A convenient procedure for the synthesis of substituted 4-methylaminocoumarins

Article abstract of DOI:10.3987/COM-05-10472

3-Bromo-7-methoxy-4-methylcoumarin and 3-bromo-4,7-dimethyl-coumarin give a mixture of the corresponding 3-aminocoumarins and 4-aminomethylcoumarins upon the reaction with a number of secondary amines. In addition, the reaction of 7-methoxy- and 7-methyl-4-bromomethylcoumarins with secondary diamines affords the corresponding, N,N-dicoumarinmethyldiamine.

Full text of DOI:10.3987/COM-05-10472

HETEROCYCLES, Vol. 65, No. 12, 2005
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HETEROCYCLES, Vol. 65, No. 12, 2005, pp. 2937 - 2947
Received, 6th June, 2005, Accepted, 13th October, 2005, Published online, 14th October, 2005
A CONVENIENT PROCEDURE FOR THE SYNTHESIS OF
SUBSTITUTED 4-METHYLAMINOCOUMARINS
Khadeejh H. Al-Zghoul,a Kifah S. M. Salih,a Mikdad T. Ayoub,*b and
Mohammad S. Mubarak *a
aChemistry Department, Faculty of Science, University of Jordan, Amman, Jordan
bChemistry Department, Faculty of Sciences and Arts, The Hashemite University,
Zarqa, Jordan
* E-mail: mmubarak@ju.edu.jo , also corresponding author mik@hu.edu.jo
Abstract- 3-Bromo-7-methoxy-4-methylcoumarin and 3-bromo-4,7-dimethyl-
coumarin give a mixture of the corresponding 3-aminocoumarins and 4-
aminomethylcoumarins upon the reaction with a number of secondary amines. In
addition, the reaction of 7-methoxy- and 7-methyl-4-bromomethylcoumarins with
secondary diamines affords the corresponding N,N`-dicoumarinmethyldiamine.
INTRODUCTION
Coumarins and related derivatives have continued to attract attention for their interesting biological
activities. Their anticoagulant and antithrombiotics activities are well known.1 They display antibiotic and
antifungal,2 anti-inflammatory,3 and antiviral activities including human immunodeficiency virus.4 They
have also been used as additives in food and cosmetics,5 and in the preparation of optical brighteners,
dispersed fluorescent, and laser dyes.6
There have been relatively few previous reports concerning the synthesis of aminocoumarins; heating
o-hydroxybenzaldehyde derivatives with glycine in acetic anhydride,7 and nitration of coumarins followed
by reduction8 afforded the corresponding aminocoumarins. Joshi and Usgaonkar9 and Desai and Mehta,10
reported the synthesis of 4-aminomethyl-7-methoxycoumarin by condensation of 4-halomethyl-7-
methoxycoumarin with amines. Kelkar et al,11 reported that the reaction of 3-bromo-4-methylcoumarin
with secondary amines gave 4-aminomethylcoumarin as a major product, and 3-amino-4-methylcoumarin as
a minor product. On the other hand, 3-bromocoumarin reacted with amines to give substituted and
rearranged product of benzofuran-2-carboxamides.12 As part of our ongoing research on coumarin
derivatives,13 we report on the synthesis and spectral properties of a number of 3-amino-4-methylcoumarins
and 4-aminomethyl-coumarins through the amination of 3-bromo-4-methylcoumarins and 4-
bromomethylcoumarins.

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HETEROCYCLES, Vol. 65, No. 12, 2005
RESULTS AND DISCUSSION
Bromination of coumarin derivatives has been achieved using different experimental conditions; Ghiya and
Marathey14 reported that bromination of 7-hydroxy-4-methylcoumarin using Br2 gave the 3-bromo
derivative, but in excess bromine, the 3,6-dibromo- and the 3,8-dibromo derivatives were obtained.15
However, the 3-bromo derivative was obtained when bromine in acetic acid, chloroform, dioxane, and
carbon tetrachloride at room temperature was used.16
The synthesis of 3-bromo-7-methoxy-4-methylcoumarin (IIIa) was achieved by treating 7-methoxy-4-
methylcoumarin (Ia) with NBS in chloroform and few milligrams of dibenzoyl peroxide (DBP). However,
the reaction of Ia with NBS in carbon tetrachloride with stepwise addition of DBP afforded 3-bromo-4-
bromomethyl-7-methoxycoumarin (IIa). Additionally, compound IIIa was obtained, along with 3,6-
dibromo-7-methoxy-4-methylcoumarin (IVa) as a side-product,17 when I was treated with bromine in
glacial acetic acid (Scheme 1).
Br
Scheme 1
Br
i
Me
Me
O
Br
Y
Br
O
Y
Y
O
(II)
O
iii
(III)
Me
Y
O
O
Br
O
(I)
(IV)
ii
a: Y = OMe
i) NBS, DBP, CCl4, 20 h, 40%. ii) NBS, DBP, CHCl3, 5 h, 91%
iii) Br2, AcOH, 2 h
O
(III)
The NBS method, however, failed in the preparation of 4-bromomethylcoumarins as a monobromo
derivative; we based our procedures for preparation of these compounds on a synthesis reported recently.
