Regioselective Chlorination and Suzuki–Miyaura Cross-Coupling of 4-Alkoxycoumarins, 4-Alkoxy-2-pyrones, and Related Heterocycles

Article abstract of DOI:10.1002/ejoc.201700837

Chlorination of the coumarin framework was achieved by using trichloroisocyanuric acid, which has several advantages over N-chlorosuccinimide, particularly with respect to cost-effectiveness and toxicity. The Suzuki–Miyaura cross-coupling of the chlorinat

Full text of DOI:10.1002/ejoc.201700837

A Journal of
Accepted Article
Title: Regioselective Chlorination and Suzuki-Miyaura Cross-Coupling
of 4-Alkoxy-2-Coumarins, 2-Pyrones and Related Heterocycles
Authors: Gerard P. McGlacken and Aisling Prendergast
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700837
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700837
Supported by

10.1002/ejoc.201700837
European Journal of Organic Chemistry
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Regioselective Chlorination and Suzuki-Miyaura Cross-Coupling
of 4-Alkoxy-2-Coumarins, 2-Pyrones and Related Heterocycles
Aisling M. Prendergast[a] and Gerard P. McGlacken*[a]
Abstract: Chlorination of the 2-coumarin framework is achieved using
trichloroisocyanuric acid in ethyl acetate, which offers several
advantages over N-chlorosuccinimide, particularly with respect to
cost-effectiveness and toxicity. The Suzuki-Miyaura cross-coupling of
the chlorinated 4-alkoxy-2-coumarins with a range of aryl and
heteroaryl boronic acids using Pd(OAc)2 and SPhos in an
environmentally benign solvent was developed, with yields up to 99%.
Sensitive functional groups such as aldehydes and nitriles are
tolerated, and the conditions were demonstrated on gram scale.
Extension of the cross-coupling methodology to the related 2-pyrone,
2-pyridone and 2-quinolone moieties was highly successful and yields
Figure 1. Regioselective chlorination and Suzuki-Miyaura cross-coupling.
of up to 96% were achieved, which is the first time cross-coupling
conditions have been demonstrated to be general across this range
of heterocyclic substrates. Demethylation of the Suzuki-Miyaura
Results and Discussion
products allows access to 3-aryl-4-hydroxy-2-coumarins.
While N-chlorosuccinimide (NCS) is the reagent of choice in many
cases for introducing chloride to heteroaromatic compounds,
trichloroisocyanuric acid (TCCA) is more atom-economic, more
soluble, less toxic and cheaper.[10] Using TCCA, the optimal
Introduction
conditions for the chlorination of 2-coumarins from 1 to 2 were
found to involve refluxing in EtOAc for 1 h (Scheme 1). While
TCCA is soluble in the reaction mixture, the by-product cyanuric
acid is largely insoluble. Thus the products can be purified via a
simple filtration, followed by recrystallization from EtOH.[11] The
use of TCCA to chlorinate 2-coumarins represents a significant
improvement in efficiency over the previously reported
conditions,[12] for example, 2-coumarin 2b was previously
synthesized in 67% isolated yield after 72 h at 55 °C using a
combination of NCS and trifluoroacetic acid (TFA)[12] whereas
here, using TCCA, 2b can be produced in 64% isolated yield after
1 h at 85 °C.
The formation of aryl-heteroaryl (Ar-HetAr) bonds is an important
transformation in organic synthesis[1] due to the abundance of the
Ar-HetAr moiety in natural products and pharmaceuticals.[2]
Despite the development of modern methods such as direct
arylation,[3] the Suzuki-Miyaura reaction remains, by far, the most
common cross-coupling reaction for large-scale synthesis (>100
mmol scale),[4] and usually involves the cross-coupling of an
organohalide and an organoboron species.[5] Iodides and
bromides have been largely preferred as the organohalide partner
due to their propensity for oxidative addition. However,
organochlorides are more attractive substrates from a cost and
availability viewpoint.[6] In addition, top pharmaceutical companies
are seeking to execute these reactions in more benign solvents.[7]
This report focuses on the application of these principles to
regioselective chlorination and Suzuki-Miyaura cross-coupling of
2-coumarins (Figure 1), which as a substrate class, has been
shown to display a remarkable biological profile including
anticancer, antimicrobial, anti-inflammatory, antithrombotic and
antipsychotic effects.[8] Previous work on Suzuki-Miyaura
reactions at the C-3 position of 4-alkoxy-2-coumarins has
involved bromides.[9]
OR
OR
TCCA (0.5 equiv.)
H
O
Cl
O
EtOAc
85 °C, 1 h
O
O
1
2
O
O
O
Cl
O
Cl
[a]
Department of Chemistry and Analytical and Biological Research
Facility (ABCRF)
University College Cork
O
O
64%
2a
2b
58%
Cork, Ireland.
E-mail: g.mcglacken@ucc.ie;
Scheme 1. Chlorination of 2-coumarins.
http://research.ucc.ie/profiles/D004/gmcglacken
Supporting Information for this article is given via a link at the end of
the document. It contains 1H, 13C and 19F spectra for all novel
compounds, key intermediates and final products; optimization table
for Suzuki-Miyaura cross-coupling of 4a.
This procedure can be extended to the related 2-pyrone
framework (Scheme 2).[11] 2-Pyrones are a less robust substrate
than the corresponding 2-coumarins, which may explain the lower
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10.1002/ejoc.201700837
European Journal of Organic Chemistry
FULL PAPER
yields. It is pleasing, however, that chlorination proceeds cleanly,
Table 1. Optimisation of reaction conditions.
even in the presence of mesyl (4b) and tosyl (4d) groups.
OR
OR
TCCA (0.5 equiv.)
H
O
Cl
O
EtOAc
85 °C, 4-24 h
O
O
3
4
Entry
Ligand
SPhos
SPhos
SPhos
SPhos[d]
RuPhos
PPh3
Base
Solvent
EtOH[b]
2-MeTHF[b]
iPrOAc
iPrOAc
iPrOAc
iPrOAc
iPrOAc
iPrOAc
Conversion (%)
Yield (%)[a]
1
2
3
4
5
6
7
8
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
KOAc
100
63
22[c]
54
O
O
S
S
O
O
O
O
O
O
O
97
80
Cl
Cl
O
Cl
Cl
O
90
70
O
O
O
27%
O
O
4c
4a
4d 40%
57%
4b 31%
100
14
80
12
Scheme 2. Chlorination of 2-pyrones.
SPhos
SPhos
36
29
With the desired 3-chloro-2-coumarins 2 in hand, we sought
reaction conditions which would allow the Suzuki-Miyaura
reaction to occur at this challenging site[13] (Table 1). Suzuki-
Miyaura reactions involving a chloride at the C-3 position of 2-
coumarins have been reported for 4-hydro-[14] and 4-alkyl-2-
coumarins,[15] however, we have observed that the electronic
changes caused by introducing 4-alkoxy groups can cause these
reported conditions to fail.[16] We used a solvent selection guide
to limit our solvent choices to greener options.[7b] The use of EtOH
as solvent (Table 1, entry 1) allowed the full consumption of
starting material 2a, with a low, 22% yield of desired product 5a
along with a 45% yield of dechlorinated side-product 1a.
Switching to an aprotic polar solvent, 2-MeTHF gave a 54% yield
of the desired product without significant dechlorination (Table 1,
entry 2). The optimal solvent was determined to be isopropyl
acetate (iPrOAc) which gave 5a in 80% yield (Table 1, entry 3).
