Synthesis and antimicrobial activity of some new coumarin and dicoumarol derivatives

Article abstract of DOI:10.1002/jhet.3873

PTC reaction of coumarin derivative 1 with alkyl halides afforded C₄ oxygen alkylation products 2a-d in appreciative yield, whereas with phenyl isothiocyanate gives the C₃ addition product 4; also, one-pot three-component PTC reactio

Full text of DOI:10.1002/jhet.3873

Received: 6 November 2019
DOI: 10.1002/jhet.3873
Revised: 8 December 2019
Accepted: 10 December 2019
A R T I C L E
Synthesis and antimicrobial activity of some new coumarin
and dicoumarol derivatives
Mohsen K.A. Regal1 | Safa S. Shaban1
| Souad A. El-Metwally2
1Chemistry Department, Faculty of
Abstract
Science, Ain Shams University, Cairo,
Egypt
PTC reaction of coumarin derivative 1 with alkyl halides afforded C4 oxygen
alkylation products 2a-d in appreciative yield, whereas with phenyl isothiocya-
nate gives the C3 addition product 4; also, one-pot three-component PTC reac-
tion was investigated. Treatment of coumarin 1 with aromatic aldehydes in
different molar ratios gives 3-arylidene derivatives 7a,b and the dicoumarol
derivatives 8a,b. Pyrano chromene 9 and pyrano pyridine 10 were obtained by
reaction of arylidene 7a with ethyl acetoacetate through Michael cycloaddition
reaction. The stability of pyrone ring in 3-arylidene 7 and dicoumarol 8 towards
different nucleophilic reagents under reflux and/or fusion conditions has been
studied by the action of hydrazine hydrate, ammonium acetate, methyl amine,
and p-toluidine afforded compounds 11 and 13a-c. The antimicrobial activity
of some synthesized compounds has been investigated.
2Basic Science Department, Higher
Technological Institute, 10th of Ramadan
City, Egypt
Correspondence
Safa S. Shaban, Chemistry Department,
Faculty of Science, Ain Shams University,
Cairo 11566, Egypt.
Email: safashaban@ymail.com
1 | INTRODUCTION
combined with low side effects and little toxicity.[20]
Dicoumarol was brought to light as a naturally occurring
Coumarins (1,2-benzopyrones) are worthy scaffold
among heterocyclic compounds; many coumarins
have been synthesized and also are present in nature
(exist in therapeutic plants, flavors, and vegetables).
Over the past decades, coumarin-linked and fused
heterocyclic derivatives have attracted strong scien-
tific interest arising from their broad spectrum of
pharmacological and biochemical activities, acting as
antidepressants,[1] antimicrobials,[2] anti-oxidants,[3]
anti-inflammatories,[4] antinociceptives,[5] anti-tumor
agents,[6] antiasthmatics,[7] antiviral (including anti-
HIV),[8] and anti-coagulants.[9] 4-Hydroxycoumarins
(Figure 1) have gained a lot of attention due to their
important pharmacological features, including
analgesic,[10] anti-arthritis,[11] anti-inflammatory,[12] anti-
pyretic,[13] anti-bacterial,[14] anti-viral,[15] and antican-
cer.[16] 4-Hydroxycoumarin and its derivatives have been
effectively and efficiently utilized as anticoagulants for
the treatment of thrombophlebitis[17] and pulmonary
embolism[18] and treatment of limited and specific car-
diac cases[19] and have shown good anticoagulant activity
anticoagulant.[21] Different dicoumarol derivatives also
show antimicrobial and antioxidant activity.[22]
2 | RESULTS AND DISCUSSION
In continuation to our previous studies on the synthesis
and reactivity of coumarin and their derivatives,[23–26] the
present work is aimed to synthesize new coumarins and
dicoumarol derivatives and to study their antimicrobial
activity. Reaction of coumarin 1 with primary alkyl
halides such as allyl chloride, benzyl chloride, p-nitro
benzyl chloride, and/or ethyl chloro acetate under phase
transfer catalysis conditions, using potassium carbonate
as base and tetra butyl ammonium chloride as catalyst,
results in oxygen alkylation through nucleophilic dis-
placement to give 2a-d in appreciative yield and smaller
amount of C3 alkylation product 3 in case of benzyl chlo-
ride (Scheme 1). The success of O-alkylation over C3
alkylation may be explained by using primary alkyl
halides (sp3 C-X) through nucleophilic displacement
J Heterocycl Chem. 2020;1–11.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals, Inc.
1

2
REGAL ET AL.
FIGURE 1 Structure of
4-hydroxycoumarin and coumarin
derivatives have antimicrobial activity
SCHEME 1 PTC reaction of coumarin derivative 1 with alkyl halides, phenyl isothiocyanate, and CS2
reactions, whereas C3-alkylation reaction of coumarin
1 with compounds containing multiple bonds (sp2 and/or
sp) through addition reactions. The structure of com-
pounds 2a-d was evidenced by studying their spectral
data. Their IR spectra showed absorption bands for C=O
lactone as well as C=O for ester in case of compound 2d
and devoid of any absorption for OH and/or ketonic car-
bonyl groups. The appearance of a singlet signal for the
olefinic protons at C3– as well as signals of O-CH2 and
absence of any exchangeable singlet signal in the down
field region corresponding to OH proton in their 1HNMR
spectra is a good evidence for O-alkylation rather than

REGAL ET AL.