This method involved bromination of ethyl acetoacetate with bromine to give ethyl 4-bromoacetoacetate in
high yield.18 Cyclization of the later with the desired phenol in the presence of Lewis acid afforded
selectively the corresponding 4-bromomethylcoumarins.19, 20
Reaction of 3-bromo-4-methylcoumarins (III) with secondary amines (V) in dimethylformamide (DMF)
gave the corresponding 3-aminocoumarins (VI) as the minor product and 4-aminomethylcoumarins (VII) as
a major product (Scheme 2). The products were separated and their structures were confirmed by means of
1H- and 13C-NMR spectrometry. In the case of six-membered ring secondary amines, piperidine, morpholine
and thiomorpholine (V1-3), the first spot (with higher Rf value), as shown by TLC analysis, was VI, while
1
the second spot was VII. The H-NMR spectra of compound VI revealed the absence of H-3 and the
presence of methyl protons at C-4, while the presence of H-3, in the range 6.32-6.40 ppm confirms the
identity of VII.
In the case of the five-membered ring secondary amine, pyrrolidine (V4), two products were also obtained;
the first product was the expected VI, while the second was N-pyrrolidinyl-3-methylbenzofuran-2-
carboxamide (VIII) (Scheme 2). The later compound may be formed by nucleophilic addition reaction of

HETEROCYCLES, Vol. 65, No. 12, 2005
2939
less sterically hindered amine, i.e. five membered ring, followed by cyclization of phenolate to give
benzofuran-3-carboxamide (VIII) (Scheme 3)
Scheme 2
R1
N
Me
R1
N
Me
O
R1
N
R2
O
Me
Br
O
R1
DMF
reflux
R2
HN
R2
/ or
/ or
R2
Y
O
Y
O
Y
O
O
Y
O
(III)
(V)1-5
a: Y= OMe, b: Y= Me
(VI)
(VII)
(VIII)
Amine
Products
VII (%)
a (65)
a (80)
b (83)
-
Substituents
V
1
VI (%)
a (19)
a (13)
b (9)
b (23)
b (22)
-
VIII (%)
-
-
-
R1, R2 = (CH2)5
2
3
4
4
5
5
R1, R2 = [(CH2)2]2O
R1, R2 = [(CH2)2]2S
R1, R2 = (CH2)4
R1, R2 = (CH2)4
R1 = benzyl, R2 = 2-pyridyl
R1 = benzyl, R2 = 2-pyridyl
a (9.5)
b (13)
-
a (25)
b (35)
-
-
-
The IR spectra of compounds (VIII) exhibited characteristic bands at ~ 1615 cm-1 due to the C=O stretching
vibration of amide moiety in contrast to that of the coumarin which displays an absorption band in the 1750-
1
1734 cm–1 region. The H-NMR, 13C-NMR, and MS spectra of these compounds are similar to those of
authentic samples prepared through a modified procedure reported by Lele and S. Sethna21 (Scheme 3).
Scheme 3
Me
Me
Br
Me
O
Br
O
N
H
N
- HBr
N
O
Y
O
Y
O
Y
OH
(III)
(VIII)
Me
i
iii
iv
OH
Y
O
ii
(IX)
O
a: Y = OMe; b: Y = Me
i) KOH, EtOH, reflux 2 h, 85%. ii) HCl. iii) SOCl2,. iv) Pyrrolidine, Py, 50%.
Moreover, N-(2-pyridyl)benzylamine (V5), apparently a bulk amine, gave one product, 4-[2-(pyridyl)-
benzylaminomethyl]coumarins (VII5), when reacted with III. These observations may suggest that steric
factors may play a role in this reaction. The formation of these products can be explained by Michael
addition of one mole of the amine, followed by intramolecular nucleophilic attack of the formed tertiary
amine on C-3 to displace the bromide through aziridinium intermediate. The addition of a second molecule
of amine to the intermediate followed by deamination affords compound (VI). The mechanism for the
formation of compound (VII) was not clear, but it may involve 1,2-migration of amino group followed by
dehydrobromination as presented in Scheme 4.

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HETEROCYCLES, Vol. 65, No. 12, 2005
Scheme 4
R1
R1
N
Br
R2
Me
O
Me
Me
N
R2
Br
Br
O
SN2
R1
R2
DMF
HN
Y
O
O
Y
Y
O
O
(III)
+ HN(R1, R2)
1,2-migration
R1
N
R1
Me
R2
R1
R2
N
Br
N
R2
H
O
a: Y = OMe
b: Y = Me
Y
O
O
Y
O
for R1, R2 see Scheme 2
HN(R , R )
- HBr
-
1
2
R1
N
Me
R1
N
R2
O
R2
/ or
Y
O
(VII)
Y
O
O
(VI)
Compound (VII) could also be prepared from the amination of 4-bromomethylcoumarins (X);22, 23
condensastion of coumarin (Xb) with amines (V2,4,6) afforded VII as shown in Scheme 5.
