Expedient synthesis of biologically potent aryloxycoumarins and (aryloxyimino)ethylcoumarins via copper(II)-promoted chan-lam coupling reaction

Article abstract of DOI:10.1080/00397911.2011.594544

A convenient protocol for the efficient synthesis of aryloxycoumarins and (aryloxyimino)ethylcoumarins is described. The synthetic route developed involves the Cu-promoted C-O and N-O coupling reactions from readily available hydroxycoumarin and (hydroxyi

Full text of DOI:10.1080/00397911.2011.594544

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Expedient Synthesis of Biologically
Potent Aryloxycoumarins and
(Aryloxyimino)ethylcoumarins via
Copper(II)-Promoted Chan–Lam Coupling
Reaction
Arunima Medda a , Gargi Pal a , Raghunath Singha b , Tabassum
Hossain c , Achintya Saha c & Asish R. Das a
a Department of Chemistry, University of Calcutta, Kolkata, India
b Chemgen Pharma International Pvt. Limited, Kolkata, India
c Department of Chemical Technology, University of Calcutta,
Kolkata, India
Accepted author version posted online: 01 Feb 2012.Version of
record first published: 18 Oct 2012.
To cite this article: Arunima Medda , Gargi Pal , Raghunath Singha , Tabassum Hossain , Achintya
Saha & Asish R. Das (2013): Expedient Synthesis of Biologically Potent Aryloxycoumarins and
(Aryloxyimino)ethylcoumarins via Copper(II)-Promoted Chan–Lam Coupling Reaction, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:2, 169-181
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Synthetic Communications1, 43: 169–181, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.594544
EXPEDIENT SYNTHESIS OF BIOLOGICALLY POTENT
ARYLOXYCOUMARINS AND
(ARYLOXYIMINO)ETHYLCOUMARINS VIA
COPPER(II)-PROMOTED CHAN–LAM COUPLING
REACTION
Arunima Medda,1 Gargi Pal,1 Raghunath Singha,2 Tabassum
Hossain,3 Achintya Saha,3 and Asish R. Das1
1Department of Chemistry, University of Calcutta, Kolkata, India
2Chemgen Pharma International Pvt. Limited, Kolkata, India
3Department of Chemical Technology, University of Calcutta, Kolkata, India
GRAPHICAL ABSTRACT
Abstract A convenient protocol for the efficient synthesis of aryloxycoumarins and (arylox-
yimino)ethylcoumarins is described. The synthetic route developed involves the
Cu-promoted C-O and N-O coupling reactions from readily available hydroxycoumarin
and (hydroxyimino)ethylcoumarin derivatives in the presence of the catalytic system
Cu(OAc)2/Et3N. By applying this condition, a series of arylboronic acids have been
successfully reacted to afford the coupled products in fair to good yields.
Keywords Arylboronic acids; Chan–Lam protocol; coumarin; cross-coupling reactions;
Cu(OAc)2
Received April 8, 2011.
Address correspondence to Asish R. Das, Department of Chemistry, University of Calcutta,
Kolkata 700009, India. E-mail: ardchem@caluniv.ac.in; ardas66@rediffmail.com
169