Changing to a palladium(0) source reduced both conversion and
yield (Table 1, entry 4), while changing to the bulkier RuPhos
ligand (Table 1, entry 5) or PPh3 (Table 1, entry 6) offered no
advantages over SPhos. Employing KOAc as base hindered the
reaction (Table 1, entry 7). The best conditions for the reaction
were found when K2CO3 was used as the base, which gave 100%
conversion to the desired product in 82% isolated yield (Table 1,
entry 8). With our optimized conditions in hand, we sought to
demonstrate the variety of aryl boronic acids which were tolerated
by our reaction conditions (Scheme 3). A range of para-
substituted phenylboronic acids were tested, and no significant
electronic effects were observed, with p-OMe phenylboronic acid
giving 5c in 79% yield, while p-CF3 phenylboronic acid gave 5d in
76% yield.
K2CO3
100
84 (82)
[a] Yields were determined using 1H NMR spectroscopy with 1,3,5-
trimethoxybenzene as the internal standard for quantification. Isolated yields in
parenthesis. [b] Temperature was 90 °C. [c] A 45% yield of dechlorinated side-
product 1a was determined from the 1H NMR spectrum of the crude reaction
mixture. [d] Pd2(dba)3 (5 mol-%) was used instead of Pd(OAc)2.
Sensitive functional groups such as aldehydes and esters also
survived the coupling conditions, with 5g and 5h being isolated in
48% and 91% yield respectively. Substituents which could
potential ligate to Pd and inhibit the reaction were well-tolerated,
giving products such as nitrile 5j, primary amine 5l and the nitro
5n in good yields. 4-Styrylboronic acid coupled to give 5k in 77%
isolated yield, with the alkenyl functionality remaining untouched.
Meta-substituted phenylboronic acids gave higher yields that the
corresponding para-substituted phenylboronic acids, e.g. m-OMe
phenylboronic acid gave 5o in 91% yield. A somewhat sterically
hindered ortho-substituted phenylboronic acid also coupled to
give 5p in 56% yield. Having achieved success with a wide range
of substituted phenylboronic acids, we turned our attention
towards more challenging heteroaryl boronic acids (Scheme 4).
2- and 3-Furanylboronic acids coupled successfully to give 5q and
5r in 68% and 64% yield respectively, with the 3-thiopheneboronic
acid giving 5t in 93% isolated yield.
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10.1002/ejoc.201700837
European Journal of Organic Chemistry
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conditions to give the Suzuki-Miyaura products in good to
excellent yields, with the highest yield for this study obtained for
5v in 99% yield.
Scheme 4. Variety of heteroaryl boronic acids tolerated under reaction
conditions.
In addition, a Boc-protected indole boronic acid successfully
underwent the Suzuki-Miyaura cross-coupling (Scheme 5). The
Boc group was deprotected in situ to give 5w as the main product
of the reaction in 55% isolated yield.
Scheme 5. Successful Suzuki-Miyaura cross-coupling and in situ deprotection
of an indole boronic acid.
Given the diverse range of both aryl and heteroaryl boronic acids
which are tolerated by these reaction conditions, we questioned
whether the conditions might also be general for the structurally-
related 3-chloro-2-pyrone, -2-pyridone and -2-quinolone. These
heterocycles, while structurally-related, are chemically quite
different. The nitrogen of the 2-quinolone could potentially ligate
to Pd, inhibiting the reaction, while 2-pyrones and 2-pyridones are
suspected to be less aromatic in character than the corresponding
2-coumarins and 2-quinolones. 2-Pyrones in particular have been
demonstrated to have a rich variety of chemical properties and
can behave like aromatics,[17] dienes[18] and enones.[19] Moreover,
the framework can ring-open under certain cross-coupling
conditions.[20] Thus, 2-pyrones in particular, present significant
chemoselectivity challenges.
Scheme 3. Variety of phenylboronic acids tolerated under reaction conditions.
Benzothiophene 5u, dibenzofuran 5s and dibenzothiophene 5v
substituents were introduced at the 3-position using our
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In the face of these potential challenges, 2-pyrone 4a was
subjected to the Suzuki-Miyaura conditions which had been
developed for 2-coumarin 2a and, to our satisfaction, 2-pyrone 6
could be isolated in 75% yield. 2-Pyridone 7 and 2-quinolone 9
were also coupled in excellent yields,[21] and were isolated in 96%
and 89% respectively (Scheme 6). As far as we are aware, this is
the first time that Suzuki-Miyaura conditions optimized for one of
these heterocyclic substrates has demonstrated generality across
the range of difficult 2-coumarins, 2-pyrones, 2-pyridones and 2-
quinolones substrates.
Scheme 7. Variation of 4-OR groups.
In addition to the important biological activity of 4-alkoxy-2-
coumarins and related heterocycles,[22] many important
coumarins contain a 4-hydroxy-2-coumarin motif, e.g. the anti-
coagulant warfarin. Thus, we sought to gain access to 3-aryl-4-
hydroxy coumarins via –OH protection, chlorination, Suzuki-
Miyaura coupling and deprotection. However, several common
hydroxyl protecting groups (e.g. benzyl and silyl), when present
on our substrates, either shut down the desired chlorination, or
the subsequent Suzuki-Miyaura coupling (see SI for details).
Pleasingly however, a remarkably facile method to cleave the
methyl ether of compound 5a at room temperature was
discovered. Thus arylated coumarin 5a was converted to the
hydroxyl compound 13 in 51% yield using TMSI[23] (formed in situ
from TMSCl and NaI[24]), followed by an acidic workup. It is
noteworthy that previous routes to compound such as 13 require
cyclisation of the appropriate diester,[25] reactions of
diaryliodonium salts[26] or hazardous diazo compounds.[27] It is our
opinion that the presented conditions represent the best route to
diverse substrates of this class.
Scheme 6. Variety of 3-chloro heterocycles tolerated under reaction conditions.
Next, we tested the effect of varying the 4-OR group. The 4-OPh
group can prove more sterically demanding than the 4-OMe group,
and yet it did not hinder the progress of the reaction (Scheme 7).
Compounds 2b and 4c were coupled with phenylboronic acid to
give 11 and 12 in 85% and 76% yields respectively. It is
particularly interesting that no products as a result of an
intramolecular direct arylation process[12] were observed in the
crude reaction mixture. Unfortunately, attempts to couple 4b and
4d gave a mixture of mono- and di-arylated products. Interestingly,
4d gave the 3-Ph-4-OTs-2-pyrone as the major product, with both
the 3-Cl-4-Ph-2-pyrone and the 3,4-diarylated product also
observed. These preliminary results are under further
development, and any successes will be reported in due course.
1. TMSCl, NaI
CH3CN, 25 °C, 20 h
O
OH
2. aq. HCl
O
O
O
O
5a
13
51%
Scheme 8. Demethylation to give 4-hydroxy-2-coumarin.
To further demonstrate the utility and practicality of these
conditions, the synthesis of 5a was performed on a gram-scale,
giving 5a in an isolated yield of 84% without chromatography
(Scheme 9). This constitutes a successful 20x scale-up from the
demonstrated reaction conditions, and no loss of yield is observed.