3
C-alkylation. The structure of compound 3 was proved by
CH=, in addition to signals at 5.94 ppm for CH2O2 and
3.69 for OCH3 in case of 7a and 7b, respectively. Its mass
spectrum also showed a parent peak at m/z 308 (85%) of
[M]+ and 307 (100%) for [M-1]+. The structure of both
8a and 8b was confirmed by the presence of a band at
3400 cm−1 corresponding to enolic –OH and carbonyl
absorption bands at 1670 and 1680 cm−1, respectively.
The 1HNMR spectra of both two compounds showed
signals corresponding to double number of protons for
CH3 at 2.44 ppm relative to CH2O2 at 5.96 ppm
corresponding to 8a while in 8b showed singlet signal
for CH3 and OCH3 protons at δ 2.45 3.79 ppm. Further
evidence was gained from their mass spectra that rev-
ealed molecular ion peaks as well as some of important
peaks.
The arylidene derivative of 7a can be considered as
α,β-unsaturated ketone, which undergoes Michael type of
cycloaddition reactions, when react with ethyl acetoacetate
in the presence of sodium methoxide and/or ammonium
acetate as base catalyst under fusion conditions, to give
the cyclo addition products of pyranochromene 9 and
pyrano pyridone 10, respectively. The pyranochromene
9 was also obtained by one-pot three-component reaction
of coumarin 1 with piperonal and ethyl acetoacetate in the
presence of sodium methoxide as a base catalyst under
fusion condition (Scheme 3).
IR spectrum that established a band for OH group as well
1
as HNMR that revealed an exchangeable singlet signal
for OH proton at δ 13.8 ppm and lack of signal for the
olefinic proton at C3–.
PTC reaction of the coumarin derivative 1 with
phenylisothiocyanate in equimolar amount at room tem-
perature proceed via carbanion C3– addition on the car-
bon nitrogen double bond of the isothiocyanate to give
3-(N-phenyl) thiocarbamido coumarin 4. One-pot three-
component phase transfer catalysis reaction of the cou-
marin derivative 1 with carbon disulfide and different
alkyl halides and/or aroyl halides, to form the
dithioalkylation and/or dithioacylation at C3 of the cou-
marin 1 through ambident anion intermediate 5, using
K2CO3 as base and triethylbenzyl ammonium chloride
(TEBAC) as catalyst failed, this may be attributed to the
high stability of the dithiolate anion 5 and more
crowding around the nucleophilic center (Scheme 1). The
1
IR and HNMR spectral data were in accordance with
the proposed structure of the dithiolate derivative 5
Reaction of coumarin 1 with aromatic aldehydes,
namely, 3,4-methylene dioxybenzaldehyde and/or 4-methoxy
benzaldehyde in equal molar ratio in the presence of piperi-
dine as a base catalyst, afforded the condensation product
3-arylidene-6-methyl-4-oxocomarin (7a,b),[27–30] but when
the reaction is repeated in excess of 4-hydroxy coumarin 1,
the dicoumarol derivatives 8a,b were obtained in high yield.
Also, the dicoumarol 8a[31] was prepared authentically by
the addition of coumarin 1 to 3-arylidine of 7a in the pres-
ence of base as piperidine. (Scheme 2).
The structures of compounds 9 and 10 were substanti-
ated from their spectral data. Their IR spectra exhibited
absorption bands for C=O lactone and ketone as well as
C=O amide in case of compound 10. Further evidence
1
was gained from their HNMR spectra that revealed sig-
The structure of the 3-arylidene 7a,b was proved from
its IR spectrum by the appearance of an absorption bands
at 1685 and 1660 cm−1 for 7a and 1690 and 1650 cm−1 for
7b due to the conjugated carbonyl group of lactone and
ketone, respectively; also, the HNMR spectrum for 7a,b
showed two singlet peak at 6.2 ppm due to two proton of
nals for existence of two methine protons. The appearance
of two exchangeable broad singlet signals in the down field
region at δ 8.4 ppm (N–H) and 12.42 ppm (O–H) with an
equimolar ratio in case of compound 10 is a good evidence
for its existence as a mixture of lactam 10A and lactim
10B tautomers (Scheme 3).
1
SCHEME 2 Reaction of coumarin
derivative 1 with aromatic aldehydes

4
REGAL ET AL.
SCHEME 3 Michael cycloaddition reactions of coumarin derivative 1 with ethyl acetoacetate
SCHEME 4 Reaction of 3-arylidenes 7a,b and/or dicoumarols 8a,b with nitrogen nucleophiles
The reaction of hydrazine hydrate with 3-arylidenes
7a,b and/or dicoumarols 8a,b in boiling ethanol afforded
the corresponding 1,2-dibenzyldene hydrazine derivatives
11a,b beside the starting coumarin 1 instead of the
expected product of pyrazolocoumarin 12 (Scheme 4). A
chemical proof for the suggested structure is gained by

REGAL ET AL.
