 3.31; N, 6.57. Found:
C, 67.50; H, 3.36; N, 6.42.
12
7
3
A solution of 2 (2.43 g, 10 mmol) and appropriate amount of
14 or 18 (10 mmol) in acetic anhydride (50 ml), was refluxed for
3 hours, then left to cool. The deposited solids were isolated by
filtration and recrystallized to give 17 and 21, respectively.
Reaction of Compound 2 with Hydrazines.
To a solution of 2 (2.43 g, 10 mmol) in ethanol (30 ml), either
hydrazine hydrate (2 ml) or phenylhydrazine (1.5 ml) were
added. The reaction mixture was heated under reflux for 4 hours,
then left to cool. The solid products, so formed, were isolated by
filtration, washed with ethanol and dried. Recrystallization from
ethanol yielded colorless crystals of 6a,b.
3-Benzamido-6-(coumarin-3'-yl)pyran-2-one (17).
Compound 17 was obtained as canary yellow crystals from
DMF yield 75%, mp 284 °C; ir (potassium bromide): ν 3396
(NH), 1726 (ring CO), 1695 (ring CO), 1664 (amide CO) cm ;
-1
1
H NMR (dimethyl-d sulfoxide): δ 7.35-7.50 (m, 2H, arom-H),
6
7.3-7.6 (m, 7H, arom-H), 7.85 (d, J = 8 Hz, 1H, pyrane H-5), 8.30
(d, J = 8 Hz, 1h, pyrane H-4), 8.75 (s, 1H, coumarinyl H-4), 9.74
(s, 1H, NH); ms: 359 (M ).
3-(Coumarin-3'-yl)pyrazole (6a).
Compound 6a was obtained in 60% yield mp 237 °C; ir (potas-
+
-1
sium bromide): ν 3200 (NH), 1736 (ring CO), 1626 (C=N) cm ;
Anal. Calcd. for C
H NO : C, 70.19; H, 3.65; N, 3.90.
21 13 5
1
H-NMR (dimethyl-d sulfoxide): δ 5.9 (d, J = 3 Hz, 1H, pyra-
6
Found: C, 70.31; H, 4.10; N, 4.02.
zole H-4), 7.35-7.75 (m, 4H, Ar-H), 8.45 (d, J = 3 Hz, 1H, pyra-
3-Benzylthiocarboxamido-6-(coumarin-3'-yl)pyran-2-one (21).
zole H-5), 9.0 (s, 1H, coumarin H-4), 11.1 (s, 1H, NH); ms: 212
+
(M ).
Compound 21 was obtained as buff crystals from
ethanol/DMF yield 70%, mp 225 °C; ir (potassium bromide): ν
3450 (NH), 1746 ( CO), 1720 (ring CO) cm ; H NMR
Anal. Calcd. for C H N O : C, 67.92; H, 3.80; N, 13.20.
12
8 2 2
-1
1
Found: C, 67.78; H, 3.5; N, 13.11.
(dimethyl-d sulfoxide): δ 2.84 (s, 2H, CH ), 6.78 (d, J = 8 Hz,
6
2
1-Phenyl-3-(coumarin-3'-yl)pyrazole (6b).
Compound 6b was obtained in 60% yield, mp 135 °C; ir
1H, pyrone H-4), 7.25-7.59 (m, 9H, Ar-H), 7.89 (d, J = 8 Hz, 1H,
pyrone H-5), 8.30 (s, 1H, coumarinyl H-4), 8.34 (s, 1H, NH); ms:
-1
1
+
(potassium bromide): ν 1736 (ring CO), cm ; H-NMR
421 (M ).
(dimethyl-d sulfoxide): δ 6.8 (d, J = 3Hz, 1H, pyrazole H-4),
Anal. Calcd. for C H NO S : C, 62.69; H, 3.59; N, 3.32.
6
22 15
4 2
7.35-7.83 (m, 4H, Ar-H), 7.84 (d, J = 3Hz, 1H, pyrazole H-5),
Found: C, 62.63; H, 3.41; N, 3.22.
+
8.21 (s, 1H, coumarin H-4); ms: 2289 (M ).
2-(Coumarin-3'-yl)-5-(coumarin-3'-oyl)pyridine (23).
Anal. Calcd. for C H N O : C, 74.99; H, 4.20; N, 9.72.
18 12
2 2
Found: C, 74.89; H, 4.12; N, 9.69.
Compound 2 (2.43 g, 10 mmol) and (0.77g, 10 mmol) of
ammonium acetate were refluxed in glacial acetic acid (30 ml)
for 0.5 hour, then left to cool to room temperature. The precipi-
tated material upon cooling was isolated by filtration and recrys-
tallized from DMF to give 23 as buff crystals yield 65%, mp
265 °C; ir (potassium bromide): ν 1730 (ring CO), 1680 (CO)
4-(Coumarin-3'-yl)-2-phenylpyrimidine (10).
