Regioselective synthesis of bromo-substituted 3-arylcoumarins

Article abstract of DOI:10.1055/s-0029-1218835

Regioselective syntheses of 3-arylcoumarins possessing a bromine substituent either on the 3-aryl ring, the coumarin moiety or on a lateral chain of a coumarin is reported. The regioselectivity is influenced by the substituents present in the substrates.

Full text of DOI:10.1055/s-0029-1218835

PAPER
2763
Regioselective Synthesis of Bromo-Substituted 3-Arylcoumarins
R
egioselective Synthes
a
is of Brom
r
o-Substit
i
ute
d
3-
a
A
rylcoumarins João Matos,*a Giovanna Delogu,b Gianni Podda,b Lourdes Santana,a Eugenio Uriartea
a
Spain
Fax +34(981)594912; E-mail: mariacmatos@gmail.com
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Cagliari, 09124 Cagliari, Italy
b
Received 4 March 2010; revised 6 May 2010
Halogenation of aromatic and heteroaromatic compounds
is an important reaction in synthetic organic chemistry.11
Aryl and heteroaryl bromides are potential antioxidant,
antibacterial and antitumor agents.12 They also represent
Abstract: Regioselective syntheses of 3-arylcoumarins possessing
a bromine substituent either on the 3-aryl ring, the coumarin moiety
or on a lateral chain of a coumarin is reported. The regioselectivity
is influenced by the substituents present in the substrates. Two dif-
ferent bromination methods are described and compared. Perkin interesting precursors to many substituted analogues.
condensation of 5-methylsalicylaldehyde and phenylacetic acid or
para-methoxyphenylacetic acid affords the desired coumarins.
Three different bromine substitution patterns are accessed starting
ammonium tribromide,13 1,8-diazabicyclo[5.4.0]undec-7-
from 5-methylsalicylaldehyde.
Hence, bromination reactions are versatile and have been
studied extensively. Brominating agents such as tetraalkyl-
ene hydrobromide perbromide (DBUHBr3),14 hexameth-
ylenetetramine tribromide15 and N-bromosuccinimide
Key words: natural products, halogenation, bromine, regioselec-
tivity, coumarins
(NBS)16,17 are known to facilitate monobromination of
aromatic compounds and their derivatives. However, as a
result of its ready availability and ease of handling, the lat-
Phenylcoumarins are synthetic compounds in which an
ter reagent is the most commonly used brominating agent.
The use of N-bromosuccinimide in the solid state,18 or in
traditional solution reactions, enables efficient monobro-
mination of aromatics and derivatives such as cou-
marins.19,20 N-Bromosuccinimide has been used for
bromination and/or oxidation reactions.21–24 It is also used
for the conversion of benzaldehydes into the correspond-
ing benzoyl bromides and for bromolactonization of un-
saturated acids and their derivatives.25–27 Mild reaction
conditions, good yields, and simple, rapid reactions are
some of the advantages of using N-bromosuccinimide. It
has been reported that bromination of coumarins occurs
mainly at C-3, leading to the corresponding monobromo
derivatives.17 In the present compounds this position is
blocked by a phenyl ring leading to a change in the reac-
tivity of the coumarin. Side-chain bromination in benzyl
or allylic systems can be mediated by free radical initia-
tors, while aromatic bromination requires a catalyst.28
Electron-rich aromatic compounds are easily brominated
using N-bromosuccinimide.18 Several studies on regiose-
lective bromination of coumarins have been performed
with the aim of synthesizing bioactive natural prod-
ucts.29,30
additional phenyl ring is present as a substituent at any
position on the coumarin nucleus. They are easily pre-
pared using two general methods: 1) coumarin phenyl-
ation,1 or 2) via construction of the coumarin nucleus with
the aryl ring already in place, e.g., by way of Perkin,2
Pechmann,3,4 Mukaiyama,5 Knoevenagel6 or Perkin–
Oglialoro7 reactions. In the present work we utilize the
second method, and specifically the classical Perkin con-
densation.8 This represents a direct and general method
for preparing 3-phenylcoumarins.
A number of natural products and synthetic analogues
featuring the coumarin structural motif display a broad
spectrum of biological activity.9 Structurally, 3-phenyl-
coumarins can be considered as coumarin–resveratrol hy-
brids (Figure 1); these are very important molecular
frameworks and are synthetically versatile.10 The C3–C4
double bond of the coumarin nucleus fixes the trans dis-
position of the t-resveratrol-type double bond.3 The inter-
esting pharmacological properties of trans-resveratrol has
led to increased interest in synthetic studies toward its an-
alogues.3,10
OH
As part of our research on 3-arylcoumarins, we previously
reported the synthesis of 6-methyl-3-arylcoumarins with
the aryl ring being mono- (compound 2), di- or tri-meth-
oxy-substituted.10 The 3-phenylcoumarins demonstrated
important roles in monoamine oxidase (MAO) enzymatic
inhibition.10 We found that the presence of a methoxy
group on the 3-phenyl ring was important, especially a
para-methoxy group, in order to improve the monoamine
oxidase inhibitor (MAOI) activity.
HO
O
O
OH
Figure 1 6,8-Dihydroxy-3-(4¢-hydroxyphenyl)coumarin (a couma-
rin–resveratrol hybrid)
SYNTHESIS 2010, No. 16, pp 2763–2766
Advanced online publication: 25.06.2010
DOI: 10.1055/s-0029-1218835; Art ID: T05010SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
0
In this paper, we report the direct and selective synthesis
of various bromo-substituted 6-alkyl-3-arylcoumarins.

