Improved synthesis of 3-(aminoaryl)coumarins

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Improved Synthesis of 3-
(Aminoaryl)coumarins
Maria João Matos a b , Alexandra Gaspar a , Fernanda Borges a
Eugenio Uriarte b & Lourdes Santana b
,
a CIQUP/Departamento de Química e Bioquímica, Faculdade de
Ciências, Universidade do Porto, 4169-007, Porto, Portugal
b Departamento de Química Orgánica, Facultad de Farmacia,
Universidad de Santiago de Compostela, Santiago de Compostela,
15782, Spain
Version of record first published: 05 Nov 2012.
To cite this article: Maria João Matos, Alexandra Gaspar, Fernanda Borges, Eugenio Uriarte & Lourdes
Santana (2012): Improved Synthesis of 3-(Aminoaryl)coumarins, Organic Preparations and Procedures
International: The New Journal for Organic Synthesis, 44:6, 522-526
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Organic Preparations and Procedures International, 44:522–526, 2012
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2012.730937
OPPI BRIEFS
Improved Synthesis of 3-(Aminoaryl)coumarins
Maria Joa˜o Matos,1,2 Alexandra Gaspar,1 Fernanda Borges,1
Eugenio Uriarte,2 and Lourdes Santana2
1CIQUP/Departamento de Qu´ımica e Bioqu´ımica, Faculdade de Cieˆncias,
Universidade do Porto, 4169-007 Porto, Portugal
2Departamento de Qu´ımica Orga´nica, Facultad de Farmacia, Universidad de
Santiago de Compostela, Santiago de Compostela, 15782 Spain
Coumarins(benzopyrones) are widely distributed in the vegetable kingdom, either in
free or combined state,1 and occupy an important place in the realm of natural prod-
ucts and synthetic organic chemistry.2 They have been used as antioxidants,2 anti-HIV,3
anti-cancer,4 vasorelaxants,5 or enzymatic inhibitors.6 Over the last few years, our research
group has paid special attention to the synthesis of new biologically active coumarins
as enzymatic inhibitors;7–12 in particular, 3-arylcoumarins have been the focal point of
our recent studies13,14 as they play an important role in the monoamino oxidase (MAO)
inhibition.7–10 Various strategies have been used to obtain arylcoumarins,14 e. g., the
Wittig,15 Pechmann,6,7,16 Perkin,6–13,17–21 or Knoevenagel22,23 reactions starting from phe-
nols or aromatic carbonyl compounds. We now describe the synthesis of aminoaryl
coumarins 4a–e24 by the previously unreported copper-catalyzed C-N cross-coupling of
bromoaryl coumarins with trifluoroacetamide (TFA).
Perkin condensation of differently substituted 2-hydroxybenzaldehydes (1) with aryl-
acetic acids (2) afforded the corresponding coumarins (3a–e)10,12,25 in 59%–69% yields;
brominated compound 3e had to be prepared by the NBS bromination of the Perkin con-
densation product 3f, since the required (4-bromothien-3-yl)acetic acid is not commer-
cially available for the direct Perkin reaction. Since previous studies26,27 indicated N,Nꢀ-
dimethylethylenediamine (DMEDA) to be the best ligand to catalyze the CuI coupling of
the coumarinyl aryl bromides10,12 with TFA, the CuI/DMEDA catalytic system was used
to promote the amination of 3a–e with TFA and potassium carbonate in dioxane at 70◦C
to give aminoaryl coumarins 4a–e in 88%–94% yields. It is likely that this method using
TFA could be useful for the amination of other aryl bromides.
Received March 9, 2012.
