Palladium-catalyzed decarboxylative cross-coupling reactions: A route for regioselective functionalization of coumarins

Article abstract of DOI:10.1021/jo302778d

A straightforward, regioselective, and step-economical ligand-free palladium-catalyzed decarboxylative functionalization of coumarin-3-carboxylic acids is devised. This protocol is compatible with a wide variety of electron-donating and -withdrawing substituents and allows for construction of various biologically important π-electron extended coumarins.

Full text of DOI:10.1021/jo302778d

Article
pubs.acs.org/joc
Palladium-Catalyzed Decarboxylative Cross-Coupling Reactions: A
Route for Regioselective Functionalization of Coumarins
Farnaz Jafarpour,* Samaneh Zarei,† Mina Barzegar Amiri Olia,† Nafiseh Jalalimanesh,
and Soraya Rahiminejadan
School of Chemistry, College of Science, University of Tehran, P.O. Box 14155-6455, Tehran, Iran
S
* Supporting Information
ABSTRACT: A straightforward, regioselective, and step-economical ligand-free palladium-catalyzed decarboxylative
functionalization of coumarin-3-carboxylic acids is devised. This protocol is compatible with a wide variety of electron-donating
and -withdrawing substituents and allows for construction of various biologically important π-electron extended coumarins.
3-arylated coumarin was not detected. In our continuing
investigations, we next turned our attention to construction of
3-arylcoumarins. These structural motifs have attracted
considerable attention as they are widely found in natural
products exhibiting notable biological and pharmaceutical
properties. For example, isoprenoid-substituted 3-arylcoumar-
ins, isolated from Glycyrrhiza aspera9 and G. Glabra10 natural
sources, are known to exhibit significant PPAR-γ ligand-binding
activity. Furthermore, fluorescent dyes of coumarins are of great
interest in view of their possible applications as fluorescent
labels in biological systems.11
The main synthetic strategy to construct these privileged
scaffolds is based on the Suzuki reaction of coumarinyl halides
and boronic acid/esters, which still requires prefunctionaliza-
tion of the coumarin moiety and suffers from a lack of step
economy.12 An alternative method is zincation of coumarin at
C-3 followed by a Negishi cross-coupling.13 Outside of these
contributions, there have been no focused efforts on direct
functionalization of coumarins at C-3. Although a direct 3-
arylation of coumarins via Pd-catalyzed coupling of coumarins
and iodoarenes was recently disclosed, the process was limited
by its low functional group tolerance and low yields of the
adducts.14
INTRODUCTION
■
Transition-metal-catalyzed biaryl formation traditionally in-
volves the coupling of two activated aryl halide or sulfonate and
the organometallic units.1 Despite tremendous developments in
this procedure, the requirement of prefunctionalization of
coupling partners is wasteful since it requires the installation
and then subsequent disposal of stoichiometric activating
agents. On the other hand, the rapidly growing metal-promoted
decarboxylative cross-coupling reaction, compared with pre-
vious transition-metal-catalyzed cross-coupling reactions, takes
advantage of regioselective functionalizations and step-saving
consequences.2 Furthermore, it applies greener arenecarboxylic
acid coupling partners with broad availability and low cost
which produce nontoxic CO2 byproduct. In 2002, Myers et al.
introduced a novel Pd-catalyzed decarboxylative Heck reaction
to form vinyl arenes.3 Next, ground-breaking reports from two
individual groups, Gooßen et al. and Forgione and Bilodeau et
al., showed that arenecarboxylic acids acting as organometallic
reagent equivalents can be used to couple with carbon
electrophiles.4 The represented milestone was further devel-
oped with several groups for expedient synthesis of a wide
range of structurally diverse molecules.5,6 Although some of the
basic foundations of decarboxylation reaction of electron-poor
arenecarboxylic acids have been arranged, decarboxylative
functionalization of heteroarene carboxylic acids has received
much less attention. Some focused efforts include decarbox-
ylative arylation of pyrroles, indoles, (benzo)furans, (benzo)-
thiophenes, and azoles.7 Given the broad spectrum of
interesting biological properties of functionalized heteroarenes,
there remains much to be explored on the extension of reaction
scope for heteroarenecarboxylic acid partners.
On the other hand, the convenient ring-closure reaction of
active methylenes and arylaldehydes for construction of
coumarins15 leaves behind a surplus carboxylate group at C-3
which should be removed before functionalization of
coumarins. One might therefore expect that decarboxylative
functionalization of these scaffolds would find significant utility
in organic synthesis. In this context, decarboxylative allylation
of coumarins has recently been achieved.16
As part of our continuing efforts in Pd-catalyzed direct
functionalization of heterocycles,8 we reported a regioselective
direct arylation of coumarins via oxidative boron Heck-type
reaction.8d The regioselectivity was in bias of C-4 arylation, and
Received: December 21, 2012
© XXXX American Chemical Society
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Table 1. Optimization of Decarboxylative Arylation of Coumarin-3-carboxylic Acid (1a)
b
entry
[Pd]
Pd(OAc)2
L
base
solvent
T (°C)
time (h)
yield (%)
1
KOAc
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
100
160
160
160
5
5
24
51
74
48
58
2
Pd(OAc)2
Pd(OAc)2
Pd(dba)2
Cs2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
3
5
4
5
5
Pd(OH)2/C
5
c
d
6
PdCl2
5
96 (92)
7
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PPh3
PCy3
dppe
phen
5
80
8
5
78
9
5
83
10
11
12
13
14
15
5
84
5
85
DMA
5
74
DME
5
58
DMSO
DMSO
DMSO
DMSO
NMP
5
0
Ag2CO3
Ag2CO3
Ag2CO3
K2CO3
K2CO3
K2CO3
5
0
e
16
PdCl2
5
50
17
PdCl2
5
80
f
18
Pd(acac)2/CuI
Pd(acac)2/CuCl
Pd(acac)2/Cu(OAc)2
phen
phen
phen
24
24
24
trace
trace
trace
f
19
f
NMP
20
NMP
a
Reaction conditions: coumarin-3-carboxylic acid (1a) (0.25 mmol, 1.0 equiv), iodobenzene (1.3 equiv), Pd catalyst (10 mol %), ligand (20 mol %),
b
c
d
e
base (3.0 equiv), and solvent (3.0 mL). GC yields. Catalyst loading as low at 5 mol %. Isolated yield in parentheses. Ag2CO3 (1.0 equiv) was
used. Following reaction conditions was used: iodobenzene (0.2 mmol, 1.0 equiv), coumarin-3-carboxylic acid (1a) (3.0 equiv), Pd catalyst (1 mol
f
%), cocatalyst (3 mol %), ligand (5 mol %), base (1.5 equiv), 3 Å MS (52 mg), and NMP (0.4 mL).