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10.1002/ejoc.201700837
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EtOH to yield the product as an off-white solid (4.693 g, 86%); m.p. 116-
118 °C (lit.[28] 122-124 °C); 1H NMR (300 MHz, CDCl3) δ 7.81 (dd, J = 7.9,
1.5, 1H), 7.55 (ddd, J = 8.6, 7.4, 1.6, 1H), 7.36 – 7.22 (m, 2H), 5.70 (s, 1H),
4.00 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.5, 162.9, 153.3, 132.4, 123.9,
123.0, 116.8, 115.6, 90.1, 56.4; m/z (ES+): 177 ([M+H]+ 100%).
4-Phenoxy-2-coumarin (1b). See ref.[12]
4-Methoxy-6-methyl-2-pyrone (3a). See ref.[29]
4-Mesyloxy-6-Methyl-2-pyrone (3b):[30]
A stirring suspension of 4-
Scheme 9. Gram-scale synthesis of 5a via Suzuki-Miyaura cross-coupling.
hydroxy-2-pyrone (2.0 g, 15.86 mmol) and K2CO3 (2.6 g, 19.03 mmol) in
acetone (50 mL) was stirred at ambient temperature for 10 min. Mesyl
chloride (1.5 mL, 19.03 mmol) was added, and the mixture was stirred at
ambient temperature for 2 h. The reaction mixture was concentrated under
reduced pressure, and the residue was recrystallized from EtOH to give
the product as an off-white solid (2.619 g, 81%); m.p. 84-85 oC; IRνmax
(film) 1720, 1646, 1571, 1372, 1319; 1H NMR (300 MHz, CDCl3) δ 6.08 (s,
2H), 3.28 (s, 3H), 2.30 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.7, 162.7,
161.4, 100.2, 100.2, 39.0, 20.2; m/z (ES+): 205 ((M+H)+ 30%); HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C7H9O5S 205.0171; Found 205.0168.
Conclusions
We have developed the Suzuki-Miyaura cross-coupling of 4-
alkoxy-3-chloro-2-coumarins in iPrOAc with excellent yields.
Chlorination of the 2-coumarin and 2-pyrone framework is
achieved through reaction with TCCA,
a
cheap and
environmentally-friendly chlorinating agent. The presented
Suzuki-Miyaura reaction conditions are tolerant of a diverse range
of aryl and heteroaryl boronic acids. Conditions can be applied to
the 2-pyrone, 2-pyridone and 2-quinolone frameworks with equal
success. Demethylation of the Suzuki-Miyaura products allows
6-Methyl-4-phenoxy-2-pyrone (3c). See ref.[31]
6-Methyl-4-tosyloxy-2-pyrone (3d). See ref.[32]
access to 3-aryl-4-hydroxy-2-coumarins.
reaction was successfully scaled up to gram quantities.
A Suzuki-Miyaura
4-Methoxy-1,6-dimethyl-2-pyridone:[33]
A mixture of 4-hydroxy-1,6-
dimethyl-2-pyridone (5.0 g, 35.93 mmol), trimethylphosphate (8.8 mL,
75.46 mmol) and K2CO3 (6.0 g, 43.12 mmol) was stirred at 140 °C for 18
h. While still warm, the reaction mixture was diluted with H2O (50 mL) and
extracted with EtOAc (3 x 50 mL). The combined organic layers were dried
over MgSO4 and concentrated under reduced pressure. The residue was
recrystallized from DCM/hexanes to yield the product as a yellow solid
(3.194 g, 58%); m.p. 56-58 °C (lit.[33] 115-116 °C); 1H NMR (300 MHz,
CDCl3) δ 5.83 (d, J = 2.8, 1H), 5.79 – 5.74 (m, 1H), 3.74 (s, 3H), 3.46 (s,
3H), 2.30 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.2, 165.4, 146.0, 100.7,
94.5, 55.2, 30.5, 20.9; m/z (ES+): 154 ([M+H]+ 100%).
Experimental Section
1. General Information: Melting point determinations were performed by
the open capillary method and are reported uncorrected. 1H, 13C and 19F
NMR spectra were recorded at 25 ºC in CDCl3 at 300, 75 and 282 MHz
unless otherwise specified, with TMS as the internal standard for
calibration. Chemical shifts (δH, δC and δF) were expressed as parts per
million (ppm) positive shift being downfield from TMS; coupling constants
(J) are expressed in Hertz (Hz). High-resolution mass spectra (HRMS)
were obtained on a TOF MS instrument with ESI source. Literature
citations are provided for known compounds and representative
characterization data. IR spectra were recorded on an FT-IR spectrometer
as a thin film (liquid samples) or applied as a solution in dichloromethane,
and the dichloromethane was allowed to evaporate (solid samples).
Column chromatography was carried out using 60 Å (35-70 μm) silica. TLC
was carried out on pre-coated silica gel plates (Merck 60 PF254).
Visualisation was achieved by UV light. Reagents were used as purchased
from commercial sources. Isopropyl acetate was distilled over potassium
carbonate and stored under nitrogen prior to use. HPLC grade CH3CN was
stored over 4Å molecular sieves prior to use in reactions. Temperatures
(°C) are reported as the temperature set-point of the oil bath.
1-Ethyl-4-methoxy-2-quinolone:
A mixture of 1-ethyl-4-hydroxy-2-
quinolone (0.5 g, 2.64 mmol), trimethylphosphate (0.7 mL, 5.55 mmol) and
K2CO3 (0.4 g, 3.17 mmol) was stirred at 140 °C for 2 h. While still warm,
the reaction mixture was diluted with H2O (30 mL) and extracted with
EtOAc (3 x 30 mL). The combined organic layers were dried over MgSO4
and concentrated under reduced pressure. The residue was recrystallized
from EtOH to yield the product as an orange solid (0.353 g, 66%); m.p. 60-
63 °C; IRνmax (film) 2981, 1634, 1575, 1324, 1122; 1H NMR (400 MHz,
CDCl3) δ 7.98 (dd, J = 8.0, 1.5, 1H), 7.58 (ddd, J = 9.6, 7.2, 1.6, 1H), 7.36
(d, J = 8.6, 1H), 7.21 (td, J = 7.6, 0.7, 1H), 6.03 (s, 1H), 4.33 (q, J = 7.1,
2H), 3.94 (s, 3H), 1.34 (t, J = 7.1, 3H); 13C NMR (100 MHz, CDCl3) δ 163.4,
162.6, 138.7, 131.2, 123.6, 121.4, 116.7, 113.9, 96.5, 55.8, 36.8, 12.9; m/z
(ES+): 204 ([M+H]+ 100%); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C12H14O2N 204.1025; Found 204.1023.
2. Experimental Procedures
2.2 Typical procedure for chlorination of 2-coumarins (1) and 2-
pyrones (3): To a mixture of 2-coumarin or 2-pyrone (1.0 equiv.) and
trichloroisocyanuric acid (0.5 equiv.) was slowly added EtOAc (3 mL/mmol
substrate). The mixture was stirred at 85 °C until judged to be complete by
TLC analysis (1 h for 2-coumarins 1, 6-24 h for 2-pyrones 3), then cooled
to ambient temperature. The reaction mixture was filtered through fluted
filter paper to remove the insoluble material, and the filtrate was
concentrated under reduced pressure. The residues were recrystallized
from EtOH to yield the products.