170
A. MEDDA ET AL.
INTRODUCTION
Compounds containing the coumarin framework are widely occurring
secondary metabolites that occur naturally in several plant families and essential oils.
They have been used as fragrances in food and cosmetic products.[1] The coumarin
nucleus is well represented in a variety of pharmacologically active compounds.
Recently reported examples include coumarin-7-xylosides oral antithrombotic
agents;[2] synthetic analogs of naturally occurring anti-bacterials, novobiocin and
chlorobiocin;[3] geiparvarin, possessing the most representative anticancer activity;[4]
and khellactone derivatives, potential HIV-1 inhibitors.[5] The naturally occurring
3-substituted biscoumarinyl ethers, particularly daphnoretin,[6] are reported to be
new protein kinase C activators. Glyasperin E was the first natural 3-phenoxychro-
mone widely used in Chinese folk medicine.[7] Alkoxy coumarins and their deriva-
tives showed nematicidal activity against the phytopathogenic nematode.[8]
Recently, substituted coumarins tethered to 3-hydroxy-N,N-dimethylanilino moiety
were evaluated as cholinesterase inhibitors.[9] 4-Phenoxycoumarins are also reported
to have herbicidal properties.[10] In addition O-aryloxime ethers are not only useful
synthetic intermediates but also potential precursors to benzofurans and benzoisox-
azoles,[11] and they are present in a growing number of bioactive compounds.[12] In
light of our interest in coumarin chemistry,[13] we needed an efficient method to
develop an aryloxycoumarin and (aryloxyimino)ethylcoumarin-based library, with
a hope to find more potent hits or leads for our particular biological assays.
The literature reveals a few synthetic routes to these aryloxycoumarins, and the
most common route is undoubtedly the modified Perkin–Oglialoro reaction, by con-
densation of substituted salicylaldehydes with the sodium salts of the corresponding
aryloxyacetic acids.[14] This approach is, however, of restricted use for the preparation
of diverse derivatives of aryloxycoumarins because of the limited availability of substi-
tuted starting materials. To the best of our knowledge, copper-catalyzed C-O and N-O
bond formation reactionsofhydroxycoumarin and(hydroxyimino)ethylcoumarin with
arylboronic acids have not been accomplished yet. Recently, the other C-O and N-O
bond cross-coupling with arylboronic acids and a current review of the Cham–Lam
reaction have been discussed.[15] Herein we describe a detailed synthesis for a number
of aryloxycoumarins and (aryloxyimino)ethylcoumarins by applying the Chan–Lam
protocol.[16] Although significant advances have occurred in the metal-catalyzed[17]
ether formation of arylhalides and phenolic derivatives during the past decade, appli-
cation of this coupling to coumarin moieties is still a relatively unexplored process.
An O-arylation process conducted under very mild reaction conditions is the
oxidative cross-coupling of OH-containing substrates with phenylboronic acids.[16]
This process is mediated by a stoichiometric amount of copper(II) salt in the pres-
ence of a weak base and atmospheric oxygen. We envisaged that such an O- or
N-arylation process between hydroxycoumarins or (hydroxyimino)ethylcoumarins
and arylboronic acids would provide a simple and general method for the synthesis
of arloxycoumarins or (aryloxyimino)ethylcoumarins.
RESULTS AND DISCUSSION
In our first phase of screening experiment, 4-methoxyphenylboronic acid (2a)
and 3-hydroxy coumarin (1) were used as model substrates to explore the conditions

ARYLOXYCOUMARINS VIA CHAN–LAM PROTOCOL
171
Table 1. Optimization of bases, solvents, and copper saltsa
Entry
[Cu]
Ligand
Base
Solvent
Yield of 3a (%)b
1c
2c
3c
4
CuI
—
—
Et3N
Et3N
Et3N
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
0
0
Cu(acac)2
Cu(acac)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuI
DMG
BINAP
—
0
Et3N
Et3N
Trace
86
0
5
6
—
—
Cs2CO3
Pyridine
DMAP
DBU
7
45
<20
0
8
—
—
9
10
11
12c
13
14
15
16d
—
—
Et3N
Et3N
0
Dioxane
DMSO
CH2Cl2
Toluene
CH2Cl2
CH2Cl2
52
0
—
—
K3PO4
K2CO3
Et3N
Cu(OAc)2
Cu(OAc)2
—
0
—
—
30
0
Et3N
Et3N
Cu(OAc)2
—
48
aConditions: 1 (1 mmol), 2a (2 mmol), Cu(OAc)2 (1 mmol).
bIsolated yield (in some cases minor amounts of biaryl ether and=or phenol products were isolated).
cAmount of CuI and Cu(acac)2 used: 1 mmol.
dConditions: 1 (1 mmol), 2a (2 mmol), Cu(OAc)2 (0.5 mmol).
required for the copper-promoted cross-coupling (Table 1, Scheme 1). Thus, 1
equivalent of both 3-hydroxycoumarin (1) and Cu(OAc)2 and 2 equivalents of both
the 4-methoxyphenylboronic acid (2a) and an amine base were allowed to react at
˚
room temperature in 1,2-dichloromethane with 4 A molecular sieves for a period
of 24 h under ambient atmospheric conditions.
It is known that the amine plays a crucial role, acting as both a base and a
ligand, and varies according to the specific copper-promoted cross-coupling pro-
cess.[16,17] In this case, triethylamine was found to be the best amine, with 5 equiva-
lents required for optimal yields of 3a (Table 1, entry 5). Amines such as pyridine,
DBU and DMAP either suppressed or did not improve the cross-coupling reaction
(Table 1, entries 7–9). Triethylamine is an active base with PKa 9.8 where as pyri-
dine, 1,8-diaza bicyclo[5.4.0]undec-7-enc (DBU), and dimethylamino pyridine
(DMAP) are passive bases as well as highly nucleophilic in origin. The noncoordi-
nating nature of triethylamine on steric ground confirmed its supremacy over other
organic bases. As coumarins are sensitive substrates in basic conditions and may
result in the opening of the lactone ring, we carefully applied the basic conditions
Scheme 1.