Address correspondence to Maria Joa˜o Matos, Departamento de Qu´ımica Orga´nica, Facultad de
Farmacia, Universidad de Santiago de Compostela, Santiago de Compostela, 15782 Spain. E-mail:
mariacmatos@gmail.com
522

Synthesis of 3-(Aminoaryl)coumarins
523
R
CHO
OH
R
Ar'
O
R
Ar
O
i
iii
R1
1
O
O
R1
R1
3a-e
4a-e
ArCH2CO2H
2
Scheme 1
In conclusion, a novel and versatile route for the synthesis of 3-(aminoaryl)coumarins
has been developed. The advantage of Cu-catalyzed cross-coupling method compared
with classical cross-coupling reactions28–31 is its versatility, allowing the preparation of
differently functionalized derivatives in addition to the use of trifluoroacetamide as a good
ammonia substitute and of CuI/DMEDA as an effective catalytic system for the amination
reaction of activated bromides, under mild conditions.
Experimental Section
Melting points were obtained using a Reichert Kofler-Thermophan or in capillary tubes
with a Bu¨chi 510 apparatus and are uncorrected.13C (75.4 MHz) and 1H NMR (300 MHz)
spectra were recorded on a Bruker AMX 300 MHz spectrometer. Chemical shifts (δ, J
in Hz) are reported in ppm relative to TMS as the internal standard. Mass spectra were
obtained using a Hewlett-Packard 5988A spectrometer. Elemental analyses were carried
out on a Perkin-Elmer 240B microanalyzer. Silica gel (Merck 60, 230–400 mesh) was used

524
Matos et al.
for flash chromatography. Analytical TLC was performed on plates precoated with silica
gel (Merck 60 F254, 0.25 mm). The preparation and characterization of 3c, 3d, and 3f have
been described in references 10, 12, and 25.
General Procedure for the Preparation of 3-Arylcoumarins 3a, 3b, and 3e. A solution
of the substituted 2-hydroxybenzaldehyde (1, 7.34 mmol), the corresponding arylacetic acid
(2, 9.18 mmol) and N,N-dicyclohexylcarbodiimide (DCC, 2.36 g, 11.46 mmol), in DMSO
(5 ml), was heated at 110◦C in an oil bath for 24 h. Ice (20 g) and AcOH (10 ml) were
added and the mixture was stirred at r.t. for 2 h, and then extracted with Et2O (3 × 25 ml).
The combined organic layer was washed with 5% aq. NaHCO3 solution (50 ml) and H2O
(20 ml), and dried (Na2SO4). The solvent was evaporated under vacuum and the residue
was purified by flash chromatography (hexane/EtOAc, 9:1) to give the desired coumarins.
3-(4-Bromophenyl)-6-methylcoumarin (3a). Colorless solid, 62% yield, mp.
1
197◦C–198◦C. H NMR (CDCl3): δ 2.44 (s, 3H, CH3), 7.24 (dd, J = 7.9, 1.6 Hz, 1H,
H-7), 7.36 (dd, J = 7.9, 1.7 Hz, 2H, H-5, H-8), 7.56–7.62 (m, 4H, H-2ꢀ, H-3ꢀ, H-5ꢀ, H-6ꢀ),
7.78 (s, 1H, H-4). 13C NMR (CDCl3): δ 20.8, 116.2, 119.2, 123.0, 127.7, 130.1, 131.6,
132.8, 133.7, 134.3, 139.9, 151.7, 160.5. MS (EI): m/z (%) = 317 (18), 316 (99), 315 (19),
314 (100) [M+], 288 (34), 287 (22), 286 (34), 285 (17), 179 (17), 178 (36), 152 (9), 118
(14), 89 (11), 76 (12).
Anal. Calcd for C16H11BrO2: C, 60.98; H, 3.52. Found: C, 61.00; H, 3.56.
3-(2-Bromophenyl)-6-methylcoumarin (3b). Colorless solid, 59% yield, mp.