2.1 Synthesis of 4-alkoxy-2-coumarins, 2-pyrones, 2-pyridone and 2-
quinolone
4-Methoxy-2-coumarin (1a):[28] A mixture of 4-hydroxy-2-coumarin (5.0 g,
30.84 mmol), trimethylphosphate (7.6 mL, 64.76 mmol) and K2CO3 (5.1 g,
37.01 mmol) was stirred at 140 °C for 1 h. While still warm, the reaction
mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 x 50
mL). The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure. The residue was recrystallized from
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3-Chloro-4-methoxy-2-coumarin (2a):[34] Cream solid (1.112 g, 47%
[from 2.0 g (11.35 mmol) 1a]); m.p. 84-85 °C (lit.[34] 87.9-88.6 °C); 1H NMR
(300 MHz, CDCl3) δ 7.85 – 7.75 (m, 1H), 7.63 – 7.51 (m, 1H), 7.38 – 7.28
(m, 2H), 4.34 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.1, 159.6, 151.2,
132.4, 124.6, 123.4, 117.2, 116.7, 106.0, 61.6; m/z (ES+) 211 (35Cl (M+H)+
100%), 213 (37Cl (M+H)+ 32%).
3H); 13C NMR (75 MHz, CDCl3) δ 161.7, 160.7, 145.3, 105.2, 94.7, 56.4,
31.9, 21.4; m/z (ES+): 188 (35Cl (M+H)+) 78%, 190 (37Cl (M+H)+) 26%;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C8H11NO2Cl 188.0478; Found
188.0480.
3-Chloro-1-ethyl-4-methoxy-2-quinolone (9): (EtOAc:hexanes 50:50),
yellow solid (1.033 g, 68% [from 1.3 g (6.40 mmol) 4-methoxy-1-ethyl-2-
quinolone]); m.p. 73-76 °C; IRνmax (film) 1652, 1615, 1598, 1113, 755; 1H
NMR (300 MHz, CDCl3) δ 7.92 (dd, J = 8.0, 1.4, 1H), 7.60 (ddd, J = 8.7,
7.2, 1.6, 1H), 7.40 (d, J = 8.5, 1H), 7.33 – 7.22 (m, 1H), 4.40 (q, J = 7.1,
2H), 4.12 (s, 3H), 1.37 (t, J = 7.1, 3H); 13C NMR (101 MHz, CDCl3) δ 159.7,
159.4, 137.1, 131.3, 123.8, 122.4, 117.8, 115.0, 114.2, 61.1, 38.6, 12.7;
m/z (ES+) 238 (35Cl (M+H)+ 14%), 240 (37Cl (M+H)+ 6%); HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C12H13O2NCl 238.0635; Found 238.0632.
3-Chloro-4-phenoxy-2-coumarin (2b):[12] Pale orange solid (0.727 g,
64% [from 1.0 g (4.20 mmol) 1b]); m.p. 70-75 °C (lit.[12] 74-75 °C); 1H NMR
(300 MHz, CDCl3) δ 7.71 – 7.53 (m, 2H), 7.47 – 7.24 (m, 4H), 7.14 (t, J =
7.4, 1H), 7.05 – 6.94 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 158.8, 158.4,
155.6, 151.7, 132.8, 130.1, 125.0, 124.1, 123.8, 117.0, 116.7, 116.1,
112.0; m/z (ES+) 273 (35Cl (M+H)+ 58%), 275 (37Cl (M+H)+ 18%).
3-Chloro-4-methoxy-6-methyl-2-pyrone (4a):[35] Yellow solid (1.534 g,
57% [from 2.17 g (15.48 mmol) 3a]); m.p. 140-142 °C (lit.[35] 147-148 °C);
IRνmax (film) 1704 , 1537, 1322, 1233, 737; 1H NMR (300 MHz, CDCl3) δ
6.14 (d, J = 0.6, 1H), 4.00 (s, 3H), 2.31 (d, J = 0.7, 3H); 13C NMR (75 MHz,
CDCl3) δ 165.2, 161.9, 160.9, 99.3, 95.2, 57.3, 20.3; m/z (ES+) 175 (35Cl
(M+H)+ 100%), 177 (37Cl (M+H)+ 40%); HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C7H8ClO3 175.0162; Found 175.0154; Anal. Calc. for C7H7ClO3:
C, 48.16; H, 4.04; Found: C, 48.27; H, 4.08.
2.4 Typical procedure for Suzuki-Miyaura cross-coupling (synthesis
of compounds 5, 8, 10, 11, 12): A Schlenk tube was heated under
vacuum and refilled with N2 three times, then the Schlenk tube was allowed
to cool. Substrate 2, 4c, 7 or 9 (0.237 mmol), boronic acid (0.356 mmol),
Pd(OAc)2 (0.012 mmol), SPhos (0.036 mmol) and K2CO3 (0.521 mmol)
were added. The Schlenk tube was evacuated and refilled with N2 three
times. iPrOAc (7 mL) was added via syringe. The Schlenk tube was placed
in an oil bath preheated to 100 °C. The reaction was stirred at this
temperature for 16 h, then cooled to ambient temperature. The reaction
mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 x 10
mL). The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure. The residue was purified by column
chromatography (eluent in parenthesis) to afford the title compounds.
3-Chloro-4-mesyloxy-6-methyl-2-pyrone (4b): Off-white solid (0.736 g,
31% [from 2.0 g (9.79 mmol) 3b]); m.p. 107-110 oC; IRνmax (film) 1738,
1642, 1556, 1376, 1189, 790; 1H NMR (400 MHz, CDCl3) δ 6.37 (d, J =
0.7, 1H), 3.37 (d, J = 0.5, 3H), 2.32 (d, J = 0.6, 3H); 13C NMR (101 MHz,
CDCl3) δ 161.4, 159.7, 156.2, 109.6, 101.7, 40.1, 20.0; m/z (ES+): 239
(
35Cl (M+H)+ 50%), 241 (37Cl (M+H)+ 26%); HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C7H8O5SCl 238.9781; Found 238.9787.
4-Methoxy-3-phenyl-2-coumarin (5a):[36] (DCM), yellow solid (0.049 g,
82%); m.p. 111-114 °C (lit.[36] 117-119 °C); 1H NMR (300 MHz, CDCl3) δ
7.87 (dd, J = 7.9, 1.3, 1H), 7.60 – 7.51 (m, 1H), 7.50 – 7.26 (m, 7H), 3.56
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.4, 162.9, 152.5, 132.4, 132.0,
131.0, 128.4, 128.3, 124.0, 123.9, 117.8, 116.5, 111.1, 61.3; m/z (ES+)
253 ((M+H)+ 12%).
3-Chloro-6-methyl-4-phenoxy-2-pyrone (4c):[12] Purified by column
chromatography (EtOAc:hexanes 30:70), pale yellow solid (0.078 g, 27%
[from 0.16 g (0.80 mmol) 3c]); m.p. 100-103 °C (lit.[12] 96-97 °C); 1H NMR
(300 MHz, CDCl3) δ 7.52-7.41 (m, 2H), 7.40-7.26 (m, 1H), 7.16-7.04 (m,
2H), 5.68 (s, 1H), 2.19 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.6, 161.4,
160.9, 152.8, 130.4, 126.5, 120.8, 101.7, 97.6, 20.1; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C12H10ClO3 237.0318; Found 237.0312.