5
SCHEME 5 The suggested mechanism for the formation of compound 11
preparing an authentic sample through reacting of pipero-
nal and/or p-anisaldehyde with hydrazine hydrate. It was
identical in all respects mp, mmp, and TLC with com-
pounds 11a,b.[32] The mechanistic pathway for the forma-
tion of compound 11 is depicted in Scheme 5. Whereas
treatment of dicoumarol 8b with ammonium acetate,
methyl amine, and/or p-toluidine in boiling ethanol under
reflux condition, it gives the corresponding pyridine deriv-
atives 13a-c, respectively, through cyclocondensation reac-
tion of two carbonyl groups with nitrogen nucleophiles.
above at the same concentration and solvents. DMSO was
used as solvent. The zone of inhibition of bacterial and fun-
gal growth was observed. The % activity index was calcu-
lated using the following formula:
%Activity Index
Zone of inhibition by test compound ðdiameterÞ
=
× 100:
Zone of inhibition by standard ðdiametreÞ
The results showed that most of the compounds (81%)
were active against the most of the screened microorgan-
isms. Only two compounds (7a and 7b) had no activity.
Minimum antimicrobial activities were exhibited by com-
pounds 2c-d whose activity index value did not exceed
40%. Compounds 2a, 2b, 4, 8a, 8b, 9, and 10 showed
promising antibacterial and antifungal activity. The activ-
ity index value ranged between 50% and 87%.
2.1 | Antimicrobial activity
Antimicrobial activity of newly synthesized products has
been evaluated.[33] The results are listed in Table 1.
The selected compounds were tested in vitro for
antibacterial activity against Gram-positive bacteria (Staphy-
lococcus aureus) and Gram-negative bacteria (Escherichia
coli). The antifungal activity of the compounds was tested
against Candida albicans, using disc diffusion method[34] at
1 mg/mL disc concentration. The antibacterial activity of a
common standard antibiotic ampicillin and antifungal
colitrimazole was also recorded using the same procedure as
3 | EXPERIMENTAL
All melting points were recorded on a Gallen Kamp elec-
tric melting point apparatus (Shimadzu, Japan) and

6
REGAL ET AL.
TABLE 1 : Response of diverse microorganisms toward some selected products in in vitro culture
Escherichia coli, mg/mL
Staphylococcus aureus, mg/mL
Candida albicans, mg/mL
Diameter of
Inhibition
No. Compound Zone, mm
%
Diameter of
Inhibition
Zone, mm
%
Diameter of
Inhibition
Zone, mm
%
Activity
Index
Activity
Index
Activity
Index
1
2a
2b
2c
2d
4
14
14
9
56
12
50
14
54
2
56
12
50
15
58
3
36
10
42
9
35
4
8
32
ND
20
—
83
ND
22
—
85
5
21
ND
ND
18
19
22
22
18
25
ND
84
6
7a
7b
8a
8b
9
—-
—-
72
ND
ND
19
—
—
79
ND
ND
14
—
—
54
7
8
9
76
20
83
16
62
10
11
12
88
20
83
22
85
10
13a
88
19
79
21
81
72
18
75
16
62
Ampicillin
100
——
24
100
——
ND
26
——
100
Colitrimazole
ND
Abbreviation: ND, not detected.
uncorrected. All the infrared spectra were recorded on a
PyeUnicamSP-3-300 infrared spectrophotometer (Thermo
Scientific, Nitolet is in waltham,MA02451, USA) using
chloride, and/or ethyl chloro acetate (0.01 mol) in ace-
tone (30 mL), was stirred at room temperature for
3 hours. When the reaction was completed, the organic
layer was separated, the solvent was evaporated, and the
solid products crystallized from the appropriate solvent.
1
potassium bromide disks. H NMR spectra were run at
200 MHz, on a Varian Mercury VX-200 NMR spectropho-
tometer (Billerica, Massachusetts) using TMS as an inter-
nal standard in deuterated dimethyl sulfoxide and
deuterated chloroform. Chemical shifts are quoted in ppm.
The mass spectra were recorded on Shimadzu GCMS-QP-
1000EX mass spectrophotometer at 70eV All the spectral
measurements were carried out at the NMR laboratory of
Faculty of Science, Cairo University, Egypt, at the NMR
laboratory of Faculty of Pharmacy, Ain Shams University,
and Mass laboratory, Al-Azhar University, Egypt. The
micro analytical data were measured in Central Lab of
Faculty of Science, Cairo University, Egypt, and the Minis-
try of Defense Chemical Laboratories, Egypt. All the
chemical reactions were monitored by TLC on silica gel
coated aluminum sheets (Silica Gel 60 F254, Merck).
