Synthesis, characterization, and biological activities of new benzofuran derivatives

Article abstract of DOI:10.3987/com-07-11052

A number of new benzofuran derivatives, ethyl 3-[(alkylamino)methyl]-6-methoxy-1-benzofuran-2-carboxylates (5a-i), were obtained via the reaction between ethyl 3-(bromomethyl)-6-methoxy-1-benzofuran-2-carboxylate (3) and amines or amino acid ethyl esters. In addition, 1,4-bis[(ethyl 6-methoxy-1-benzofuran-3-yl-2-carboxylate)methyl]piperazine (9), N,N′-diethyl-N,N′-bis[(6-methoxy-1-benzofuran-3-yl-2-carboxy late)methyl]but-2-ene-1,4-diamine (10) and 1,2-bis[(ethyl 6-methoxy-1-benzofuran-3-yl-2-carboxylate)methyl]- 1,2-dimethyl-hydrazine (11) were also obtained from the reaction of 3 with diamines. Their in vitro anti-HIV-1 (strain IIIB) and HIV-2 (strain ROD) activities of the synthesized compounds in human T-lymphocyte were tested; ethyl 3-bromomethyl-6-methoxycoumarlate displayed an ability to inhibit HIV-1 and HIV-2 replication in cell culture at non-toxic concentrations.

Full text of DOI:10.3987/com-07-11052

HETEROCYCLES, Vol. 71, No. 7, 2007
1577
HETEROCYCLES, Vol. 71, No. 7, 2007, pp. 1577 - 1587. © The Japan Institute of Heterocyclic Chemistry
Received, 12th March, 2007, Accepted, 23rd April, 2007, Published online, 24th April, 2007. COM-07-11052
SYNTHESIS, CHARACTERIZATION, AND BIOLOGICAL ACTIVITIES
OF NEW BENZOFURAN DERIVATIVES
a
b
a
Kifah S. M. Salih, Mikdad T. Ayoub, Haythem A. Saadeh, Najim A. Al-
c
a
Masoudi, and Mohammad S. Mubarak*
a
Chemistry Department, Faculty of Science, University of Jordan, Amman 11942,
Jordan
b
Chemistry Department, Faculty of Sciences, The Hashemite University, Zarqa,
Jordan
c
Fachbereich Chemie, Universität Konstanz, Postfach 5560, D-78457 Konstanz,
Germany (Formerly)
*
E-mail: mmubarak@ju.edu.jo
Abstract- A number of new benzofuran derivatives, ethyl 3-[(alkylamino)methyl]-
-methoxy-1-benzofuran-2-carboxylates (5a-i), were obtained via the reaction
6
between ethyl 3-(bromomethyl)-6-methoxy-1-benzofuran-2-carboxylate (3) and
amines or amino acid ethyl esters. In addition, 1,4-bis[(ethyl 6-methoxy-1-
benzofuran-3-yl-2-carboxylate)methyl]piperazine (9), N,N'-diethyl-N,N'-bis[(6-
methoxy-1-benzofuran-3-yl-2-carboxylate)methyl]but-2-ene-1,4-diamine (10) and
1
,2-bis[(ethyl 6-methoxy-1-benzofuran-3-yl-2-carboxylate)methyl]-1,2-dimethyl-
hydrazine (11) were also obtained from the reaction of 3 with diamines. Their in
vitro anti-HIV-1 (strain III ) and HIV-2 (strain ROD) activities of the synthesized
B
compounds in human T-lymphocyte were tested; ethyl 3-bromomethyl-6-
methoxycoumarlate displayed an ability to inhibit HIV-1 and HIV-2 replication in
cell culture at non-toxic concentrations.
INTRODUCTION
Benzofurans have been found to exist in nature since the late 19th century, and at that time their
1
investigations have revealed many avenues of understanding their properties. Recently, isolation of
benzofuran derivatives was reported along with other natural subunit derivatives, from the roots of
2
3
Leontopodium alpinum and L. leontopodioides and from seeds of styrax officinalis. A wide variety of
4,5
pharmacological properties have been shown to be associated with benzofuran derivatives. New
6
cytotoxic of cyclopenta[b]benzofuran derivatives, exhibited potent cytotoxicity against some cell lines.
7
The insecticidal activity of 2-carboxylbenzofuran and their coumarin precursors were demonstrated. In
continuation of our research on the synthesis of new heterocyclic compounds of pharmacological

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HETEROCYCLES, Vol. 71, No. 7, 2007
8
,9
interest, we report, herein, on the synthesis, characterization, and anti HIV activities of new compounds
containing a benzofuran skeleton combined with amines, amino acid ethyl esters, and diamines.
RESULTS AND DISCUSSION
The starting material, ethyl 6-methoxy-3-methyl-1-benzofuran-2-carboxylate (1) was synthesized through
9
the steps depicted in Scheme 1.
Me
O
Me
O
Br
O
O
O
i
ii
+
Me
OEt
OEt
MeO
OH
MeO
O
MeO
Me
Me
OH
O
iii
iv
v
O
O
MeO
O
MeO
(1)
Scheme 1. Reagents and conditions: (i) H
2
SO
4
, 18 h, 80%; (ii) NBS, DBP, CHCl
3
, reflux 5 h, 91%; (iii)
KOH, EtOH, reflux 2 h; (iv) dil. HCl, 85%; (v) EtBr, K CO , acetone, reflux 12 h, 70%.