4-Methoxy-3-tolyl-2-coumarin (5b): (DCM), white solid (0.056 g, 89%);
m.p. 128-130 °C; IR νmax (film) 1702, 1608, 1571, 1345, 1106; 1H NMR
(300 MHz, CDCl3) δ 7.86 (dd, J = 7.9, 1.4, 1H), 7.54 (ddd, J = 8.4, 7.3, 1.6,
1H), 7.40 – 7.20 (m, 6H), 3.57 (s, 3H), 2.40 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 163.6, 162.7, 152.4, 138.3, 131.8, 130.8, 129.3, 129.1, 124.0,
123.8, 117.8, 116.4, 111.0, 61.2, 21.4; m/z (ES+) 267 ((M+H)+ 100%);
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H15O3 267.1021; Found
267.1011.
3-Chloro-6-methyl-4-tosyloxy-2-pyrone (4d): Pale yellow solid (0.673 g,
40% [from 1.5 g (5.35 mmol) 3d]); m.p. 144-147 °C; IRνmax (film) 1741,
1547, 1386, 1195, 666; 1H NMR (300 MHz, CDCl3) δ 7.86 (d, J = 8.4, 2H),
7.39 (d, J = 8.1, 2H), 6.43 (d, J = 0.8, 1H), 2.48 (s, 3H), 2.30 (d, J = 0.7,
3H); 13C NMR (75 MHz, CDCl3) δ 161.0, 159.8, 156.5, 147.0, 131.9, 130.3,
128.5, 110.0, 101.6, 21.9, 19.9; m/z (ES+) 315 (35Cl (M+H)+ 100%), 317
(
37Cl (M+H)+ 40%); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C13H12ClSO5
4-Methoxy-3-(4-methoxyphenyl)-2-coumarin (5c): (DCM), yellow solid
(0.053 g, 79%); m.p. 134-138 °C; IR νmax (film) 1710, 1606, 1512, 1347,
1246, 1109; 1H NMR (300 MHz, CDCl3) δ 7.86 (dd, J = 7.9, 1.4, 1H), 7.60
– 7.47 (m, 1H), 7.45 – 7.36 (m, 2H), 7.36 – 7.24 (m, 2H), 7.06 – 6.90 (m,
2H), 3.85 (s, 3H), 3.58 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.7, 162.7,
159.6, 152.4, 132.1, 131.8, 124.3, 124.0, 123.8, 117.9, 116.4, 113.8, 111.0,
61.1, 55.3; m/z (ES+) 283 ((M+H)+ 100%); HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C17H15O4 283.0970; Found 283.0970.
315.0094; Found 315.0086.
2.3 Typical procedure for chlorination of 2-pyridone (7) and 2-
quinolone (9): To a stirring solution of substrate (1.0 equiv.) and N-
chlorosuccinimide (1.2 equiv.) in CHCl3 (5 mL/mmol substrate) in a round-
bottomed flask was added trifluoroacetic acid (1.2 equiv.). The flask was
covered in aluminium foil and the reaction mixture was stirred at 55 °C
overnight. The reaction mixture was allowed to cool to ambient
temperature. The mixture was washed with saturated aqueous NaHCO3
(1 x 20 mL) and H2O (2 x 20 mL). The organic layer was dried over MgSO4
and concentrated under reduced pressure. The residue was purified by
column chromatography (eluent in parenthesis) to yield the title products.
4-Methoxy-3-(4-(trifluoromethyl)phenyl)-2-coumarin (5d): (DCM),
yellow solid (0.058 g, 76%); m.p. 153-156 °C; IR νmax 1700, 1612, 1567,
1327, 1121; 1H NMR (300 MHz, CDCl3) δ 7.89 (dd, J = 8.0, 1.5, 1H), 7.71
(d, J = 8.2, 2H), 7.67 – 7.53 (m, 3H), 7.41 – 7.28 (m, 2H), 3.59 (s, 3H); 13
C
NMR (75 MHz, CDCl3) δ 163.7, 162.9, 152.6, 136.2, 132.5, 131.4, 130.5
(q, J = 32), 125.2 (q, J = 4), 124.3, 124.0, 124.0 (q, J = 272), 117.4, 116.6,
110.2, 61.6; 19F NMR (282 MHz, CDCl3) δ -63; m/z (ES+) 321 ((M+H)+
100%); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H12O3F3 321.0739;
Found 321.0735.
3-Chloro-4-methoxy-1,6-dimethyl-2-pyridone (7): (DCM), white solid
(0.445 g, 30% [from 1.2
g (7.83 mmol) 4-methoxy-1,6-dimethyl-2-
pyridone]); m.p. 180-182 °C; IRνmax (film) 1647, 1589, 1535, 1083, 751; 1H
NMR (300 MHz, CDCl3) δ 5.97 (s, 1H), 3.92 (s, 3H), 3.54 (s, 3H), 2.38 (s,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700837
European Journal of Organic Chemistry
FULL PAPER
4-Methoxy-3-(4-fluorophenyl)-2-coumarin (5e): (DCM), yellow solid
(0.046 g, 72%); m.p. 135-137 °C; IR νmax (film) 1699, 1609, 1570, 1222,
1161; 1H NMR (300 MHz, CDCl3) δ 7.87 (dd, J = 7.9, 1.6, 1H), 7.56 (ddd,
J = 8.4, 7.3, 1.6, 1H), 7.51 – 7.41 (m, 2H), 7.39 – 7.27 (m, 2H), 7.21 – 7.08
(m, 2H), 3.58 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.3, 163.2, 162.6 (d,
J = 248), 152.5, 132.8 (d, J = 8), 132.2, 128.1 (d, J = 4), 124.1, 123.9,
117.6, 116.5, 115.4 (d, J = 22), 110.4, 61.3; 19F NMR (282 MHz, CDCl3) δ
-113; m/z (ES+) 271 ((M+H)+ 100%); HRMS (ESI-TOF) m/z: [M+H]+ Calcd
for C16H12O3F 271.0770; Found 271.0770.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H15O3 279.1021; Found
279.1025.
3-(3-Aminophenyl)-4-methoxy-2-coumarin (5l): (DCM), orange solid
(0.050 g, 79%); m.p. 131-136 °C; IR νmax (film) 3367, 1712, 1645, 1610,
1570, 1266, 738; 1H NMR (300 MHz, CDCl3) δ 7.90 – 7.81 (m, 1H), 7.53
(ddd, J = 8.4, 7.3, 1.6, 1H), 7.38 – 7.14 (m, 3H), 6.86 – 6.76 (m, 2H), 6.71
(ddd, J = 8.0, 2.4, 1.0, 1H), 3.63 (s, 3H), 3.53 (br s, 2H); 13C NMR (75 MHz,
CDCl3) δ 163.5, 162.6, 152.4, 146.4, 133.3, 131.9, 129.2, 124.0, 123.9,
121.5, 117.8, 117.7, 116.4, 115.4, 110.8, 61.1; m/z (ES+) 268 ((M+H)+
100%); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H14NO3 268.0974;
Found 268.0961.
4-Methoxy-3-(4-(trifluoromethoxy)phenyl)-2-coumarin (5f): (DCM),
pale yellow solid (0.061 g, 77%); m.p. 145-146 °C; IR νmax (film) 1700, 1616,
1570, 1351, 1258, 1211; 1H NMR (300 MHz, CDCl3) δ 7.88 (dd, J = 7.9,
1.4, 1H), 7.62 – 7.48 (m, 3H), 7.41 – 7.27 (m, 4H), 3.59 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 163.5, 163.1, 152.6, 149.1 (q, J = 2), 132.5, 132.3,
130.9, 124.2, 123.9, 120.6, 120.5 (q, J = 258), 117.5, 116.6, 110.2, 61.4;
19F NMR (282 MHz, CDCl3) δ -58; m/z (ES+) 337 ((M+H)+ 100%); HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C17H12O4F3 337.0688; Found 337.0671.
