Efficient synthesis of novel coumarin-3-carboxamides (=2-oxo-2h-1- benzopyran-3-carboxamides) containing lipophilic spacers

Article abstract of DOI:10.1002/hlca.201100238

The novel coumarin-3-carboxamides (=2-oxo-2H-1-benzopyran-3-carboxamides) 5a-5g containing lipophilic spacers were synthesized through the Ugi-four-component reaction (Scheme 1). The reactions of aromatic aldehydes 1, 4,4'-oxybis[benzenamine] or 4,4'-methylenebis[benzenamine] as diamine 2, coumarin-3-carboxylic acid (=2-oxo-2H-benzopyran-3-carboxylic acid; 3), and alkyl isocyanides 4 lead to the desired substituted coumarin-3-carboxamides 5a-5g at room temperature with high bond-forming efficiency. These novel coumarin derivatives exhibit brilliant fluorescence at 544 nm in CHCl ₃. Copyright

Full text of DOI:10.1002/hlca.201100238

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Helvetica Chimica Acta – Vol. 95 (2012)
Efficient Synthesis of Novel Coumarin-3-carboxamides (¼2-Oxo-2H-1-
benzopyran-3-carboxamides) Containing Lipophilic Spacers
by Saeed Balalaie*a), Mohammad Ali Bigdeli*b), Enayatollah Sheikhhosseinib)c), Azizollah Habibib),
Hamed Piri Moghadamd), and Mehrnoush Naderid)
a) Peptide Chemistry Research Center, K. N. Toosi University of Technology, P.O. Box 15875-4416,
Tehran, Iran (fax: þ 98-21-22853650, e-mail: balalaie@kntu.ac.ir)
b) Faculty of Chemistry, Tarbiat Moallem University, No. 49, Mofateh Ave., Tehran, Iran
(e-mail: mabig397@yahoo.com)
c) Faculty of Science, Department of Chemistry, Islamic Azad University, Kerman Branch, Kerman, Iran
d) Department of Chemistry, Sharif University of Technology, Tehran, Iran
Dedicated to Prof. Rolf Gleiter on the occasion of his 75th birthday
The novel coumarin-3-carboxamides (¼2-oxo-2H-1-benzopyran-3-carboxamides) 5a – 5g containing
lipophilic spacers were synthesized through the Ugi-four-component reaction (Scheme 1). The reactions
of aromatic aldehydes 1, 4,4’-oxybis[benzenamine] or 4,4’-methylenebis[benzenamine] as diamine 2,
coumarin-3-carboxylic acid (¼2-oxo-2H-benzopyran-3-carboxylic acid; 3), and alkyl isocyanides 4 lead
to the desired substituted coumarin-3-carboxamides 5a – 5g at room temperature with high bond-forming
efficiency. These novel coumarin derivatives exhibit brilliant fluorescence at 544 nm in CHCl3.
Introduction. – Coumarins (¼2H-1-benzopyran-2-ones), and their analogs have
attracted considerable attention in organic and medicinal chemistry [1]. They have
wide applications in food, pharmaceutical, and optical chemistry [2 – 4]. Natural
coumarins and their synthetic structural analogs show broad biological activities [5],
such as antimicrobial [6], antitumor [7], and antiviral activities [8]. Meanwhile, some
coumarin derivatives could affect human immunodeficiency virus integrase inhibitors
[9]. Some coumarins have inhibitory activity against some serine proteases and matrix
metalloproteases (MMPs) [10], and also act as a selective antiproliferative agent [11 –
14].
It was shown that the existence of the amide group in coumarin-3-carboxamides
(¼2-oxo-2H-1-benzopyran-3-carboxamides) improve the biological activity of these
compounds [15 – 18]. The presence of some nonpolar spacers could affect their ability
to penetrate the bloodꢀbrain barrier [19][20]. These compounds showed anti-
Helicobacter pylori activity and also inhibition of breast cancer growth. Recently,
some novel coumarin-3-carboxamides with effective anticoagulant activity [21] and
also inhibitory activity against human monoamine oxidase (MAO) were synthesized
[22].