2 3
9
Following our previous literature route; bromination of compound 1 by NBS in carbon tetrachloride and
a few milligrams of dibenzoyl peroxide (DBP), as an initiator, afforded two products, ethyl 3-
(
dibromomethyl)-6-methoxy-1-benzofuran-2-carboxylate (2) and ethyl 3-(bromomethyl)-6-methoxy-1-
benzofuran-2-carboxylate (3) in 17% and 57% yield, respectively (Scheme 2). However, when 1 was
9
10
treated with portionwise addition of NBS, and illumination with 100 W bulb, or by refluxing the
mixture of ethyl coumarlate and NBS in CCl for 48 h without using dibenzoyl peroxide (DBP), the two
4
products were obtained in nearly the same percentages.
Br
Br
Br
Me
OEt
OEt
i
OEt
O
MeO
O
O
O
MeO
O
MeO
O
(
1)
(2)
(3)
i) NBS, DBP, CCl4, reflux 10 h, 74 %
(17 %)
(57 %)
4
Scheme 2. Reagents and conditions: (i) NBS, DBP, CCl , reflux 10 h, 74%.
Reaction of 3 with amines and amino acid ethyl ester hydrochlorides (cyclopropylamine (4a), L-alanine
4b), L-leucine (4c), S-proline (4d), pyrrolidine (4e), piperidine (4f), morpholine (4g), thiomorpholine
(

HETEROCYCLES, Vol. 71, No. 7, 2007
1579
(
4h), and N-methylpiperazine (4i)) yielded the corresponding ethyl 3-[(alkylamino)methyl]-6-methoxy-1-
benzofuran-2-carboxylates (5a-i) (Scheme 3). The prepared compounds were separated, purified, and
1
13
their structures were confirmed by means of H NMR, C NMR, mass spectrometry, IR, and elemental
analysis. Moreover, the newly synthesized heterocycles are expected to display some biological activities,
due to the important functional subunits used in the synthesis, which were found in many naturally
1
1
occurring compounds.
R1
Br
N
R2
OEt
O
R1
OEt
DMF
HN
O
R2
MeO
O
O
MeO
(
3)
(4a-f)
(5a-f)
Scheme 3
Table 1. Yields percentages of the reaction of 3 with different amines
Amines
Products
5a
Yield
47 %
51 %
53 %
68 %
72 %
86 %
81 %
87 %
83 %
Substituents
4
a
R
1
R
1
R
1
R
1
R
1
R
1
R
1
R
1
R
1
= H, R
= H, R
= H, R
2
2
2
= CH(CH
= CH(CH
= CH[CH
2
3
2
)
2
)CO
4b
5b
5c
5d
5e
5f
5g
5h
5i
2
Et
4
c
CH(CH ) ]CO Et
3 2 2
4d
, R
, R
, R
, R
, R
, R
2
2
2
2
2
2
2 2 3
= CH(CO Et)(CH )
= (CH
= (CH
= [(CH
= [(CH
= [(CH
4
e
2
)
)
2
2
2
4
4
f
2
5
4
g
)
2 2
] O
4h
)
)
2
]
]
2
S
4
i
2
2
N-CH
3
In case of the primary amines and amino acid ethyl ester hydrochlorides (these were synthesized by a
1
2
standard procedure from amino acids via the acid chloride), the products were obtained in moderate
yield. However, high yields were obtained with secondary amines.
Additionally, some known naturally occurring bis(coumarinyl)ethers were reported to display some
biological activities; daphnoretin for example was found to have antinocoplastic activity and inhibition of
1
3,14
DNA-producing enzymes or proteins and nucleic acid synthesis in vivo.
This has attracted our
9
attention towards the synthesis of dimers of substituted coumarins and the dimeric analogues of
benzofurans. When compound 3 was treated with the diamines, piperazine (6), N,N'-diethylbut-2-ene-1,4-
diamine (7), and 1,2-dimethylhydrazine dihydrochloride (8), 1,4-bis[(ethyl 6-methoxy-1-benzofuran-3-yl-
2
-carboxylate)methyl]piperazine
(9),
N,N'-diethyl-N,N'-bis[(6-methoxy-1-benzofuran-3-yl-2-
carboxylate)methyl]but-2-ene-1,4-diamine (10) and 1,2-bis[(ethyl 6-methoxy-1-benzofuran-3-yl-2-
carboxylate)methyl]-1,2-dimethylhydrazine (11), were produced, respectively (Scheme 4).

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HETEROCYCLES, Vol. 71, No. 7, 2007
O
O
OMe
NH
EtO
Br
N
(9)
HN
(6)
OEt
O
DMF
75%
N
O
MeO
Na CO
2
3
OEt
(3)
OMe
HN(Me)-NH(Me)
O
O
DMF
MeO
2
HCl (8)
5%
Na CO
O
2
3
3
O
MeO
O
O
Et
Et
H
OEt
N-CH -CH=CH-CH -N
2
2
Et
H
(7)
N-CH -CH=CH-CH -N
OEt
2
2
Me
Et
10)
OEt
N
Me
N
60%
(
O
EtO
(11)
O
O
O
OMe
MeO
Scheme 4
1
13
The H-NMR and C-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 mass spectral
+·
data; mass spectra of the prepared compounds showed 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.