4-Methoxy-3-(3-(trifluoromethyl)phenyl)-2-coumarin (5m): (DCM),
yellow solid (0.066 g, 87%); m.p. 95-97 °C; IR νmax (film) 1716, 1610, 1570,
1330, 1125; 1H NMR (300 MHz, CDCl3) δ 7.93 – 7.84 (m, 1H), 7.79 – 7.53
(m, 5H), 7.40 – 7.28 (m, 2H), 3.57 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
163.7, 162.9, 152.6, 134.4, 133.2, 132.5, 130.8 (q, J = 33), 128.8, 127.8
(q, J = 4), 125.2 (q, J = 4), 124.3, 124.0, 124.0 (q, J = 273), 117.4, 116.6,
110.1, 61.6; 19F NMR (282 MHz, CDCl3) δ -63; m/z (ES+) 321 ((M+H)+
100%); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H12O3F3 321.0739
Found 321.0734.
4-Methoxy-3-(4-formylphenyl)-2-coumarin (5g): (DCM:MeOH 99:1),
yellow solid (0.032 g, 48%); m.p. 154-155 °C; IR νmax (film) 2729, 1701,
1607, 1567, 1348, 1207; 1H NMR (300 MHz, CDCl3) δ 10.07 (s, 1H), 8.02
– 7.93 (m, 2H), 7.89 (dd, J = 8.0, 1.3, 1H), 7.74 – 7.65 (m, 2H), 7.64 – 7.53
(m, 1H), 7.42 – 7.28 (m, 2H), 3.60 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
191.7, 163.8, 162.7, 152.7, 138.9, 136.0, 132.6, 131.8, 129.5, 124.3, 124.0,
117.4, 116.6, 110.3, 61.7; m/z (ES+) 281 ((M+H)+ 100%); HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C17H13O4 281.0814; Found 281.0815.
4-Methoxy-3-(3-nitrophenyl)-2-coumarin (5n): (DCM), yellow solid
(0.058 g, 82%); m.p. 153-155 °C; IR νmax (film) 1714, 1611, 1570, 1528,
1349, 1298, 1106; 1H NMR (300 MHz, CDCl3) δ 8.39 (t, J = 1.9, 1H), 8.26
(ddd, J = 8.3, 2.3, 1.1, 1H), 7.95 – 7.82 (m, 2H), 7.69 – 7.57 (m, 2H), 7.42
– 7.31 (m, 2H), 3.62 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.2, 162.7,
152.7, 148.2, 137.1, 134.1, 132.8, 129.3, 125.9, 124.5, 124.1, 123.3, 117.2,
116.7, 109.6, 61.9; m/z (ES+) 298 ((M+H)+ 100%); HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C16H12NO5 298.0715; Found 298.0720.
Ethyl 4-(4-methoxy-2-oxo-2H-chromen-3-yl)benzoate (5h): (DCM),
yellow solid (0.070 g, 91%); m.p. 131-133 °C; IR νmax (film) 1715, 1610,
1573, 1348, 1274; 1H NMR (300 MHz, CDCl3) δ 8.18 – 8.07 (m, 2H), 7.88
(dd, J = 8.0, 1.3, 1H), 7.64 – 7.52 (m, 3H), 7.41 – 7.28 (m, 2H), 4.41 (q, J
= 7.1, 2H), 3.57 (s, 3H), 1.41 (t, J = 7.1, 3H); 13C NMR (75 MHz, CDCl3) δ
166.2, 163.5, 162.9, 152.6, 137.2, 132.4, 131.1, 130.4, 129.4, 124.2, 124.0,
117.5, 116.6, 110.4, 61.5, 61.1, 14.3; m/z (ES+) 325 ((M+H)+ 100%);
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H17O5 325.1076; Found
325.1079.
4-Methoxy-3-(3-methoxyphenyl)-2-coumarin (5o): (DCM), yellow oil
(0.061 g, 91%); IR νmax (film) 1715, 1611, 1572, 1347, 1214, 1106; 1H NMR
(300 MHz, CDCl3) δ 7.87 (dd, J = 7.9, 1.4, 1H), 7.55 (ddd, J = 8.6, 7.4, 1.6,
1H), 7.44 – 7.22 (m, 3H), 7.10 – 6.87 (m, 3H), 3.83 (s, 3H), 3.60 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 163.3, 162.8, 159.4, 152.5, 133.7, 132.0,
129.3, 124.0, 123.9, 123.5, 117.7, 116.6, 116.4, 114.1, 110.7, 61.1, 55.3;
m/z (ES+) 283 ((M+H)+ 100%); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C17H15O4 283.0970; Found 283.0961.
3-(4-Acetylphenyl)-4-methoxy-2-coumarin (5i): (DCM), white solid
(0.053 g, 76%); m.p. 183-187 °C; IR νmax (film) 1712, 1682, 1611, 1571,
1347, 1267; 1H NMR (300 MHz, CDCl3) δ 8.10 – 7.99 (m, 2H), 7.89 (dd, J
= 7.9, 1.5, 1H), 7.65 – 7.52 (m, 3H), 7.41 – 7.28 (m, 2H), 3.59 (s, 3H), 2.65
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 197.6, 163.6, 162.9, 152.6, 137.5,
136.8, 132.5, 131.3, 128.2, 124.2, 124.0, 117.5, 116.6, 110.3, 61.6, 26.7;
m/z (ES+) 295 ((M+H)+ 100%); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C18H15O4 295.0970; Found 295.0952.
4-Methoxy-3-(2-(trifluoromethyl)phenyl)-2-coumarin (5p): (DCM),
yellow oil (0.042 g, 56%); IR νmax (film) 1716, 1613, 1573, 1350, 1315; 1H
NMR (300 MHz, CDCl3) δ 7.89 (dd, J = 8.0, 1.3, 1H), 7.82 – 7.74 (m, 1H),
7.68 – 7.45 (m, 4H), 7.41 – 7.27 (m, 2H), 3.56 (s, 3H); 13C NMR (151 MHz,
CDCl3) δ 163.0, 161.5, 152.6, 133.7, 132.5 (q, J = 29), 132.3, 131.7, 130.7
(q, J = 30), 129.2, 126.6 (q, J = 5), 124.2, 124.1, 123.9 (d, J = 274), 116.9,
116.6, 105.7, 60.3; 19F NMR (282 MHz, CDCl3) δ -61; m/z (ES+) 321
((M+H)+ 100%); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H12O3F3
321.0739; Found 321.0726.
3-(4-Cyanophenyl)-4-methoxy-2-coumarin (5j): (DCM), white solid
(0.055 g, 83%); m.p. 199-202 °C; IR νmax (film) 2225, 1699, 1610, 1454,
1351; 1H NMR (300 MHz, CDCl3) δ 7.89 (dd, J = 8.0, 1.3, 1H), 7.79 – 7.71
(m, 2H), 7.68 – 7.56 (m, 3H), 7.41 – 7.30 (m, 2H), 3.60 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 164.1, 162.5, 152.7, 137.4, 132.8, 132.0, 131.8, 124.4,
124.1, 118.5, 117.2, 116.7, 112.2, 110.0, 61.8; m/z (ES+) 278 ((M+H)+
100%); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H12NO3 278.0817;
Found 278.0808.
