Nucleophilic addition reactions on 3-carbethoxy-5,7-dimethoxycoumarin

Article abstract of DOI:10.1081/SCC-120002505

3-Carbethoxy-5,7-dimethoxycoumarin (2) underwent Michael addition and addition-cyclization of some active methylene compounds under different reaction conditions to give the adducts (3-7). Addition of phenylmagnesium bromide onto (2) yielded the tertiary alcohol (8). Addition of ammonia derivatives on (2) afforded the 3-carboxamides (9a-c) and azine (10). Furthermore, alcoholysis and hydrolysis yielded the coumarins (11a-c).

Full text of DOI:10.1081/SCC-120002505

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NUCLEOPHILIC ADDITION REACTIONS ON 3-
CARBETHOXY- 5,7-DIMETHOXYCOUMARIN
M. A. Hassan a , S. A. Shiba a , N. S. Harb a , M. K. Abou-El-Regal a & S. A. El-Metwally a
a Chemistry Department , Faculty of Science , Ain Shams University , Cairo, Egypt
Published online: 16 Aug 2006.
To cite this article: M. A. Hassan , S. A. Shiba , N. S. Harb , M. K. Abou-El-Regal & S. A. El-Metwally (2002) NUCLEOPHILIC
ADDITION REACTIONS ON 3-CARBETHOXY- 5,7-DIMETHOXYCOUMARIN, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 32:5, 679-688, DOI: 10.1081/SCC-120002505
To link to this article: http://dx.doi.org/10.1081/SCC-120002505
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SYNTHETIC COMMUNICATIONS, 32(5), 679–688 (2002)
NUCLEOPHILIC ADDITION
REACTIONS ON 3-CARBETHOXY-
5,7-DIMETHOXYCOUMARIN
M. A. Hassan,* S. A. Shiba, N. S. Harb,
M. K. Abou-El-Regal, and S. A. El-Metwally
Chemistry Department, Faculty of Science,
Ain Shams University, Cairo, Egypt
ABSTRACT
3-Carbethoxy-5,7-dimethoxycoumarin (2) underwent Michael
addition and addition–cyclization of some active methylene
compounds under different reaction conditions to give the
adducts (3–7). Addition of phenylmagnesium bromide onto
(2) yielded the tertiary alcohol (8). Addition of ammonia
derivatives on (2) afforded the 3-carboxamides (9a–c) and
azine (10). Furthermore, alcoholysis and hydrolysis yielded
the coumarins (11a–c).
In continuation of our interest1–3 on the synthesis and reactions
of novel coumarins, we report here the synthesis of 3-carbethoxy-5,7-
dimethoxycoumarin (2) and its reactions with some nucleophilic reagents
aiming to synthesis some new coumarin derivatives which might have
enhanced biological activities.
*Corresponding author.
679
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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HASSAN ET AL.
Knoevenagel condensation of 4,6-dimethoxy-2-hydroxy-benzaldehyde
(1) with diethyl malonate in the presence of piperidine afforded the
coumarin (2) in quantitative yield (Scheme 1).
Scheme 1.
Base catalyzed addition–cyclization4,5 of some active methylene com-
pound, such as cycloalkanone, malononitrile, acetylacetone, ethyle aceto
or cyanoacetate have been investigated under different reaction conditions.
Addition of cyclohexanone on coumarin (2) in the presence of
ammonium acetate at 160ꢀC underwent Michael addition with nucleophilic
addition of ammonia to the carbonyl pyrone followed with ring closure
and subsequent ammonolysis of the ester group to its corresponding amide
to give 5,7-dimethoxy-4-(10-oxo-cyclohexan-20-yl)-1,2,3,4-tetrahydroquino-
lin-2-one-3-carboxamide (3a) (Scheme 1), while cycloheptanone proceeds
by normal Michael addition with ammonolysis of the ester group to
give 5-7-dimethoxy-4-(10-oxo-cycloheptanon-20-yl)-3,4-dihydro-coumarin-3-
carboxamide (3b) (Scheme 1).
Base-catalyzed addition of malononitrile to (2) in the presence of
sodium methoxide in boiling methanol proceeds by normal Michael
addition with transesterification6 to give 3-carbethoxy-4-dicyanomethyl-
3,4-dihydro-5,7-dimethoxycoumarin (4) (Scheme 1).
Treatment of coumarin (2) with acetylacetone and/or ethyl aceto-
acetate in the presence of sodium methoxide at 160ꢀC yielded 10-acelyl

