Synthesis of substituted coumarins via Bronsted acid mediated condensation of allenes with substituted phenols or anisoles

Article abstract of DOI:10.1021/jo301086k

Coumarins were obtained from the condensation of electron-rich arenes with allenes in the presence of TfOH in good yield. Depending on the substituent pattern of allenes employed, the general synthetic method of 4-substituted and 3,4-disubstituted 3-arylc

Full text of DOI:10.1021/jo301086k

Article
pubs.acs.org/joc
Synthesis of Substituted Coumarins via Brønsted Acid Mediated
Condensation of Allenes with Substituted Phenols or Anisoles
Sundae Kim, Dongjin Kang, Chang-Hee Lee, and Phil Ho Lee*
Department of Chemistry, Kangwon National University, Chuncheon 200-701, Republic of Korea
S
* Supporting Information
ABSTRACT: Coumarins were obtained from the condensation of
electron-rich arenes with allenes in the presence of TfOH in good yield.
Depending on the substituent pattern of allenes employed, the general
synthetic method of 4-substituted and 3,4-disubstituted 3-arylcoumar-
ins has been developed. Readily available allenes were employed as the
three-carbon atom sources constituting the coumarin skeleton.
of a preformed coumarin nucleus.12 Thus, it is of great interest
INTRODUCTION
■
to develop a novel synthetic route to coumarins having diverse
While coumarins have been used as an important phamaco-
substituents from intermolecular reaction of a new precursor
phore displaying interesting biological activities,1 they are also
without using preformed coumarins. Herein, we report a
frequently employed in materials science as highly efficient
versatile synthetic method of coumarins using allenes, and
organoelectroluminescent materials, especially in recent years.2
depending on the substituent pattern of those readily available
This aspect has led to extensive synthetic efforts to obtain more
starting materials, a general synthetic method of 4-substituted
diverse coumarin derivatives. For example, Pechmann, Perkin,
and 3,4-disubstituted 3-arylcoumarins is also described (eq 4).
Knoevenagel, Reformatsky, and Wittig reactions were conven-
tionally employed for the synthesis of the coumarin skeleton.3
Among these, the Pechmann reaction is the most widely used
method (eq 1), consisting of the condensation of phenols with
β-ketoesters in the presence of a variety of reagents, mainly
producing 4-substituted coumarins.3,4 Several acid catalysts
have been used in the Pechmann reaction, including sulfuric
acid, aluminum chloride, phosphorus pentoxide, or trifluoro-
acetic acid.3−5 However, these catalysts have to be used in
excess and, in some cases, the reaction provides undesired side
products, such as chromones, in addition to coumarins.
Recently, a wide range of Lewis acids have been examined as
an alternative to the conventional acids in the Pechmann
reaction for the formation of coumarins.6 More recent research
emphasis has been centered on the use of Pd-catalyzed C−C
bond formation producing 3- or 4-substituted coumarins.7
Trost et al. developed an atom-economic synthesis of
coumarins from the intermolecular reaction of propiolic acids
with phenols in the presence of palladium catalysts in formic
RESULTS AND DISCUSSION
acid (eq 2).8 Fujiwara et al. also reported a direct synthesis of
■
Recently, we have been interested in the transition-metal-
catalyzed intermolecular hydroarylation and, thus, examined the
reaction of 1,3,5-trimethoxybenzene (1a) with ethyl 2-benzyl-
2,3-butadienoate (2a). However, a condensing product, 3-
benzyl-5,7-dimethoxy-4-methylcoumarin (3a), was unexpect-
edly detected instead of a desired hydroarylated product.
Considering the fact that there are few synthetic methods of
coumarins using allenes13 and that a direct introduction of 3,4-
coumarins by Pd-catalyzed inter- and intramolecular hydro-
arylation of aryl propiolates.9 Unfortunately, these methods
could not be applied to the synthesis of coumarins having
substituents at the 3-position. Larock et al. described that Pd-
catalyzed annulation of internal alkynes by o-iodophenols in the
presence of CO results in formation of coumarins (eq 3).10
However, the generation of regioisomeric mixtures is
unavoidable when unsymmetrical alkynes are employed.
Although the synthetic strategies to functionalized coumarins
by using other transition-metal-catalyzed reactions have also
been reported,11 most of them depend on the functionalization
Received: May 26, 2012
Published: July 13, 2012
© 2012 American Chemical Society
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disubstituents, including the 3-aryl group, on coumarins from
an intermolecular reaction is highly challenging, we decided to
further investigate the condensation reaction of 1a with 2a
under various conditions (Table 1). Another important
Table 2. TfOH-Mediated Preparation of Coumarins
Table 1. Optimization for Preparation of Coumarins
entry
acid (equiv)
time (h)
yield (%)
1
2
3
4
5
6
7
CH3CO2H (1)
CF3CO2H (1)
p-TsOH (1)
24
24
15
15
48
24
10
0
0
0
a
PPTS (1)
0
TfOH (0.05)
TfOH (0.1)
TfOH (1)
21
35
86
a
Pyridinium p-toluene sulfonate.