In vitro anti-HIV assay
Compounds 3, 5d, 5e, 5f, 5g, 5h, 5i, 9, 10, and 11 were tested for their in vitro anti-HIV-1 (strain IIIB)
1
5
and HIV-2 (strain ROD) activity in human T-lymphocyte (MT-4) cells using the MT-4/MTT assay. The
results are summarized in Table 1. The antiviral activity was compared with that of known and approved
1
6
17
antiviral drugs efavirenz and capravirine. The gp41 subunit of the human immunodeficiency virus
type 1 (HIV-1) envelope glycoprotein plays an important role in HIV-1 entry and serves as an attractive
1
8
target for the development of HIV-1 entry inhibitors. A new class of anti-HIV drugs, triggered by gp120
binding to CD4 and a coreceptor, gp41 undergoes a conformation shift from a native prefusogenic state to
a fusogenic state, in which the N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR)
associate to form a six-helix bundle, representing the fusion-active gp41 core. Any compound that
disrupts the gp41 sixhelix bundle formation may inhibit the gp41-mediated membrane fusion, thereby
1
9
blocking HIV-1 entry into target cells. Our target was the distruption of the gp41 sixhelix bundle

HETEROCYCLES, Vol. 71, No. 7, 2007
1581
formation by the newly synthesized compounds, leading to inhibition of HIV. None of the in vitro tested
compounds 5d, 5e, 5f, 5g, 5h, 5i, 9, 10, and 11 were found to inhibit HIV-replication, at EC50 lower than
17
the CC50 compared to the antiviral agents efavirenz (EFV) and azidothymidine capravirine. However 3
was found to be the only compound in the series to inhibit HIV-1 and HIV-2 replication in cell culture
with EC50 = >6.60 µg/ml at non-toxic concentration, with no selectivity witnessed. Results are displayed
in Table 2.
a
b
Table 2. In vitro anti-HIV-1 and HIV-2 of some new benzofuran derivative
c
d
e
Compound Virus strai
III
ROD
III
ROD
III
ROD
III
ROD
III
ROD
III
ROD
III
ROD
III
ROD
III
ROD
III
ROD
EC50 (µg/ml)
>6.60
CC50 (µg/ml)
6.60 ± 5.59
6.60 ± 5.59
SI
3
B
<1
<1
>6.60
5
d
B
>66.88
>66.88
>63.20
>63.20
>83.38
>83.38
>97.17
>97.17
>73.58
>73.58
>83.15
>83.15
>87.0
66.88 ± 10.49
66.88 ± 10.49
63.20 ± 12.77
63.20 ± 12.77
83.83 ± 7.62
83.83 ± 7.62
97.17 ± 11.12
97.17 ± 11.12
73.58 ± 7.94
73.58 ± 7.94
83.15± 13.70
83.15± 13.70
≥87.0
<1
<1
5
f
B
<1
<1
5
g
B
<1
<1
5
h
B
<1
<1
5
i
B
<1
<1
5
e
B
<1
<1
1
0
B
≤1
>87.0
≥87.0
≤1
9
B
>70.95
>70.95
≥93.70
≥93.70
0.003
70.95± 26.88
70.95± 26.88
≥93.70
<1
<1
1
1
B
≤1
≥93.70
≤1
Efavirenz
III
III
B
B
40
13,333
7,857
Capravirine
0.0014
11
a
b
c
Anti-HIV-1 activity measured with strain III
B
. Anti-HIV-2 activity measured with strain ROD. Compound
concentration required to achieve 50% protection of MT-4 cells from the HIV-1- and 2-induced cytopathogenic
d
e
effect. Compound concentration that reduces the viability of mock-infected MT-4 cells by 50%. SI: Selectivity
index (CC /EC )
50
50

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HETEROCYCLES, Vol. 71, No. 7, 2007
CONCLUSION
The structure activity relationship showed that the substituted benzofuran ring by haloalkyl groups having
more HIV inhibition than the corresponding nitrogen analogues. This result might lead us to optimize the
anti-HIV activity through the modification of our new target molecules by introducing various potent
substituted alkyl halide groups.
EXPERIMENTAL
General consideration
Melting points were measured on an electrothermal melting point apparatus and are uncorrected. The IR
spectra were acquired, as KBr discs, with the aid of a Thermo Nicolet Nexus 670 FT-IR instrument. The
1
13
H-NMR and C-NMR spectra were recorded with a Bruker DPX-300 spectrometers and are reported in
ppm (δ) relative to tetramethylsilane as internal reference and deuterated chloroform as a solvent. EIMS
spectra were obtained using a Finnegan MAT TSQ-70 spectrometer at 70 eV. ESI-MS spectra were
acquired with an AP15000 LC-MS instrument from Applied Biosystems. Elemental analyses were
acquired with the aid of Eurovector Euro EA3000, CHNS-O elemental analyzer. TLC was carried out
using pre-coated silica gel (E. Merck Kiesegel 60 F254 layer thickness 0.25 mm).