Furthermore, very recently, Messaoudi and Alami developed
a PdBr2/DPEphos catalytic system for decarboxylative arylation
of quinolinone-3-carboxylic acids and disclosed two examples of
arylated coumarins.17 In spite of the importance of this
contribution, the yields of arylated coumarins were moderate
and the substrate scope was limited. Driven by the need for an
efficient synthetic route to these privileged motifs, we
hypothesized the development of an efficient, step-economical,
and regioselective arylation as well as alkenylation of coumarins
at C-3 via a palladium-catalyzed decarboxylative cross-coupling
protocol.
ligand-free conditions were established for later investigations.
Replacing DMSO with other solvents such as DMF, DMA, and
DME also did not improve the yield (entries 11−13).
Furthermore, it turned out that no arylated coumarin was
observed in the absence of the base and palladium catalyst
(entries 14 and 15). Next the effect of silver loading was
investigated. In conventional bimetallic Pd/Ag systems, silver
salt is employed to serve a dual purpose: as a base as well as a
comediator to facilitate decarboxylation. It is also believed to
prolong the lifetime of the active catalyst. However in the
presence of haloarenes as the coupling partners of decarbox-
ylative arylation reactions, silver salts form insoluble silver
halides. Accordingly, a reduction in the amount of silver salts
appears to be hardly feasible and stoichiometric amounts are
necessary.5a,d,19 Our result was in accord with the previous
reports and showed that with lower amounts of the Ag salt,
lower yields of the desired product were obtained (entry 16).
Attempts to lower the temperature to 100 °C afforded 3a in
a decreased yield of 80% (entry 17). Additionally, a Gooßen-
type protocol applying Pd/Cu bimetallic catalytic systems was
explored (entries 18−20).5a However, the results were not
satisfactory, and only traces of the desired product were
obtained.18
RESULTS AND DISCUSSION
■
In this work, we disclose a convenient method for regioselective
functionalization of coumarins at C-3. This protocol should
give economically viable and environmentally attractive access
to 3-aryl- and vinylcoumarins. To begin, coumarin 1a and
iodobenzene were chosen, and the reaction parameters
(catalyst, solvent, base, etc.) were varied to achieve
decarboxylative arylation (Table 1). While bases such as
KOAc and Cs2CO3 resulted in only low to moderate yields,
with Ag2CO3, 3-arylcoumarin 3a was constructed in 74% yield
(entries 1−3). Replacing Pd(OAc)2 with other palladium
sources such as PdCl2, Pd(dba)2, and Pd(OH)2/C proved
PdCl2 (catalyst loading as low at 5 mol %) as the most active
catalyst, where 3a was gratifyingly obtained in almost
quantitative yield (entries 4−6). Screening reactions with
respect to ligands including PPh3, PCy3, and bidendate ligands
such as dppe and phenanthroline resulted in only comparable
or lower yields of the product (entries 7−10). Therefore,
We were delighted to see that under the optimized reaction
conditions, iodoarene (1.3 equiv), PdCl2 (5 mol %), and
Ag2CO3 (3.0 equiv) in DMSO at 120 °C for 5 h (similar to
Becht’s19 and Tan’s20 conditions), the biaryl product 3a was
formed in 92% yield (Table 2, entry 1). It is noteworthy that
the reaction proceeded with high selectivity relative to the
protodecarboxylation side reaction. Protodecarboxylation, the
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with this reaction (68% yield, entry 10). Notably, even the o-
trifluoromethyl-substituted iodoarene, which due to its inferior
reactivity is rarely used as a coupling partner in direct arylation
reactions, was compatible with the reaction conditions (58%
yield, entry 11).
Table 2. Scope of the Arylation Reaction
To expand the scope further, unsubstituted as well as
methoxy- and nitro- substituted coumarin-3-carboxylic acids
were probed. While moderate yields were obtained with
coumarin itself (entry 12), methoxy-substituted coumarins
gratifyingly afforded 3-arylcoumarins 3n−p in yields ranging
from 72 to 93% (entries 14−16). Replacing iodobenzene with
bromobenzene gave no biaryl product, and protodecarbox-
ylation proceeded smoothly instead, leading to undesired
coumarin formation (entry 13).21 Thus, suppression of the
competitive protonation reaction could not be effectively
achieved using a bromoarene partner with lower reactivity.
Unfortunately, arylation of coumarin-3-carboxylic acid
bearing a strongly electron-withdrawing NO2 group was not
successful. The substrate was readily subjected to proto-
decarboxylation instead, resulting in unwanted 6-nitrocoumarin
side product. We further focused on optimizing the
decarboxylative arylation of 6-nitrocoumarin-3-carboxylic acid
1e individually. A beneficial effect was observed for replacing
PdCl2 with Pd(CH3CN)2Cl2 and increasing the reaction time
to 24 h.18 Under the altered reaction conditions, the nitro
derivative of 3-arylcoumarin 3q was obtained albeit in low yield
(entry 17).