In continuation of our research work [23] to design novel one-pot reactions, we wish
herein to report an approach to the synthesis of some new amidated coumarins which
contain a lipophilic moiety and several amide bonds via the Ugi-four-component
reaction (Ugi-4CR). Recently, Che, Yang and co-workers reported sequential Ugi-4CR
ꢀ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 95 (2012)
529
and intramolecular Michael addition with coumarin-3-carboxylic acid to construct
chromeno[3,4-c]pyrrole-3,4-diones (¼ [1]benzopyrans[3,4-c]pyrrol-3,4-diones) [24].
Results and Discussion. – The Ugi-4CR of an aromatic aldehyde 1, 4,4’-oxy-
bis[benzenamine] (2a) or 4,4’-methylenebis[benzenamine] (2b), coumarin-3-carbox-
ylic acid (¼2-oxo-2H-1-benzopyran-3-carboxylic acid; 3), and alkyl isocyanides 4 led to
functionalized bis-coumarins 5a – 5g in good to high yields.
Scheme 1. Synthesis of Coumarin-3-carboxamides 5a – 5g through an Ugi-4CR. See Table for Ar an R.
Coumarin-3-carboxylic acid (3) was obtained from the reaction of salicylaldehyde
(¼2-hydroxybenzaldehyde) and Meldrumꢂs acid (¼2,2-dimethyl-1,3-dioxane-4,6-di-
one) in H2O [25]. Then, treatment of 3, 2,4-dimethoxybenzaldehyde (1b), bis-amine
2b, and cyclohexyl isocyanide (4a, R ¼ Chx) was selected as a model reaction in MeOH
at room temperature. The desired product 5f was isolated in 68% yield (Table, Entry
6). Encouraged by this result, we turned our attention to other substituted
benzaldehydes and bis-amines. Thus, all aromatic aldehydes 1, bis-amines 2, coumar-
in-3-carboxylic acid (3), and alkyl isocyanides 4 in MeOH at room temperature
(Scheme 1) underwent a smooth 2 :1:2 :2 condensation reaction, to give amidated
coumarins 5a – 5g in 68 – 76% yields (Table).
The structures of compounds 5a – 5g were deduced from their spectroscopic data
and high-resolution mass spectra (HR-ESI-MS). The distinguished peak at d(H) 6.10 –
1
6.42 in the H-NMR spectra of the products arose from the ArꢀCHN protons. For
1
instance, the H-NMR spectra of 5d displayed a s at d(H) 6.10, and the NH-protons
resonated at d(H) 7.26. The 13C-NMR spectrum revealed two distinct peaks at d(C)
165.3 and 168.2 for the amide C¼O groups, and the lactone C¼O groups appeared at
d(C) 157.9.
According to the commonly accepted Ugi-4CR mechanism, the amine, the
aldehyde, and the acid are in equilibrium with the iminium carboxylate 6 in the
reaction medium. The addition of the carbenoid C-atom of the isocyanide onto the
iminium group (a) in Scheme 2 followed by the addition of the carboxylate ion onto the

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Helvetica Chimica Acta – Vol. 95 (2012)
Table. Synthesis of Coumarin-3-carboxamides 5a – 5g through an Ugi-4CR of Aldehyde 1, Diamine 2, Acid 3,
and Isocyanide 4a)
Entry
1
1
2
4 (R)b)
Ugi product 5
Yield [%]
70
4a (Chx)
2
4a (Chx)
75
3
4a (Chx)
76
4
4b (tBu)
70

Helvetica Chimica Acta – Vol. 95 (2012)
531
Table (cont.)
Entry
5
1
2
4 (R)b)
4b (tBu)
Ugi product 5
Yield [%]
70
6
4a (Chx)
68
7
4a (Chx)
70
a) In all cases, coumarin-3-carboxylic acid (3) was used. b) Chx ¼ cyclohexyl.
C-atom of the nitrilium ion (b) in Scheme 2 leads to the formation of the primary four-
component adduct 7, which undergoes an intramolecular acylation known as Mumm
rearrangement to give the stable Ugi adduct 5.