3.1.1 | 6-Methyl-4(2-propenyloxy)-2H-
chromen-2-one (2a)
Crystallized from benzene as white crystals, Yield: 1.87 g
(87%); m.p.: 106ꢀC. IR (KBr) no absorption bands for
(OH) and (C=O) of ketone, but showed band at 1720 cm−1
1
for (C=O lactone); HNMR (CDCl3) δ (ppm): 2.35 (s, 3H,
CH3), 4.02 (d, J = 6 Hz, 2H, CH2–O), 5.19 (d, J = 6.2 Hz,
1H, =CH), 5.31 (d, J = 13.3 Hz, 1H, =CH), 5.6 (s, 1H, C3–
H), 5.88-5.9 (m, 1H, =CH), 7.05 (d, J = 8.1 Hz, 1H, aro-
matic CH), 7.42 (d, J = 8.2 Hz, 1H, aromatic CH), 7.71 (s,
1H, aromatic CH). Anal for C13H12O3 (216.24). Calcd: C,
72.21; H, 5.59; Found: C, 71.98; H, 5.56.
3.1 | General procedure for the
formation of 4-alkoxy and 3-alkyl-6-methyl
coumarin derivatives 2a-d and 3
3.1.2 | 4-(Benzyloxy)-6-methyl-2H-
chromen-2-one (2b)
A mixture of coumarin 1 (1.76 g; 0.01 mol), anhydrous
potassium carbonate (5 g; 0.16 mol), tetra butyl ammo-
nium chloride (0.5 g; 0.01 mol), and alkyl halides,
namely, allyl chloride, benzyl chloride, p-nitrobenzyl
Crystallized from petroleum ether (60-80) as white crys-
tals, Yield: 2.2 g (83%), m.p.: 150ꢀC. IR (KBr) no absorp-
tion bands for (OH) and (C=O) of ketone, but showed
1
band at 1750 cm−1 for (C=O lactone); HNMR (CDCl3) δ

REGAL ET AL.
7
(ppm): 2.39 (s, 3H, CH3) 5.19 (s, 2H, CH2O), 5.76 (s, 1H,
C3–H), 7.08-7.56 (m, 7H, aromatic CH), 7.70 (s, 1H, aro-
matic CH). Anal for C17H14O3 (266.30). Calcd: C,
76.68; H, 5.30; Found: C, 76.53; H, 5.15.
butyl ammonium chloride (0.5 g; 0.01 mol), and phenyl
isothiocyanate (1.3 g; 0.01 mol) in acetone (30 mL) was
stirred for 24 hours at room temperature. When the reac-
tion being completed, the organic layer was separated,
the solvent was evaporated, and the solid product was
obtained crystallized from petroleum ether (40-60), to
give 4 as yellow crystals, Yield: 0.93 g (30%), m.p.:
174-176ꢀC. IR (KBr) cm−1 showed absorption bands at
3450 cm−1 (OH), 3300 cm−1 (NH), 1640 cm−1 (chelated
C=O). 1HNMR (CDCl3) δ (ppm): 2.42 (s, 3H, CH3),
6.87-7.42 (m, 8H, aromatic CH), 12.40 (br.s, 1H, NH);
14.45 (br.s, 1H, OH); MS showed the parent peak at m/z:
(% abundance) 311(8) [M+]. Anal for C17H13NO3S
(311.36). Calcd: C, 65.58; H, 4.21; N, 4.50; Found:
65.49; H, 4.16; N, 4.43.
3.1.3 | 6-Methyl-4-(4-nitrobenzyloxy)-2H-
chromen-2-one (2c)
Crystallized from benzene/methanol with ratio (1:1) as yel-
low crystals, Yield: 2.64 g (85%), m.p.: 252ꢀC. IR (KBr) no
absorption bands for (OH) and (C=O) of ketone, but showed
band at 1700 cm−1 (C=O lactone); 1HNMR (CDCl3) δ
(ppm): 2.42 (s, 3H, CH3), 5.30 (s, 2H, CH2O), 5.70 (s, 1H,
C3–H), 7.16 (d, J = 8 Hz, 1H, aromatic CH), 7.38 (d,
J = 8.1 Hz, 1H, aromatic CH), 7.64 (d, J = 8.6 Hz, 2H, aro-
matic CH), 7.72 (s, 1H, aromatic CH), 8.31 (d, J = 8.5 Hz,
2H, aromatic CH). Anal for C17H13NO5 (311.26). Calcd: C,
65.59; H, 4.21; N, 4.50; Found: C, 65.51; H, 4.12; N4.45.