motivation for this study is the ready availability of allenes
with wide structural diversity based on our previous work,14 in
which highly practical syntheses of allenes were achieved by the
Pd-catalyzed cross-coupling reactions of organoindium re-
agents. Reactions of 1a with 2a in the presence of a wide
range of acids, such as acetic acid, trifluoroacetic acid, p-
toluenesulfonic acid, and PPTS, in DCE at 100 °C did not
proceed (Table 1, entries 1−4). Treatment of 1a and 2a with
trifluoromethanesulfonic acid (TfOH, 5 mol %) furnished 3a in
21% yield (entry 5). Increasing the amount of TfOH to 10 mol
% in DCE (100 °C, 24 h) afforded the better result (35% yield,
entry 6). Finally, the best result was obtained with 1 equiv of
TfOH, producing 3a in 86% yield in DCE at 100 °C after 10 h
(entry 7).
the condensation reaction with similar efficiency, producing 3e
in 71% yield. Electronic variation (2-methyl, 4-bromo, 4-iodo,
and 3-nitro groups) on the phenyl ring did not much influence
the reaction efficiency, although an iodo substituent slightly
lowered the product yield. Direct introduction of bromo- and
iodo-phenyl groups at the 3-position of coumarin is very
important for further functionalizations via cross-coupling
reactions. Reaction of ethyl 2-phenyl-2,3-pentadienoate (2j),
which is a 1,1,3-trisubstituted allene, with 1a afforded 4-ethyl-3-
phenylcoumarin (3j) in 80% yield. 1,3-Dimethoxybenzene (1b)
underwent the regioselective condensation with 2a to give 3-
benzyl-7-methoxy-4-methylcoumarin (3k) in 81% yield. Im-
portantly, a constitutional isomer of 3k, 3-benzyl-5-methoxy-4-
methylcoumarin, was not detected in this reaction. 1,1-
Disubstituted allenes (2d and 2f) bearing phenyl and o-tolyl
groups also gave good yields of the desired coumarins (3l and
3m). High functional group tolerance was observed, as
demonstrated in the reaction of allenes bearing an ethox-
ycarbonyl group. The condensation reaction of 1,1,3-trisub-
stituted allenes 2l took place in high yield to afford 3o.
With the optimal conditions in hand, we next examined the
scope and limitation of our method (Table 3). 1,3-
Dihydroxybenzene (1c) was condensed with ethyl 2,3-
butadienoate (2m) to produce selectively 7-hydroxy-4-methyl-
coumarin (4a) in 81% yield. When 1c was reacted with 1,3-
disubstituted allenes (2b and 2n), the corresponding coumarins
(4b and 4c) having 4-n-propyl and benzyl groups were
obtained. 1,1-Disubstituted allenes (2a, 2o, and 2p) worked
equally well in the condensation with 1c, producing 3,4-
disubstituted coumarins, including 3-benzyl-7-hydroxy-4-meth-
ylcoumarin derivatives (4d, 4e, and 4f), in good yields. In
addition, we were pleased to obtain 3-benzyl-4-ethyl-7-
With this newly developed protocol, a variety of allenes
(Scheme 1), which can be readily prepared by a Pd-catalyzed
Scheme 1. A Variety of Allenes
cross-coupling reaction with organoindium reagents, were
subjected to undergo the intermolecular condensation reaction
(Table 2). Treatment of electron-rich arene 1a with 1,3-
disubstituted allene 2b in the presence of TfOH (1 equiv)
produced 4-n-propylcoumarin 3b in 79% yield. 1,1-Disubsti-
tuted allene 2c bearing a 4-iodo benzyl group at the 2-position
proceeded efficiently to provide 3,4-disubstituted coumarin 3c
in 80% yield. Although the introduction of an aryl group on the
3-position of coumarin is generally difficult, 4-methyl-3-
phenylcoumarin (3d) was obtained in 84% yield when 1a
was treated with 2d under the optimized reaction conditions.
Encouraged by these results, we extended the scope of the
reaction further with a wide range of 1,1-disubstituted allenes 2
having an aryl group. 2-(1-Naphthyl)allenoate (2e) underwent
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bis(allenes) (2s and 2t) in the presence of TfOH (1 equiv)
produced efficiently bis(coumarins) 5a and 5b in 61% and 65%
yields, respectively. In the case whereby one more carbon
between the phenyl and allenyl groups was extended, 1c
underwent the 2-fold condensation with 2u and 2v, leading to
bis(coumarins) 5c and 5d in moderate yield under the standard
reaction conditions.