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3-CARBETHOXY-5,7-DIMETHOXYCOUMARIN
681
and/or 10-carbethoxy-7,9-dihydroxy-1,3-dimethoxy-6-oxo-6H-dibenzo(b,d)-
pyrans (5a,5b) respectively (Scheme 1). The reaction proceeds via base-
catalyzed addition–cyclization with subsequent dehydrogenation under
reaction conditions.
On the other hand, base-catalyzed addition–cyclization of acetyl-
acetone on coumarin (2) in the presence of sodium methoxide in boiling
methanol afforded acetyl-8,10-dimethoxy-2-methyl-4,5-dihydro-4,5-dioxo-
pyrano[3,4-c]-benzopyran (6) (Scheme 1).
Furthermore, coumarin (2) underwent base-catalyzed addition–
cyclization of ethyl cyanoacetate in the presence of sodium methoxide
at 160ꢀC to give 1-cyano-8,10-dimethoxy-2-ethoxy-4-hydroxy-5-oxo-
4,4a,5,10a-tetrahydropyrano-[3,4-c]-benzopyran (7) (Scheme 1).
Scheme 2.

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HASSAN ET AL.
Table 1. Physical Data of Prepared Compounds (2–11)
Color
Yield
(%)
Molecular
Formula
(M.Wt.)
Analysis, Calc./Found (%)
Compound M.P. (ꢀC)
No.
Solvent
C
H
N
2
160
E
190–3
E
225Colorless
E
218–22
E
220
E
252–4
A
225
A
220–5
EA
Yellow
(96)
Yellow
(55)
C
(74)
Colorless C19H23NO6
(68) (361.38)
Yellow C16H14N2O6
(33)
Yellow
(73)
Colorless
(78)
Pale
yellow
(37)
C14H14O6
(278.30)
C36H30O4
(526.63)
18H22N2O5
(346.39)
60.43
60.39
82.11
82.26
62.41
62.41
63.14
63.03
58.18
57.95
61.454.85 –
61.63
60.00
60.30
61.82
61.98
5.07
5.05
5.74
5.71
6.40
6.54
6.42
6.47
4.24
4.16
–
–
–
–
8.09
8.18
3.87
3.88
8.48
8.40
8
3a
3b
4
(330.30)
C17H14O7
(330.26)
C18H16O8
(360.29)
5a
5b
6
4.86
4.48
4.82
4.24
4.30
–
–
–
–
–
C17H14O7
(330.27)
7
194–6
E
235–7
A
243
A
222–4
EA
280–2
A
188–90
EA
235–7
A
141–3
M
Orange
(76)
Yellow
(64)
Yellow
(82)
Brown
(50)
Yellow C18H20N2O6
(77)
Yellow
(63)
Yellow
(88)
Pale
C17H15NO7
(345.30)
C12H11NO5
(249.22)
C19H17NO5
(339.35)
C18H16N2O5
(340.34)
59.13
59.23
57.83
57.91
.6075.42.5153
67.36
63.51
63.50
59.95
60.11
59.09
59.18
57.60
57.44
64.07
64.19
4.38
4.36
4.45
4.53
4.06
3.93
5.62
5.70
9a
9b
9c
5.19
4.73
4.84
5.59
5.64
4.58
4.77
4.03
3.93
4.88
5.07
4.24
8.23
8.33
7.78
8.02
–
–
–
–
–
10
(360.37)
C13H12O6
(264.20)
C12H10O6
(250.19)
11a
11b
11c
C11H10O4
(206.12)
yellow
(57)
–
A—acetic acid; E—ethanol; EA—ethylacetate; M—methanol.