172
A. MEDDA ET AL.
for the coupling between 1 and 2a. In fact, hydroxycoumarins (1, 4, 6) completely
disappeared within a few hours when treated with arylboronic acids (2a) in the pres-
ence of either Cs2CO3, K2CO3, K3PO4. However, no desired ether product (Table 1,
entries 6, 12, and 13) was obtained. In spite of this difficulty, the etherification pro-
ceeded reasonably well, as can be seen in Tables 2–4 and Schemes 2–4.
A limited examination of solvents revealed that 1,2-dichloromethane was opti-
mal (Table 1, entry 5) when compared to 1,4-dioxane and toluene (Table 1, entries
11 and 14). Surprisingly, no desired product was obtained when acetonitrile was used
as a solvent (Table 1, entry 10). The nonapplicability of acetonitrile can be explained
by the polarity index (PI). The PI values of CH2Cl2 and CH3CN are 3.1 and 5.8,
respectively. So, CH3CN participates with copper ion, thereby changing its hybridiza-
tion, and as a result there is no vacant side for coordination with substrate. However
CH2Cl2 is a noncoordinating solvent. Finally, CuI and Cu(acac)2 were applied as a
copper source but failed to improve the desired yield of 3a (Table 1, entries 1–3 and
12). In the absence of catalyst, no product was obtained (Table 1, entry 15), showing
that Cu(OAc)2 is essential (Table 1, entry 5) to promote the O-arylation. Use of ligands
such as 2,20-bis(diphenylphosphino)-1,10-binaphthyl (BINAP) or dimethylglyoxime
(DMG) remained slient to this coupling reaction (Table 1, entries 3 and 4). The use
of lesser amount of Cu(OAc)2 (0.5 equiv) reduced the yield (48%) of 3a (Table 1, entry
16). To our delight, expected product 3-(4-methoxyphenoxy)coumarin (3a) was gener-
ated in 86% yield when the reaction was performed in the presence of catalyst
˚
Cu(OAc)2 (1 equiv), the base Et3N in CH2Cl2, and 4-A molecular sieves at room tem-
perature (Table 1, entry 5). The reaction went to completion within 24 h. Analysis of
the unpurified reaction mixtures by Liquid Chromatography–Mass Spectrometry
(LC=MS) revealed the formation of phenolic derivative and biaryl ether as unwanted
reaction products. It was assumed that the side reactions that resulted in diminished
yields were the competitive arylation of water and the subsequent competition of phe-
nol analogs with the hydroxyl coumarin substrate. Because significant quantities of
both the side products were generated even under seemingly anhydrous conditions,
we concluded that water was being generated from arylboronic acid through triphenyl-
boroxine formation. The preceding analysis was confirmed by the addition of dry
˚
powdered 4-A molecular sieves to the reaction mixture, which suppressed phenol
and biaryl ether formation and increased the product yields. During the optimization
process, it was noticed that exposure of the reaction to oxygen was not at all
advantageous. Instead, it reduced the percentage of yield and increased the
by-products. However, under nitrogen atmosphere only Cu(OAc)2 yielded the
3-(4-methoxyphenoxy)coumarin (3a).
Analyzing these preliminary results, we then investigated the Cu(OAc)2-
mediated O-arylation of 3-hydroxycoumarin (1), 4-hydroxycoumarin (4), and
4-methyl-7-hydroxycoumarin (6) with a set of structurally and electronically diverse
arylboronic acids (2a–k) (Tables 2–4). We observed that there is a marked relation-
ship between the electronic properties of aryl boronic acids and their reactivity pro-
file where yields were generally good with para-substitution. Electron-rich aryl
boronic acids underwent arylation most efficiently, whereas for ortho- or meta-
substituted aryl boronic acids yields were little depressed (Table 2). Use of more
electron-deficient 4-trifluoromethylboronic acid (2k) resulted in a slight decrease in
yield (Table 2, entry 11). In general, a second equivalent of arylboronic acid was

ARYLOXYCOUMARINS VIA CHAN–LAM PROTOCOL
173
Table 2. Cu(OAc)2-promoted O-arylation of 3-hydroxycoumarin (1) with arylboronic acids (2a–k)
Entry
1
Arylboronic acid
3-Aryloxycoumarin
Isolated yield (%)
86
2
3
73
80
4
5
74
58
6
7
66
70
8
9
56
63
10
11
76
69
All products showed analytical and spectral characteristics consistent with their structures.