Table 3. TfOH-Mediated Preparation of Coumarins
Since 3-(4-bromophenyl)coumarin (3g) or 3-(4-
iodophenyl)coumarin (3h) are in hand now, we explored the
possibility of further transformation via a cross-coupling
reaction (Table 4). The reaction of 3h with In(S-n-Pr)3,
Table 4. Coumarin Derivatization via Cross-Coupling
ab c
, ,
Reaction
hydroxycoumarin (4g) from 1,1,3-trisubstituted allene (2q). In
addition, phenyl or 4-iodophenyl groups at the 3-position of
coumarin could be efficiently introduced by the current
method, which was demonstrated by obtaining the 3,4-
disubstituted coumarins (4h and 4i). No regioisomeric
coumarin products, such as 5-hydroxycoumarin, were isolated
in all cases. The present method turned out to be compatible
with the reaction of 1,3-dihydroxy-5-methylbenzene (1d) with
2a and 2r, resulting in selectively 4j and 4k in 74% and 78%
yields, respectively. 3,5-Dimethylphenol (1e) did not diminish
the condensation efficiency, albeit requiring a longer reaction
time (6 h).
a
Pd(OAc)2 (4 mol %), Xantphos (4.2 mol %), DIPEA (100 mol %),
b
In(SR5)3 (34 mol %), DMF, 100 °C, 1 h. Pd2(dba3)CHCl3 (2 mol
%), Ph3P (16 mol %), CuI (10 mol %), Et3N (300 mol %),
phenylacetylene (1.2 equiv), DMF, 100 °C, 3 h. Pd2(dba3)CHCl3 (2
mol %), Ph3P (16 mol %), LiCl (300 mol %), In (100 mol %),
c
propargyl bromide (150 mol %), DMF, 100 °C, 3 h
In(SPh)3,15 and phenylacetylene in the presence of palladium
catalyst proceeded efficiently to produce the synthetically
valuable 3,4-disubstituted coumarins (6a, 6b, and 6c), including
the π-extended coumarin. Also, 3c was converted into the
functionalized 3,4-disubstituted coumarins (6d, 6e, 6f, and 6g)
in good yields through indium-mediated thiopropyl, thiophen-
yl, and allenyl coupling reactions16 and the Sonogashira
reaction.17
We were also interested in the synthesis of bis(coumarins)
from the reaction of electron-rich arenes with bis(allenes)
through a 2-fold condensation reaction in one pot (Scheme 2).
Treatment of 1c (1 equiv) with 0.5 equiv of 1,3- or 1,4-
a
Scheme 2. TfOH-Catalyzed Preparation of Bis(coumarins)
Although the mechanism of the present reaction has not
been fully established at the present stage, a possible reaction
pathway is shown in Scheme 3. Nucleophilic 1,4-addition of the
aromatic carbon of the trimethoxybenzene (1a) to the proton-
activated allenyl ester 7 might have occurred to afford 8.
Intramolecular addition and aromatization, followed by
hydrolysis, could then give the corresponding 3,4-disubstituted
Scheme 3. Plausible Mechanism
a
Conditions: 2s−2v, (50 mol %) and TfOH (100 mol %) were used,
DCE, 100 °C.
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822 cm−1; HRMS (EI) m/z calcd for C19H17IO4, 436.0172; found,
436.0173.
coumarins 3. Exclusive formation of coumarins having an
oxygen atom on the 7-position can be attributed to steric and
electronic effects.
5,7-Dimethoxy-4-methyl-3-phenylcoumarin (3d): 84% yield
1
(74.7 mg), pale yellow solid, melting point 154−157 °C; H NMR
(400 MHz, CDCl3, 25 °C, TMS) δ 7.45−7.41 (m, 2H), 7.38−7.34 (m,
1H), 7.28−7.25 (m, 2H), 6.48 (s, 1H), 6.33 (s, 1H), 3.86 (s, 6H), 2.39
(s, 3H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS) δ 162.8, 161.5,
159.8, 156.3, 150.5, 135.7, 130.8, 128.8, 128.1, 123.8, 105.8, 96.1, 93.6,
56.2, 56.1, 21.9; IR (KBr) 2940, 2843, 1714, 1616, 1592, 1459, 1159,
1113 cm−1; HRMS (EI) m/z calcd for C18H16O4, 296.1049; found,
296.1052.
5,7-Dimethoxy-4-methyl-3-(1-naphthyl)coumarin (3e): 71%
yield (73.8 mg), pale green solid, melting point 178−181 °C; 1H
NMR (400 MHz, CDCl3, 25 °C, TMS) δ 7.91−7.84 (m, 2H), 7.62−
7.37 (m, 5H), 6.56 (s, 1H), 6.37 (s, 1H), 3.89 (s, 3H), 3.86 (s, 3H),
2.26 (s, 3H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS) δ 162.6,
160.9, 159.5, 156.3, 152.0, 133.8, 133.0, 132.1, 128.6, 128.4, 128.1,
126.4, 125.9, 125.6, 124.9, 121.4, 95.7, 93.3, 55.8, 55.7, 21.5; IR (KBr)
2933, 1708, 1589, 1186, 1156, 1124 cm−1; HRMS (EI) m/z calcd for
C22H18O4, 346.1205; found, 346.1204.
5,7-Dimethoxy-4-methyl-3-(2-methylphenyl)coumarin (3f):
82% yield (76.3 mg), pale yellow solid, melting point 168−171 °C;
1H NMR (400 MHz, CDCl3, 25 °C, TMS) δ 7.30−7.23 (m, 3H), 7.10
(d, J = 6.8 Hz, 1H), 6.51 (s, J = 2.42 Hz, 1H), 6.35 (s, J = 2.54 Hz,
1H), 3.87 (s, 3H), 3.86 (s, 3H), 2.30 (s, 3H), 2.16 (s, 3H); 13C NMR
(100 MHz, CDCl3, 25 °C, TMS) δ 162.8, 160.9, 159.8, 156.5, 151.0,
137.5, 135.3, 130.6, 130.5, 128.5, 126.5, 123.3, 105.6, 95.1, 93.6, 56.2,
56.1, 21.3, 19.9; IR (KBr) 2941, 1714, 1616, 1593, 1158 cm−1; HRMS
(EI) m/z calcd for C19H18O4, 310.1205; found, 310.1205.