Since some coumarin derivatives could be used as fluorophors [26][27], we were
interested in the fluorescence property of the synthesized compounds. The fluorescence
property of our novel coumarin-3-carboxamides 5a, 5e, and 5g were investigated in
CHCl3, MeCN, and DMF. Excitations were carried out with the four different
wavelengths 200, 210, 220, and 230 nm, and the emission was investigated in the range

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Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 2. Proposed Mechanism for the Synthesis of Coumarin-3-carboxamides 5a – 5g through an Ugi-
4CR
300 – 700 nm. In the case of 5a, the maximum emission occurred at the excitation
wavelength 200 nm, and the maximum emissions were observed at 442, 486, and
544 nm, respectively. The fluorescence study of 5a, 5e, and 5g revealed that all three
bis-coumarins possess similar excitation and emission maxima (Fig.).
Conclusion. – We reported an efficient approach for the synthesis of functionalized
bis[coumarin-3-carboxamides] of the type 5. The simplicity of the synthetic protocol
and availability of diverse starting materials make this an attractive strategy for
obtaining functionalized coumarins. The method offers several advantages such as high
yields of products, mild reaction conditions, cleaner reaction profiles, operational
simplicity, and also chemical library. Some of the products had maximum emission at
544 nm.
S. B. would like to thank the Iran National Science Foundation (INSF) for financial support.
Experimental Part
General. Commercially available materials were used without further purification. TLC: silica gel 60
F254 (SiO2; Merck). M.p.: Electrothermal-9100 apparatus; uncorrected. Fluorescence spectra (Fig.):
Photon-Technology-International-MP1 steady-state fluorimeter; at r.t. in NSG Precision Cells Inc.

Helvetica Chimica Acta – Vol. 95 (2012)
533
Figure. Emission spectra of compounds 5a, 5e, and 5g in CHCl3
(Farmingdale, NY) ES (Extrasil) quartz cuvettes (190 – 2000 nm). IR Spectra: ABB-FT-IR FTLA-2000
spectrometer; ˜n in cmꢀ1. 1H- and 13C-NMR Spectra: Bruker spectrometers; at 300 MHz (1H) and 75 MHz
(13C); CDCl3 and (D6)DMSO as solvent; d in ppm rel. to Me4Si as internal standard, J in Hz. HR-MS:
Mass-ESI-POS (Apex-Qe-FT-ICR instrument) spectrometer; in m/z.
Coumarin-3-carboxylic Acid (¼2-Oxo-2H-1-benzopyran-3-carboxylic Acid; 3) [25]. A mixture of
salicylaldehyde (10 mmol, 1.22 g) and Meldrumꢂs acid (12 mmol, 1.73 g) in H2O (20 ml) was heated under
reflux and stirring for 10 h. The mixture was cooled and filtered through a Bꢀchner funnel. Further
purification was achieved by crystallization from MeOH: 3 (1.805 g, 95%).
Chromene-3-carboxamides 5a – 5g: General Procedure. Primary bis-amine 2 (0.5 mmol) was added to
a soln. of aldehyde 1 (1 mmol) in MeOH (5 ml), and the mixture was stirred at r.t. for 1 h. Then, 3
(1 mmol) was added, and stirring was continued for 15 min, followed by addition of alkyl isocyanide 4
(1 mmol). The resulting soln. was stirred at r.t. for 18 – 24 h. After completion of the reaction (TLC
monitoring), the solvent was evaporated, and the product was precipitated by addition of H2O. Further
purification was achieved by CC (SiO2, AcOEt/petroleum ether 1:3).