174
Table 3. Cu(OAc)2-promoted O-arylation of 4-hydroxycoumarin (4) with arylboronic acids (2c, g)
Entry Arylboronic acids 4-Aryloxycoumarin Isolated yield (%)
A. MEDDA ET AL.
1
70
2
66
All products showed analytical and spectral characteristics consistent with their structures.
required for successful coupling and synthetically valuable product output. In all
cases, the arylboronic acid was consumed during the reaction, while in few cases
unreacted 3-hydroxy coumarin was isolated. The O-arylation of 3-hydroxy coumarin
(1) with pyridyl-3-boronic acid (2f) also proceeded smoothly.
With a suitable set of cross-coupling conditions in hand for the synthesis of
aryloxycoumarins (3, 5 and 7), we investigated the Cu(OAc)2-promoted O-arylation
of (hydroxyimino)ethylcoumarins (8, 9) with three different arylboronic acids (2b,
2c, 2j) (Table 5, Scheme 5). 3-(Hydroxyimino)ethylcoumarin is readily obtained from
3-acetylcoumarin and hydroxylamine. Thus, 1 equivalent of both (hydroxyimino)
ethylcoumarin and Cu(OAc)2 2 equivalents of arylboronic acid (2b or 2c or 2j)
and 5 equivalents of Et3N base were allowed to interact at room temperature in
˚
1,2-dicholromethane with 4-A molecular sieves for a period of 24 h under N2
Table 4. Cu(OAc)2-promoted O-arylation of 7-hydroxy-4-methylcoumarin (6) with arylboronic acids
(2a, 2e, 2k)
Entry
Arylboronic acids
7-Aryloxy-4-methylcoumarin
Isolated yield (%)
1
82
2
3
54
68
All products showed analytical and spectral characteristics consistent with their structures.

ARYLOXYCOUMARINS VIA CHAN–LAM PROTOCOL
175
Scheme 2.
Scheme 3.
atmosphere and ambient temperature to provide (aryloxyimino)ethylcoumarins (10,
11) in satisfactory yield (Table 5). A significantly better O-arylating agent was phe-
nylboronic acid (2c), which afforded (phenoxyimino)ethylcoumarin (10c) and
(phenoxyimino)ethyl-7-methoxycoumarin (11c) in 70% and 75% isolated yields
respectively (Table 5, entries 1 and 3). When the cross-coupling of (hydroxyimi-
no)ethylcoumarin 8 with 4-fluoroboronic acid (2b) and 4-tert-butylphenylboronic
acid (2j) were examined, it was found that the corresponding O-arylated product
was formed in moderate yields (Table 5, entries 2 and 3).
The functional-group tolerance in this coupling reaction is satisfactory. Parti-
cularly the coupled products 3b, 3g, 3i, 5g and 10b are more interesting because these
Scheme 4.
Scheme 5.

176
A. MEDDA ET AL.
Table 5. Cu(OAc)2-promoted O-arylation of (hydroxyimino)ethylcoumarin (8, 9) with arylboronic acids
(2b, 2c, 2j)[18]
Entry
Arylboronic acid
(Aryloxyimino)-ethylcoumarin
Isolated yield (%)
1
70
2
3
4
55
62
75
All products showed analytical and spectral characteristics consistent with their structures.
may allow further functionalization of the products, as the scaffold still contained
either fluorine, chlorine, or bromine as the substituents. Overall, these results
(Tables 2–5) indicate that the efficacy of this copper(II)-promoted cross-coupling
process is not greatly influenced by the electronic nature of the hydroxyl coumarin
or (hydroxyimino)ethylcoumarin, but significantly affected by the electronic nature
of the arylboronic acid partner.
We speculate that cupric acetate forms a complex with the hydroxycoumarin
(1, 4, 6) and (hydroxyimino)ethylcoumarin (8, 9) and transmetallation with aryl-
boronic acid (2), and the resulting aryl-copper-coumarin-complex then undergoes
subsequent reductive elimination to the aryloxycoumarins (3a–k, 5c and 5g, and
7a, 7e, and 7k) and (aryloxyimino)ethylcoumarin (10c, 10b, and 10j and 11c).
Furthermore, 10 synthesized 3-aryloxycoumarins (3a–3j) were assessed to
evaluate their bioactivities involving 3D structure-based drug design (3D-QSAR).
The compounds thatresulted (3a–3j) were potent pharmacologically toward aroma-
tase inhibition and xanthine oxidase inhibition. From the binding interaction, it was
observed that compound 3h was the most active and the degree of activity was in the
order of compounds 3h > 3e > 3a > 3b, 3i, 3g, 3f > 3c, 3d, 3j.
In conclusion, we have developed a novel system for the arylation of hydroxy-
coumarins and (hydroxyimino)ethylcoumarins in good to excellent yields by means
of cross-coupling with arylboronic acids in the presence of Cu(OAc)2 and Et3N. This
synthetic method is the first general metal-mediated coupling of a hydroxycoumarin
nucleophile with arylboronic acids reported to date. This work expands the utility of
the Chan–Lam reaction to the use of arylboronic acids, a class reagent that has been