2764
M. J. Matos et al.
PAPER
The bromine atom can be installed on the 3-phenyl ring described above (Scheme 1). The ortho position relative
(compound 3) or on the aromatic ring of the coumarin to the hydroxy substituent, and meta to the aldehyde, was
(compound 5). In addition, conditions which allow the the most active, and as such was the position at which bro-
bromine atom to be substituted on a lateral chain (com- mination occurred.
pound 7) are described.
5-Bromomethyl-2-hydroxybenzaldehyde (6) was ob-
3-Arylcoumarins with different substitution patterns were tained in 34% yield via irradiation of precursor 1 and bro-
prepared via a direct synthetic route involving the classi- mine in carbon tetrachloride using a tungsten light source.
cal Perkin procedure.8,10,31–33 The reactions were accom- The ability to brominate salicylaldehyde 1, regioselective-
plished by condensation of appropriately substituted ly, enabled the synthesis of 3-arylcoumarins 5 (from 4)
salicylaldehydes with phenylacetic or p-methoxyphenyl- and 7 (from 6), via the classical Perkin condensation, in
acetic acids, using N,N¢-dicyclohexylcarbodiimide (DCC) 50% and 60% yields, respectively. Thus, bromination of 1
as the dehydrating agent, in dimethyl sulfoxide, at 110 ºC using different reaction conditions allowed the position of
for 24 hours (Scheme 1).8,31,32 Coumarins 210 and 5 were the bromine atom in the final coumarin product to be var-
obtained in yields of 61% and 50%, respectively, by reac- ied.
tion of salicylaldehydes 1 and 48,31,32 with p-methoxyphen-
ylacetic acid.
It is interesting to note that with compounds 1 and 2,
which both possess benzylic protons, treatment with N-
Treatment of 6-methyl-3-(4¢-methoxyphenyl)coumarin bromosuccinimide using conditions (b) did not afford the
(2) with N-bromosuccinimide, at reflux in carbon tetra- corresponding bromomethyl derivatives. These substrates
chloride, using 2,2¢-azobis(isobutyronitrile) (AIBN) as contain a strong electron-donating group, and hence aro-
the catalyst, afforded brominated phenylcoumarin 3 in a matic substitution occurs instead of benzylic substitution.
yield of 41%. The regioselective formation of 3 occurred
as a result of activation of the ortho position in substrate 2
by the electron-donating methoxy group. Under these
conditions, the 6-methyl group was not sufficiently acti-
vating to direct bromination onto the coumarin moiety.
3-Bromo-2-hydroxy-5-methylbenzaldehyde (4),31–33 the occurring. Thus, in a substrate without strong activating
brominated precursor of coumarin 5, was prepared from 1 groups, the presence of an alkyl substituent could lead to
in 44% yield, using the same brominating conditions as benzylic halogenation instead of aromatic substitution.
On the other hand, unsubsituted 3-phenylcoumarin34 was
prepared and then treated with N-bromosuccinimide using
the above-mentioned conditions, however, no bromo de-
rivative was obtained. The absence of an activating sub-
stituent prevents the electrophilic aromatic substitution
CHO
OH
1
(a)
(a)
OMe
(c)
(b)
O
O
O
O
8
68%
2
61%
BrH2C
CHO
OH
CHO
OH
(b)
6
34%
Br
4
OMe
Br
(b)
44%
(a)
(a)
O
O
OMe
3
41%
Br
O
O
O
O
7
Br
49–60%
5
50%
Scheme 1 Reagents and conditions: (a) phenylacetic acid or p-methoxyphenylacetic acid (1.25 equiv), DCC (1.56 equiv), DMSO, 110 ºC, 24
h; (b) NBS (1.2 equiv), AIBN (cat.), CCl4, reflux, 18 h; (c) Br2 (1.4 equiv), tungsten light source, CCl4, 8 h.
Synthesis 2010, No. 16, 2763–2766 © Thieme Stuttgart · New York