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683
Treatment of coumarin (2) with excess phenylmagnesium bromide
(1 : 8) afforded (5,7-dimethoxy-2,2-diphenylbenzo-2H-pyran-3-yl)diphenyl-
carbinol (8) (Scheme 2). The reaction proceeds with nucleophilic addition
of Grignard reagent on both carbonyl groups of ester and lactone to give the
ditertiary alcohols followed by ring closure to give (8).
Heating of (2) with ammonium acetate at 160ꢀC and/or treatment of it
with p-toluidine in boiling ethanol yielded the corresponding 3-carboxamide
derivatives (9a,b) respectively (Scheme 2).
Reaction of coumarin (2) with hydrazine hydrate or phenylhydrazine
in boiling ethanol gave 2-hydroxy-4,6-dimethoxybenzalazine7 (10) and/or
5,7-dimethoxy-3-phenylcarbohydrazide coumarin (9), respectively (Scheme 2).
Formation of azine (10) may be attributable for the formation of 2-hydroxy-
4,6-dimethoxy-benzaldehyde (1) as an intermediate product, which is con-
densed with hydrazine hydrate giving (10), which is proved authentically7
giving same product.
With oxygen nucleophiles, like, methoxide or hydroxide, coumarin (2)
underwent transesterifications,6 hydrolysis of ester group and/or hydrolysis
of ester group with decarboxylation depending on the reaction conditions to
give the corresponding coumarins (11a–c) respectively (Scheme 2).
EXPERIMENTAL
Melting points reported are uncorrected. IR spectra were recorded on
Pye-Unicam SP 2000 Spectrophotometer, Perkin-Elmer 983 Spectro-
photometer and Maltson-1000 Series FT-IR Spectrophotometer using
1
KBr Wafer technique. The H- and 13C-NMR spectra were determined on
Gimini 200 MHz, and Bruker AC 200, AMX 300 and DRX 500, using TMS
as internal standard. 13C-signals assigned on the basis of the DEPT 135/90
spectra. The chemical shifts are recorded in d-scale in ppm. The mass spectra
were measured by AMD 604 Spectrophotometer using single focusing mass
spectrophotometer with direct inlet at Beam energy 70 eV. Elemental ana-
lysis were estimated by Perkin-Elmer 2400 CHN analyzer and Carlo-Erba
1106 CHN analyzer.
3-Carbethoxy-5,7-dimethoxycoumarin (2)
A mixture of dimethoxysalicylaldehyde (1) (3.6 g, 0.02 mol), diethyl
malonat (3.8 ml, 0.02 mol) and piperidine (0.5ml) was heated on water-
bath for 1 h. The mixture was left at room temperature for 3 h, and then
washed with cold hydrochloric acid (3 Â 30 ml 10%). The solid was filtered,

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HASSAN ET AL.

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685

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HASSAN ET AL.
washed with sodium bicarbonate (3 Â 50 ml, 10%) and finally with water
(3 Â 30 ml), dried and crystallized to give (2).
Addition of Cyclohexanone and Cycloheptanone to Coumarin (2)
in the Presence of Ammonium Acetate. Formation of (3a,b)
A mixture of dimethoxycoumarin (2) (1.4 g, 0.005mol), ammonium
acetate (5.0 g, 0.06 mol), cyclohexanone or cycloheptanone (0.006 mol) was
heated at 160ꢀC for 5h, then triturated with hot water (30 ml). The solid was
filtered, dried and crystallized to give (3a,b).
Addition of Malononitrile and Acetylacetone in the Presence of
Sodium Methoxide in Boiling Methanol. Formation of (4,6)
General procedure: To a solution of sodium methoxide (0.5g, 0.01 mol)
in absolute methanol (30 ml), malononitrile and/or acetylacetone (0.006 mol)
was added and the solution was refluxed for 15min, then dimethoxycoumarin
(2) (1.40 g, 0.005mol) was added and the reaction mixture was refluxed
for 4 h. The solid product was filtered, washed with cold hydrochloric acid
(2 Â 30 ml, 10%), and water (2 Â 30 ml), dried and crystallized to give (4) and
(6) respectively.
Addition of Acetylacetone, Ethyl Acetoacetate and
Ethyl Cyano-Acetate to (2) in the Presence of
Sodium Methoxide at 160ꢀC. Formation of (5a,b, and 7)
General procedure: A mixture of (2) (1.4 g, 0.005mol), active methylene
compounds (0.006 mol) and sodium methoxide (0.5g, 0.01 mol) was heated
without solvent at 160ꢀC for 5h. The reaction mixture was cooled tritura-
ted with cold hydrochloric acid (30 ml, 10%). The solid was filtered,
washed with water (2 Â 20 ml), dried and crystallized to give (5a,b) and (7)
respectively.
5,7-Dimethoxy-2,2-diphenyl-3-(diphenyl,hydroxy)
Methyl Coumarin (8)
To a solution of 3-carbethoxy-5,7-dimethoxycoumarin (2) (0.2 g,
0.001 mol) in dry THF (100 ml) phenylmagnesium bromide (0.008 mol in