We also investigated the possibility of whether the proposed
catalytic system could be effective toward the alkenylation of
coumarin-3-carboxylic acids via a decarboxylative Heck-type
coupling.22 C-3 alkenyl groups on coumarins extend the
delocalized π-electron system, which leads to longer wavelength
absorption bands and more promising fluorescent behavior.23
For the alkenylation reaction, we started with coumarin-3-
carboxylic acid 1b (R = H) and methylacrylate 4a. To our
delight, the extension of the π-electron system of the coumarin
was simply achieved using the Heck-type palladium-catalyzed
decarboxylative cross-coupling reaction under slightly altered
reaction conditions,18 and adduct 5a was obtained in almost
quantitative yield (Table 3, entry 1). Motivated by this result,
we next investigated the substrate scope of both coumarin and
alkene substrates, as summarized in Table 3. Reactions
involving alkenes conjugated with ethyl ester group 4b led to
good to excellent yields of the alkenylated coumarins 5b−d
(entries 2−4). Alkenes conjugated with an n-butyl group were
also alkenylated on coumarins. While with 7-methoxycoumarin
only a moderate yield of the desired product 5f was obtained,
coumarin- and 7-diethylaminocoumarin-3-carboxylic acid sub-
strates resulted in good to excellent yields of the products 5e
and 5g, respectively (entries 5−7). Notably, when 7-
diethylaminocoumarin-3-carboxylic acid was reacted with
methyl methacrylate, the β-elimination reaction was processed
in bias of the formation of the less substituted alkene, and the
allylated coumarin 5h was obtained as the main product (entry
8).
a
b
All reactions were run under the optimized conditions. Bromo-
c
benzene was used. The following conditions were used: Pd-
(CH3CN)2Cl2 (10 mol %), and Ag2CO3 (3.0 equiv) in DMSO
(0.08 M) at 160 °C for 24 h.
simplest case of a catalytic activation of carboxylic acids, which
usually requires the addition of a transition-metal mediator,
generally a copper, silver, or mercury salt for CO2 extrusion, is
well established.21
Motivated by these results, we next sought to explore the
scope of the ligand-free Pd-catalyzed decarboxylative cross-
coupling reaction with iodoarenes possessing various steric and
electronic properties (Table 2). The results indicated that the
scope of the reaction was quite broad given that alkyl, alkoxy,
halo, and nitro substituents were tolerated. The p-methoxy-
substituted iodoarene afforded the corresponding cross-coupled
product 3b in excellent yield (entry 2). As expected, 2-
iodoanisole showed inferior reactivity in this reaction, providing
biaryl 3c in only 68% yield (entry 3). In addition, the sterically
demanding substitution patterns were tolerated toward the
cross-coupling reaction of 1a, leading to biaryls 3d−f in good
yields. Next, the scope of the reaction with electron-deficient
iodoarenes was monitored. While comparable results were
obtained with mononitro-substituted iodoarenes (81% and 88%
of 3g and 3h respectively, entries 7 and 8), the dinitro-
substituted iodoarene showed superior reactivity, resulting in
the desired product in almost quantitative yield (91%, entry 9).
Interestingly, less activated 2-fluoroiodobenzene, a good
partner for further functionalizations, showed compatibility
Next, the scope of a nonactivated alkene such as styrene was
explored. Although coumarin-3-carboxylic acid provided only a
moderate yield of the product 5i, coumarin 1a was alkenylated
in 91% yield (entries 9 and 10). Finally, we were pleased to find
that acrylonitrile 4f was also tolerated in this reaction and led to
product 5k as a potential fluorescent probe for cyanide ions24 in
55% yield (entry 11).
C
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Table 3. Scope of the Alkenylation Reaction
Scheme 1. Competition between Protodecarboxylation/
Direct Functionalization and Decarboxylative Cross-
Coupling Reactions
Ag2CO3 (0.75 mmol, 3.0 equiv). Dry degassed DMSO (3 mL) was
then added, and the vial was capped. The resulting mixture was heated
in an oil bath at 120 °C for 5 h, cooled, and then filtered through a
short plug of silica. Removal of the solvent gave a crude mixture which
was purified by flash column chromatography (hexanes/EtOAc
gradient, 10%).
a
Reaction conditions: coumarin-3-carboxylic acid (0.2 mmol, 1.0
equiv), alkene (1.5 equiv), Pd(OAc)2 (10 mol %), and Ag2CO3 (3.0
equiv) in DMSO/DMF (1/20) were heated in a sealed tube at 90 °C
for 5 h.
7-(Diethylamino)-3-phenyl-2H-chromen-2-one (3a): yellowish oil
1
(67 mg, 92%); H NMR (500 MHz, CDCl3) δ 1.23 (t, J = 7.1 Hz,
To clarify participation of competing pathway of proto-
decarboxylation/direct arylation or alkenylation of coumarins in
this protocol (Scheme 1, path A), we explored direct
functionalization of coumarin with iodoarene and electron-
deficient alkene under the optimized reaction conditions
(Scheme 1). Direct arylation reaction of coumarin 6 with
iodobenzene resulted in only 48% of the desired product 3a.
Furthermore, oxidative Heck reaction of coumarin 6 with
ethylacrylate was unsuccessful under the optimized reaction
condition. These results indicate a preference for the
decarboxylative cross-coupling pathway (Scheme 1, path B)
in both arylation and alkenylation reactions.
In summary, we developed a versatile, regioselective, and
step-economical decarboxylative arylation and alkenylation of
coumarin-3-carboxylic acids via a palladium catalytic system.
The protocol exhibited a broad substrate scope with respect to
substrates used. Furthermore, ligand-free conditions were
established in this approach, which was not feasible in most
of the previously reported decarboxylative coupling reactions.
This protocol may provide an appealing alternative to the
existing approaches to construct functionalized coumarins as
the key intermediates in the synthesis of drug candidates and
fluorescent dyes.
6H), 3.43 (q, J = 7.1 Hz, 4H), 6.54 (d, J = 2.2 Hz, 1H), 6.60 (dd, J =
8.7, 2.2 Hz, 1H), 7.31−7.34 (m, 2H), 7.39−7.42 (t, J= 7.6 Hz, 2H),
7.69−7.70 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 12.9, 45.3, 97.7,
109.4, 128.2, 128.6, 128.7, 129.3, 136.3, 141.0, 156.6, 162.1; IR 1015,
1260, 1704, 2964 cm−1; MS m/z 293 (M•+, 72), 278 (100), 250 (20),
221 (13.4). Anal. Calcd for C19H19NO2: C, 77.79; H, 6.53; N, 4.77.