R1
N
Scheme 5
Br
R2
R1
R2
Benzene, Et3N
HN
Y
O
O
Y
O
O
Reflux
(X)
(V)2,4,6
(VII)
VIIb2: 83%
VIIb4: 53%
VIIb6: 71%
V2: R1, R2 = [(CH2)2]2O
V4: R1, R2 = (CH2)4
V6: R1 = H, R2 = piperonyl
a: Y = OMe
b: Y = Me
The antinocoplastic activity and inhibition of DNA-producing enzymes or proteins and nucleic acid
synthesis, in vivo, shown by some known naturally occurring bis(coumarinyl)ethers; darphnoretin,24, 25
attracted our attention towards the synthesis of dimeric compounds. Thus, compounds (XI) and (XII) were
obtained when X was treated with the secondary diamines, piprazine and N,N`-diethyl-2-butene-1,4-diamine,
respectively (Scheme 6).
1H-NMR and 13C-NMR spectra of all prepared compounds are in total agreement with the suggested
structures; DEPT experiments were employed to differentiate secondary and quaternary carbons from
primary and tertiary carbons. Additional support of the proposed structures comes from MS spectrum; MS
spectrum of the prepared compounds show the correct molecular ions, M+·, as suggested by their molecular
formulas. Analyses of the molecular ions and the fragmentation pattern are used in the identification and
characterization of these compounds.

HETEROCYCLES, Vol. 65, No. 12, 2005
2941
O
Scheme 6
NH
Y
O
N
O
HN
N
75%
O
Y
Y
(XI)
Br
O
Benzene
O
Et3N
24 h
reflux
Y
O
O
Et
N
Et
N
(X)
N
H
H
N
Et
Et
a: Y = OMe
b: Y = Me
60%
(XII)
O
Y
O
EXPERIMENTAL
General consideration
Melting points were measured on an electrothermal melting point apparatus and are uncorrected. The IR
spectra were recorded, as KBr discs, on a Thermo Nicolet Nexus 670 FT-IR instrument. The 1H-NMR and
13C-NMR spectra were recorded on a Bruker DPX-300 and Bruker WM-400 spectrometers and are reported
in ppm (δ) relative to tetramethylsilane as internal reference. EIMS spectra were obtained using a Finnegan
MAT TSQ-70 spectrometer at 70 eV. Elemental analyses were acquired with the aid of Eurovector Euro
EA3000, CHNS-O elemental analyzer.
7-Methoxy-4-methylcoumarin (Ia)
This compound was prepared according to literature procedure,13 or by methylation of 7-hydroxy-4-
methylcoumarin by refluxing, with stirring, a mixture of 26.4 g (0.15 mol) of 7-hydroxy-4-methylcoumarin,
28 mL (0.45 mol) of methyl iodide, and 23.9 g (0.225 mol) of anhydrous sodium carbonate in 150 mL of
methanol for 12 h. Methanol was removed under vacuum and the solid product was treated with 300 mL of
water and neutralized with 15% HCl, to remove the excess of sodium carbonate. The product was filtered
and recrystallized from aqueous ethanol. Yield of Ia 95%, mp 159-160 OC (lit.,13 158-159 OC).
4,7-Dimethylcoumarin (Ib)
This compound was prepared according to literature procedure.26
3-Bromo-4-bromomethyl-7-methoxycoumarin (IIa)
A mixture of 1.9 g (10 mmol) of 7-methoxy-4-methylcoumarin (Ia), 3.91 g (22 mmol) of NBS and 30 mg of
dibenzoyl peroxide in carbon tetrachloride (100 mL) was refluxed for 24 h; additional amounts of 30 mg
each of dibenzoyl peroxide were added every 2 h for four times (total amount of the initiator was 150 mg).
The hot mixture was filtered and concentrated under vacuum and the precipitate was recrystallized from
benzene. Yield of IIa 40%; mp 183-184 OC; IR (cm-1): 1705 (C=O), 1615 (C=C); 1H-NMR (CDCl3) δ: 3.86
(s, 3H), 4.66 (s, 2H), 6.85 (d, 1H, J = 2.5 Hz), 6.92 (dd, 1H, J = 2.5, 8.9 Hz), 7.58 (d, 1H, J = 8.9 Hz); 13C-
NMR (DMSO-d6) δ: 28.6, 56.6, 101.4, 110.4, 110.9, 113.5, 127.2, 149.8, 154.1, 157.0, 163.3; MS
(C11H8O3Br2), m/z (% rel. int.): 350 (M+, 27), 348 (M+, 60), 346 (M+, 30), 270 (100), 189 (20),

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HETEROCYCLES, Vol. 65, No. 12, 2005
161 (29); Anal. Calcd for C11H8O3Br2: C, 37.97; H, 2.32; Br, 45.92. Found: C, 37.95; H, 2.30; Br, 45.93.
3-Bromo-7-methoxy-4-methylcoumarin (IIIa)
A mixture of 1.9 g (10 mmol) of 7-methoxy-4-methylcoumarin (Ia), 2.67 g (15 mmol) of NBS and 20 mg of
DBP in 100 mL of CHCl3 was refluxed for 5 h. The chloroform layer was concentrated under vacuum and
the precipitate was stirred with 500 mL of warm water to remove the succinimide, filtered and recrystallized
from aqueous ethanol. Yield of IIIa 91%; mp 148 OC (lit.,17 147); IR (cm-1): 1705 (C=O), 1615 (C=C); 1H-
NMR (CDCl3) δ: 2.38 (s, 3H), 3.95 (s, 3H), 6.75 (d, 1H, J = 2.3 ), 6.88 (dd, 1H, J = 8.5, 2.3), 7.53 (d, 1H, J
13
= 8.5 ); C-NMR (CDCl3) δ: 19.2, 55.8, 99.5, 100.7, 113.0, 113.3, 126.1, 151.1, 153.7, 157.5, 163.1; MS
(C11H9O3Br), m/z (% rel. int.): 270 (M+, 100), 268 (M+, 97), 225 (32), 189 (26).