3-(4-Bromophenyl)-5,7-dimethoxy-4-methylcoumarin (3g):
78% yield (87.8 mg), pale yellow solid, melting point 147−150 °C;
1H NMR (400 MHz, CDCl3, 25 °C, TMS) δ 7.56 (d, J = 8.3 Hz, 2H),
7.15 (d, J = 8.3 Hz, 2H), 6.48 (s, 1H), 6.34 (s, 1H), 3.87 (s, 6H), 2.39
(s, 3H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS) δ 161.6, 159.8,
158.4, 154.9, 149.5, 133.2, 131.1, 130.6, 104.2, 94.8, 92.2, 54.8, 54,7,
20.5; IR (KBr) 1694, 1613, 1594, 1158, 1093, 822 cm−1; HRMS (EI)
m/z calcd for C18H15BrO4, 374.0154; found, 374.0157.
CONCLUSION
■
In conclusion, we have developed a highly efficient and
practical route to substituted coumarins using a Brønsted acid
mediated condensation reaction under metal-free conditions.
Coumarins having 4-substituents, 3,4-disubstituents, and 2-aryl
groups could be obtained, which were not easily accessible
through the precedent procedures. Significantly, readily
available allenes were employed as a three-carbon atom source
constituting the coumarin skeleton. Considering the fact that a
wide range of diversely substituted allenes can be easily
prepared by our previous Pd-catalyzed cross-coupling reactions,
the present synthetic procedure of coumarins is anticipated to
be widely applied in organic synthesis, medicinal chemistry, and
materials science.
EXPERIMENTAL SECTION
■
General Methods. A variety of chemical reagents were
commercially purchased and used without further purification.
Analytical TLC was carried out on precoated plates and visualized
with UV light or stained with potassium permanganate. H and 13C
1
NMR spectra were measured at 298 K on a 400 Fourier Transform
NMR spectrometer. Chemical shifts were reported in δ (parts per
million), relative to the internal standard of TMS. The signals
observed were described as follows: s (singlet), d (doublet), t (triplet),
q (quartet), and m (multiplets). The number of protons (n) for a
given resonance was indicated as nH. Coupling constants are reported
as J values in hertz. 13C NMR are reported as δ (parts per million) in
downfield from TMS and relative to the signal of chloroform-d (δ
77.00, triplet). Mass spectrometry was performed on a GC/HRMS
spectrometer (KBSI) under the electron impact (EI) ionization
technique (magnetic sector−electric sector double focusing mass
analyzer).
Synthesis of 3-Benzyl-5,7-dimethoxy-4-methylcoumarin
(3a). In a V-vial, 1,3,5-trimethoxybenzene (50.0 mg, 0.3 mmol) was
added to a solution of ethyl 2-benzyl-2,3-butadienoate (61.0 mg, 0.3
mmol) and TfOH (45.0 mg, 0.3 mmol) in dichloroethane (1.0 mL).
The reaction mixture was stirred at 100 °C for 10 h. The reaction
mixture was concentrated under reduced pressure. The crude product
was purified by silica gel column chromatography to give 3-benzyl-5,7-
dimethoxy-4-methylcoumarin 3a (80.0 mg, 86%). Yellow solid,
melting point 166−168 °C; 1H NMR (400 MHz, CDCl3, 25 °C,
TMS) δ 7.26−7.24 (m, 4H), 7.18−7.16 (m, 1H), 6.44 (s, 1H), 6.29 (s,
1H), 4.03 (s, 2H), 3.83 (s, 6H), 2.55 (s, 3H); 13C NMR (100 MHz,
CDCl3, 25 °C, TMS) 162.5, 162.4, 159.4, 155.8, 150.6, 139.9, 128.8,
128.6, 126.5, 121.2, 105.9, 96.1, 93.5, 56.1, 56.0, 32.9, 20.3; IR (KBr)
2939, 1706, 1597, 1455, 1224, 1205 cm−1; HRMS (EI) m/z calcd for
C19H18O4, 310.1205; found, 310.1207.
3-(4-Iodophenyl)-5,7-dimethoxy-4-methylcoumarin (3h):
71% yield (89.9 mg), pale brown solid, melting point 178−179 °C;
1H NMR (400 MHz, CDCl3, 25 °C, TMS) δ 7.77 (d, J = 8.3 Hz, 2H),
7.02 (d, J = 8.3 Hz, 2H), 6.48 (s, 1H), 6.34 (s, 1H), 3.87 (s, 6H), 2.40
(s, 3H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS) δ 163.0, 161.2,
159.8, 156.3, 150.8, 138.0, 135.3, 132.8, 122.8, 105.7, 96.2, 94.1, 93.6,
56.2, 56.1, 22.0; IR (KBr) 1704, 1612, 1593, 1111, 1058, 823 cm−1;
HRMS (EI) m/z calcd for C18H15IO4, 422.0015; found, 422.0017.