ARYLOXYCOUMARINS VIA CHAN–LAM PROTOCOL
177
problematic in cross-coupling protocols with other nucleophiles. It also extends the
utility of the copper-promoted cross-coupling reactions in the field of
O-functionalization of coumarin nucleus, and it will surely find considerable appli-
cation in the synthesis of complex organic molecules.
EXPERIMENTAL
Column chromatography was performed using silica gel (100–200 mesh). Infra-
red (IR) spectra were recorded as KBr discs with a Perkins-Elmer Fourier transform
1
(FT) spectrometer. H NMR and 13C NMR spectra were recorded at 500 MHz and
300 MHz respectively on a Bruker instruments and mass spectra were recorded in
LC-MS-MS on a Water micromass instrument. High-resolution mass spectrometric
analysis was recorded on a micromass Q-TOF HRMS.
General Procedure for the Copper-Promoted Cross-Coupling of
Hydroxy Coumarins (1, 4, 6) or (Hydroxyimino)ethylcoumarins (8, 9)
with Arylboronic Acids (2)
Et3N (0.7 mL, 5 mmol) was added to a mixture of hydroxycoumarin or (hydro-
xyimino)ethylcoumarin (1 mmol), Cu(OAc)2 (182 mg, 1 mmol), and arylboronic acid
(2 mmol) in CH2Cl2 (8 mL). This resulted in a light green solution to which freshly
0
˚
activated and powdered 4-A MS (ca. 500 mg) was also added. The reaction was stir-
red at rt under N2 atmosphere. The progress of the reaction was monitored by
thin-layer chromatography (TLC). The color of the reaction mixture changed from
light green to deep green as the reaction proceeded. After stirring at rt for 24 h the
reaction mixture was filtered through a small pad of silica gel (eluting with CH2Cl2),
and the solvent was removed under reduced pressure. The resulting crude product
was purified by silica gel (100–200 mesh) column chromatography (eluting with
10% EtOAc–hexane) to obtain pure aryloxycoumarins (3, 5, 7) or (aryloxyimi-
no)ethylcoumarins (10, 11) in 56–86% isolated yields.
Spectroscopic Data
3-(4-Methoxyphenoxy)coumarin (Table 2, Entry 1, 3a). 1H NMR
(300 MHz, CDCl3): d ¼ 7.25 (m, 4H), 7.01 (q, J ¼ 3 Hz, 2H), 6.89 (q, J ¼ 4 Hz,
2H), 6.72 (s, 1H), 3.77 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3): d ¼ 157.06,
150.30, 147.70, 144.30, 129.23, 126.78, 124.73, 121.31, 118.66, 116.39, 115.21,
55.66 ppm. MS (ESIþ): m=z ¼ 269.1 [M þ 1]. IR (KBr) cmꢀ1: 1098 (-C-O-C-), 1728
=
(-O-C O). HRMS (m=z) for C16H12O4(M þ H) calcd. 269.0815, found 269.0807
(highest ion peak).
3-(4-Fluorophenoxy)coumarin (Table 2, Entry 2, 3b). 1H NMR (300 MHz,
CDCl3): d ¼ 7.28 (m, 4H), 7.05 (t, J ¼ 6 Hz, 4H), 6.86 (s, 1H) ppm. 13C NMR
(75 MHz, CDCl3): d ¼ 157.11, 153.61, 150.89, 142.31, 129.74, 126.98, 124.85,
121.0, 118.99, 116.70 ppm. MS (ESIþ): m=z ¼ 257.0 [M þ 1]. IR (KBr) cmꢀ1: 1101
=
(-C-O-C-), 1724 (-O-C O). HRMS (m=z) for C15H9FO3(M þ H) calcd. 257.0615,
found 257.0608 (highest ion peak).