3-Bromo-4,7-dimethylcoumarin (IIIb)
This compound was prepared according to literature procedure.11
3-Amino- and 4-aminomethylcoumarins (VI-VII), general procedure
A mixture of (2 mmol) of 3-bromo-4-methylcoumarin (IIIa,b), 8 mmol of the appropriate secondary amine
(V1-5) and 5 mL of DMF was refluxed for 0.5-5 h. After cooling, the solution was poured onto 100 mL of
saturated solution of sodium chloride. The precipitate was filtered, dried, and column chromotographed on
silica gel column using ethyl acetate/hexane (1/4) as eluent. The earlier fractions afforded the 3-
aminocoumarins (VIa,b1-4) as the minor product, while the later fractions gave the 4-aminomethylcoumarins
(VIIa,b1-3,5) as the major product. The products were then recrystallized from aqueous ethanol. N-
Pyrrolidinyl-3-methyl-6-(methoxy or methyl)benzofuran-2-carboxamide (VIIIa,b) was isolated from the
reaction of (IIIa,b) with pyrrolidine. Presented below are the yields, melting points, and the spectral
properties of the different 3-amino- and 4-aminomethylcoumarines prepared using this method.
7-Methoxy-4-methyl-3-(N-piperidino)coumarin (VIa1)
Yield 19%, mp 90-91 OC; IR (cm-1): 1705 (C=O), 1615 (C=C); 1H-NMR (CDCl3) δ: 1.54 (br, 2H), 1.63 (br,
4H), 2.44 (s, 3H), 2.99 (br, 4H), 3.82 (s, 3H), 6.75 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 2.4, 8.8 Hz, 1H); 7.44
13
(d, J = 8.8 Hz, 1H); C-NMR (CDCl3) δ: 13.3, 24.0, 26.2, 51.1, 55.6, 100.4, 112.0, 114.6, 126.1, 133.1,
146.0, 153.4, 159.2, 161.4; HRMS exact molar mass calculated for C16H19NO3 (M+) 273.1364, found:
273.1336. Anal. Calcd for C16H19NO3: C, 70.31; H, 7.01; N, 5.12. Found: C, 70.36; H, 7.25; N, 5.29.
7-Methoxy-4-methyl-3-(N-morpholino)coumarin (VIa2)
Yield 13%, mp 170-171 OC; IR (cm-1): 1711 (C=O), 1608 (C=C); 1H-NMR (CDCl3) δ: 2.48 (s, 3H),
3.08 (t, J = 4.6 Hz, 4H), 3.79 (t, J = 4.6 Hz, 4H), 3.84 (s, 3H), 6.76 (d, J = 2.4 Hz, 1H), 6.83 (dd, J = 2.4, 8.8
13
Hz, 1H); 7.47 (d, J = 8.8 Hz, 1H); C-NMR (CDCl3) δ: 13.3, 50.0, 55.7, 67.5, 100.5, 112.2, 114.2, 126.2,
131.4, 147.1, 153.4, 158.9, 161.7; HRMS exact molar mass calculated for C15H17NO4 (M+) 275.1157,
found: 275.1137. Anal. Calcd for C15H17NO4: C, 65.44; H, 6.22; N, 5.09. Found: C, 65.21; H, 6.53; N, 5.22.
7-Methoxy-4-methyl-3-(N-pyrrolidino)coumarin (VIa4)
Yield 23%, mp 90-91 OC; IR (cm-1): 1724 (C=O), 1608 (C=C); 1H-NMR (CDCl3) δ: 1.92 (t, J = 12.0 Hz,

HETEROCYCLES, Vol. 65, No. 12, 2005
2943
4H), 2.41 (s, 3H), 3.10 (br, 4H), 3.82 (s, 3H), 6.76 (d, J = 2.3 Hz, 1H), 6.81 (dd, J = 2.3, 8.7 Hz, 1H), 7.44
13
(d, J = 8.7 Hz, 1H); C-NMR (CDCl3) δ: 13.5, 26.0, 50.6, 55.7, 100.3, 112.0, 114.6, 125.9, 130.1, 147.3,
153.2, 159.0, 161.2; MS (C15H17NO3), m/z (% rel. int.): 259 (M+, 100), 231 (22), 190 (11), 174 (14), 162
(8); Anal. Calcd for C15H17NO3: C, 69.48; H, 6.61; N, 5.40. Found: C, 69.34; H, 6.51; N, 5.62.