Found: C, 77.95; H, 6.61; N, 4.86.
7-(Diethylamino)-3-(4-methoxyphenyl)-2H-chromen-2-one (3b):
1
yellowish oil (76 mg, 94%); H NMR (500 MHz, CDCl3) δ 1.23 (t, J
= 7.1 Hz, 6H), 3.42 (q, J = 7.1 Hz, 4H), 3.84 (s, 3H), 6.53 (d, J = 2.5
Hz, 1H), 6.59 (dd, J = 8.8, 2.5 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 7.29
(d, J = 8.8 Hz, 1H), 7.63−7.65 (m, 3H); 13C NMR (125 MHz,
CDCl3) δ 12.9, 45.3, 55.8, 97.8, 109.3, 114.2, 129.3, 129.9, 139.8,
156.4, 159.7, 162.2; IR 1030, 1127, 1251, 1605, 1719, 2963 cm−1; MS
m/z 323 (M•+, 100), 308 (97), 279 (24), 149 (80), 55 (33), 41 (55).
Anal. Calcd for C20H21NO3: C, 74.28; H, 6.55; N, 4.33. Found: C,
74.45; H, 6.66; N, 4.21.
7-(Diethylamino)-3-(2-methoxyphenyl)-2H-chromen-2-one (3c):
1
yellowish solid (55 mg, 68%); mp 90−92 °C; H NMR (500 MHz,
CDCl3) δ 1.21 (t, J = 7.1 Hz, 6H, 2CH3), 3.42 (q, J = 7.1 Hz, 4H),
3.82 (s, 3H), 6.54−6.59 (m, 2H), 6.96 (d, J = 8.2 Hz, 1H), 7.01 (t, J =
7.1 Hz, 1H), 7.28−7.30 (m, 1H), 7.30−7.38 (m, 2H), 7.60 (s, 1H);
13C NMR (125 MHz, CDCl3) δ 12.9, 45.3, 56.2, 97.8, 109.0, 109.1,
111.7, 120.9, 129.2, 129.8, 130.6, 131.5, 142.9, 145.1, 156.8, 157.8,
161.9; IR 1124, 1237, 1593, 1708, 2925 cm−1; MS m/z 323 (M•+, 45),
308 (100), 217 (53), 202 (56), 174 (18), 149 (25). Anal. Calcd for
C20H21NO3: C, 74.28; H, 6.55; N, 4.33. Found: C, 74.41; H, 6.43; N,
4.24.
EXPERIMENTAL SECTION
■
Typical Experimental Procedure for Decarboxylative Ar-
ylation of Coumarin-3-carboxylic Acids. A vial equipped with a
stir bar was charged with coumarin-3-carboxylic acid (0.25 mmol, 1.0
equiv), aryl iodide (0.33 mmol, 1.3 equiv), PdCl2 (5 mol %), and
7-(Diethylamino)-3-o-tolyl-2H-chromen-2-one (3d): yellowish
solid (55 mg, 72%); mp 105−107 °C; 1H NMR (500 MHz,
CDCl3) δ 1.26 (t, J = 6.8 Hz, 6H), 2.33 (s, 3H), 3.47 (q, J = 6.8 Hz,
D
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4H), 6.60 (s, 1H), 6.62 (d, J = 8.4 Hz, 1H), 7.27−7.32 (m, 5H), 7.53
(s, 1H); 13C NMR (125 MHz, CDCl3) δ 12.9, 20.5, 45.3, 97.8, 109.1,
109.3, 126.2, 128.6, 129.2, 130.5, 130.6, 136.2, 137.6, 142.7, 150.9,
156.9, 161.8; IR 1220, 1271, 1368, 1605, 1731, 2965 cm−1; MS m/z
307 (M•+, 33), 292 (57), 149 (100), 57 (58), 41(80). Anal. Calcd for
C20H21NO2: C, 78.15; H, 6.89; N, 4.56. Found: C, 78.37; H, 6.80; N,
4.67.
m/z 311 (M•+, 27), 296 (49), 149 (100), 84 (80), 57 (74), 41 (58).
Anal. Calcd for C19H18FNO2: C, 73.29; H, 5.83; N, 4.50. Found: C,
73.35; H, 5.74; N, 4.42.
3-(2-(Trifluoromethyl)phenyl)-2H-chromen-2-one (3k): yellowish
solid (52 mg, 58%); mp 138−139 °C; 1H NMR (500 MHz, CDCl3) δ
1.22 (t, J = 7.1 Hz, 6H), 3.43 (q, J = 7.1 Hz, 4H), 6.54 (d, J = 2.3 Hz,
1H), 6.59 (dd, J = 8.8, 2.3 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 7.42 (d, J
= 7.6 Hz, 1H) 7.46−7.49 (m, 2H), 7.57 (t, J = 7.5 Hz, 1H), 7.74 (d, J
= 7.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 12.9, 45.3, 97.7, 108.6,
109.4, 119.7, 126.6 (q, J = 272.2 Hz), 126.7 (q, J = 6.6 Hz), 128.6,
129.6, 129.9 (q, J = 29.6 Hz), 132.0, 132.9, 135.0, 142.9, 151.3, 157.1,
161.9; IR 1113, 1306, 1569, 1700, 2969 cm−1; MS m/z 361 (M•+, 80),
346 (100), 318 (22), 149 (66), 41 (25). Anal. Calcd for C20H18F3NO2:
C, 66.48; H, 5.02; N, 3.88. Found: C, 66.67; H, 5.13; N, 3.77.