5,7-Dimethoxy-4-methyl-3-(3-nitrophenyl)coumarin (3i):
1
82% yield (84.0 mg), white solid, melting point 118−123 °C; H
NMR (400 MHz, CDCl3, 25 °C, TMS) δ 8.15−8.12 (m, 1H), 8.06 (s,
1H), 7.55−7.49 (m, 2H), 6.40 (s, 1H), 6.26 (s, 1H), 3.78 (s, 3H), 3.78
(s, 3H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS) δ
163.4, 161.1, 160.0, 156.4, 151.9, 148.7, 121.4, 105.4, 96.4, 93.7, 56.3,
56.2, 22.1; IR (KBr) 2249, 1711, 1608, 1160, 1084 cm−1; HRMS (EI)
m/z calcd for C18H15NO6, 341.0899; found, 341.0896.
4-Ethyl-5,7-dimethoxy-3-phenylcoumarin (3j): 80% yield
5,7-Dimethoxy-4-propylcoumarin (3b):18 79% yield (58.8 mg),
white solid, melting point 117−120 °C; H NMR (400 MHz, CDCl3,
25 °C, TMS) δ 6.46 (s, 1H), 6.31 (s, 1H), 5.97 (s, 1H), 3.88 (s, 3H),
3.85 (s, 3H), 2.86 (dd, J = 7.5, 7.8 Hz, 2H), 1.64−1.59 (m, 2H), 1.01
(t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS) δ
163.0, 161.7, 159.1, 158.6, 157.7, 111.1, 104.7, 96.0, 94.0, 56.2, 56.1,
38.9, 23.2, 14.5; IR (KBr) 2961, 1709, 1601, 1449, 1156, 1116 cm−1.
3-(4-Iodobenzyl)-5,7-dimethoxy-4-methylcoumarin (3c):
(74.5 mg), white solid, melting point 172−175 °C; H NMR (400
1
1
MHz, CDCl3, 25 °C, TMS) δ 7.46−7.42 (m, 2H), 7.40−7.36 (m, 1H),
7.26−7.24 (m, 2H), 6.52 (s, 1H), 6.36 (s, 1H), 3.89 (s, 3H), 3.87 (s,
3H), 2.79 (q, J = 7.3 Hz, 2H), 1.06 (t, J = 7.3 Hz, 3H); 13C NMR (100
MHz, CDCl3, 25 °C, TMS) δ 162.3, 161.4, 158.8, 156.6, 155.6, 135.3,
130.0 128.5, 127.7, 123.4, 104.3, 95.8, 93.5, 55.9, 55.7, 26.2, 14.6; IR
(KBr) 2977, 1706, 1590, 1378, 1114, 1079 cm−1; HRMS (EI) m/z
calcd for C19H18O4, 310.1205; found, 310.1207.
1
80% yield (104.7 mg), white solid, melting point 110−115 °C; H
3-Benzyl-7-methoxy-4-methylcoumarin (3k): 81% yield (68.1
1
NMR (400 MHz, CDCl3, 25 °C, TMS) δ 7.57 (dt, J = 8.25, 2.35 Hz,
2H), 7.00 (d, J = 8.33 Hz, 2H), 6.45 (d, J = 2.46 Hz, 1H), 6.31 (d, J =
2.46 Hz, 1H), 3.96 (s, 2H), 3.85 (d, J = 1.95 Hz, 6H), 2.54 (s, 3H);
13C NMR (100 MHz, CDCl3, 25 °C, TMS) δ 162.1, 162.0, 159.0,
155.5, 139.3, 137.5, 130.3, 120.2, 105.4, 95.8, 93.1, 91.2, 55.8, 55.7,
32.1, 20.0; IR (film) 3006, 2964, 2939, 1704, 1616, 1596, 1158, 1133,
mg), white solid, melting point 115−118 °C; H NMR (400 MHz,
CDCl3, 25 °C, TMS) δ 7.49 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 4.4 Hz,
4H), 7.19−7.15 (m, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.80 (s, 1H), 4.03
(s, 2H), 3.85 (s, 3H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3, 25
°C, TMS) δ 162.7, 162.3, 154.4, 148.2, 139.6, 128.9, 128.7, 126.7,
126.1, 126.0, 122.5, 114.5, 112.6, 101.0, 56.1, 33.2, 15.8 ; IR (KBr)
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2936, 1712, 1608, 1385, 1285, 1161 cm−1; HRMS (EI) m/z calcd for
C18H16O3, 280.1099; found, 280.1097.
= 8.8 Hz, 1H), 6.70 (s, 1H), 3.92 (s, 2H), 2.38 (s, 3H); 13C NMR
(100 MHz, DMSO-d6, 25 °C) δ 161.7, 160.9, 153.8, 149.2, 139.3,
131.6, 130.7, 127.2, 112.0, 119.4, 113.3, 112.7, 102.3, 31.9, 15.5; IR
(KBr) 3206, 1653, 1571, 1487, 1449, 1384, 1228, 853, 827 cm−1;
HRMS (EI) m/z calcd. for C17H13BrO3, 344.0048; found, 344.0050.