4,7-Dimethyl-3-(N-thiomorpholino)coumarin (VIb3)
-1
1
O
Yield 9%, mp 152-154 C; IR (cm ): 1711 (C=O), 1615 (C=C); H-NMR (CDCl3) δ: 2.40 (s, 3H), 2.45 (s,
3H), 2.74 (br, 4H), 3.30 (br, 4H), 7.05 (br, 1H), 7.07 (s, 1H), 7.44 (d, J = 8.5 Hz, 1H); 13C-NMR (CDCl3) δ:
13.5, 21.5, 28.5, 52.3, 116.7, 118.3, 125.0, 125.3, 134.3, 141.5, 146.1, 151.8, 159.3; MS (C15H17NO2S), m/z
(% rel. int.): 275 (M+, 100), 215 (24), 189 (16), 174 (48), 145 (18), 115 (16); Anal. Calcd for C15H17NO2S:
C, 65.43; H, 6.22; N, 5.09; S, 11.64. Found: C, 65.42; H, 6.22; N, 4.77; S, 11.72.
4,7-Dimethyl-3-(N-pyrrolidino)coumarin (VIb4)
Yield 22%, mp 91-93 OC; IR (cm-1): 1724 (C=O), 1608 (C=C); 1H-NMR (CDCl3) δ: 1.93 (quint, J = 3.2 Hz,
4H), 2.38 (s, 3H), 2.41 (s, 3H), 3.14 (t, J = 6.4 Hz, 4H), 7.02 (br, 1H), 7.04 (s, 1H), 7.40 (d, J = 8.6 Hz, 1H);
13C-NMR (CDCl3) δ: 13.6, 21.4, 26.0, 50.9, 116.5, 118.6, 124.7, 125.2, 131.3, 140.8, 146.5, 151.6, 158.8;
MS (C15H17NO2), m/z (% rel. int.): 243 (M+, 100), 215 (55), 174 (37), 145 (13), 115 (15); Anal. Calcd for
C15H17NO2: C, 74.05; H, 7.04; N, 5.76. Found: C, 74.02; H, 7.06; N, 5.78.
7-Methoxy-4-(N-piperidinomethyl)coumarin (VIIa1)
-1
1
O
Yield 65%, mp 114-115 C; IR (cm ): 1724 (C=O), 1608 (C=C); H-NMR (CDCl3) δ: 1.43 (br, 2H), 1.57
(br, 4H), 2.43 (br, 4H), 3.51 (s, 2H), 3.84 (s, 3H), 6.34 (s, 1H), 6.78 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 2.4,
8.8 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H); 13C-NMR (CDCl3) δ: 24.0, 25.9, 54.9, 55.7, 59.9, 100.8, 111.8, 112.1,
112.7, 125.9, 151.8, 155.7, 161.4, 162.5; HRMS exact molar mass calculated for C16H19NO3 (M+) 273.1364,
found: 273.1397; Anal. Calcd for C16H19NO3: C, 70.31; H, 7.01; N, 5.12. Found: C, 70.34; H, 7.33; N, 5.29.
7-Methoxy-4-(N-morpholinomethyl)coumarin(VIIa2)
-1
1
O
Yield 80%, mp 129-131 C; IR (cm ): 1705 (C=O), 1615 (C=C); H-NMR (CDCl3) δ: 2.50 (t, J = 4.5 Hz,
4H), 3.55 (s, 2H), 3.68 (t, J = 4.5 Hz, 4H), 3.83 (s, 3H), 6.32 (s, 1H), 6.77 (d, J = 2.4 Hz, 1H), 6.80 (dd, J =
2.4, 8.8 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H); 13C-NMR (CDCl3) δ: 53.8, 55.7, 59.5, 66.9, 100.9, 112.0, 112.2,
112.4, 125.8, 151.5, 155.7, 161.2, 162.6; HRMS exact molar mass calculated for C15H17NO4 (M+) 275.1157,
found: 275.1179; Anal. Calcd for C15H17NO4: C, 65.44; H, 6.22; N, 5.09. Found: C, 65.21; H, 6.32; N, 5.21.
7-Methoxy-4-[2-(N-pyridyl)-N-benzylaminomethyl]coumarin (VIIa5)
Yield 25%, mp 127-128 OC; IR (cm-1): 1705 (C=O), 1615 (C=C); 1H-NMR (CDCl3) δ: 3.84 (s, 3H), 4.74 (s,
2H), 4.96 (d, J = 0.9 Hz, 2H), 6.08 (s, 1H), 6.79 (d, J = 2.5 Hz, 1H), 6.82 (br, 1H), 7.49 (d, J = 9.2 Hz, 1H),
13
6.49-8.15 (m, 9H); C-NMR (CDCl3) δ: 48.0, 51.6, 55.8, 101.0, 105.9, 109.4, 111.9, 112.4, 113.3, 124.7,
126.7, 127.4, 128.8, 137.3, 137.8, 148.1, 151.9, 155.6, 157.6, 161.5, 162.7; MS (C23H20N2O3), m/z (% rel.
int.): 372 (M+, 34), 330 (30), 253 (43), 239 (7), 183 (100), 149 (14), 105 (10), 91 (80); Anal. Calcd for
C23H20N2O3: C, 74.18; H, 5.41; N, 7.52. Found: C, 74.32; H, 5.56; N, 7.63.