Ethyl 6-methoxy-3-methyl-1-benzofuran-2-carboxylate (1)
9
A mixture of of 6-methoxy-3-methylcoumarlic acid (2.06 g, 10.0 mmol), anhyd. K
2
CO
3
(2.07 g, 15.0
mmol) and EtBr (2.5 mL, 30.0 mmol) in dry acetone (100 mL) was refluxed for 12 h. Acetone was
removed under vacuum and the solid product was treated with 100 mL of water to remove the excess of
potassium carbonate and the formed potassium bromide. The product was filtered, washed, and
O
15
O
-1
recrystallized from aqueous EtOH. Yield of 1 = 1.64 g (70%); mp 71-72 C (lit., 74-75 C); IR (cm ):
1
1
7
1
705 (C=O), 1624 (C=C); H-NMR: δ 1.39 (t, 3H, J = 7.0 Hz), 2.50 (s, 3H), 3.81 (s, 3H), 4.39 (q, 2H, J =
1
3
.0 Hz), 6.88 (dd, 1H, J = 2, 9 Hz), 6.97 (d, 1H, J = 2.0 Hz), 7.42 (d, 1H, J = 9.0 Hz); C-NMR: δ 9.5,
4.5, 55.7, 60.9, 95.5, 113.2, 121.4, 122.5, 126.2, 140.3, 155.7, 160.6, 160.7; MS (C13 ), m/z (% rel.
14 4
H O
+·
int.): 234 (M , 100), 190 (100), 147 (26), 118 (23), 88 (34).
Bromination of ethyl 6-methoxy-3-methyl-1-benzofuran-2-carboxylate
A mixture of 1 (2.34 g, 10 mmol), NBS (2.31 g, 13.0 mmol) and dibenzoyl peroxide (DBP) (0.01 g) in
2
0
CCl
4
(75 mL) was refluxed for 12 h. The hot mixture was filtered, concentrated under vacuum and was
Cl /hexane (2:1) as eluent. The earlier fractions afforded
chromatographed on silica gel plates using CH
2
2
ethyl 3-(dibromomethyl)-6-methoxy-1-benzofuran-2-carboxylate (2) as the minor product, while the later
fractions gave ethyl 3-(bromomethyl)-6-methoxy-1-benzofuran-2-carboxylate (3) as the major
product. The products were pure enough to be used in subsequent steps without further purification.

HETEROCYCLES, Vol. 71, No. 7, 2007
1583
Ethyl 3-(dibromomethyl)-6-methoxy-1-benzofuran-2-carboxylate (2)
O
-1
1
Yield of 2 = 0.67 g (17%), mp 132-133 C; IR (cm ): 1703 (C=O), 1590 (C=C); H-NMR: δ 1.23 (s, 1H),
1
8
1
.43 (t, 3H, J = 7.0 Hz), 3.85 (s, 3H), 4.45 (q, 2H, J = 7.0 Hz), 7.04 (dd, 1H, J = 2.0, 9.0 Hz), 7.72 (s, 1H),
1
3
.08 (d, 1H, J = 9.0 Hz); C-NMR: δ 14.4, 28.6, 55.8, 61.9, 95.7, 114.1, 118.9, 123.4, 129.0, 135.4,
+·
+·
+·
56.3, 159.4, 161.2; MS (C13
H12Br
2
O
4
), m/z (% rel. int.): 392 (M , 7), 390 (M , 12), 388 (M , 6), 312
Br : C, 39.83; H, 3.09. Found: C, 40.13; H, 3.37.
(
48), 202 (100). Anal. Calcd for C13
H
12
O
4
2
Ethyl 3-(bromomethyl)-6-methoxy-1-benzofuran-2-carboxylate (3)
O
-1
1
Yield of 3 = 1.78 g (57%), mp 97-98 C; IR (cm ): 1705 (C=O), 1589 (C=C); H-NMR: δ 1.40 (t, 3H, J =
7.0 Hz), 3.80 (s, 3H), 4.42 (q, 2H, J = 7.0 Hz), 4.92 (s, 2H), 6.93 (dd, 1H, J = 2.0, 9.0 Hz), 6.98 (d, 1H, J
1
3
=
2.0 Hz), 7.58 (d, 1H, J = 9.0 Hz); C-NMR: δ 14.4, 20.8, 55.7, 61.5, 95.7, 114.0, 120.0, 121.6, 125.5,
+
·
+·
1
2
40.4, 155.9, 159.6, 161.1; MS (C13
H
13BrO
4
), m/z (% rel. int.): 313 (M , 37), 311 (M , 35), 232 (85),
04 (100), 189 (13). Anal. Calcd for C13
H O Br: C, 49.86; H, 4.18. Found: C, 50.02; H, 3.91.
13 4
Ethyl 3-[(alkylamino)methyl]-6-methoxy-1-benzofuran-2-carboxylates (5a-f), general procedure
2
1
22
By a modified procedure, the appropriate amine or amino acid ethyl ester hydrochloride (4a-i) (1.5
mmol) was added to a stirred solution of 3 (172 mg, 0.55 mmol) in dry DMF (3 mL). After stirring for 30
min, 25 mL of water (25 mL) and of 5% aqueous NaHCO
with Et O (50 mL x 3). The combined organic extract was washed with water (50 mL x 2), dried, and the
solvent was removed under vacuum. The crude product was purified by TLC plates with EtOAc: hexane
1:1.5) as eluent and was recrystallized from hexane-EtOH.