A solution of 2 (2.43 g, 10 mmol) in dry pyridine (20 ml), and
(1.55 g, 10 mmol) of benzamidine hydrochloride were refluxed
for 3 hours. The solvent was reduced under vacuo, to half vol-
ume. The solid product, obtained, was isolated by filtration, dried
-1
1
cm ; H NMR (dimethyl-d sulfoxide): δ 7.35-7.72 (m, 8H,
6

984
F. M. A. A. El-Taweel and M. H. Elnagdi
Vol. 38
Ar-H), 7.89 (d, J = 8 Hz, 1H, pyridine H-3), 8.20 (d, J = 8 Hz, 1H,
pyridine H-4), 8.50 (d, J = 8 Hz, 1H, pyridine H-5), 8.9, 9.0
(2s, 2H, coumarinyl H-4), 9.34 (s, 1H, NH); ms: 395(M ).
Anal. Calcd. for C H O : C, 70.59; H, 3.29. Found: C,
18 10 5
70.31; H, 3.46.
+
5-Hydroxy-3-(coumarin-3'-oyl)naphtho[1,2-b]furan (28).
Anal. Calcd. for C
H NO : C, 72.91; H, 3.31; N, 3.54.
24 13 5
Found: C, 72.85; H, 3.24; N, 3.46.
Compound 28 was obtained as yellow crystals from DMF
yield 60%, mp 280 °C; ir (potassium bromide): ν 1725 (ring CO),
2,6-Bis(coumarin-3'-yl)pyridine (24).
-1
1
1640 (CO) cm ; H NMR (dimethyl-d sulfoxide): δ 7.34-8.29
6
A mixture of 2 (2.43 g, 10 mmol) and (1.88 g, 10 mmol) of
3-acetylcoumarin 1 in glacial acetic acid (30 ml) and (0.77 g, 10
mmol) of ammonium acetate, was refluxed for 1 hour. The
precipitated material was isolated by filtration and recrystallized.
Compound 24 was obtained as yellow crystals from
ethanol/DMF yield 65%, mp 280 °C; ir (potassium bromide): ν
(m, 9H, Ar-H), 8.50 (s, 1H, OH), 9.0 (s, H, coumarinyl H-4), 10.4
(s, 1H, CHO).
Anal. Calcd. for C
H O : C, 74.16; H, 3.39. Found: C,
22 12 5
74.23; H, 3.51.
REFERENCES AND NOTES
-1
1
1730 (ring CO), 1673 (CO) cm ; H NMR (dimethyl-d
6
sulfoxide): δ 7.6-8.4 (m, 11H, Ar-H), 9.03, 9.06 (2s, 2H,
[1] F. Al-Omran, M. M. Abdel-Khalik, A. Abuel-Khair, and
M. H. Elnagdi, Synthesis, 91, (1997).
[2] K. M. Al-Zaydi and E. A. Hafez, J. Chem. Res. (S) 360; (M)
1621 (1999).
+
coumarinyl H-4); ms: 367 (M ).
Anal. Calcd. for C
H NO : C, 75.20; H, 3.57; N, 3.81.
23 13 4
Found: C, 75.33; H, 3.61; N, 3.49.
General Method for Preparation of 26 and 28.
[3] A. A. Al-Naggar; M. M. Abdel-Khalik and M. H. Elnagdi
J. Chem. Research (S), 648, (M), 2801, (1999).
To a stirred solution of 2 (2.43 g, 10 mmol) in glacial acetic
acid (50 ml), each of p-benzoquinone and 1,4-naphthoquinone
(10 mmol) was added. Stirring was continued over night at room
temperature. The reaction mixture was evaporated in vacuo and
the solid products obtained were isolated by filtration and
recrystallized.
[4] B. Al-Saleh, N. A. Al-Awedi, H. Al-Kandari, M. M. Abdel-
Khalik, and M. H. Elnagdi, J. Chem. Research (S), 16; (M), 201, (2000).
[5] M. H. Elnagdi, S. O. Abdallah, K. M. Ghoneim, E. M. Ebeid
and K. N. Kassab, J. Chem. Research (S), 44 (1997).
[6] F. Al-Omran; N. A. Al-Awedi, M. M. Abdel-Khalik,K. Kaul,
A. Abuel-Khair, and M. H. Elnagdi, J. Chem. Research (S), 84; (M), 601,
(1997).
[7] E. A. Hafez, M. H. Elnagdi, A. A. Elagamey, F. M. A. El-
Taweel, Heterocycles, 26, 903, (1987).
[8] V. Kepe, M. Kocevar and S. Polanc, J. Heterocyclic. Chem.,
33, 1707, (1996).
5-Hydroxy-3-(coumarin-3'-oyl)benzo[b]furan (26).
Compound 26 was obtained as colorless crystals from
ethanol/DMF yield 70%, mp 284 °C; ir (potassium bromide): ν
3337 (OH), 1714 (ring CO), 1690 (CO) cm ; H NMR
-1
1
(dimethyl-d sulfoxide): δ 7.35-7.98 (m, 7H, Ar-H), 8.47 (s, 1H,
[9] P. Fossa, R. Boggia, E. Lo Presti, L. Mosti, P. Dorigo and
M. Floreani, Il. Farmaco, 52, 523, (1997).
6
+
OH); ms: 306 (M ).