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7-Methyl-4-(N-thiomorpholinomethyl)coumarin (VIIb3)
Yield 83%, mp 136-138 OC; IR (cm-1): 1711 (C=O), 1621 (C=C); 1H-NMR (CDCl3) δ: 2.39 (s, 3H), 2.64 (br,
4H), 2.74 (br, 4H), 3.57 (s, 2H), 6.40 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 7.08 (s, 1H), 7.61 (d, J = 8.0 Hz,
13
1H); C-NMR (CDCl3) δ: 21.6, 28.0, 55.3, 59.5, 113.6, 116.3, 117.2, 124.3, 125.3, 142.9, 151.9, 153.8,
161.2; MS (C15H17NO2S), m/z (% rel. int.): 275 (M+, 65), 214 (15), 186 (18), 174 (100); Anal. Calcd for
C15H17NO2S: C, 65.43; H, 6.22; N, 5.09; S, 11.64. Found: C, 65.46; H, 6.20; N, 4.98; S, 11.71.
7-Methyl-4-[2-(N-pyridyl)-N-benzylaminomethyl]coumarin (VIIb5)
Yield 35%, mp 155-156 OC; IR (cm-1): 1705 (C=O), 1615 (C=C); 1H-NMR (CDCl3) δ: 2.42 (s, 3H), 4.76 (s,
2H), 4.99 (s, 2H), 6.16 (s, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.14 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 6.49-8.15 (m,
13
9H); C-NMR (CDCl3) δ: 21.6, 48.4, 53.2, 101.0, 108.1, 108.6, 112.4, 116.1, 117.3, 121.3, 123.7, 125.3,
133.4, 142.8, 146.8, 147.8, 153.6, 153.8, 161.4; MS (C23H20N2O2), m/z (% rel. int.): 356 (M+, 23), 315 (9),
265 (15), 236 (20), 183 (100)
4-Aminomethylcoumarins (VIIb2,4,6), general procedure
A mixture of 0.51 g (2 mmol) of 4-bromomethyl-7-methylcoumarin (Xb), 5 mmol of the appropriate amine
(V)2,4,6 and 15 mL of dry benzene was refluxed for 4-10 h. The solvent was removed under vacuum and the
residue was washed with water, to remove the ammonium salt, and recrystallized from ethanol.
7-Methyl-4-(N-morpholinomethyl)coumarin (VIIb2)
11
-1
1
O
Yield 87%, mp 138-139 C (lit., 141); IR (cm ): 1711 (C=O), 1621 (C=C); H-NMR (CDCl3) δ: 2.41 (s,
3H), 2.51 (t, J = 4.5 Hz, 4H), 3.58 (s, 2H), 3.70 (t, J = 4.5 Hz, 4H), 6.45 (s, 1H), 7.05 (d, J = 8.0 Hz, 1H),
13
7.11 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H); C-NMR (CDCl3) δ: 21.6, 53.8, 59.2, 66.9, 113.9, 116.3, 117.2,
124.4, 125.3, 142.9, 151.5, 153.9, 161.2; MS (C15H17NO3), m/z (% rel. int.): 259 (M+, 10), 214 (5), 186 (12),
174 (100); Anal. Calcd for C15H17NO3: C, 69.48; H, 6.61; N, 5.40. Found: C, 69.62; H, 6.55; N, 5.34.
7-Methyl-4-(N-pyrrolidinomethyl)coumarin (VIIb4)
-1
1
O
Yield 53%, mp 74-75 C; IR (cm ): 1706 (C=O), 1621 (C=C); H-NMR (CDCl3) δ: 2.41 (s, 3H), 1.81
(quint, J = 3.0 Hz, 4H), 2.61 (t, J = 15.0 Hz, 4H), 3.75 (s, 2H), 6.45 (s, 1H), 7.07 (d, J = 8.0 Hz, 1H), 7.12
13
(s, 1H), 7.67 (d, J = 8.0 Hz, 1H); C-NMR (CDCl3) δ: 21.6, 23.7, 54.5, 56.4, 113.6, 116.4, 117.2, 124.4,
125.3, 142.8, 153.8, 153.9, 161.4; MS (C15H17NO2), m/z (% rel. int.): 243 (M+, 47), 174 (100), 146 (55), 70
(48); Anal. Calcd for C15H17NO2: C, 74.05; H, 7.04; N, 5.76. Found: C, 74.02; H, 7.06; N, 5.79.
7-Methyl-4-(N-piperonylinomethyl)coumarin (VIIb6)
Yield 71%, mp 143-144 OC; IR (cm-1): 3330 (N−H ), 1711 (C=O), 1615 (C=C); 1H-NMR (CDCl3) δ: 2.39 (s,
3H), 3.77 (s, 2H), 3.88 (s, 2H), 5.91-6.83 (m, 3H), 6.49 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 7.09 (s, 1H), 7.46
(d, J = 8.0 Hz, 1H); 13C-NMR (CDCl3) δ: 21.6, 48.4, 53.2, 101.1, 108.1, 108.6, 112.3, 116.1, 117.3, 121.3,
123.7, 125.3, 133.4, 142.8, 146.8, 147.8, 153.6, 153.8, 161.4; MS (C19H17NO4), m/z (% rel. int.): 323 (M+,
27), 149 (37), 135 (100); Anal. Calcd for C19H17NO4: C, 70.58; H, 5.30; N, 4.33. Found: C, 70.28; H, 5.29;
N, 3.91.