3
(5 mL) were added, followed by extraction
2
(
Presented below are the yields, physical states, and the spectral properties of the different ethyl 3-(N-
aminomethyl)-6-methoxycoumarlates prepared using this method.
Ethyl 3-(cyclopropylaminomethyl)-6-methoxy-1-benzofuran-2-carboxylate (5a)
-1
1
Yield = 75 mg (47%), oily; IR (cm ): 1703 (C=O), 1624 (C=C); H-NMR (CDCl
3
): δ 0.41 (d, 4H, J = 5.0
Hz), 1.42 (t, 3H, J = 7.0 Hz), 2.09 (m, 1H, J = 5.0 Hz), 2.23 (br s, 1H), 3.83 (s, 3H), 4.20 (s, 2H), 4.43 (q,
1
3
2
H, J = 7.0 Hz), 6.92 (dd, 1H, J = 2.0, 9.0 Hz), 7.01 (d, 1H, J = 2.0 Hz), 7.62 (d, 1H, J = 9.0 Hz); C-
NMR (CDCl
60.8; MS (C16
Found: C, 66.39; H, 6.60; N, 4.79.
3
): δ 6.6, 14.5, 30.0, 42.2, 55.7, 61.3, 95.6, 113.7, 121.8, 121.9, 128.8, 140.8, 155.8, 160.2,
+
1
H19NO
4
), m/z: 290 [M+1] . Anal. Calcd for C16
H19NO
4
: C, 66.42; H, 6.62; N, 4.84.
Ethyl N-[(6-methoxy-2-carbethoxy-1-benzofuran-3-yl)methyl]alaninate (5b)
-1
1
Yield = 98 mg (51%), oily; IR (cm ): 1703 (C=O), 1624 (C=C); H-NMR (CDCl ): δ 1.21 (m, 3H), 1.30
3
(d, 3H, J = 7.0 Hz), 1.40 (t, 3H, J = 2 Hz), 2.36 (br s, 1H), 3.38 (q, 1H, J = 7.0 Hz), 3.82 (s, 3H), 4.11 (q,
2H, J = 7.0 Hz), 4.18 (s, 2H), 4.41 (q, 2H, J = 7.0 Hz), 6.91 (dd, 1H, J = 3.0, 9.0 Hz), 6.99 (d, 1H, J = 3.0

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HETEROCYCLES, Vol. 71, No. 7, 2007
1
3
Hz), 7.68 (d, 1H, J = 9.0 Hz); C-NMR (CDCl
3
): δ 14.2, 14.4, 19.1, 41.2, 55.7, 56.2, 60.8, 61.2, 95.6,
13.7, 121.4, 122.2, 127.7, 140.9, 155.9, 160.1, 160.8, 175.3; MS (C18 ), m/z (% rel. int.): 348 [M-
: C, 61.88; H, 6.64; N, 4.01.
1
1
H
23NO
6
+·
] (10), 275 (72), 232 (85), 204 (100), 189 (17). Anal. Calcd for C18
H23NO
6
Found: C, 62.20; H, 6.15; N, 4.32.
Ethyl N-[(6-methoxy-2-carbethoxy-1-benzofuran-3-yl)methyl]leucinate (5c)
-1
1
Yield = 114 mg (53%), oily; IR (cm ): 1705 (C=O), 1615 (C=C); H-NMR (CDCl ): δ 0.78 (d, 3H, J =
3
7
1
6
4
.0 Hz), 0.86 (d, 3H, J = 7.0 Hz), 1.19-1.46 (m, 8H), 1.69 (sept, 1H, J = 7.0 Hz), 2.04 (br s, 1H), 3.2 (t,
H, J = 7.0 Hz), 3.82 (s, 3H), 4.06-4.16 (m, 4H), 4.41 (q, 2H, J = 7.0 Hz), 6.91 (dd, 1H, J = 2.0, 9.0 Hz),
1
3
.99 (d, 1H, J = 2.0 Hz), 7.68 (d, 1H, J = 9.0 Hz); C-NMR (CDCl
3
): δ 14.2, 14.4, 22.1, 22.4, 24.9, 41.6,
2.8, 55.7, 59.5, 60.6, 61.2, 95.5, 113.6, 121.4, 122.4, 127.9, 140.9, 155.9, 160.1, 160.7, 175.8; MS
+·
(
C H NO ), m/z (% rel. int.): 390 [M-1] (5), 317 (100), 232 (53), 204 (86), 189 (11). Anal. Calcd for
1
8
23
6
C
21
H29NO
6
: C, 64.43; H, 7.47; N, 3.58. Found: C, 65.12; H, 7.73; N, 3.18.