141◦C–142◦C. 1H NMR (CDCl3): δ 2.45 (s, 3H, CH3), 7.26–7.29 (m, 1H, H-4ꢀ), 7.31–7.39
(m, 2H, H-7, H-8); 7.32–7.49 (m, 3H, H-5, H-5ꢀ, H-6ꢀ); 7.69 (d, J = 7.8, 1H, H-3ꢀ); 7.71
(s, 1H, H-4). 13C NMR (CDCl3): δ 20.8, 116.4, 118.7, 123.6, 127.4, 127.9, 128.6, 130.1,
131.3, 132.9, 133.0, 134.3, 135.9, 142.6, 152.0, 160.0. MS (EI): m/z (%) = 316 (5), 315
(38), 314 (100) [M+], 236 (32), 235 (80), 178 (22), 117 (7), 89 (7), 76 (9).
Anal. Calcd for C16H11BrO2: C, 60.98; H, 3.52. Found: C, 60.93; H, 3.48.
Preparation of the 3-(4-Bromothien-3-yl)-6-methylcoumarin (3e). A solution of 6-
methyl-3-(thien-3-yl)coumarin 3f (1.0 g, 3.76 mmol), NBS (0.8 g, 4.51 mmol), and AIBN
(cat.) in CCl4 (5 ml) was stirred under reflux for 18 h. The resulting suspension was filtered
to remove succinimide. The solvent was evaporated under vacuum and purified by flash
chromatography (hexane/EtOAc, 95:5) to give the desired bromo derivative 3e (1.0 g, 75%)
as a colorless solid, mp. 175◦C–176◦C. 1H NMR (CDCl3): δ 2.43 (s, 3H, CH3), 7.25–7.37
(m, 5H, H-5, H-7, H-8, H-2ꢀ, H-5ꢀ), 7.9 (s, 1H, H-4). 13C RMN (CDCl3): δ 20.8, 112.0,
116.4, 118.8, 122.2, 125.6, 127.8, 129.3, 132.9, 134.3, 134.5, 142.6, 151.8, 160.2. MS (EI):
m/z (%) = 320 (100) [M+], 242 (18), 241 (10), 184 (18) 152 (8), 138 (11), 115 (10), 92
(12), 63 (11), 58 (14).
Anal. Calcd for C14H9BrO2S: C, 52.35; H, 2.82. Found: C, 52.32; H, 2.79.
General Procedure for the Preparation of 3-(Aminoaryl)coumarins 4a–e. To a dry
20 ml two-neck round-bottom flask, a catalytic amount of CuI (8 mg, 5 mol%), K2CO3
(0.276 g, 2.0 mmol), and molecular sieves (4 AMS, 0.500 g) were added. The two-neck
round-bottom flask was evacuated and back filled with argon. Then, the bromo coumarin
(0.263 g, 1.0 mmol), 2,2,2-trifluoroacetamide (0.170 g, 1.5 mmol), DMEDA (0.012 ml,
10 mol%), and dioxane (2 ml) were added and the mixture was stirred for 24 h, at 75◦C. The
mixture was then cooled to room temperature and a mixture of methanol/H2O (3:3 ml) was
added. The suspension was stirred for 5 h and then extracted with EtOAc (3 × 20 ml). The

Synthesis of 3-(Aminoaryl)coumarins
525
residue obtained after evaporation of the solvent was purified by column chromatography
(hexane/EtOAc, 9:1) to give the desired aminocoumarins.
3-(4-Aminophenyl)-6-methylcoumarin (4a). Colorless solid; yield 92%; mp.
1
191◦C–192◦C. H NMR (CDCl3): δ 2.43 (s, 3H, CH3), 3.70 (s, 2H, NH2), 7.24–7.36
(m, 3H, H-3ꢀ, H-5ꢀ, H-6), 7.54–7.65 (m, 4H, H-2ꢀ, H-6ꢀ, H-5, H-7), 7.76 (s, 1H, H-4). 13
C
NMR (CDCl3): δ 21.8, 114.4, 115.2, 117.0, 122.3, 124.6, 124.9, 127.4, 129.6, 130.2, 132.0,
135.3, 139.9, 142.0, 157.8, 160.0. MS (EI): m/z 252 (21), 251 (100) [M+], 236 (20), 152
(21), 134 (45), 129 (23), 112 (31).