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N-Pyrrolidinyl-6-methoxy-3-methylbenzofuran-2-carboxamide (VIIIa4)
Yield 9.5%, mp 126-127 OC; IR (cm-1): 1615 (C=O), 1602 (C=C); 1H-NMR (CDCl3) δ: 1.91 (m, 4H), 2.51 (s,
3H), 3.63 (t, J = 6.5 Hz, 2H), 3.82 (s, 3H), 3.86 (t, J = 6.5 Hz, 2H), 6.88 (dd, J = 2.0, 8.5 Hz, 1H), 6.92 (d, J
= 2.0 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H); 13C-NMR (CDCl3) δ: 9.4, 23.8, 26.6, 46.8, 47.9, 55.7, 95.4, 112.4,
120.9, 122.7, 122.8, 143.8, 154.5, 159.7, 160.3; MS (C15H17NO3), m/z (% rel. int.): 259 (M+, 100), 189 (75);
Anal. Calcd for C15H17NO3: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.80; H, 7.68; N, 5.09.
N-Pyrrolidinyl-3,6-dimethylbenzofuran-2-carboxamide (VIIIb4)
Yield 13%, mp 127-129 OC; IR (cm-1): 1615 (C=O), 1608 (C=C); 1H-NMR (CDCl3) δ: 1.93 (m, 4H), 2.45 (s,
3H), 2.52 (s, 3H), 3.86 (t, J = 6.5 Hz, 2H), 3.90 (t, J = 6.5 Hz, 2H), 7.08 (d, J = 8.0 Hz, 1H), 7.22 (s, 1H),
7.45 (d, J = 8.0 Hz, 1H); 13C-NMR (CDCl3) δ: 9.4, 21.8, 23.8, 26.5, 46.8, 48.0, 111.65, 120.1, 122.4, 124.4,
126.9, 136.9, 144.0, 153.8, 160.2; MS (C15H17NO2), m/z (% rel. int.): 243 (M+, 85), 200 (15), 187 (40); Anal.
Calcd for C15H17NO2: C, 74.05; H, 7.04; N, 5.76. Found: C, 74.02; H, 7.06; N, 5.79.
Coumarlic acids (IXa,b), general procedure
By a modified procedure,21 1 g of 7-substituted 3-bromo-4-methylcoumarin (IIIa,b) was refluxed with 50
mL of 10% ethanolic potassium hydroxide (100 mmol) for 2 h. The product was obtained on acidification of
the diluted solution, filtered, washed with water, and recrystallized from ethanol.
6-Methoxy-3-methylcoumarlic acid (IXa)
21
-1
1
O
Yield 85%, mp 190 C. (lit., 186); IR (cm ): 1672 (C=O), 1615 (C=C); H-NMR (DMSO-d6) δ: 2.43 (s,
3H), 3.77 (s, 3H), 6.90 (d, J = 8.5 Hz, 1H), 7.16 (s, 1H), 7.56 (d, J = 8.5 Hz, 1H), 13.16 (s, 1H); 13C-NMR
(DMSO-d6) δ: 9.6, 56.1, 96.1, 113.5, 122.2, 122.4, 125.4, 140.9, 155.5, 160.7, 161.5; MS (C11H10O4), m/z
(% rel. int.): 206 (M+, 100), 190 (100), 163 (17), 132 (5), 88 (15).
6-Methyl-3-methylcoumarlic acid (IXb)
Yield 87%, mp 218-220 OC. (lit.,27 216-219); IR (cm-1): 1672 (C=O), 1615 (C=C); 1H-NMR (DMSO-d6) δ:
2.38 (s, 3H), 2.43 (s, 3H), 7.09 (d, J = 8.0 Hz, 1H), 7.35 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 13.29 (s, 1H);
13C-NMR (DMSO-d6) δ: 9.6, 21.8, 112.1, 121.3, 124.9, 125.2, 126.7, 138.5, 141.1, 154.4, 161.6; MS
(C11H10O3), m/z (% rel. int.): 190 (M+, 100), 173 (12), 145 (77), 115 (44), 90 (27).
N-Pyrrolidinyl-6-(methoxy or methyl)benzofuran-2-carboxamide (VIIIa,b4), general procedure
To 5 mmol of dried acids (IXa,b), 5 mL (70 mmol) of thionyl chloride was added and the mixture was
heated at gentle reflux for 30 min and excess thionyl chloride was removed under vacuum. To the residual
acid chloride, 5 mL of pyridine followed by 0.85 g (12 mmol) of pyrrolidine was added and the mixture was
stirred at rt for 3 h. The product was precipitated in water, filtered and then recrystallized from aqueous
ethanol. Yields of VIIIa4 and VIIIb4 54% and 48%, respectively.