3-(Furan-2-yl)-4-methoxy-2-coumarin (5q): (DCM), yellow oil (0.039 g,
68%); IR νmax (film) 1723, 1625, 1610, 1549, 1348, 1328, 1124; 1H NMR
(300 MHz, CDCl3) δ 7.91 – 7.84 (m, 1H), 7.61 – 7.51 (m, 2H), 7.37 – 7.27
(m, 2H), 6.82 (dd, J = 3.3, 0.8, 1H), 6.55 (dd, J = 3.3, 1.9, 1H), 3.80 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 163.9, 161.9, 152.4, 144.5, 142.9, 132.5,
124.2, 124.0, 117.3, 116.6, 113.9, 111.6, 101.4, 60.5; m/z (ES+) 243
((M+H)+ 100%); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C14H11O4
243.0657; Found 243.0652.
4-Methoxy-3-(4-vinylphenyl)-2-coumarin (5k): (DCM), yellow solid
(0.051 g, 77%); m.p. 102-104 °C; IR νmax (film) 1713, 1608, 1571, 1346;
1H NMR (300 MHz, CDCl3) δ 7.92 – 7.82 (m, 1H), 7.60 – 7.41 (m, 5H),
7.39 – 7.26 (m, 2H), 6.76 (dd, J = 17.6, 10.9, 1H), 5.81 (dd, J = 17.6, 0.8,
1H), 5.30 (dd, J = 10.9, 0.8, 1H), 3.59 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 163.3, 163.0, 152.5, 137.7, 136.4, 132.0, 131.7, 131.1, 126.1, 124.1,
123.9, 117.7, 116.5, 114.6, 110.9, 61.3; m/z (ES+) 279 ((M+H)+ 100%);
3-(Furan-3-yl)-4-methoxy-2-coumarin (5r): (EtOAc:hexanes 10:90),
white solid (0.037 g, 64%); m.p. 97-99 °C; IR νmax (film) 1710, 1614, 1602,
1538, 1329, 1161; 1H NMR (300 MHz, CDCl3) δ 8.18 (d, J = 0.6, 1H), 7.80
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700837
European Journal of Organic Chemistry
FULL PAPER
(dd, J = 7.9, 1.4, 1H), 7.54 (ddd, J = 10.2, 5.3, 1.6, 2H), 7.42 – 7.28 (m,
2H), 7.10 – 6.92 (m, 1H), 3.87 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.7,
162.1, 152.2, 144.3, 142.5, 131.7, 124.3, 123.4, 117.5, 116.6, 115.8, 111.2,
108.1, 60.8; m/z (ES+) 243 ((M+H)+ 100%); HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C14H11O4 243.0657; Found 243.0656.
31.4, 21.6; m/z (ES+) 230 ((M+H)+ 100%); HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C14H16NO2 230.1181; Found 230.1180.
1-Ethyl-4-methoxy-3-phenyl-2-quinolone (10): (EtOAc:hexanes 10:90),
clear colourless oil (0.032 g, 91%); IR νmax (film) 1635, 1593, 1356, 1111;
1H NMR (400 MHz, CDCl3) δ 8.03 (dd, J = 8.0, 1.3, 1H), 7.66 – 7.56 (m,
1H), 7.55 – 7.48 (m, 2H), 7.48 – 7.31 (m, 4H), 7.30 – 7.20 (m, 1H), 4.39 (q,
J = 7.1, 2H), 3.50 (s, 3H), 1.38 (t, J = 7.1, 3H); 13C NMR (101 MHz, CDCl3)
δ 162.9, 160.4, 138.4, 133.5, 130.9, 130.9, 128.1, 127.7, 124.4, 121.7,
119.3, 118.5, 113.8, 60.8, 37.8, 12.8; m/z (ES+) 280 ((M+H)+ 100%);
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H18NO2 280.1338; Found
280.1335.
3-(Dibenzo[b,d]furan-4-yl)-4-methoxy-2-coumarin (5s): (DCM), white
solid (0.068 g, 84%); m.p. 196-198 °C; IR νmax (film) 1714, 1645, 1570,
1349; 1H NMR (300 MHz, CDCl3) δ 8.05 – 7.90 (m, 3H), 7.64 – 7.49 (m,
3H), 7.49 – 7.29 (m, 5H), 3.50 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.7,
162.8, 156.2, 154.7, 152.7, 132.3, 130.0, 127.4, 124.5, 124.2, 124.1, 124.1,
123.0, 122.8, 121.2, 120.8, 117.6, 117.3, 116.6, 112.0, 104.3, 60.6; m/z
(ES+) 343 ((M+H)+ 100%); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C22H15O4 343.0970; Found 343.0960.
4-Phenoxy-3-phenyl-2-coumarin (11): (EtOAc:hexanes 10:90), white
solid (0.063 g, 85%); m.p. 191-194 °C; IR νmax (film) 1723 1625, 1483,
1350, 1207; 1H NMR (300 MHz, CDCl3) δ 7.63 (dd, J = 8.0, 1.5, 1H), 7.56
(ddd, J = 8.8, 7.3, 1.6, 1H), 7.47 – 7.32 (m, 3H), 7.31 – 7.10 (m, 6H), 7.00
– 6.90 (m, 1H), 6.84 – 6.75 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.4,
158.6, 156.5, 153.1, 132.3, 130.4, 130.1, 129.7, 128.4, 128.0, 124.4, 124.3,
123.2, 118.3, 117.0, 116.8, 116.3; m/z (ES+) 315 ((M+H)+ 100%); HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C21H15O3 315.1021; Found 315.1013.
4-Methoxy-3-(thiophen-3-yl)-2-coumarin (5t): (DCM), yellow oil (0.057
g, 93%); IR νmax (film) 1717, 1610, 1573, 1341, 1326, 756; 1H NMR (300
MHz, CDCl3) δ 7.85 (dd, J = 7.9, 1.6, 1H), 7.68 – 7.63 (m, 1H), 7.54 (ddd,
J = 8.7, 7.3, 1.6, 1H), 7.43 – 7.27 (m, 4H), 3.66 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 163.4, 162.8, 152.3, 132.0, 131.2, 129.6, 126.9, 124.9, 124.2,
123.8, 117.7, 116.5, 107.9, 60.8; m/z (ES+) 259 ((M+H)+ 100%); HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C14H11O3S 259.0429; Found 259.0432.
6-Methyl-4-phenoxy-3-phenyl-2-pyrone (12): (EtOAc:hexanes 8:92),
off-white solid (0.050 g, 76%); m.p. 129-133 °C; IR νmax (film) 1716, 1647,
1566, 1489, 1345, 1220; 1H NMR (300 MHz, CDCl3) δ 7.59 – 7.50 (m, 2H),
7.44 – 7.33 (m, 4H), 7.33 – 7.19 (m, 2H), 7.07 – 6.98 (m, 2H), 5.72 (d, J =
0.8, 1H), 2.20 (d, J = 0.8, 3H); 13C NMR (75 MHz, CDCl3) δ 164.2, 163.9,
162.1, 153.7, 130.8, 130.4, 130.2, 128.0, 127.8, 125.6, 120.5, 108.7, 98.4,
20.2; m/z (ES+) 279 ((M+H)+ 100%); HRMS (ESI-TOF) m/z: [M+H]+ Calcd
for C18H15O3 279.1021; Found 279.1018.