3.1.7 | Synthesis of diammonium salt of
dithiolate anion 5
A mixture of coumarin derivative 1 (1.76 g; 0.01 mol),
anhydrous potassium carbonate (5 g; 0.16 mol), benzyl
triethyl ammonium chloride (0.5 g; 0.01 mol), carbon
disulfide (20 mL) in acetone (30 mL), and added differ-
ent aryl halides, namely, benzyl chloride and/or p-nitro
benzyl chloride (0.01 mol), was stirred at room tempera-
ture for 3 hours. The solid layer was separated and
washed by dil. HCl (100 mL, 10%) and then filtered off,
dried, and crystallized from ethanol afforded compound
5 as yellow crystals, Yield: 5.1 g (80%); m.p.: above
350ꢀC. IR (KBr) showed absorption bands at 1690 and
1680 cm−1 (C=O) of lactone and ketone; 1HNMR
(CDCl3) δ (ppm): 0.94-0.96 (m, 6H, 2CH3), 1.21-1.23 (m,
12H, 4CH3), 2.34 (s, 3H, CH3), 2.72 (q,4H, 2CH2-N), 3.42
(q, 8H, 4CH2-N), 4.62 (S, 4H, 2CH2-ph), 7.15-8.4 (m,
13H, aromatic CH). Anal for C37H50N2O3S2 (634.56).
Calcd: C, 69.98; H, 7.93; N, 4.41; Found: C, 70.14; H,
7.81; N, 4.59.
3.1.4 | Ethyl 2-((6-methyl-2-oxo-2H-
chromen-4-yl) oxy) acetate (2d)
Crystallized from diethyl ether as white crystals, Yield:
2.1 g (93%), m.p.: 120ꢀC. IR (KBr) no absorption bands for
(OH) and (C=O) of ketone, but showed bands at 1760,
1720 cm−1 (C=O) lactone and ester, respectively. HNMR
1
(CDCl3) δ (ppm): 1.35 (t, J = 6.9 Hz, 3H, CH2–CH3), 2.35
(s,3H, CH3), 4.30 (q, J = 6.9 Hz, 2H, CH2-CH3), 4.70 (s,
2H, CH2), 5.56 (s, 1H, C3-H), 7.20 (d, J = 8.1 Hz, 1H, aro-
matic CH), 7.67(d, J = 8 Hz, 1H, aromatic CH), 7.80 (s,
1H, aromatic CH). Anal for C14H14O5 (262.08). Calcd: C,
64.12; H, 5.38; Found: C, 63.98; H, 5.28.
3.1.5 | 3-Benzyl-4-hydroxy-6-methyl-2H-
chromen-2-one (3)
Crystallized from ethanol as white crystals, Yield: 0.13 g (5%),
m.p.: 180ꢀC. IR (KBr) showed absorption bands at 3300 cm−1
(OH) and 1715 cm−1 (C=O lactone); 1HNMR (CDCl3) δ
(ppm): 2.42 (s, 3H, CH3), 2.90 (s, 2H, CH2), 7.20-7.56 (m, 8H,
aromatic CH), 13.8 (br.s, 1H, –OH). Anal for C17H14O3
(266.30). Calcd: C, 76.68; H, 5.30; Found: C, 76.64; H, 5.26.
3.2 | General procedure for the reaction
of 4-hydroxy-6-methylcoumarin 1 with
aromatic aldehydes
A mixture of 4-hydroxy coumarin derivative 1 (1.76 g;
0.01 mol) and aromatic aldehydes such as piperonal
and/or p-anisaldehyde (0.01 mol) and piperidine
(0.5 mL) as a base catalyst in ethanol (20 mL) was
refluxed for 1 hour. After completion, the reaction was
left to cool and poured onto crushed ice and then acidi-
fied with dilute HCl solution (10 mL, 10%); the separated
solid was filtered off, washed with water, dried, and crys-
tallized from the appropriate solvent.
3.1.6 | Synthesis of 4-hydroxy-6-methyl-
2-oxo-N-phenyl-2H-chromene-
3-carboxamide (4)
A mixture of the coumarin derivative 1 (1.76 g; 0.01 mol),
anhydrous potassium carbonate (5 g; 0.16 mol), tetra

8
REGAL ET AL.
3.2.1 | 3-(Benzo[d][1,3]dioxol-
5-ylmethylene)-6-methylchroman-
2,4-dione 7a
3.3.1 | 3,4-Methylenedioxy phenyl bis
(4-hydroxy-6-methyl coumarin-3-yl)
methane 8a
Crystallized from methanol as yellow crystals, Yield:
2.93 g (95%); m.p.: 213-215ꢀC. IR (KBr) showed absorp-
tion bands at 1685 and 1660 cm−1 of conjugated (C=O)
lactone and ester, respectively. 1HNMR (DMSO-d6) δ
(ppm): 2.38 (s, 3H, CH3), 5.94 (s, 2H, CH2O2), 6.2 (s,
1H, =CH), 6.68 (d, J = 8.1 Hz, 1H, aromatic CH), 6.89
(s, 1H, aromatic CH), 6.79 (d, J = 8.2 Hz, 1H, aromatic
CH), 7.27 (d, J = 8.1 Hz, 1H, aromatic CH), 7.42 (d,
J = 8.1 Hz, 1H, aromatic CH), 7.71 (s, 1H, aromatic
CH). MS showed the parent peak at m/z: (% abundance)
308 (85%) [M+], and the following fragments 307 (100)
[M+-1], 279 (14), 176 (29), 134 (66). Anal for C18H12O5
(308.29). Calcd: C, 70.13; H, 3.92; Found: C,
69.95; H, 4.07.