Anal. Calcd for C16H13NO2: C, 76.48; H, 5.21. Found: C, 76.41; H, 5.19.
3-(2-Aminophenyl)-6-methylcoumarin (4b). Colorless solid, 90% yield, mp.
1
139◦C–140◦C. H NMR (CDCl3): δ 2.43 (s, 3H, CH3), 3.99 (s, 2H, NH2), 7.09–7.12
(m, 1H, H-3ꢀ), 7.28–7.33 (m, 2H, H-4ꢀ, H-5ꢀ), 7.37–7.43 (m, 2H, H-7, H-8), 7.57–7.60 (m,
1H, H-6ꢀ), 7.67 (d, J = 1.9, 1H, H-5), 7.80 (s, 1H, H-4). 13C NMR (CDCl3): δ 25.1, 113.4,
116.4, 119.4, 124.5, 127.4, 127.9, 130.1, 131.4, 131.6, 132.9, 133.1, 134.1, 140.0, 142.6,
155.9. MS (EI): m/z (%) = 252 (20), 251 (89) [M+], 236 (29), 235 (12), 178 (23), 152 (33),
76 (13).
Anal. Calcd for C16H13NO2: C, 76.48; H, 5.21. Found: C, 76.44; 5.19.
6-Amino-8-methoxy-3-phenylcoumarin (4d). Pale yellow solid, 88% yield, mp.
1
172◦C–173◦C. H NMR (CDCl3): δ 3.85 (s, 3H, -CH3), 3.97 (s, 2H, -NH2), 6.97 (s,
2H, H-7), 7.13 (s, 1H, H-5), 7.24–7.26 (m, 3H, H-2ꢀ, H-4ꢀ, H-6ꢀ), 7.63–7.69 (m, 2H, H-3ꢀ,
H-5ꢀ) 7.81 (s, 1H, H-4). 13C NMR (CDCl3): δ 56.4, 113.87, 115.9, 116.5, 121.2, 121.4,
126.4, 129.1, 129.8, 136.9, 147.5, 159.4, 160.3. MS (EI): m/z (%) = 268 (23), 267 (100)
[M+], 248 (9), 182 (13), 167 (16), 139 (17).
Ana. Calcd for C16H13O3: C, 71.90; H, 4.90. Found: C, 71.91; H, 4.92.
3-(5-Aminothien-3-yl)-6-methylcoumarin (4e). Colorless solid, 94% yield, mp.
1
170◦C–171◦C. H NMR (CDCl3): δ 2.46 (s, 3H, CH3), 7.27 (s, 1H, H-5ꢀ), 7.29 (s, 2H,
NH2), 7.36 (s, 1H, H-2ꢀ), 7.40 (dd, J = 7.2, 2.0 Hz, 2H, H-7, H-8,), 7.56 (d, J = 1.9 Hz,
1H, H-5), 7.93 (s, 1H, H-4). 13C RMN (CDCl3): δ 22.0, 116.7, 119.8, 122.0, 124.8, 125.6,
126.6, 127.2, 132.3, 135.2, 138.9, 147.2, 150.61, 160.3. MS (EI): m/z (%) = 258 (15), 257
(100) [M+], 242 (18), 152 (10).
Anal. Calcd for C14H11NO2S: C, 65.35; H, 4.31. Found: C, 65.32; H, 4.29.
Acknowledgment
The authors thank the Spanish Ministry (PS09/00501) and Xunta da Galicia
(PGIDIT09CSA030203PR and INCITE09E2R203035ES) for partial financial support.
Maria Joa˜o Matos (SFRH/BD/61262/2009) and Alexandra Gaspar (SFRH/BD/43531/2008)
thank Fundac¸a˜o de Cieˆncia e Tecnologia for the scholarships.
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