7-Hydroxy-4-methyl-3-((2-naphthyl)methyl)coumarin (4f):
7-Methoxy-4-methyl-3-phenylcoumarin (3l):19 76% yield
1
(60.7 mg), yellow solid, melting point 96−100 °C; H NMR (400
MHz, CDCl3, 25 °C, TMS) δ 7.57 (d, J = 8.7 Hz, 1H), 7.47−7.43 (m,
2H), 7.40−7.36 (m, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 8.7 Hz,
1H), 6.86 (s, 1H), 3.89 (s, 3H), 2.28 (s, 3H); 13C NMR (100 MHz,
CDCl3, 25 °C, TMS) δ 162.7, 161.8, 154.8, 148.3, 135.1, 130.6, 128.8,
128.4, 126.6, 124.7, 114.5, 112.8, 101.0, 56.2, 17.0; IR (KBr) 2936,
1714, 1606, 1381, 1269 cm−1.
1
80% yield (75.9 mg), white solid, melting point 226−229 °C; H
NMR (400 MHz, DMSO-d6, 25 °C) δ 10.5 (s, 1H), 7.87−7.82 (m,
3H), 7.68 (s, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.49−7.41 (m, 3H), 6.82
(d, J = 8.8 Hz, 1H), 6.73 (s, 1H), 4.10 (s, 2H); 13C NMR (100 MHz,
DMSO-d6, 25 °C) δ 161.8, 160.9, 153.9, 149.3, 137.5, 133.5, 132.0,
128.3, 127.8, 127.4, 127.2, 126.4, 126.1, 125.7, 120.2, 113.3, 112.9,
102.3, 32.7, 15.6; IR (KBr) 3326, 1665, 1611, 1566, 1304, 1240, 1145,
1087 cm−1; HRMS (EI) m/z calcd for C21H16O3, 316.1099; found,
316.1101.
7-Methoxy-4-methyl-3-(2-methylphenyl)coumarin (3m):20
1
88% yield (74.0 mg), white solid, melting point 109−113 °C; H
NMR (400 MHz, CDCl3, 25 °C, TMS) δ 7.58 (d, J = 8.7 Hz, 1H),
7.31−7.26 (m, 3H), 7.12 (d, J = 7.2 Hz, 1H), 6.92−6.88 (m, 2H), 3.90
(s, 3H), 2.17 (s, 3H), 2.16 (s, 3H); 13C NMR (100 MHz, CDCl3, 25
°C, TMS) δ 162.8, 161.2, 155.0, 149.0, 137.4, 134.7, 130.7, 130.4,
128.8, 126.5, 124.4, 114.3, 112.7, 101.1, 56.2, 20.0, 16.6 ; IR (KBr)
1713, 1607, 1509, 1382, 1286, 1264 cm−1.
3-Benzyl-4-ethyl-7-hydroxycoumarin (4g): 78% yield (65.6
1
mg), white solid, melting point 173−175 °C; H NMR (400 MHz,
DMSO-d6, 25 °C) δ 10.4 (s, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.29−7.18
(m, 5H), 6.82 (d, J = 8.8 Hz, 1H), 6.73 (s, 1H), 3.92 (s, 2H), 2.82 (q, J
= 7.5 Hz, 2H), 1.02 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, DMSO-
d6, 25 °C) δ 161.6, 160.0, 153.9, 153.7, 139.6, 128.3, 127.8, 126.4,
125.9, 119.1, 113.0, 110.9, 102.1, 31.6, 21.5, 13.4; IR (KBr) 3245,
1668, 1593, 1451, 1381, 1227 cm−1; HRMS (EI) m/z calcd for
C18H16O3, 280.1099; found, 280.1096.
3-(4-Ethoxycarbonylphenyl)-7-methoxy-4-methylcoumarin
(3n): 74% yield (75.1 mg), white solid, melting point 159−163 °C; 1H
NMR (400 MHz, CDCl3, 25 °C, TMS) δ 8.13 (d, J = 8.3 Hz, 2H),
7.59 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 8.3 Hz, 2H), 6.91 (d, J = 8.9 Hz,
1H), 6.87 (s, 1H), 4.41 (q, J = 7.1 Hz, 2H), 3.90 (s, 3H), 2.28 (s, 3H),
1.41 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS) δ
166.7, 163.0, 161.3, 154.9, 148.8, 139.8, 130.8, 130.5, 130.0, 126.6,
123.8, 114.2, 112.9, 101.1, 61.5, 56.2, 14.8; IR (KBr) 2995, 1702, 1603,
1287, 1257 cm−1; HRMS (EI) m/z calcd for C20H18O5, 338.1154;
found, 338.1157.
7-Hydroxy-4-methyl-3-phenylcoumarin (4h): 80% yield (60.5
1
mg), white solid, melting point 225−227 °C; H NMR (400 MHz,
DMSO-d6, 25 °C) δ 10.5 (s, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.46−7.38
(m, 3H), 7.30−7.28 (m, 2H), 6.84 (dd, J = 8.7 Hz, 1H), 6.75 (d, J =
2.39 Hz, 1H), 2.21 (s, 3H); 13C NMR (100 MHz, DMSO-d6, 25 °C) δ
161.2, 160.6, 154.2, 148.6, 135.2, 130.6, 128.4, 127.9, 127.5, 122.7,
113.3, 112.7, 102.3, 16.7; IR (KBr) 3227, 2921, 2853, 1670, 1375,
1226, 1131, 1106, 1072 cm−1; HRMS (EI) m/z calcd for C16H12O3,
252.0786; found, 252.0784.