Ethyl 1-{[2-(ethoxycarbonyl)-6-methoxy-1-benzofuran-3-yl]methyl}prolinate (5d)
-1
1
Yield = 140 mg (68%), oily; IR (cm ): 1705 (C=O), 1615 (C=C); H-NMR (CDCl
3
): δ 1.23-1.43 (m, 6H),
1
1
2
1
.70-3.33 (m, 7H), 3.83 (s, 3H), 4.15 (q, 2H, J = 7.0 Hz), 4.26 (s, 2H), 4.41 (q, 2H, J = 7.0 Hz), 6.91 (dd,
13
H, J = 2.0, 9.0 Hz), 6.99 (d, 1H, J = 2.0 Hz), 7.95 (d, 1H, J = 9.0 Hz); C-NMR (CDCl
3
): δ 14.3, 14.4,
3.1, 29.5, 47.4, 53.3, 55.7, 60.6, 61.1, 65.3, 95.2, 113.6, 122.0, 123.7, 124.0, 140.7, 155.8, 160.3, 160.7,
+·
74.3; MS (C20
H25NO
6
), m/z (% rel. int.): 375 (M , 5), 301 (100), 232 (45), 204 (74), 189 (13). Anal.
Calcd for C20
H25NO
6
: C, 63.99; H, 6.71; N, 3.73. Found: C, 63.61; H, 6.41; N, 3.41.
Ethyl 6-methoxy-3-(pyrrolidin-1-ylmethyl)-1-benzofuran-2-carboxylate (5e)
-1
1
Yield = 120 mg (72%), oily; IR (cm ): 1703 (C=O), 1590 (C=C); H-NMR: δ 1.40 (t, 3H, J = 7.0 Hz),
1
6
4
.74 (quint, 4H, J = 3.0 Hz), 2.56 (t, 4H, J = 7.0 Hz), 3.82 (s, 3H), 4.12 (s, 2H), 4.40 (q, 2H, J = 7.0 Hz),
13
.88 (dd, 1H, J = 2.0, 9.0 Hz), 6.99 (d, 1H, J = 2.0 Hz), 7.78 (d, 1H, J = 9.0 Hz); C-NMR: δ 14.5, 23.6,
4
9.0, 54.2, 55.7, 61.1, 95.3, 113.5, 122.0, 123.3, 127.4, 140.7, 155.8, 160.3, 160.6; ESI-MS (C17H21NO ),
+
m/z 304 [M+1] . Anal. Calcd for C17
H21NO
4
: C, 67.31; H, 6.98; N, 4.62. Found: C, 67.28; H, 7.05; N,
4
.59.
Ethyl 6-methoxy-3-(piperidin-1-ylmethyl)-1-benzofuran-2-carboxylate (5f)
-1
1
Yield = 150 mg (86%), oily; IR (cm ): 1705 (C=O), 1589 (C=C); H-NMR: δ 1.40 (m, 5H), 1.56 (quint,
4
9
6
H, J = 5.0 Hz), 2.47 (br s, 4H), 3.84 (s, 3H), 4.01 (s, 2H), 4.41 (q, 2H, J = 7.0 Hz), 6.90 (dd, 1H, J = 2.0,
13
.0 Hz), 7.00 (d, 1H, J = 2.0 Hz), 7.90 (d, 1H, J = 9.0 Hz); C-NMR: δ 14.5, 24.1, 26.6, 52.8, 54.6, 55.7,
+
1.1, 95.3, 113.4, 122.0, 123.9, 124.5, 141.0, 155.9, 160.4, 160.6; ESI-MS (C18
H23NO
4
), m/z 318 [M+1] .
Anal. Calcd for C18H23NO
4
: C, 68.12; H, 7.30; N, 4.41. Found: C, 68.10; H, 7.37; N, 4.35.

HETEROCYCLES, Vol. 71, No. 7, 2007
1585
Ethyl 6-methoxy-3-(morpholin-4-ylmethyl)-1-benzofuran-2-carboxylate (5g)
O
-1
1
Yield = 142 mg (81%), mp 106-107 C; IR (cm ): 1692 (C=O), 1589 (C=C); H-NMR: δ 1.41 (t, 3H, J =
7
.0 Hz), 2.50 (t, 4H, J = 5.0 Hz), 3.68 (t, 4H, J = 5.0 Hz), 3.84 (s, 3H), 4.01 (s, 2H), 4.41 (q, 2H, J = 7.0
1
3
Hz), 6.90 (dd, 1H, J = 2.0, 9.0 Hz), 7.00 (d, 1H, J = 2.0 Hz), 7.85 (d, 1H, J = 9.0 Hz); C-NMR: δ 14.5,
5
2.7, 53.8, 55.7, 61.2, 67.1, 95.4, 113.6, 121.7, 123.5, 126.4, 141.1, 155.9, 160.3, 160.7; ESI-MS
+
(
C
17
H21NO
5
), m/z 320 [M+1] . Anal. Calcd for C17
H21NO
5
: C, 63.94; H, 6.63; N, 4.39. Found: C, 63.90;
H, 6.58; N, 4.43.