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687
30 ml dry ether) was added dropwise with stirring. After complete addition
the reaction mixture was refluxed for 24 h. After cooling the reaction mix-
ture was extracted with saturated solution of ammonium chloride
(2 Â 30 ml) and then water (2 Â 30 ml). The ethereal layer was separated
and dried over anhydrous sodium sulphate. Ether was then evaporated
and the solid product obtained was crystallized to give (8).
3-Carboxamide-5,7-dimethoxycoumarin (9a)
In dry RB flask, a mixture of carbethoxycoumarin (2) (1.4 g,
ꢀ
0.005mol) and ammonium acetate (5g, 0.06 mol) was heated at 160 C for
4 h. The reaction mixture was then cooled and the solid product was filtered,
washed with water (2 Â 30 ml), dried, and finally crystallized from appro-
priate solvent to give (9a).
3-(N-p-Tolyl)carboxamide-5,7-dimethoxycoumarin (9b)
A
mixture of carbethoxycoumarin (2) (1.4 g, 0.005mol) and
p-toluidine (1.10 g, 0.01 mol) in absolute ethanol (40 ml) was boiled under
reflux for 5h. The crystalline product was filtered and crystallized from the
appropriate solvent to give (9b).
2-Hydroxy-4,6-dimethoxybenzalazine (10) and/or
5,7-Dimethoxycoumarin-3-phenylhydrazide (9c)
A mixture of carbethoxycoumarin (2) (1.4 g, 0.005mol) and hydrazine
hydrate or phenyl hydrazine (0.01 mol) in absolute ethanol (40 ml) was
boiled under reflux for 5h, then the reaction mixture was left to cool. The
crystalline product formed on cooling was filtered and crystallized to give
(10) and (9c) respectively.
5,7-Dimethoxy-3-carbomethoxycoumarin (11a)
A mixture of dimethoxycoumarin (2) (1.40 g, 0.005mol) in sodium
methoxide solution (0.5g, 0.12 mol, in 30 ml methanol) was boiled under
reflux for 4 h to precipitate a yellow crystals after cooling. The product was
filtered and crystallized from appropriate solvent to give (11a).

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HASSAN ET AL.
Synthesis of 5,7-Dimethoxycoumarin (11c)
A mixture of dimethoxycoumarin (2) (1.40 g, 0.005mol) and sodium
hydroxide (0.5g, 0.13 mol) was heated at 160 ꢀC for 4 h. The reaction mix-
ture was cooled, acidified with dilute hydrochloric acid (10%). The solid
separated was filtered, washed with water (2 Â 30 ml), dried and crystallized
from appropriate solvent to give (11c).
REFERENCES
1. Shiba, S.A.; Harb, N.; Hassan, M.A.; El-Kasaby, M.A.; Abou-El-Regal,
M. Egypt. J. Chem. 1996, 39, 83.
2. El-Kasaby, M.A.; Hassan, M.A.; Shiba, S.A.; Abou-El-Regal, M.
Indian. J. Chem. 1991, 30B, 662.
3. Ibid 1990, 29B, 928.
4. Herber, D.; Berghas, T. J. Heterocyclic Chem. 1994, 31, 1353.
5. Ivanov, I.C.; Raev, L.D. Arch. Pharm. 1995, 53, 328.
6. March, J. Advanced Organic Chemistry, 3rd Ed.; Wiley Interscience:
New York, 1985; p. 351.
7. Walf; Westphal. Ann. 1962, 39, 657.
Received in the UK September 19, 2000

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