PAPER
Regioselective Synthesis of Bromo-Substituted 3-Arylcoumarins
2765
6-Methyl-3-phenylcoumarin (8),10 with no substituent on
the 3-phenyl ring, was reacted under the same brominat-
ing conditions to afford 6-bromomethyl-3-phenylcou-
marin (7) in a yield of 49% (Scheme 1). In this case, with
no sufficiently strong activating group for aromatic bro-
mination, the bromine atom was instead directed to the
lateral chain. This reaction sequence represents another
method to obtain bromoalkylcoumarin 7.
DCC (0.37 g, 1.81 mmol), in DMSO (2.0 mL), was heated at 100–
110 °C in an oil bath for 24 h. Ice (20 g) and AcOH (3.0 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 soln (50 mL) and H2O (20 mL), and dried
(Na2SO4). The solvent was evaporated under vacuum and the resi-
due was purified by flash chromatography (hexane–EtOAc, 9:1) to
give coumarin 5.
White solid; yield: 50%; mp 144–145 °C.
1H NMR (CDCl3): d = 2.41 (s, 3 H, CH3), 3.86 (s, 3 H, OCH3), 6.98
(d, J = 7.1 Hz, 2 H, H-3¢, H-5¢), 7.26 (s, 1 H, H-7), 7.56 (s, 1 H, H-
5), 7.65–7.69 (m, 3 H, H-2¢, H-6¢, H-4).
13C NMR (CDCl3): d = 20.5, 55.4, 109.3, 114.0, 120.7, 126.7,
126.9, 128.5, 129.9, 135.2, 137.8, 148.1, 159.9, 160.3.
MS (EI): m/z (%) = 346 (99), 345 (15), 344 (100) [M+], 303 (53),
301 (54), 275 (15), 207 (15), 166 (17), 165 (72), 138 (17), 89 (13),
76 (14), 58 (41).
Comparing the formation of arylcoumarins 3 and 7 from
6-methyl-3-arylcoumarins 2 and 8, respectively, the pres-
ence of a methoxy group results in bromination on the 3-
aryl ring, whilst the absence of a methoxy group leads to
bromine substitution on the lateral chain. Introduction of
a bromine atom on the coumarin ring is possible by aro-
matic bromination of the precursor salicylaldehyde. In
this specific case, the hydroxy substituent on the benzene
ring directs substitution of the bromine atom at the appro-
priate position.
Anal. Calcd for C17H13BrO3: C, 59.15; H, 3.80. Found: C, 59.27; H,
3.82.
In conclusion, convenient procedures have been devel-
oped starting from the 5-methylsalicylaldehyde (1), that
enable bromination on the aryl, methyl or coumarin moi-
5-Bromomethylsalicylaldehyde (6)
To a soln of 5-methylsalicylaldehyde (1) (2.0 g, 14.69 mmol) in
CCl4 (23.0 mL), under reflux and with tungsten light irradiation
eties in differently substituted arylcoumarins. The 3-aryl- (300 W, Philips Reflector R125 35°), was added Br2 (3.29 g, 20.57
mmol) over a period of 3 h. The soln was stirred at r.t. for a further
coumarin products can be used as precursors for other
15 h and the resulting precipitate was filtered and washed with CCl4
molecules and for pharmacological evaluation.
to give aldehyde 6.
White solid; yield: 34%; mp 148 °C.
Melting points were obtained using a Reichert Kofler Thermophan
or in capillary tubes with a Büchi 510 apparatus and are uncorrect-
1H NMR (CDCl3): d = 4.43 (s, 2 H, CH2), 6.96 (d, J = 8.4 Hz, 1 H,
H-3), 7.49–7.53 (m, 2 H, H-4, H-6), 9.88 (s, 1 H, CHO), 10.21 (s, 1
H, OH).
13C NMR (CDCl3): d = 33.2, 115.2, 128.4, 130.9, 131.0, 136.4,
162.0, 191.4.