3-(2-Methyl-4-nitrophenyl)-2H-chromen-2-one (3l): white solid
(38 mg, 54%); mp 155−157 °C; 1H NMR (500 MHz, CDCl3) δ 2.50
(s, 3H), 7.31−7.40 (m, 3H), 7.50−7.58 (m, 3H), 7.73 (s, 1H), 7.96 (s,
1H); 13C NMR (125 MHz, CDCl3) δ 21.4, 117.3, 119.6, 125.1, 125.8,
127.8, 128.1, 128.4, 132.1, 132.2, 134.6, 139.7, 141.2, 154.1; IR 1016,
1258, 1459, 2921 cm−1; MS m/z 281 (M•+, 9), 85 (60), 71 (83), 57
(100), 43 (94). Anal. Calcd for C16H11NO4: C, 68.32; H, 3.94; N,
4.98. Found: C, 68.53; H, 4.08; N, 5.12.
7-(Diethylamino)-3-(2,4-dimethylphenyl)-2H-chromen-2-one
1
(3e): yellowish solid (44 mg, 55%); mp 105−106 °C; H NMR (500
MHz, CDCl3) δ 1.26 (t, J = 7.0 Hz, 6H), 2.29 (s, 3H), 2.38 (s, 3H),
3.47 (q, J = 7.0 Hz, 4H), 6.59 (s, 1H), 6.63 (d, J = 8.6 Hz, 1H), 7.07
(d, J = 7.5 Hz, 1H), 7.12 (s, 1H), 7.17 (d, J = 7.6 Hz, 1H), 7.31 (d, J =
8.6 Hz, 1H), 7.51 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 12.9, 20.4,
21.6, 45.3, 97.8, 109.2, 109.3, 126.9, 129.1, 130.4, 131.5, 133.3, 137.3,
138.3, 142.5, 150.9, 156.9, 161.9; IR 1073, 1127, 1269, 1606, 1719,
2964 cm−1; MS m/z 321 (M•+, 59), 306 (79), 149 (100), 57 (33), 41
(39). Anal. Calcd for C21H23NO2: C, 78.47; H, 7.21; N, 4.36. Found:
C, 78.65; H, 7.31; N, 4.49.
7-(Diethylamino)-3-(naphthalen-1-yl)-2H-chromen-2-one (3f):
yellowish solid (57 mg, 67%); mp 140−141 °C; 1H NMR (500
MHz, CDCl3) δ 1.28 (t, J = 7.1 Hz, 6H), 3.48 (q, J = 7.1 Hz, 4H),
6.66−6.67 (m, 1H), 7.34 (d, J = 8.9 Hz, 1H), 7.48−7.57 (m, 4H), 7.69
(s, 1H), 7.88−7.93 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 12.9,
45.4, 97.8, 109.2, 109.4, 121.1, 125.8, 126.0, 126.3, 126.6, 128.2, 128.9,
129.1, 129.4, 132.4, 134.2, 134.3, 143.9, 151.1, 157.1, 162.4; IR 1126,
1274, 1605, 1725, 2923 cm−1; MS m/z 343 (M•+, 13), 329 (34), 314
(33), 279 (20), 167 (55), 149 (100), 71 (58), 57 (92), 43 (65). Anal.
Calcd for C23H21NO2: C, 80.44; H, 6.16; N, 4.08. Found: C, 80.69; H,
6.01; N, 3.95.
7-(Diethylamino)-3-(2-methyl-4-nitrophenyl)-2H-chromen-2-one
(3g): yellowish oil (71 mg, 81%); 1H NMR (500 MHz, CDCl3) δ 1.23
(t, J = 7.1 Hz, 6H), 2.39 (s, 3H), 3.44 (q, J = 7.1 Hz, 4H), 6.55 (s,
1H), 6.63 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.42 (d, J = 8.8
Hz, 1H), 7.53 (s, 1H), 8.06 (d, J = 8.2 Hz, 1H), 8.12 (s, 1H); 13C
NMR (125 MHz, CDCl3) δ 12.9, 20.7, 45.4, 97.6, 108.6, 109.7, 119.9,
121.3, 125.4, 129.7, 131.6, 139.7, 143.2, 143.5, 147.8, 151.6, 157.3,
161.0; IR 1212, 1266, 1339, 1511, 1712, 2966 cm−1; MS m/z 352
(M•+, 8), 307 (78), 292 (100), 149 (87), 89 (44), 75 (44), 55 (61), 41
(96). Anal. Calcd for C20H20N2O4: C, 68.17; H, 5.72; N, 7.95. Found:
C, 68.31; H, 5.81; N, 7.88.
8-Methoxy-3-phenyl-2H-chromen-2-one (3n): white solid (59 mg,
93%); mp 153−155 °C (lit.25 mp 154−155 °C); 1H NMR (500 MHz,
CDCl3) δ 3.98 (s, 3H), 7.08−7.78 (m, 9H). Anal. Calcd for C16H12O3:
C, 76.18; H, 4.79. Found: C, 75.99; H, 4.69.
8-Methoxy-3-(4-methoxyphenyl)-2H-chromen-2-one (3o): fawn
solid (51 mg, 72%); mp 148−149 °C (lit.26 mp 149−150 °C); H
1
NMR (500 MHz, CDCl3) δ 3.80 (s, 3H), 3.93 (s, 3H), 6.81−7.22 (m,
5H), 7.61 (d, J = 8.0 Hz, 2H), 7.62 (s, 1H). Anal. Calcd for C17H14O4:
C, 72.33; H, 5.00. Found: C, 72.55; H, 5.11.
5-Methoxy-3-phenyl-2H-chromen-2-one (3p): white solid (55 mg,
88%); mp 123−124 °C (lit.25 mp 124−125 °C); 1H NMR (500 MHz,
CDCl3) δ 3.90 (s, 3H), 7.10−7.88 (m, 9H). Anal. Calcd for C16H12O3:
C, 76.18; H, 4.79. Found: C, 76.37; H, 4.88.