4-Ethyl-3-(4-iodophenyl)-7-methoxycoumarin (3o): 79% yield
1
(96.3 mg), pale brown solid, melting point 170−174 °C; H NMR
(400 MHz, CDCl3, 25 °C, TMS) δ 7.79 (d, J = 8.3 Hz, 2H), 7.58 (d, J
= 8.8 Hz, 1H), 7.04 (d, J = 8.3 Hz, 2H), 6.90 (d, J = 8.8 Hz, 1H), 6.87
(s, 1H), 2.63 (q, J = 7.6 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3, 25 °C, TMS) δ 162.8, 161.7, 155.4, 154.4, 138.1,
134.7, 132.1, 122.6, 123.1, 113.0, 112.9, 101.4, 94.5, 56.2, 23.3, 14.7; IR
(KBr) 2978, 1701, 1615, 1304, 1158 cm−1; HRMS (EI) m/z calcd for
C18H15IO3, 406.0066; found, 406.0063.
7-Hydroxy-3-(4-iodophenyl)-4-methylcoumarin (4i): 71%
1
yield (80.5 mg), white solid, melting point 266−269 °C; H NMR
(400 MHz, DMSO-d6, 25 °C) δ 10.6 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H),
7.68 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 6.84 (d, J = 8.8 Hz,
1H), 6.75 (s, 1H), 2.20 (s, 3H); 13C NMR (100 MHz, DMSO-d6, 25
°C) δ 161.3, 160.4, 154.2, 149.0, 137.3, 134.9, 133.0, 127.7, 121.7,
113.5, 112.7, 102.3, 94.5, 16.8; IR (KBr) 3388, 1681, 1608, 1583, 1134,
773 cm−1; HRMS (EI) m/z calcd for C16H11IO3, 377.9753; found,
377.9751.
7-Hydroxy-4-methylcoumarin (4a):21 81% yield (42.8 mg),
white solid, melting point 186−189 °C; 1H NMR (400 MHz, DMSO-
d6, 25 °C) δ 10.5 (s, 1H), 7.60 (d, J = 8.7 Hz, 1H), 6.80 (d, J = 8.7 Hz,
1H), 6.71 (s, 1H), 6.13 (s, 1H), 2.36 (s, 3H); 13C NMR (100 MHz,
DMSO-d6, 25 °C) δ 161.5, 160.7, 155.2, 153.9, 127.0, 113.2, 112.4,
110.6, 102.5, 18.5; IR (KBr) 3231, 3033, 1695, 1585, 1255, 1080 cm−1.
7-Hydroxy-4-propylcoumarin (4b):22 75% yield (45.9 mg),
white solid, melting point 190−193 °C; 1H NMR (400 MHz, DMSO-
d6, 25 °C) δ 10.5 (s, 1H), 7.62 (d, J = 8.7 Hz, 1H), 6.79 (d, J = 8.7 Hz,
1H), 6.70 (s, 1H), 6.06 (s, 1H), 2.68 (t, J = 7.4 Hz, 2H), 1.66−1.56
(m, 2H), 0.95 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, DMSO-d6, 25
°C) δ 161.4, 160.7, 157.2, 155.5, 126.7, 113.3, 111.6, 109.7, 102.7,
33.2, 21.7, 14.0; IR (KBr) 3350, 3053, 1678, 1615, 1235, 1077 cm−1.
4-Benzyl-7-hydroxycoumarin (4c): 80% yield (60.5 mg), white
solid, melting point 214−217 °C; 1H NMR (400 MHz, DMSO-d6, 25
°C) δ 10.5 (s, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.35−7.31 (m, 4H),
7.28−7.22 (m, 1H), 6.76 (d, J = 8.7 Hz, 1H), 6.71 (s, 1H), 4.13 (s,
2H); 13C NMR (100 MHz, DMSO-d6, 25 °C) δ 162.0, 161.2, 156.6,
156.0, 138.1, 129.8, 129.5, 127.7, 127.6, 113.8, 112.0, 111.5, 103.2,
37.8; IR (KBr) 3221, 1690, 1617, 1559, 1291, 1136 cm−1; HRMS (EI)
m/z calcd for C16H12O3, 252.0786; found, 252.0785.
3-Benzyl-7-hydroxy-4,5-dimethylcoumarin (4j): 74% yield
1
(62.2 mg), pale green solid, melting point 211−214 °C; H NMR
(400 MHz, DMSO-d6, 25 °C) δ 10.2 (s, 1H), 7.16−7.13 (m, 2H),
7.08−7.03 (m, 3H), 6.50 (s, 1H), 6.45 (s, 1H), 3.81 (s, 2H), 2.49 (s,
3H), 2.38 (s, 3H); 13C NMR (100 MHz, DMSO-d6, 25 °C) δ 161.8,
159.9, 155.6, 151.8, 140.3, 139.5, 129.3, 128.7, 126.8, 121.2, 118.1,
113.0, 101.5, 33.0, 25.7, 21.1; IR (KBr) 3163, 1658, 1578, 1385, 1169,
860 cm−1; HRMS (EI) m/z calcd for C18H16O3, 280.1099; found,
280.1102.