MS (EI): m/z (%) = 216 (14), 215 (61), 214 (100) [M+], 184 (17),
168 (12), 121 (15), 17 (10).
ed.13C (75 MHz) and 1H NMR (300 MHz) spectra were recorded on
a Bruker AMX 300 MHz spectrometer. Chemical shifts (d, J in Hz)
are reported in ppm relative to TMS as the internal standard. Mass
spectra were obtained using a Hewlett-Packard 5988A spectrome-
ter. Elemental analyses were recorded on a Perkin-Elmer 240B mi-
croanalyzer. Silica gel (Merck 60, 230–400 mesh) was used for
flash chromatography. Analytical TLC was performed on plates
precoated with silica gel (Merck 60 F254, 0.25 mm).
Anal. Calcd for C8H7BrO2: C, 44.68; H, 3.28. Found: C, 44.66; H,
3.23.
3-(3¢-Bromo-4¢-methoxyphenyl)-6-methylcoumarin (3)
A soln of 6-methyl-3-(4¢-methoxyphenyl)coumarin (2) (1.0 g, 3.76
mmol), NBS (0.80 g, 4.51 mmol) and AIBN (cat.) in CCl4 (5.0 mL)
was stirred under reflux for 18 h. The resulting soln was filtered to
remove succinimide. The solvent was evaporated under vacuum
and purified by flash chromatography (hexane–EtOAc, 95:5) to
give compound 3.
6-Bromomethyl-3-phenylcoumarin (7)
Coumarin 7 was obtained in 60% yield starting from 5-bromometh-
ylsalicylaldehyde (6), according to the procedure described for the
synthesis of compound 5. The same product was also obtained in
49% yield starting from coumarin 8 using an identical method to
that described for the preparation of 3.
White solid; mp 174–175 °C.
White solid; yield: 41%; mp 206–207 °C.
1H NMR (CDCl3): d = 4.56 (s, 2 H, CH2), 7.34–7.72 (m, 8 H, H-2¢,
H-3¢, H-4¢, H-5¢, H-6¢, H-5, H-7, H-8), 7.79 (s, 1 H, H-4).
13C NMR (CDCl3): d = 32.1, 117.0, 119.7, 128.2, 128.5, 128.9,
129.0, 132.0, 134.3, 134.4, 139.2, 153.1, 160.2.
1H NMR (CDCl3): d = 2.42 (s, 3 H, CH3), 3.94 (s, 3 H, OCH3), 6.97
(d, J = 8.7 Hz, 1 H, H-5¢), 7.23–7.35 (m, 3 H, H-2¢, H-6¢, H-5),
7.69–7.74 (m, 2 H, H-7, H-8), 7.89 (s, 1 H, H-4).
13C NMR (CDCl3): d = 20.8, 56.3, 111.5, 111.6, 116.1, 119.3,
126.3, 127.6, 128.5, 129.0, 132.5, 133.1, 134.2, 139.1, 151.5, 156.2,
160.6.
MS (EI): m/z (%) = 347 (18), 346 (98), 345 (19), 344 (100) [M+],
303 (45), 301 (45), 275 (11), 250 (17), 222 (13), 194 (11), 178 (13),
165 (58), 163 (11), 139 (15), 132 (42), 82 (18), 76 (14), 63 (19), 50
(14).
MS (EI): m/z (%) = 315 (23), 314 (100), 179 (21), 176 (40), 152
(12), 118 (19), 89 (15), 76 (16).
Anal. Calcd for C16H11BrO2: C, 60.98; H, 3.52. Found: C, 60.89; H,
3.47.
Acknowledgment
Anal. Calcd for C17H13BrO3: C, 59.15; H, 3.80. Found: C, 59.10; H,
3.71.
The authors thank the Spanish Ministry (PI061457 and P509/
00501) and Xunta da Galicia (PXIB20304PR) for financial support.
M.J.M. thanks Fundação de Ciência e Tecnologia for the SFRH/
BD/61262/2009 scholarship.
8-Bromo-3-(4¢-methoxyphenyl)-6-methylcoumarin (5)
A soln of 3-bromo-2-hydroxy-5-methylbenzaldehyde (4) (0.25 g,
1.16 mmol), p-methoxyphenylacetic acid (0.24 g, 1.45 mmol) and
Synthesis 2010, No. 16, 2763–2766 © Thieme Stuttgart · New York

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Synthesis 2010, No. 16, 2763–2766 © Thieme Stuttgart · New York