6-Nitro-3-(p-tolyl)-2H-chromen-2-one (3q): brown solid (18 mg,
25%); mp 209−210 °C (lit.27 mp 210−211 °C); 1H NMR (500 MHz,
CDCl3) δ: 2.43 (s, 3H), 7.27−7.29 (m, 2H), 7.51−7.54 (m, 1H),
7.64−7.67 (m, 2H), 8.08 (s, 1H), 8.39−8.41 (m, 1H), 8.57−8.59 (m,
1H). Anal. Calcd for C16H11NO4: C, 68.32; H, 3.94; N, 4.98. Found:
C, 68.61; H, 4.08; N, 5.18.
Typical Experimental Procedure for Decarboxylative Alke-
nylation of Coumarin-3-carboxylic Acids. A vial equipped with a
stir bar was charged with coumarin-3-carboxylic acid (0.2 mmol, 1.0
equiv), aryl iodide (0.3 mmol, 1.5 equiv), Pd(OAc)2 (10 mol %), and
Ag2CO3 (0.6 mmol, 3.0 equiv). Dry degassed DMSO (0.12 mL) and
DMF (2.4 mL) were then added, and the vial was capped. The
resulting mixture was heated in an oil bath at 90 °C for 5 h, cooled,
and then filtered through a short plug of silica. Removal of the solvent
gave a crude mixture which was purified by flash column
chromatography (hexanes/EtOAc gradient).
7-(Diethylamino)-3-(4-methyl-2-nitrophenyl)-2H-chromen-2-one
1
(3h): yellowish solid (77 mg, 88%); mp 187−189 °C; H NMR (500
MHz, CDCl3) δ 1.22 (t, J = 7.0 Hz, 6H), 2.46 (s, 3H), 3.42 (q, J = 7.0
Hz, 4H), 6.52 (s, 1H), 6.59 (d, J = 8.6 Hz, 1H), 7.29−7.33 (m, 2H),
7.43 (d, J = 7.6 Hz, 1H), 7.59 (s, 1H), 7.86 (s, 1H); 13C NMR (125
MHz, CDCl3) δ 12.8, 21.4, 45.3, 97.8, 109.0, 109.4, 120.0, 125.5,
128.7, 129.4, 132.2, 134.2, 139.9, 140.7, 149.2, 151.2, 156.9, 161.3; IR
1120, 1209, 1350, 1519, 1590, 1711, 2926 cm−1; MS m/z 352 (M•+,
35), 337 (62), 125 (43), 97 (90), 71 (88), 57 (100), 43 (87). Anal.
Calcd for C20H20N2O4: C, 68.17; H, 5.72; N, 7.95. Found: C, 68.35;
H, 5.86; N, 8.08.
7-(Diethylamino)-3-(2,4-dinitrophenyl)-2H-chromen-2-one (3i):
yellowish solid (87 mg, 91%); mp 193−195 °C; 1H NMR (500
MHz, CDCl3) δ 1.25 (t, J = 7.1 Hz, 6H), 3.46 (q, J = 7.1 Hz, 4H), 6.53
(d, J = 2.1 Hz, 1H), 6.65 (dd, J = 8.8, 2.2 Hz, 1H), 7.35 (d, J = 8.8 Hz,
1H), 7.69 (d, J = 8.4, 1H), 7.73 (s, 1H), 8.46 (dd, J = 8.4, 2.2 Hz, 1H),
8.86 (d, J = 2.2, 1H); 13C NMR (125 MHz, CDCl3) δ 12.9, 45.5, 97.8,
110.0, 120.7, 127.4, 130.1, 133.4, 137.9, 142.3, 147.1, 149.2, 150.8,
157.8; IR 1015, 1345, 1513, 1590, 1718, 2962 cm−1; MS m/z 383
(M•+, 73), 368 (100), 296 (42), 147 (87), 120 (39), 111 (27), 97
(39), 83 (35), 71 (39), 57 (65), 43 (48). Anal. Calcd for C19H17N3O6:
C, 59.53; H, 4.47; N, 10.96. Found: C, 59.73; H, 4.59; N, 10.83.
7-(Diethylamino)-3-(2-fluorophenyl)-2H-chromen-2-one (3j): yel-
(E)-Methyl 3-(2-oxo-2H-chromen-3-yl)acrylate (5a): yellowish
solid (44 mg, 95%); mp 175−178 °C (lit.28 mp 176−178 °C); H
1
NMR (500 MHz, CDCl3) δ 3.85 (s, 3H, 3H), 7.15 (d, J = 15.9 Hz,
1H), 7.30−7.63 (m, 5H), 7.91 (s, 1H); 13C NMR (125 MHz, CDCl3)
δ 52.3, 117.1, 119.4, 122.8, 123.8, 125.3, 128.9, 133.3, 138.5, 144.0,
154.0, 160.7, 167.8; IR 1165, 1260, 1278, 1305, 1603, 1714, 2924
cm−1; MS m/z 230 (M•+, 31), 199 (12), 171 (100), 115 (24), 85 (9),
71 (12), 57 (18). Anal. Calcd for C13H10O4: C, 67.82; H, 4.38. Found:
C, 68.10; H, 4.49.
(E)-Ethyl 3-(2-oxo-2H-chromen-3-yl)acrylate (5b): yellowish solid
(44 mg, 90%); mp 112−115 °C (lit.29 mp 115−117 °C, lit.27 mp 120−
121 °C); 1H NMR (500 MHz, CDCl3) δ 1.33 (t, J = 7.1 Hz, 3H), 4.26
(q, J = 7.1 Hz, 2H), 7.09 (d, J = 15.9 Hz, 1H), 7.26−7.59 (m, 5H),
7.87 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 14.7, 61.2, 117.1, 119.4,
122.9, 124.2, 125.2, 128.9, 133.3, 138.2, 143.8, 154.0, 159.5, 167.3; IR
1020, 1083, 1259, 1606, 1721, 2921 cm−1; MS m/z 244 (M•+, 51), 221
(20), 171 (100), 147 (14), 115 (13), 97 (18), 69 (22), 57 (35), 43
(33). Anal. Calcd for C14H12O4: C, 68.85; H, 4.95. Found: C, 68.54;
H, 4.82.