4-Bromomethyl-7-methoxycoumarin (Xa) and 4-bromomethyl-7-methylcoumarin (Xb)
These compounds were prepared according to literature procedure.20
Di-[4-substitutedcoumarinomethyl]-1,4-diamines (XIa,b and XIIa,b), general procedure

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HETEROCYCLES, Vol. 65, No. 12, 2005
A mixture of 2 mmol of 4-bromomethylcoumarins (Xa,b), 1 mmol with piperazine (86 mg) or with N,N`-
diethyl-2-butene-1,4-diamine (142 mg) and 2 mL (14 mmol) of triethylamine was refluxed in 20 mL of dry
benzene for 24 h. The solvent was removed under vacuum and the residue was washed with water and
recrystallized from ethanol.
1,4-Di-(7-methoxy-4-coumarinmethyl)piperazine (XIa)
Yield 73%, mp 257-260 OC; IR (cm-1): 1717 (C=O), 1615 (C=C); 1H-NMR (CDCl3) δ: 2.56 (s, 8H), 3.58 (s,
4H), 3.48 (s, 6H), 6.35 (s, 2H), 6.80 (dd, J = 2.5, 8.5 Hz, 2H), 6.84 (d, J = 2.5 Hz, 2H), 7.70 (d, J = 8.5 Hz,
13
2H); C-NMR (CDCl3) δ: 53.4, 55.7, 58.9, 100.8, 111.7, 112.3, 112.4, 125.8, 152.1, 155.6, 161.5, 162.6;
MS (C26H26N2O6) m/z (% rel. int.): 462 (M+, 100), 284 (55), 229 (22), 189 (72), 161 (20); Anal. Calcd for
C26H26N2O6: C, 67.52; H, 5.67; N, 6.06. Found: C, 67.68; H, 5.32; N, 6.16.
1,4-Di-(7-methyl-4-coumarinmethyl)piperazine (XIb)
Yield 75%, mp 257-259 OC. IR (cm-1): 1711 (C=O), 1615 (C=C); 1H-NMR (CDCl3) δ: 2.42 (s, 6H), 2.58 (s,
13
8H), 3.61 (s, 4H), 6.47 (s, 2H), 7.07 (d, J = 8.0 Hz, 2H), 7.13 (s, 2H), 7.65 (d, J = 8.0 Hz, 2H); C-NMR
(CDCl3) δ: 21.6, 53.4, 58.6, 113.7, 116.4, 117.2, 124.3, 125.3, 142.9, 151.9, 153.9, 161.4; MS (C26H26N2O4)
m/z (% rel. int.): 430 (M+, 100), 269 (35), 228 (15), 174 (34), 145 (25), 115 (13); Anal. Calcd for
C26H26N2O4: C, 72.54; H, 6.09; N, 6.51. Found: C, 72.38; H, 6.21; N, 6.72.
N,N`-Diethyl-N,N`-di-(7-methoxy-4-coumarinmethyl)-2-butene-1,4-diamine (XIIa)
-1
1
O
Yield 60%, mp 125-127 C; IR (cm ): 1705 (C=O), 1602 (C=C); H-NMR (CDCl3) δ: 1.00 (t, J = 7.0 Hz,
6H), 2.49 (q, J = 7.0 Hz, 4H), 3.09 (d, J = 4.7 Hz, 4H), 3.54 (s, 4H), 3.48 (s, 6H), 5.65 (s, 2H), 6.40 (s, 2H),
6.42 (dd, J = 2.5, 9.5 Hz, 2H), 6.74 (d, J = 2.5 Hz, 2H), 7.56 (d, J = 9.5 Hz, 2H); 13C-NMR (CDCl3) δ: 12.0,
48.4, 54.1, 55.7, 55.9, 100.8, 111.3, 111.9, 112.3, 125.2, 130.8, 154.0, 155.3, 161.7, 162.4; MS
(C30H34N2O6) m/z (% rel. int.): 518 (M+, 7), 328 (94), 284 (100), 231 (25), 189 (96), 161 (21), 140 (59);
Anal. Calcd for C30H34N2O6: C, 69.48; H, 6.61; N, 5.40. Found: C, 69.23; H, 6.57; N, 5.63.
N,N`-Diethyl-N,N`-di-(7-methyl-4-coumarinmethyl)-2-butene-1,4-diamine (XIIb)
-1
1
O
Yield 54%, mp 136-137 C; IR (cm ): 1711 (C=O), 1621 (C=C); H-NMR (CDCl3) δ: 0.98 (t, J = 7.0 Hz,
3H), 2.38 (s, 3H), 2.48 (q, J = 7.0 Hz, 2H), 3.09 (d, J = 4.0 Hz, 2H), 3.65 (s, 2H), 5.65 (s, 1H), 6.49 (s, 1H),
6.95 (d, J = 8.0 Hz, 1H), 7.01 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H); 13C-NMR (CDCl3) δ: 12.0, 21.6, 48.4, 53.8,
55.9, 113.2, 116.2, 117.1, 123.8, 125.2, 130.8, 142.6, 153.6, 153.9, 161.5; MS (C30H34N2O4) m/z (% rel.
int.): 486 (M+, 14), 313 (80), 269 (100), 230 (20), 216 (25), 174 (50), 146 (23), 140 (55); Anal. Calcd for
C30H34N2O4: C, 74.05; H, 7.04; N, 5.76. Found: C, 74.05; H, 7.05; N, 5.75.
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