Crystallized from diethyl ether as pale yellow crystals,
Yield: 2.76 g (57%); m.p.: 268ꢀC-270ꢀC. IR (KBr) showed
absorption bands at 3400 cm−1 of enolic (OH) and
1
1670 cm−1 (C=O) of lactone. HNMR (CDCl3) δ (ppm):
2.38 (s, 6H, 2CH3), 5.96 (s, 2H, CH2O2), 6.00 (s, 1H,
CH), 6.70 (d, J = 8 Hz, 1H, aromatic CH), 6.76 (s, 1H,
aromatic CH), 6.97 (d, J = 8.2 Hz, 1H, aromatic CH);
7.30 (d, J = 7.8 Hz, 2H, aromatic CH), 7.46 (d,
J = 7.9 Hz, 2H, aromatic CH), 7.8 (s, 2H, aromatic CH),
11.31 (br.s, 2H, 2OH). MS showed the parent peak at m/
z: (% abundance) 484 (12) [M+]. Anal for C28H20O8
(484.21). Calcd: C, 69.40; H, 4.16; Found: C,
69.63; H, 4.34.
3.3.2 | 4-Methoxyphenyl bis(4-hydroxy-
6-methyl coumarin-3-yl) methane 8b
3.2.2 | 3-(4-Methoxybenzylidine)-
6-methyl-2H-chromen-2,4-dione 7b
Crystallized from ethanol as white crystals, Yield: 2.96 g
(63%); m.p.: 256ꢀC-258ꢀC. IR (KBr) cm−1 showed absorp-
tion bands at 3400 cm−1 (OH) enolic and 1680 cm−1
Crystallized from methanol as white crystals, Yield: 1 g
(34%); m.p.: 203ꢀC-206ꢀC. IR (KBr) cm−1 showed absorp-
tion bands at 1690 and 1650 cm−1 (C=O) of conjugated
1
(C=O) of lactone. HNMR (CDCl3) δ (ppm): 2.45 (s, 6H,
1
lactone and ketone, respectively. HNMR (DMSO-d6) δ
2CH3), 3.79 (s, 3H, OCH3), 6.03 (s, 1H, CH), 6.83 (d,
J = 8.4 Hz, 2H, aromatic CH), 7.09 (d, J = 8.3 Hz, 2H,
aromatic CH), 7.29 (d, J = 7.8 Hz, 2H, aromatic CH), 7.43
(d, J = 7.8 Hz, 2H, aromatic CH), 7.83 (s, 2H, aromatic
CH), 11.62 (br.s, 2H, 2 OH enol). MS showed the parent
peak at m/z: (% abundance): 470(3) [M+], and the follow-
ing fragments 293 (100), 263 (74), 176 (22), 134 (56). Anal
for C28H22O7 (470.21). Calcd: C, 71.47; H, 4.72; Found: C,
71.61; H, 4.85.
(ppm): 2.36 (s, 3H, CH3), 3.69 (s, 3H, OCH3), 6.2 (s, 1H,
=CH), 6.71 (d, J = 8.1 Hz, 2H, aromatic CH), 7.10 (d,
J = 8 Hz, 2H, aromatic CH), 7.18 (d, J = 7.9 Hz, 1H, aro-
matic CH), 7.51 (d, J = 8 Hz, 1H, aromatic CH), 7.62 (s,
1H, aromatic CH). MS showed the parent peak at m/z: (%
abundance) 294 (56) [M+] and 293 (75) [M+-1]. Anal for
C18H14O4 (294.31). Calcd: C, 73.46; H, 4.79; Found: C,
73.45; H, 4. 68.
3.3 | General procedure for the
formation of aryl-bis(4-hydroxy-6-methyl
coumarin-3-yl) methane 8a,b
3.3.3 | Reaction of 3-arylidine derivatives
7a,b with coumarin 1: formation of
dicoumarol 8a,b
The mixture of 4-hydroxy coumarin derivative 1 (1.76 g;
0.01 mol) and aromatic aldehydes such as piperonal
and/or p-anisaldehyde (0.005 mol) and piperidine
(0.5 mL) as a base catalyst in ethanol (20 mL) was
refluxed for 3 hours. After completion, the reaction was
left to cool and poured onto crushed ice and then acidi-
fied with a solution of dilute HCl (10 mL, 10%); the
solid product obtained was washed with water and fil-
tered off, dried and crystallized from the appropriate
solvent.
Heating a mixture of 3-arylidene 7a and/or 7b (0.01 mol)
with coumarin 1 (1.76 g; 0.01 mol) and piperidine
(0.5 mL) in ethanol 50 mL under reflux condition for
2 hours. The reaction mixture was allowed to cool and
poured onto crushed ice and then acidified with dilute
HCl solution (10 mL, 10%); the separated solid was fil-
tered off, washed with water, dried, and crystallized from
the appropriate solvent to give the dicoumarol 8a and/or
8b that are identical of m.p., TLC and IR as well as the
products produced in last experiment.

REGAL ET AL.