178
A. MEDDA ET AL.
3-(Phenoxy)coumarin (Table 2, Entry 3, 3c)[14a,18] 1H NMR (300 MHz,
.
CDCl3): d ¼ 7.32 (m, 4H), 7.09 (m, 5H), 6.89 (s, 1H) ppm. 13C NMR (75 MHz,
CDCl3): d ¼ 162.30, 154.81, 150.89, 143.01, 130.12, 129.60, 126.95, 124.89, 121.17,
119.29, 116.44 ppm. MS (ESIþ): m=z ¼ 239.0 [M þ 1]. IR (KBr) cmꢀ1: 1100 (-C-O-
=
C-), 1728 (-O-C O).
3-(4-Methylphenoxy)coumarin (Table 2, Entry 4, 3d)[14b] 1H NMR
.
(300 MHz, CDCl3): d ¼ 7.24 (m, 4H), 7.03 (d, J ¼ 9 Hz, 1H), 6.95 (d, J ¼ 9 Hz,
4H), 6.81 (s, 1H), 2.30 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3): d ¼ 152.28,
150.30, 143.25, 134.90, 130.63, 129.35, 126.82, 124.71, 119.75, 116.40, 20.80 ppm.
MS (ESIþ): m=z ¼ 253.0 [M þ 1]. IR (KBr) cmꢀ1: 1104 (-C-O-C-), 1729 (-O-C O).
=
3-(2-Methylphenoxy)coumarin (Table 2, Entry 5, 3e)[19] 1H NMR
.
(300 MHz, CDCl3): d ¼ 7.30 (m, 7H), 7.03 (d, J ¼ 9 Hz, 1H), 6.66 (s, 1H), 2.26 (s,
3H) ppm. 13C NMR (75 MHz, CDCl3): d ¼ 152.28, 150.30, 143.25, 131.89, 130.05,
129.17, 127.54, 126.72, 125.69, 124.69, 120.22, 119.25, 118.13, 116.36, 15.85 ppm.
MS (ESIþ): m=z ¼ 253.1 [M þ 1]. IR (KBr) cmꢀ1: 1127 (-C-O-C-), 1731 (-O-C O).
=
3-(3-Pyridylphenoxy)coumarin (Table 2, Entry 6, 3f). 1H NMR (300 MHz,
CDCl3): d ¼ 7.30 (m, 8H), 6.99 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3): d ¼ 160.32,
156.80, 151.18, 149.31, 141.11, 140.53, 130.51, 128.19, 127.38, 126.50, 124.89, 120.41,
116.44, 114.53 ppm. MS (ESIþ): m=z ¼ 240.0 [M þ 1]. IR (KBr) cmꢀ1: 1106 (-C-O-
=
C-), 1717 (-O-C O). HRMS (m=z) for C14H9NO3 (M þ H) calcd. 240.0661; found
240.0654 (highest ion peak).
3-(4-Chlorophenoxy)coumarin (Table 2, Entry 7, 3g)[14a] 1H NMR
.
(300 MHz, CDCl3): d ¼ 7.34 (m, 4H), 7.20 (m, 2H), 7 (t, J ¼ 3 Hz, 2H), 6.97 (s,
1H) ppm. 13C NMR (75 MHz, CDCl3): d ¼ 157.11, 153.61, 150.89, 142.31, 130.06,
127.10, 124.89, 122.54,120.40, 118.88, 116.52 ppm. MS (ESIþ): m=z ¼ 273.1
[M þ 1]. IR (KBr) cmꢀ1: 1095 (-C-O-C-), 1725 (-O-C O).
=
3-(2-Methoxyphenoxy)coumarin (Table 2, Entry 8, 3h). 1H NMR
(300 MHz, CDCl3): d ¼ 7.18 (m, 7H), 6.88 (d, J ¼ 9 Hz, 1H), 6.73 (s, 1H), 3.76 (s,
3H) ppm. 13C NMR (75 MHz, CDCl3): d ¼ 157.06, 150.30, 147.70, 144.30, 129.21,
126.75, 124.70, 121.26, 119.26, 118.69, 118.15, 116.37, 115.20, 55.65 ppm. MS
(ESIþ): m=z ¼ 269.1 [M þ 1]. IR (KBr) cmꢀ1: 1099 (-C-O-C-), 1728 (-O-C O).
=
HRMS (m=z) for C16H12O4(M þ H) calcd. 269.0815; found 269.0814 (highest ion
peak).
3-(3-Bromophenoxy)coumarin (Table 2, Entry 9, 3i). 1H NMR (300 MHz,
CDCl3): d ¼ 7.30 (m, 8H), 6.96 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3): d ¼ 156.02,
151.15, 141.66, 131.15, 130.25, 127.86, 127.28, 124.93, 124.02, 123.11, 121.98, 118.84,
117.44, 116.60 ppm. MS (ESIþ): m=z ¼ 319.1 [M þ 1]. IR (KBr) cmꢀ1: 1100 (-C-O-
=
C-), 1727 (-O-C O). HRMS (m=z) for C15H9BrO3(M þ Na) calcd. 338.9635, found
338.9631 (highest ion peak).
3-(4-Tert-buytlphenoxy)coumarin (Table 2, Entry 10, 3j). 1H NMR
(300 MHz, CDCl3): d ¼ 7.33 (m, 6H), 7.04 (t, J ¼ 4.5 Hz, 2H), 6.92 (s, 1H), 1.34 (s,
9H) ppm. 13C NMR (75 MHz, CDCl3): d ¼ 152.24, 150.54, 148.08, 143.43, 129.39,
126.92, 124.70, 120.27, 119.16, 116.41, 31.43 ppm. MS (ESIþ): m=z ¼ 295.1