N,N’-[4,4’-Oxybis(4,1-phenylene)]bis[N-{2-(cyclohexylamino)-1-[4-(1-methylethyl)phenyl]-2-oxo-
ethyl}-2-oxo-2H-1-benzopyran-3-carboxamide] (5a): Yield 741 mg (70%). M.p. 233 – 2378. IR (KBr):
3278, 1719, 1651, 1608. 1H-NMR (300 MHz, (D6)DMSO): 1.07 (d, J ¼ 6.5, 4 Me); 1.07 – 1.78 (m, 10 CH2);
2.75 (m, 2 Me2CH); 3.61 – 3.63 (m, 2 CHNH); 6.11 (br. s, 4 arom. H, 2 CHN); 6.43 (br. s, 2 NH); 6.81 –
7.00 (m, 10 arom. H); 7.27 – 7.34 (m, 4 arom. H); 7.57 – 7.67 (m, 4 arom. H); 7.98 (s, 2 ¼CH); 8.08 (d, J ¼ 7.2,
2 arom. H). 13C NMR (75 MHz, (D6)DMSO): 23.6; 23.8; 24.5; 24.6; 25.2; 32.2; 32.3; 33.0; 48.0; 63.3;
116.1; 117.2; 117.6; 124.9; 125.3; 125.8; 128.9; 129.9; 132.2; 132.4; 132.7; 134.1; 142.0; 148.1; 152.9; 155.1;
157.1; 164.3; 167.9. HR-ESI-MS: 1059.49135 ([M þ H]þ, C66H67N4O9þ ; calc. 1059.49146), 1097.44649
([M þ K]þ, C66H66KN4Oþ9 ; calc. 1097.44653).
N,N’-[4,4’-Oxybis(4,1-phenylene)]bis[N-[2-(cyclohexylamino)-1-(2,4-dimethoxyphenyl)-2-oxoeth-
yl]-2-oxo-2H-1-benzopyran-3-carboxamide] (5b): Yield 821 mg (75%). M.p. 172 – 1748. IR (KBr): 3427,
1721, 1638, 1607. 1H-NMR (300 MHz, CDCl3): 1.14 – 2.04 (m, 10 CH2); 3.70 (s, 2 MeO); 3.71 (s, 2 MeO);
3.91 – 3.93 (m, 2 CHNH); 6.22 – 6.29 (m, 8 arom. H); 6.42 (s, 2 CHN); 6.65 (br. s, 2 NH); 6.94 – 6.97 (d,
J ¼ 8.0, 4 arom. H); 7.19 – 7.27 (m, 6 arom. H); 7.41 (d, J ¼ 7.5, 2 arom. H); 7.51 (t, J ¼ 7.6, 2 arom. H); 7.78
(s, 2 ¼CH). 13C NMR (75 MHz, CDCl3): 24.8; 25.0; 25.5; 32.7; 33.1; 48.8; 55.2; 55.3; 60.0; 97.9; 104.0;
114.7; 116.6; 117.9; 118.0; 124.8; 126.3; 128.4; 131.3; 132.0; 132.5; 134.2; 141.9; 153.6; 155.7; 158.2; 158.5;
161.2; 165.3 168.6. HR-ESI-MS: 1095.43941 ([M þ H]þ, C64H62N4O1þ3 ; calc. 1095.43920), 1117.41916
([M þ Na]þ, C64H61N4NaO1þ3 ; calc. 1117.41900), 1133.39223 ([M þ K]þ, C64H61KN4O1þ3 ; calc. 1133.39205).

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Helvetica Chimica Acta – Vol. 95 (2012)
N,N’-[4,4’-Oxybis(4,1-phenylene)]bis[N-[2-(cyclohexylamino)-2-oxo-1-(3,4,5-trimethoxyphenyl)eth-
yl]-2-oxo-2H-1-benzopyran-3-carboxamide] (5c): Yield 877 mg (76%). M.p. 262 – 2668. IR (KBr): 3293,
1721, 1656, 1607. 1H-NMR (300 MHz, CDCl3): 1.14 – 2.03 (m, 10 CH2); 3.69 (s, 3 MeO); 3.80 (s, 3 MeO);
3.89 – 3.94 (m, 2 CHNH); 6.12 (br. s, 2 CHN); 6.39 – 6.44 (m, 10 arom. H); 7.04 (br. s, 2 NH); 7.20 – 7.28
(m, 6 arom. H); 7.43 (d, J ¼ 7.4, 2 arom. H); 7.52 (t, J ¼ 7.4, 2 arom. H); 7.78 (s, 2 ¼ CH). 13C-NMR
(75 MHz, CDCl3): 24.8; 24.9; 25.4; 32.7; 32.8; 49.0; 56.0; 60.7; 65.9; 107.4; 116.7; 117.8; 118.4; 124.9; 125.7;
128.5; 129.2; 131.6; 132.7; 134.4; 137.9; 142.3; 152.9; 153.6; 155.9; 158.1; 165.4; 167.7. HR-ESI-MS:
1177.44235 ([M þ Na]þ, C66H66N4NaO1þ5 ; calc. 1177.44242), 119346653 ([M þ K]þ, C66H66KN4O1þ5 ; calc
1193.46662).