3-(Benzo[b]thiophen-2-yl)-4-methoxy-2-coumarin (5u): (DCM), yellow
solid (0.055 g, 75%); m.p. 132-136 °C; IR νmax (film) 1720, 1608, 1554,
1351, 1328, 749; 1H NMR (300 MHz, CDCl3) δ 7.95 (d, J = 0.6, 1H), 7.90
– 7.75 (m, 3H), 7.57 (ddd, J = 8.4, 7.3, 1.6, 1H), 7.41 – 7.28 (m, 4H), 3.90
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.8, 161.8, 152.4, 140.9, 139.1,
132.6, 132.5, 127.6, 125.0, 124.4, 124.4, 124.1, 124.0, 121.9, 117.2, 116.7,
107.8, 61.3; m/z (ES+) 309 ((M+H)+ 100%); HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C18H13O3S 309.0585; Found 309.0590.
2.5 Demethylation of Suzuki-Miyaura product (5a)
3-(Dibenzo[b,d]thiophen-4-yl)-4-methoxy-2-coumarin (5v): (DCM),
yellow solid (0.840 g, 99%); m.p. 191-196 °C; IR νmax (film) 1713, 1611,
1566, 1349, 754; 1H NMR (300 MHz, CDCl3) δ 8.27 – 8.12 (m, 2H), 7.94
(dd, J = 8.0, 1.5, 1H), 7.86 – 7.75 (m, 1H), 7.65 – 7.28 (m, 7H), 3.50 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 163.2, 162.5, 152.7, 141.7, 139.4, 135.8,
135.8, 132.4, 129.8, 127.9, 127.0, 124.7, 124.6, 124.2, 124.1, 122.9, 121.9,
121.8, 117.3, 116.6, 107.1, 60.3; m/z (ES+) 359 ((M+H)+ 100%); HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C22H15O3S 359.0742; Found 359.0746.
4-Hydroxy-3-phenyl-2-coumarin (13):[39] To an oven-dried 5 mL reaction
tube was added NaI (120 mg, 0.792 mmol) and CH3CN (1 mL), and the
mixture was stirred at ambient temperature. To the stirring mixture was
added TMSCl (0.05 mL, 0.396 mmol). The mixture was stirred at ambient
temperature for 1 h. 4-Methoxy-3-phenyl-2-coumarin 5a (50 mg, 0.198
mmol) was added to the stirring mixture. The mixture was stirred at 25 °C
overnight with the reaction tube open to the air, then poured into a beaker
containing cold 1M HCl (15 mL). The mixture was extracted with EtOAc (3
x 15 mL). The combined organic layers were washed with 5% aqueous
sodium thiosulfate (25 mL), dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by column chromatography
(gradient EtOAc:hexanes 20:80 to 50:50) to yield the product as a pale
pink solid (0.024 g, 51%); m.p. 232-233 °C (lit.[39] 232-233 °C); 1H NMR
(300 MHz, DMSO-d6) δ 8.02 (dd, J = 7.9, 1.2, 1H), 7.72 – 7.61 (m, 1H),
7.49–7.31 (m, 7H); 13C NMR (75 MHz, DMSO-d6) δ 162.4, 160.7, 152.8,
132.8, 132.5, 131.5, 128.5, 127.9, 124.4, 124.2, 116.9, 116.7, 106.6; m/z
(ES–) 237 ((M–H)– 100%).
3-(1H-Indol-2-yl)-4-methoxy-2-coumarin (5w): (DCM), yellow solid
(0.038 g, 55%); m.p. 169-174 °C; IR νmax (film) 3403, 1645, 1454, 1346,
1266, 1112; 1H NMR (300 MHz, CDCl3) δ 10.43 (br s, 1H), 7.89 – 7.81 (m,
1H), 7.67 (dd, J = 7.9, 0.9, 1H), 7.60 – 7.52 (m, 1H), 7.45 (dd, J = 8.1, 0.9,
1H), 7.42 – 7.28 (m, 3H), 7.23 (ddd, J = 8.2, 7.0, 1.2, 1H), 7.13 (ddd, J =
8.0, 7.0, 1.0, 1H), 3.98 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.4, 163.0,
152.0, 135.6, 132.0, 128.2, 128.1, 124.7, 123.7, 123.1, 120.8, 120.1, 117.6,
116.7, 111.4, 108.1, 106.6, 60.5; m/z (ES+) 292 ((M+H)+ 100%); HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C18H14NO3 292.0974; Found 292.0979.
4-Methoxy-6-methyl-3-phenyl-2-pyrone (6):[37] (DCM), yellow solid
(0.028 g, 75% [from 30.0 mg (0.172 mmol) 4a]); m.p. 155-159 °C (lit.[37]
156-157 °C); 1H NMR (300 MHz, CDCl3) δ 7.46 – 7.33 (m, 4H), 7.32 – 7.24
(m, 1H), 6.13 (d, J = 0.8, 1H), 3.82 (s, 3H), 2.32 (d, J = 0.8, 3H); 13C NMR
(75 MHz, CDCl3) δ 165.9, 164.3, 162.7, 131.4, 130.5, 127.9, 127.4, 105.3,
95.3, 56.5, 20.5; m/z (ES+) 217 ((M+H)+ 22%).
Acknowledgements
This research was supported by Science Foundation Ireland
(SFI/12/IP/1315 & SFI/12/RC/2275) and the Synthesis and Solid
State Pharmaceutical Centre (SSPC). The Authors wish to thank
David J. Jones for his suggestion to use TMSI for the
demethylation of 5a.
4-Methoxy-1,6-dimethyl-3-phenyl-2-pyridone
(8):[38]
(DCM:MeOH
99.5:0.5), yellow semi-solid (0.052 g, 96%); IR νmax (film) 1634, 1558, 1362,
1266; 1H NMR (300 MHz, CDCl3) δ 7.45 – 7.20 (m, 5H), 6.02 (d, J = 0.5,
1H), 3.75 (s, 3H), 3.54 (s, 3H), 2.40 (d, J = 0.6 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 163.7, 162.8, 146.1, 133.6, 130.8, 127.7, 126.8, 111.8, 95.3, 55.8,
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10.1002/ejoc.201700837
European Journal of Organic Chemistry
FULL PAPER
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Keywords: C-C coupling • Cross-coupling • Green chemistry •
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10.1002/ejoc.201700837
European Journal of Organic Chemistry
FULL PAPER
FULL PAPER
Cross-Coupling
Aisling M. Prendergast and Gerard P.
McGlacken*
Page No. – Page No.
Regioselective Chlorination and
Suzuki-Miyaura Cross-Coupling of 4-
Alkoxy-2-Coumarins, 2-Pyrones and
Related Heterocycles
Chlorination of biologically important 4-alkoxy-2-coumarins is achieved with
trichloroisocyanuric acid, a favourable alternative to N-chlorosuccinimide. The
Suzuki-Miyaura cross-coupling of the chlorinated 2-coumarins was developed, with
yields up to 99%, and successfully applied to the related 2-pyrone, 2-pyridone and
2-quinolone. Demethylation allows access to a 3-aryl-4-hydroxy-2-coumarin.
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