ARYLOXYCOUMARINS VIA CHAN–LAM PROTOCOL
179
[M þ 1]. IR (KBr) cmꢀ1: 1029 (-C-O-C-), 1739 (-O-C O). HRMS (m=z) for
C19H18O3(M þ Na) calcd. 317.1156; found 317.1155 (highest ion peak).
=
3-(4-Trifluoromethylphenoxy)coumarin (Table 2, Entry 11, 3k). 1H
NMR (300 MHz, CDCl3): d ¼ 7.65 (d, J ¼ 6 Hz, 2H), 7.51 (d, J ¼ 0.9 Hz, 1H),
7.44–7.38 (m, 2H), 7.33–7.26 (m, 2H), 7.17 (d, J ¼ 6 Hz, 2H) ppm. 13C NMR
(75 MHz, CDCl3): d ¼ 158.26, 157.03, 151.42, 140.80, 130.64, 127.64, 126.70,
126.43, 125.83, 125.08, 122.90, 118.74, 118.14, 116.70 ppm. MS (ESIþ): m=
z ¼ 307.1 [M þ 1]. IR (KBr) cmꢀ1: 1068 (-C-O-C-), 1729 (-O-C O). HRMS (m=z)
=
for C16H19F3O3(M þ H) calcd. 307.0582; found 307.0582 (highest ion peak).
4-(Phenoxy)coumarin (Table 3, Entry 1, 5c)[20] 1H NMR (300 MHz,
.
CDCl3): d ¼ 7.40–7.33 (m, 5H), 7.29–6.99 (m, 4H), 6.90 (s, 1H) ppm. 13C NMR
(75 MHz, CDCl3): d ¼ 162.30, 154.81, 143.01, 130.12, 129.60, 126.95, 125.03,
124.76, 121.17, 119.47, 119.11, 116.44 ppm. MS (ESIþ): m=z ¼ 239.0 [M þ 1]. IR
(KBr) cmꢀ1: 1101 (-C-O-C-), 1728 (-O-C O).
=
4-(4-Chlorophenoxy)coumarin (Table 3, Entry 2, 5g). 1H NMR
(300 MHz, CDCl3): d ¼ 7.42–7.37 (m, 2H), 7.32–7.28 (m, 2H), 7.23–7.18 (m, 2H),
7.01 (t, J ¼ 3 Hz, 2H), 6.98 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3): d ¼ 157.11,
153.61, 150.89, 142.31, 130.13, 130.00, 127.10, 124.89, 122.54, 120.40, 118.88,
116.52 ppm. MS (ESIþ): m=z ¼ 273.1 [M þ 1]. IR (KBr) cmꢀ1: 1095 (-C-O-C-),
=
1726 (-O-C O). HRMS (m=z) for C15H9ClO3(M þ Na) calcd. 295.0140, found
295.0138 (highest ion peak).
7-(4-Methoxyphenoxy)-4-methylcoumarin (Table 4, Entry 1, 7a). 1H
NMR (300 MHz, CDCl3): d ¼ 7.50 (d, J ¼ 3 Hz, 1H), 7.03–7.01 (m, 2H), 6.94–6.88
(m, 3H), 6.79 (d, J ¼ 1.5 Hz, 1H), 6.15 (s, 1H), 3.83 (s, 3H), 2.40 (s, 3H) ppm. 13C
NMR (75 MHz, CDCl3): d ¼ 162.21, 160.99, 156.92, 155.03, 152.31, 148.24,
125.74, 121.71, 115.18, 114.68, 113.54, 112.61, 104.40, 55.69, 18.68 ppm. MS (ESIþ):
m=z ¼ 283.1 [M þ 1]. IR (KBr) cmꢀ1: 1028 (-C-O-C-), 1719 (-O-C O). HRMS (m=z)
=
for C17H14O4(M þ H) calcd. 283.0971, found 283.0970 (highest ion peak).
7-(2-Methylphenoxy)-4-methylcoumarin (Table 4, Entry 2, 7e). 1H NMR
(300 MHz, CDCl3): d ¼ 7.51 (d, J ¼ 3 Hz, 1H), 7.51–7.17 (m, 2H), 6.99 (q, J ¼ 3 Hz,
1H), 6.87 (q, J ¼ 3 Hz, 1H), 6.71 (d, J ¼ 3 Hz, 1H), 6.15 (s, 1H), 2.40 (s, 3H), 2.19 (s,
3H) ppm. 13C NMR (75 MHz, CDCl3): d ¼ 162.26, 161.33, 160.94, 155.06, 152.63,
152.29, 131.81, 130.46, 127.53, 125.67, 121.00, 118.09, 113.12, 112.48, 103.85,
18.65, 15.96 ppm. MS (ESIþ): m=z ¼ 267.1 [M þ 1]. IR (KBr) cmꢀ1: 1061 (-C-O-
=
C-), 1727 (-O-C O). HRMS (m=z) for C17H14O3(M þ H) calcd. 267.1022, found
267.1021 (highest ion peak).
7-(4-Trifluorophenoxy)-4-methylcoumarin (Table 4, Entry 3, 7k). 1H
NMR (300 MHz, CDCl3): d ¼ 7.65 (d, J ¼ 6 Hz, 2H), 7.59 (d, J ¼ 6 Hz, 1H), 7.15
(d, J ¼ 3 Hz, 2H), 6.98-6.94 (m, 2H), 6.23 (s, 1H), 2.43 (s, 3H) ppm. 13C NMR
(75 MHz, CDCl3): d ¼ 160.59, 159.39, 158.56, 155.03, 152.00, 127.54, 126.14,
119.48, 116.21, 115.06, 113.67, 106.83, 18.74 ppm. MS (ESIþ): m=z ¼ 321.1
[M þ 1]. IR (KBr) cmꢀ1: 1062 (-C-O-C-), 1714 (-O-C O). HRMS (m=z) for
=
C17H11F3O3(M þ H) calcd. 321.0739; found 321.0733 (highest ion peak).