N,N’-[4,4’-Oxybis(4,1-phenylene)]bis[N-{2-[(1,1-dimethylethyl)amino]-1-[4-(1-methylethyl)phen-
yl]-2-oxoethyl}-2-oxo-2H-1-benzopyran-3-carboxamide] (5d): Yield 705 mg (70%). M.p. 175 – 1788. IR
(KBr): 3346, 1728, 1652, 1606. 1H-NMR (300 MHz, CDCl3): 1.10 (d, J ¼ 6.8, 4 Me); 1.14 (s, 2 tBu); 2.80
(m, 2 (Me)2CH); 6.10 (s, 2 CHN); 6.19 (br. s, 2 NH); 6.34 (d, J ¼ 8.3, 4 arom. H); 7.01 – 7.14 (m, 12 arom.
H); 7.18 – 7.24 (m, 4 arom. H); 7.39 (d, J ¼ 7.2, 2 arom. H); 7.50 (t, J ¼ 7.3, 2 arom. H); 7.26 (s, 2 ¼CH).
13C-NMR (75 MHz, CDCl3): 23.8; 28.6; 33.7; 51.8; 65.9; 116.6; 117.9; 118.2; 124.8; 125.8; 126.3; 128.3;
130.3; 131.2; 131.4; 132.5; 134.3; 142.0; 149.1; 153.6; 155.7; 157.9; 165.3; 168.2. HR-ESI-MS: 1007.46022
([M þ H]þ, C62H63N4Oþ9 ; calc. 1007.46033), 1029.44189 ([M þ Na]þ, C62H62N4NaOþ9 ; calc. 1029.44199),
1045.45771([M þ K]þ, C62H62KN4Oþ9 ; calc. 1045.45860).
N,N’-[4,4’-Oxybis(4,1-phenylene)]bis[1-[2,4-dimethoxyphenyl]-N-{2-[(1,1-dimethylethyl)amino]-2-
oxoethyl}-2-oxo-2H-1-benzopyran-3-carboxamide] (5e): Yield 730 mg (70%). M.p. 168 – 1728. IR (KBr):
3366, 1730, 1653, 1608. 1H-NMR (300 MHz, CDCl3): 1.42 (s, 2 tBu); 3.70 (s, MeO); 3.71 (s, MeO); 3.72 (s,
2 MeO); 6.23 – 6.31 (m, 2 CHN, 2 NH, 8 arom. H); 6.99 – 7.02 (d, J ¼ 8.0, 6 arom. H); 7.19 – 7.26 (m, 4
arom. H); 7.39 (d, J ¼ 7.3, 2 arom. H); 7.53 (t, J ¼ 7.2, 2 arom. H); 7.72 (s, 2 ¼ CH). 13C-NMR (75 MHz,
CDCl3): 28.6; 51.7; 55.1; 55.2; 55.3; 60.2; 97.8; 97.9; 104.0; 104.1; 114.8; 116.6; 117.9; 124.7; 126.1; 128.3;
131.2; 131.8; 132.4; 134.3; 141.7; 153.5; 155.8; 158.0; 158.4; 161.1; 165.2; 168.8. HR-ESI-MS: 1043.48821
([M þ H]þ, C60H59N4O1þ3 ; calc. 1043.48830), 1065.38955 ([M þ Na]þ, C60H58N4NaO1þ3 ; calc 1065.38958),
1081.36386 ([M þ K]þ, C60H58KN4O1þ3 ; calc.1081.36393).