Ethyl 6-methoxy-3-(piperazin-1-ylmethyl)-1-benzofuran-2-carboxylate (5h)
O
-1
1
Yield = 154 mg (84%), mp 103 C; IR (cm ): 1703 (C=O), 1589 (C=C); H-NMR: δ 1.40 (t, 3H, J = 7.0
Hz), 2.63 (t, 4H, J = 5.0 Hz), 2.76 (t, 4H, J = 5.0 Hz), 3.83 (s, 3H), 4.01 (s, 2H), 4.40 (q, 2H, J = 7.0 Hz),
1
3
6
5
.89 (dd, 1H, J = 2.0, 9.0 Hz), 7.99 (d, 1H, J = 2.0 Hz), 7.82 (d, 1H, J = 9.0 Hz); C-NMR: δ: 14.5, 28.1,
3.2, 55.1, 55.7, 61.2, 95.4, 113.5, 121.7, 123.6, 126.7, 141.1, 155.9, 160.3, 160.7; ESI-MS
+
(
C
17
H21NO
4
S), m/z 336 [M] . Anal. Calcd for C17
H21NO
4
S: C, 60.88; H, 6.31; N, 4.18; S, 9.56. Found: C,
6
1.01; H, 5.98; N, 4.28; S, 9.59.
Ethyl 6-methoxy-3-[(4-methylpiperazin-1-yl)methyl]-1-benzofuran-2-carboxylate (5i)
O
-1
1
Yield = 152 mg (83%), mp 66-67 C; IR (cm ): 1730 (C=O), 1589 (C=C); H-NMR: δ 1.38 (t, 3H, J =
7
.0 Hz), 2.25 (s, 3H), 2.47 (br s, 8H), 3.81 (s, 3H), 3.99 (s, 2H), 4.38 (q, 2H, J = 7.0 Hz), 6.87 (dd, 1H, J
1
3
=
2.0, 9.0 Hz), 6.97 (d, 1H, J = 2.0 Hz), 7.82 (d, 1H, J = 9.0 Hz); C-NMR: δ 14.4, 46.0, 52.3, 53.1, 55.2,
), m/z 333
M+] . Anal. Calcd for C H N O : C, 65.04; H, 7.28; N, 8.43. Found: C, 65.31; H, 7.18; N, 8.81.
5
24 2 4
5.7, 61.1, 95.3, 113.5, 121.8, 123.6, 126.7, 141.0, 155.9, 160.3, 160.6; ESI-MS (C18H N O
+
[
1
8
24
2
4
N,N`-Di[ethyl 6-methoxy-3-coumarlatemethyl]-1,4-diamines (9-11), general procedure
A mixture of 3 (235 mg, 0.75 mmol), K CO (100 mg, 0.90 mmol) and the appropriate diamine:
2
3
piperazine (32 mg), N,N`-diethyl-2-butene-1,4-diamine (53 mg) and N,N`-dimethylhydrazine
dihydrochloride (99 mg) in DMF (5 mL) was stirred at rt and left overnight. Water (40 mL) was added
2
and the product was extracted with Et O (50 mL x 5). The combined organic extracts were washed with
water (50 mL x 2), dried and the solvent was removed under vacuum. The crude was chromatographed on
TLC plates with EtOAc : hexane (2 : 1) as eluent and was then recrystallized from EtOH.
1
,4-Bis[(ethyl 6-methoxy-1-benzofuran-3-yl-2-carboxylate)methyl]piperazine (9)
O
-1
1
Yield = 155 mg (75%), mp 188 C; IR (cm ): 1711 (C=O), 1589 (C=C); H-NMR: δ 1.40 (t, 6H, J = 7.0
Hz), 2.53 (br s, 8H), 3.83 (s, 6H), 4.01 (s, 4H), 4.40 (q, 4H, J = 7.0 Hz), 6.86 (dd, 2H, J = 2.0, 9.0 Hz),
13
6
.99 (d, 2H, J = 2.0 Hz), 7.84 (d, 2H, J = 9.0 Hz); C-NMR: δ 14.5, 52.3, 53.4, 55.7, 61.1, 95.3, 113.5,
+
121.8, 123.7, 126.9, 141.0, 155.9, 160.3, 160.6; MS (C30
H
34
N
2
O
8
), m/z (% rel. int.): 550 [M] (10), 275

1586
HETEROCYCLES, Vol. 71, No. 7, 2007
(
72), 232 (85), 204 (100), 189 (17). Anal. Calcd for C30
5.28; H, 5.93; N, 5.13.
34 2 8
H N O : C, 65.44; H, 6.22; N, 5.09. Found: C,
6
N,N'-Diethyl-N,N'-bis[(6-methoxy-1-benzofuran-3-yl-2-carboxylate)methyl]but-2-ene-1,4-diamine
10)
Yield = 136 mg (60%), mp 90-91 C; IR (cm ): 1705 (C=O), 1589 (C=C); H-NMR: δ 1.01 (t, 6H, J =
(
O
-1
1
7
4
7
1
.0 Hz), 1.39 (t, 6H, J = 7.0 Hz ), 2.49 (q, 4H, J = 7.0 Hz), 3.07 (d, 4H, J = 4.0 Hz), 3.82 (s, 6H), 4.01 (s,
H), 4.38 (q, 4H, J = 7.0 Hz), 5.66 (br s, 2H), 6.84 (dd, 2H, J = 2.0, 9.0 Hz), 6.97 (d, 2H, J = 2.0 Hz),
1
3
.87 (d, 2H, J = 9.0 Hz); C-NMR: δ 11.8, 14.5, 47.6, 47.9, 55.6, 55.7, 61.1, 95.2, 113.2, 121.9, 124.0,
+
28.8, 130.8, 140.8, 155.9, 160.4, 160.6; ESI-MS (C34
H
42
N
2
O
8
), 607 [M+1] . Anal. Calcd for
C H N O : C, 67.31; H, 6.98; N, 4.62. Found: C, 67.69; H, 7.13; N, 4.88.