180
A. MEDDA ET AL.
3-(Phenoxyiminoethyl)coumarin (Table 5, Entry 1, 10c). 1H NMR
(300 MHz, CDCl3): d ¼ 8.03 (s, 1H), 7.61–7.55 (m, 2H), 7.39–7.23 (m, 6H),
7.08–7.03 (m, 1H), 2.46 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3): d ¼ 162.32,
159.18, 156.99, 154.18, 141.91, 132.46, 129.31, 128.68, 124.68, 122.66, 118.79,
118.15, 116.62, 114.98, 14.99 ppm. MS (ESIþ): m=z ¼ 280.16 [M þ 1]. IR (KBr)
cmꢀ1: 1211 (-C-O-C-), 1717 (-O-C O). HRMS (m=z) for C17H13NO3(M þ H) calcd.
=
280.0975; found 280.1591 (highest ion peak).
3-(4-tert-butylphenoxyiminoethyl)coumarin (Table 5, Entry 2, 10j). 1H
NMR (300 MHz, CDCl3): d ¼ 8.02 (s, 1H), 7.57 (t, J ¼ 6 and 9 Hz, 2H), 7.38–7.26
(m, 4H), 7.17 (d, J ¼ 6 Hz, 2H), 2.45 (s, 3H), 1.32 (s, 9H) ppm. 13C NMR
(75 MHz, CDCl3): d ¼ 162.31, 159.52, 157.01, 156.66, 154.18, 145.58, 143.15,
141.82, 132.38, 128.65, 126.10, 124.71, 118.84, 116.60, 114.72, 34.32, 31.50,
14.90 ppm. MS (ESIþ): m=z ¼ 336.2 [M þ 1]. IR (KBr) cmꢀ1: 1215 (-C-O-C-), 1722
=
(-O-C O). HRMS (m=z) for C21H21NO3(M þ H) calcd. 336.1601, found 336.2207
(highest ion peak).
3-(4-Fluorophenoxyiminoethyl)coumarin (Table 5, Enrty 3, 10b). 1H
NMR (300 MHz, CDCl3): d ¼ 7.97 (s, 1H), 7.45 (d, J ¼ 6 Hz, 1H), 7.32 (t, J ¼ 3
and 6 Hz, 2H), 7.24 (d, J ¼ 3 Hz, 1H), 7.04 (t, J ¼ 6 and 3 Hz, 1H), 6.89-6.84 (m,
2H) ppm. 13C NMR (75 MHz, CDCl3): d ¼ 163.65, 159.96, 159.43, 157.43, 156.36,
142.19, 129.86, 129.45, 122.69, 115.14, 113.32, 112.62, 100.66, 56.01, 15.14 ppm.
MS (ESIþ): m=z ¼ 310.1 [M þ 1]. IR (KBr) cmꢀ1: 1094 (-C-O-C-), 1725 (-O-C O).
=
HRMS (m=z) for C17H12FNO3(M þ H) calcd. 298.0881; found 298.1280 (highest
ion peak).
3-(Phenoxyiminoethyl)-7-methoxycoumarin (Table 5, Entry 4, 11c). 1H
NMR (300 MHz, CDCl3): d ¼ 7.93 (s, 1H), 7.54–7.49 (m, 2H), 7.32–7.09 (m, 4H),
6.99–6.92 (m, 2H), 2.38 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3): d ¼ 162.24,
157.12, 154.22, 141.90, 132.53, 128.68, 124.78, 124.52, 118.76, 118.16, 116.45,
115.72, 14.99 ppm. MS (ESIþ): m=z ¼ 298.1 [M þ 1]. IR (KBr) cmꢀ1: 1194 (-C-O-
=
C-), 1722 (-O-C O). HRMS (m=z) for C18H15NO4(M þ H) calcd. 310.1081; found
310.1431 (highest ion peak).
ACKNOWLEDGMENTS
We acknowledge the financial support from the University Grants Commission
and University of Calcutta. G. P. thanks the Council of Scientific and Industrial
Research, New Delhi, India, for her fellowship (Grant No. 09=028(792)=2010
EMR-I).
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