9
3.3.4 | Synthesis of 3-acetyl-4-(benzo[d]
[1,3]dioxol-5-yl)-9-methyl-3,4-dihydro-
2H,5H-pyrano[3,2-c]chromene-2,5-dione 9
2.40 (s, 3H, CH3-CO), 2.46 (s, 3H, CH3), 6.44 (s, 2H,
CH2O2), 7.29-7.49 (m, 5H, aromatic CH), 7.78 (s, 1H, aro-
matic CH), 8.40 (br.s, 1H, NH), 12.42 (s, 1H, OH enolic).
Anal for C22H15NO6 (389.36). Calcd: C, 67.87; H, 3.88; N,
3.60; Found: C, 67.68; H, 3.76; N, 3.55.
Method A
A mixture of arylidene derivative 7a (1.55 g; 0.005 mol),
ethyl acetoacetate (0.005 mol), and sodium methoxide
(0.53 g; 0.01 mol) was heated under fusion condition at
temperature between 160ꢀC and 170ꢀC for 3 hours,
cooling the reaction mixture, triturated with dil. HCl
solution (100 mL; 10%), and then filtered off, washing
with water (150 mL). The solid obtained was crystallized
from benzene-diethyl ether (2:1) to give the
pyranochromene derivative 9 as yellow crystals; m.p.
196ꢀC-198ꢀC; Yield 0.92 g (47%); IR (KBr) showed
absorption bands at 1740, 1720, and 1690 cm−1
corresponding to (C=O) of two lactones and ketone,
3.4 | General procedure for the
formation of 1,2-diarylidine hydrazine 11a,b
A mixture of the arylidene derivatives 7a,b and/or dicou-
marol derivatives 8a,b (0.01 mol) and hydrazine hydrate
(0.5 mL; 0.01 mol) in ethanol (50 mL) was refluxed for
2 hours, the reaction mixture was allowed to cool, and
the solid product was separated dissolve in NaCO3 solu-
tion (50 mL, 20%); the residue separated, dried, and crys-
tallized from ethanol to give 11a,b, and the filtrate
contains coumarin 1 that acidified with dilute HCl
(10 mL, 10%) was filtered off then crystallized from
ethanol.
1
respectively. HNMR (DMSO-d6) δ (ppm): 2.38 (s, 3H,
CH3-CO), 2.42 (s, 3H, CH3), 3.56 (d, J = 6.2 Hz, 1H, CH),
4.42 (d, J = 6.1 Hz, 1H, CH), 5.97 (s, 2H, CH2O2),
6.72-7.66 (m, 5H, aromatic CH), 7.72 (s, 1H, aromatic
CH). Anal for C22H16O7 (392.36). Calcd: C, 67.35; H, 4.11;
Found: C, 67.27; H, 4.0.
3.4.1 | 1,2-Bis(benzo[d][1,3]dioxol-
5-ylmethylene) hydrazine 11a
Method B
A mixture of 4-hydroxy coumarin derivative 1 (1.76 g;
0.01 mol), piperonal (1.5 g; o.o1mol), ethyl acetoacetate
(1.3 g; 0.01 mol), and sodium methoxide (0.53 g;
0.01 mol) was heated under fusion condition at tempera-
ture between 160ꢀC and 170ꢀC for 3 hours, cooling the
reaction mixture, triturated with dil. HCl solution
(100 mL; 10%) and then filtered off, washing with water
(150 mL). The solid product was crystallized from
benzene-diethyl ether (2:1) to give the pyranochromene
derivative 9 as yellow crystals; Yield 2.14 g (65%).
Crystallized from ethanol as creamy crystals, Yield:
1.27 g (43%); m.p.: 208ꢀC-210ꢀC. IR (KBr) showed absorp-
tion band at 1620 cm−1 (C=N). 1HNMR (DMSO-d6) δ
(ppm): 6.20 (s, 4H, 2CH2O2), 7.25 (d, J = 9.1 Hz, 2H, aro-
matic CH), 7.59 (s, 2H, aromatic CH), 7.54 (d, J = 9.2 Hz,
2H, aromatic CH), 8.69 (s, 2H, 2CH=N). Anal for
C16H12N2O4 (296.08). Calcd: C, 64.86; H, 4.08; N, 9.46;
Found: C, 64.82; H, 4.04; N, 9.44.
3.4.2 | 1, 2-Bis(4-methoxybenzylidene)
hydrazine 11b
3.3.5 | Synthesis of 3-acetyl-4-(benzo[d]
[1,3]dioxol-5-yl)-9-methyl-2H-chromeno
[4,3-b] pyridine-2,5(1H)-dione 10
Crystallized from ethanol as yellow crystals, Yield: 1.66 g
(62%); m.p.: 167ꢀC-168ꢀC. IR (KBr) cm−1 showed absorp-
tion band at 1620 cm−1 (C=N). 1HNMR (DMSO-d6) δ
(ppm): 3.75 (s, 6H, 2OCH3), 7.06 (d, J = 8.9 Hz, 4H, aro-
matic CH), 7.83 (d, J = 9 Hz, 4H, aromatic CH), 8.65 (s,
2H, 2CH=N). Anal for C16H16N2O2 (268.15). Calcd: C,
71.61; H, 6.01; N, 10.45; Found: C, 71.60; H,
5.97; N, 10.41.