1
lowish solid (53 mg, 68%); mp 92−93 °C; H NMR (500 MHz,
CDCl3) δ 1.26 (t, J = 7.1 Hz, 6H), 3.47 (q, J = 7.1 Hz, 4H), 6.59 (s,
1H), 6.64 (d, J = 7.5 Hz, 1H), 7.15−7.23 (m, 2H), 7.33−7.34 (m,
2H), 7.6−7.62 (m, 1H), 7.73 (s, 1H); 13C NMR (125 MHz, CDCl3) δ
12.9, 45.4, 97.8, 109.1, 109.5, 116.3 (d, J = 22.0 Hz), 124.3 (d, J = 3.5
Hz), 129.5, 129.9 (d, J = 8.0 Hz), 131.9, 143.5, 143.6, 156.9, 158.7 (d, J
= 251.2 Hz), 161.2; IR 1078, 1127, 1517, 1594, 1715, 2971 cm−1; MS
E
dx.doi.org/10.1021/jo302778d | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
(E)-Ethyl 3-(7-methoxy-2-oxo-2H-chromen-3-yl)acrylate (5c): yel-
lowish solid (51 mg, 93%); mp 180−183 °C (lit.30 mp 178−179 °C);
1H NMR (500 MHz, CDCl3) δ 1.35 (t, J = 7.0 Hz, 3H), 3.93 (s, 3H)
120.1, 122.5, 125.0, 125.4, 127.4, 128.1, 128.9, 129.2, 131.6, 132.9,
134.1, 137.2, 137.3, 153.3, 160.8; IR 1212, 1370, 1715, 2921 cm−1; MS
m/z 248 (M•+, 100), 219 (24), 191 (23), 173 (25), 105 (94), 77 (35).
Anal. Calcd for C17H12O2: C, 82.24; H, 4.87. Found: C, 82.51; H, 5.01.
(E)-7-(Diethylamino)-3-styryl-2H-chromen-2-one (5j): yellowish
solid (58 mg, 91%); mp 193−196 °C; 1H NMR (500 MHz,
CDCl3) δ 1.25 (t, J = 7.1 Hz, 6H), 3.46 (q, J = 7.1 Hz, 4H), 6.54 (d, J
= 2.4 Hz, 1H), 6.62 (dd, J = 8.8 Hz, 2.5 Hz, 1H), 7.13 (d, J = 16.3 Hz,
1H), 7.28−7.39 (m, 5H), 7.49 (d, J = 16.3 Hz, 1H), 7.55 (d, J = 7.41
Hz, 2H), 7.71 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 12.9, 45.3,
97.7, 109.6, 118.3, 123.5, 127.0, 128.0, 129.1, 129.2, 130.5, 138.1,
138.4, 156.0, 161.9; IR 1062, 1216, 1709, 2919 cm−1; MS m/z 319
(M•+, 100), 304 (57), 275 (8). Anal. Calcd for C21H21NO2: C, 78.97;
H, 6.63; N, 4.39. Found: C, 79.26; H, 6.75; N, 4.55.
4.29 (q, J = 7.1 Hz, 2H), 6.86 (d, J = 1.9 Hz, 1H), 6.92 (dd, J = 8.7 Hz,
2.2 Hz, 1H), 7.07 (d, J = 15.9 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.57
(d, J = 15.8 Hz, 1H), 7.84 (s, 1H); 13C NMR (125 MHz, CDCl3) δ
14.7, 56.3, 61.0, 100.9, 113.1, 113.8, 119.3, 122.7, 130.0, 138.69, 144.2,
156.0, 159.8, 164.3, 167.6; IR 1023, 1158, 1261, 1604, 1706, 2923
cm−1; MS m/z 274 (M•+, 73), 245 (10), 229 (35), 201 (100), 85 (13),
71 (16), 57 (18), 43 (11); Anal. Calcd for C15H14O5: C, 65.69; H,
5.15. Found: C, 65.96; H, 5.29.
(E)-Ethyl 3-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)acrylate
(5d): yellowish solid (55 mg, 87%); mp 135−137 °C (lit.29 mp
1
109−112 °C); H NMR (500 MHz, CDCl3) δ 1.23 (t, J = 7.1 Hz,
(E)-3-(7-(Diethylamino)-2-oxo-2H-chromen-3-yl)acrylonitrile
6H), 1.31 (t, J = 7.1 Hz, 3H), 3.43 (q, J = 7.1 Hz, 4H), 4.23 (q, J = 7.1
Hz, 2H), 6.47 (d, J = 2.2 Hz, 1H), 6.59 (dd, J = 8.9 Hz, 2.3 Hz, 1H),
6.93 (d, J = 15.8 Hz, 1H), 7.26−7.29 (m, 1H), 7.52 (d, J = 15.8 Hz,
1H), 7.68 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 12.9, 14.6, 45.4,
60.7, 97.4, 109.1, 109.8, 115.1, 119.9, 130.2, 139.8, 144.7, 152.1, 157.0,
160.7, 168.1; IR 1030, 1245, 1617, 1698, 2919, 2969; MS m/z 315
(M•+, 87), 300 (100), 270 (12), 198 (11), 149 (9), 59 (11). Anal.
Calcd for C18H21NO4: C, 68.55; H, 6.71; N, 4.44. Found: C, 68.86; H,
6.85; N, 4.60.
1
(5k): yellowish solid (29 mg, 54%); mp 239−241 °C; H NMR (500
MHz, CDCl3) δ 1.28 (t, J = 7.1 Hz, 6H), 3.49 (q, J = 7.1 Hz, 4H), 6.52
(d, J = 2.2 Hz, 1H), 6.64−6.68 (m, 2H), 7.14 (d, J = 16.2 Hz, 1H),
7.35− (m, 1H), 7.63 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 12.9,
45.5, 97.3, 98.2, 108.8, 110.2, 115.0, 119.8, 130.6, 145.5, 152.2, 156.9,
160.3; IR 1012, 1260, 1584, 1711, 2853, 2920 cm−1; MS m/z 268
(M•+, 75), 253 (100), 225 (34), 140 (9). Anal. Calcd for C16H16N2O2:
C, 71.62; H, 6.01; N, 10.44. Found: C, 71.89; H, 6.13; N, 10.59.