N,N’-[4,4’-Methylenebis(4,1-phenylene)]bis[N-[2-(cyclohexylamino)-1-(2,4-dimethoxyphenyl)-2-oxo-
ethyl]-2-oxo-2H-1-benzopyran-3-carboxamide] (5f): Yield 0.743 mg (68%). M.p. 1208 (dec.). IR (KBr):
3352, 1730, 1658, 1608. 1H-NMR (300 MHz, CDCl3): 1.16 – 2.02 (m, 10 CH2); 3.49 (s, ArCH2Ar); 3.59 (s,
MeO); 3.61 (s, MeO); 3.71 (s, 2 MeO); 3.85 – 3.88 (m, 2 CHNH); 6.14 – 6.16 (m, 2 arom. H); 6.20 – 6.25
(m, 2 arom. H); 6.38 (br. s, 2 CHN); 6.42 (d, J ¼ 7.5, 4 arom. H); 6.74 (br. s, 2 NH); 6.90 (d, J ¼ 6.3, 4 arom.
H); 6.99 (dd, J ¼ 6.0, 1.5, 2 arom. H); 7.16 (d, J ¼ 7.8, 2 arom. H); 7.24 (d, J ¼ 6.6, 2 arom. H); 7.39 (d, J ¼
7.7, 2 arom. H); 7.49 (td, J ¼ 7.8, 1.4, 2 arom. H); 7.74 (s, 2 ¼CH). 13C NMR (75 MHz, CDCl3): 24.8; 25.0;
25.4; 32.7; 33.1; 40.1; 48.8; 55.0; 55.3; 60.3; 97.8; 97.9; 104.0; 104.1; 114.8; 116.6; 118.0; 124.7; 126.3; 128.4;
128.5; 129.5; 131.9; 132.0; 132.4; 137.1; 139.9; 141.8; 153.5; 158.2; 158.4; 161.0; 165.2; 168.5. HR-ESI-MS:
1093.45788 ([M þ H]þ, C65H65N4O1þ2 ; calc. 1093.45773), 1115.43901 ([M þ Na]þ, C65H64N4NaOþ12
;
calc.1115.43901), 1131.41427 ([M þ K]þ, C65H64KN4O1þ2 ; calc. 1131.41417).
N,N’-[4,4’-Methylenebis(4,1-phenylene)]bis[N-[2-(cyclohexylamino)-1-(4-methoxyphenyl)-2-oxo-
ethyl]-2-oxo-2H-1-benzopyran-3-carboxamide] (5g): Yield 723 mg (70%). M.p. 1308 (dec.). IR (KBr):
3351, 1730, 1653, 1607. 1H-NMR (300 MHz, CDCl3): 1.15 – 2.05 (m, 10 CH2); 3.55 (s, ArCH2Ar); 3.72 (s,
MeO); 3.73 (s, MeO); 3.86 – 3.89 (m, 2 CHNH); 6.18 (s, 2 CHN); 6.52 (d, J ¼ 8.6, 4 arom. H); 6.61 (br. s, 2
NH); 6.67 (dd, J ¼ 8.6, 1.5, 4 arom. H); 6.90 – 6.92 (m, 4 arom. H); 7.06 (d, J ¼ 8.6, 4 arom. H); 7.19 – 7.27
(m, 4 arom. H); 7.40 (d, J ¼ 6.7, 2 arom. H); 7.53 (td, J ¼ 7.8, 1.4, 2 arom. H); 7.74 (s, 2 ¼ CH). 13C NMR
(75 MHz, CDCl3): 24.8; 24.9; 25.7; 32.7; 32.9; 40.1; 49.0; 55.2; 65.3; 113.6; 116.6; 117.9; 120.8; 124.8; 125.7;
126.0; 128.4; 128.9; 129.2; 129.9; 130.4; 131.7; 132.5; 137.1; 140.1; 142.1; 158.1; 159.3; 165.2; 168.1. HR-
ESI-MS: 1033.43883 ([M þ H]þ, C63H61N4O1þ0
;
calc. 1033.43889), 1055.42022 ([M þ Na]þ,
C63H60N4NaOþ10 ; calc. 1055.42023), 1071.39403 ([M þ K]þ, C63H60KN4O1þ0 ; calc.1071.39402).

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Received June 7, 2011