A mixture of the arylidene derivative 7a (1.55 g;
0.005 mol), ethyl acetoacetate (0.005 mol), and ammo-
nium acetate (5.0 g; 0.065 mol) is heated at temperature
between 160ꢀC and 170ꢀC for 3 hours under fusion con-
dition. The reaction mixture was cooled, triturated with
HCl solution (10%, 100 mL) and then filtered off, washed
with water (150 mL); the solid product obtained was
dried and crystallized from methanol to give pyridine
derivative 10 as yellow crystals. Yield: 0.72 g (37%), m.
p. 308ꢀC. IR (KBr) showed absorption bands at
3100 cm−1 (NH), 1760 cm−1 (C=O lactone), and
3.5 | General procedure for the
formation of pyridine derivatives 13a-c
A mixture of dicoumarol 8b (1.39 g; 0.003 mol) and
ammonium acetate, methyl amine, and/or p-toluidine
1
1650 cm−1 (C=O amide). HNMR (DMSO-d6) δ (ppm):

10
REGAL ET AL.
(0.01 mol) in ethanol (50 mL) was refluxed for 3 hours.
After the reaction being completed, it was left to cool and
poured onto crushed ice and then acidified with dilute
HCl solution (10 mL, 10%); the solid product obtained
was filtered off, washed with water, dried, and crystal-
lized from the appropriate solvent to give pyridine deriva-
tives 13a-c.
δ (ppm): 2.32 (s, 6H, 2CH3), 2.41 (s, 3H, CH3), 3.69 (s,
3H, OCH3), 6.21 (s, 1H, CH), 6.72 (d, J = 8.1 Hz, 2H, aro-
matic CH), 6.97 (d, J = 8.1 Hz, 2H, aromatic CH),
7.14-7.38 (m, 8H, aromatic CH), 7.62 (s, 2H, aromatic
CH). Anal for C35H27NO5 (541.60). Calcd: C, 77.62; H,
5.03; N, 2.59. Found: C, 77.58; H, 5.00; N, 2.66.
4 | CONCLUSION
3.5.1 | 7-(4-Methoxyphenyl)-
2,12-dimethyl-7,14-dihydro-6H,8H-
dichromeno[4,3-b:30,40-e]pyridine-
6,8-dione 13a
6-Methyl-4-hydroxy coumarin undergoes O-alkylation
easily at room temperature under PTC conditions; also, it
can form the 3-arylidene derivatives by treatment with
aromatic aldehydes in similar molar ratios, whereas in
excess of coumarin, the dicoumarol is well formed.
Pyrano coumarin can be obtained either by Michael
cycloaddition and/or one-pot reaction of coumarin with
aldehyde and ethyl acetoacetate. The arylidine group is
easily decomposed by reaction of 3-arylidine and/or
dicoumarol with hydrazine hydrate to give the
corresponding diarylidene hydrazine. Also, treatment of
dicoumarol with different amines gives pyridine deriva-
tives. Most of the synthesized compounds (81%) showed
promising antibacterial and antifungal activity.
Crystallized from ethanol as white crystals, Yield: 1.22 g
(90%); m.p.: 288ꢀC-289ꢀC. IR (KBr) cm−1 showed absorp-
tion bands at 3280 cm−1 (NH) and 1685 cm−1 (C=O) of
lactone. 1HNMR (DMSO-d6) δ (ppm): 2.34 (s, 6H, 2 CH3),
3.69 (s, 3H, OCH3), 6.17 (s, 1H, CH), 6.84 (d, J = 8.1 Hz,
2H, aromatic CH), 7.02 (d, J = 8.1 Hz, 2H, aromatic CH),
7.21-7.43 (m, 4H, aromatic CH), 7.81 (s, 2H, aromatic
CH), 17.83 (s, 1H, NH). Anal for C28H21NO5 (451.48).
Calcd: C, 74.49; H, 4.69; N, 3.10. Found: C, 74.57; H,
4.61; N, 3.18.
ORCID
3.5.2 | 7-(4-Methoxyphenyl)-
2,12,14-trimethyl-7,14-dihydro-6H,8H-
dichromeno[4,3-b:30,40-e]pyridine-
6,8-dione 13b
Safa S. Shaban https://orcid.org/0000-0002-9327-3467
Souad A. El-Metwally https://orcid.org/0000-0002-
3040-9283
REFERENCES AND NOTES
Crystallized from ethanol as white crystals, Yield: 1.32 g
(95%); m.p.: 228ꢀC-230ꢀC. IR (KBr) showed absorption
band 1690 cm−1 (C=O) of lactone and absent of bands
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How to cite this article: Regal MKA, Shaban SS,
El-Metwally SA. Synthesis and antimicrobial
activity of some new coumarin and dicoumarol
derivatives. J Heterocycl Chem. 2020;1–11. https://
doi.org/10.1002/jhet.3873