(E)-Butyl 3-(2-oxo-2H-chromen-3-yl)acrylate (5e): oil (42 mg,
78%); 1H NMR (500 MHz, CDCl3) δ 1.00 (t, J = 7.4 Hz, 3H), 1.42−
1.46 (m, 2H), 1.67−1.70 (m, 2H), 4.22 (t, J = 6.6 Hz, 2H), 7.1 (d, J =
15.9 Hz, 1H), 7.26−7.60 (m, 5H), 7.87 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ 14.1, 19.6, 31.1, 65.1, 117.1, 119.4, 122.9, 124.3, 125.2,
128.9, 133.3, 138.2, 143.8, 154.0, 159.5, 167.3; IR 1258, 1605, 1708,
2961 cm−1; MS m/z 272 (M•+, 25), 216 (13), 199 (27), 171 (100),
115 (19). Anal. Calcd for C16H16O4: C, 70.57; H, 5.92. Found: C,
70.29; H, 5.78.
ASSOCIATED CONTENT
* Supporting Information
General remarks and NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: jafarpur@khayam.ut.ac.ir.
■
(E)-Butyl 3-(7-methoxy-2-oxo-2H-chromen-3-yl)acrylate (5f): oil
1
(33 mg, 55%); H NMR (500 MHz, CDCl3) δ 1.00 (t, J = 7.4 Hz,
3H), 1.46−1.48 (m, 2H), 1.70−1.73 (m, 2H), 3.93 (s, 3H), 4.24 (t, J =
6.7 Hz, 2H), 6.87 (d, J = 2.3 Hz, 1H), 6.92 (dd, J = 8.7 Hz, 2.4 Hz,
1H), 7.08 (d, J = 15.8 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.57 (d, J =
15.8 Hz, 1H), 7.85 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 14.1,
19.6, 31.2, 56.3, 65.0, 100.9, 113.1, 113.8, 122.7, 130.0, 138.7, 144.2,
156.0, 164.3, 167.6; IR 1009, 1217, 1258, 1603, 1740, 2963 cm−1; MS
m/z 302 (M•+, 77), 246 (15), 229 (29), 201 (100), 147 (12), 73 (20),
57 (28). Anal. Calcd for C17H18O5: C, 67.54; H, 6.00. Found: C,
67.79; H, 6.11.
(E)-Butyl 3-(6-diethylamino-2-oxo-2H-3-chromenyl)-2-prope-
noate (5g): yellowish solid (65 mg, 95%); mp 130−133 °C; 1H
NMR (500 MHz, CDCl3) δ 0.95 (t, J = 7.4 Hz, 3H), 1.23 (t, J = 7.1
Hz, 6H), 1.40−1.45 (m, 2H), 1.65−1.68 (m, 2H), 3.43 (q, J = 7.1 Hz,
4H), 4.18 (t, J = 6.6 Hz, 2H), 6.47 (d, J = 2.3 Hz, 1H), 6.59 (dd, J =
8.89 Hz, 2.40 Hz, 1H), 6.94 (d, J = 15.8 Hz, 1H), 7.28−7.30 (m, 1H),
7.52 (d, J = 15.8 Hz, 1H), 7.69 (s, 1H); 13C NMR (125 MHz, CDCl3)
δ 12.9, 14.2, 19.6, 31.2, 45.4, 64.7, 97.4, 109.0, 109.8, 115.1, 119.9,
130.2, 139.7, 144.7, 152.1, 156.9, 160.7, 168.3; IR 1003, 1162, 1577,
1707, 2930 cm−1; MS m/z 343 (M•+, 71), 328 (100), 315 (22), 300
(45), 198 (69), 57 (32), 41 (91). Anal. Calcd for C20H25NO4: C,
69.95; H, 7.34; N, 4.08. Found: C, 70.22; H, 7.48; N, 4.24.
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Research Council of the University of Tehran
and Iran National Science Foundation (INSF) for financial
support of this project.
REFERENCES
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Methyl 2-((7-(Diethylamino)-2-oxo-2H-chromen-3-yl)methyl)-
1
acrylate (5h): yellowish solid (35 mg, 55%); mp 107−110 °C; H
NMR (500 MHz, CDCl3) δ 1.23 (t, J = 7.1 Hz, 6H), 3.43 (q, J = 7.1
Hz, 4H), 3.54 (s, 2H), 3.77 (s, 3H), 5.80 (d, J = 1.1 Hz, 1H), 6.33 (s,
1H), 6.52 (d, J = 2.4 Hz, 1H), 6.59 (dd, J = 8.8 Hz, 2.5 Hz, 1H), 7.25
(d, J = 8.8 Hz, 1H), 7.46 (s, 1H); 13C NMR (125 MHz, CDCl3) δ
12.9, 45.2, 52.3, 97.7, 109.1, 119.3, 128.0, 128.8, 137.6, 141.4, 151.1,
156.3, 162.9, 167.6; IR 1124, 1258, 1278, 1600, 1706, 2921 cm−1; MS
m/z 315 (M•+, 90), 300 (100), 255 (26), 111 (25), 97 (30), 71 (45),
57 (69), 43 (31). Anal. Calcd for C18H21NO4: C, 68.55; H, 6.71; N,
4.44. Found: C, 68.24; H, 6.55; N, 4.20.
(E)-3-Styryl-2H-chromen-2-one (5i): yellowish solid (23 mg, 45%);
mp 156−159 °C (lit.23 mp 162−164 °C); 1H NMR (500 MHz,
CDCl3) δ 7.16 (d, J = 16.4 Hz, 1H), 7.31−7.60 (m, 9H), 7.65 (d, J =
16.3 Hz, 1H), 7.85 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 116.9,
F
dx.doi.org/10.1021/jo302778d | J. Org. Chem. XXXX, XXX, XXX−XXX

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