3
4
42
2
8
1
,2-Bis[(ethyl-6-methoxy-1-benzofuran-3-yl-2-carboxylate)methyl]-1,2-dimethylhydrazine (11)
-1
1
Yield = 155 mg (35%), oily; IR (cm ): 1703 (C=O), 1590 (C=C); H-NMR: δ 1.41 (t, 6H, J = 7.0 Hz),
2
2
1
.43 (s, 6H), 3.83 (s, 6H), 4.21 (s, 4H), 4.40 (q, 4H, J = 7.0 Hz), 6.70 (dd, 2H, J = 2.0, 9.0 Hz), 6.90 (d,
1
3
H, J = 2.0 Hz), 7.27 (d, 2H, J = 9.0 Hz); C-NMR: δ 14.4, 34.0, 48.6, 55.6, 61.0, 95.0, 113.0, 121.8,
+
23.0, 127.9, 140.7, 155.6, 160.3, 160.4; ESI-MS (C28
H
32
N
2
O
8
), m/z 525 [M+1] . Anal. Calcd for
28 32 2 8
C H N O
: C, 64.11; H, 6.15; N, 5.34. Found: C, 63.92; H, 6.22; N, 5.30.
REFERENCES AND NOTES
1
2
. G. D. McCallion, Current Org. Chem., 1999, 3, 67.
. M. J. Dobner, E. P. Ellmerer, S. Schwaiger, O. Batsugkh, S. Narantuya, M. Stütz, and H. Stuppner,
Helv. Chim. Acta, 2003, 86, 733.
3
4
5
. Y. Y. Akgul and H. Anil, Fitoterapia, 2003, 74, 743.
. O. H. Hishmat, N. M. A. EL-Ebrashi, M. R. Shalash, and I. Ismail, Arzneimit. Forsch., 1979, 29, 8.
. J. J. Chambers, D. M. Kurrasch-Orbaugh, M. A. Parker, and D. E. Nichols, J. Med.Chem., 2001, 44,
1
003.
6
7
8
. S.-K. Wang and C.-Y. Duh, Planta Med., 2001, 67, 555.
. L. A. D. Williams, M. J. Anderson, and Y. A. Jackson, Pestic. Sci., 1994, 42, 167.
. K. S. M. Salih, K. H. A. Al-Zghoul, M. S. Mubarak, and M. T. Ayoub, J. Saudi Chem. Soc., 2005, 9,
6
23.
9
1
1
1
. K. H. Al-Zghoul, K. S. M. Salih, M. T. Ayoub, and M. S. Mubarak, Heterocycles, 2005, 65, 2937.
0. Y. A. Jackson and K.-S. C. Marriott, Heterocycles, 2002, 57, 1897.
1. S. Greve and W. Friedrichsen, Progr. Heterocycl. Chem., 1999, 11, 144.
2. H.-J. Federsel, E. Könberg, L. Lilljequist, and B.-M. Swahn, J. Org. Chem., 1990, 55, 2254.

HETEROCYCLES, Vol. 71, No. 7, 2007
1587
1
1
1
3. S. J. Torrance, J. J. Hoffmann, and J. R. Cole, J. Pharm. Soc., 1979, 68, 664.
4. G. A. Cordell, J. Nat. Prod., 1984, 47, 84.
5. R. Pauwels, J. Balzarini, M. Baba, R. Snoeck, D. Schols, P. Herdewijn, J. Desmyter, and E. De Clercq,
J. Viorol. Methods, 1988, 20, 309.
1
6. S. D. Young, S. F. Britcher, L. O. Tran, L. S. Payne, W. C. Lumma, T. A. Lyle, J. R. Huff, P. S.
Anderson, D. B. Olsen, S. S. Carroll, D. J. Pettibone, J. A. Obrien, R. G. Ball, S. K. Balani, J. H. Lin,
I. W. Chen, W. A. Schleif, V. V. Sardana, W. J. Long, V. W. Byrnes, and E. A. Emini, Antimicrob.
Agents CH., 1995, 39, 2602.
1
7. T. Fujiwara, A. Sato, M. El-Farrash, S. Miki, K. Kabe, Y. Isaka, M. Kodama, Y. M. Wu, L. B. Chen,
H. Harada, H. Sugimoto, M. Hatanaka, and Y. Hinuma, Antimicrob. Agents CH., 1998, 42, 1340.
8. M. J. Root and H. K. Steger, Curr. Pharm. Design, 2004, 10, 1805.
1
1
2
9. L. Ni, G. F. Gao and P. Tien, Biochem. Biophys. Res. Commun, 2005, 332, 831.
0. The reaction was followed by TLC and small quantities of NBS (~ 0.1 g) were added if the starting
material was still in the reaction mixture.
2
2
1. J. K. Mishra and G. Panda, Synthesis, 2005, 1881.
2. In case of amino acid ethyl ester hydrochloride, Na
mixture.
2 3
CO (0.22 g, 2.1 mmol) was added to the reaction