7-Hydroxy-4,5-dimethyl-3-(4-methylbenzyl)coumarin (4k):
1
78% yield (68.9 mg), white solid, melting point 225−229 °C; H
NMR (400 MHz, DMSO-d6, 25 °C) δ 10.4 (s, 1H), 7.07 (s, 4H), 6.61
(s, 1H), 6.56 (s, 1H), 3.83 (s, 2H), 2.62 (s, 3H), 2.51 (s, 3H), 2.24 (s,
3H); 13C NMR (100 MHz, DMSO-d6, 25 °C) δ 161.4, 159.4, 155.1,
151.2, 139.0, 136.7, 135.3, 129.4, 128.1, 121.0, 117.6, 112.6, 101.0,
32.1, 25.2, 20.9, 20.5; IR (KBr) 3279, 1672, 1624, 1458, 1272, 1176,
850, 785 cm−1; HRMS (EI) m/z calcd for C19H18O3, 294.1256; found,
294.1254.
3-Benzyl-7-hydroxy-4-methylcoumarin (4d): 78% yield (62.3
1
mg), white solid, melting point 227−230 °C; H NMR (400 MHz,
DMSO-d6, 25 °C) δ 10.5 (s, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.28−7.14
(m, 5H), 6.80 (d, J = 8.8 Hz, 1H), 6.70 (s, 1H), 3.92 (s, 2H), 2.38 (s,
3H); 13C NMR (100 MHz, DMSO-d6, 25 °C) δ 162.7, 160.9, 153.8,
148.9, 139.8, 128.8, 128.4, 127.1, 126.4, 120.4, 113.3, 112.8, 102.3,
32.4, 15.5; IR (KBr) 3209, 1660, 1576, 1451, 1236, 1097 cm−1; HRMS
(EI) m/z calcd for C17H14O3, 266.0943; found, 266.0946.
4,5,7-Trimethyl-3-phenylcoumarin (4l): 75% yield (59.5 mg),
1
white solid, melting point 136−138 °C; H NMR (400 MHz, CDCl3,
25 °C, TMS) δ 7.47−7.43 (m, 2H), 7.40−7.36 (m, 1H), 7.27 (d, J =
8.5 Hz, 2H), 7.05 (s, 1H), 6.93 (s, 1H), 2.71 (s, 3H), 2.41 (s, 3H),
2.39 (s, 3H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS) δ 161.3,
154.4, 150.3, 141.7, 137.0, 135.8, 130.5, 130.4, 129.0, 128.4, 127.7,
118.1, 116.3, 25.4, 22.9, 21.6; IR (KBr) 1693, 1614, 1585, 1384, 1165,
1092 cm−1; HRMS (EI) m/z calcd for C18H16O2, 264.1150; found,
264.1152.
3-(4-Bromobenzyl)-7-hydroxy-4-methylcoumarin (4e): 87%
1
yield (90.1 mg), pale brown solid, melting point 254−257 °C; H
NMR (400 MHz, DMSO-d6, 25 °C) δ 10.5 (s, 1H), 7.64 (d, J = 8.8
Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.80 (d, J
6534
dx.doi.org/10.1021/jo301086k | J. Org. Chem. 2012, 77, 6530−6537

The Journal of Organic Chemistry
Article
Synthesis of 3,3′-(1,3-Phenylene-bis(methylene))-bis(7-hy-
droxy-4-methylcoumarin) (5c). In a V-vial, 1,3-dihydroxybenzene
(66.0 mg, 0.6 mmol) was added to a solution of diethyl 2,2′-(1,3-
phenylene-bis(methylene))dibuta-2,3-dienoate (98.0 mg, 0.3 mmol)
and TfOH (90.0 mg, 0.6 mmol) in dichloroethane (1.0 mL). The
reaction mixture was stirred at 100 °C for 2 h. The precipitate was
collected by filtration and washed with CHCl3 (10 mL × 3) to give
3,3′-(1,3-phenylenebis(methylene))-bis(7-hydroxy-4-methylcoumarin)
5c (88.6 mg, 65%). Brown solid, melting point 307−310 °C; 1H NMR
(400 MHz, DMSO-d6, 25 °C) δ 10.4 (s, 2H), 7.60 (d, J = 8.8 Hz, 2H),
7.14 (t, J = 7.7 Hz, 1H), 7.08 (s, 1H), 6.99 (d, J = 7.7 Hz, 2H), 6.69 (s,
2H), 3.86 (s, 4H), 2.34 (s, 6H); 13C NMR (100 MHz, DMSO-d6, 25
°C) 161.7, 160.88, 153.8, 148.8, 139.8, 128.9, 128.2, 127.1, 126.0,
120.4, 113.3, 112.7, 102.3, 32.3, 15.5; IR (KBr) 3249, 1660, 1595,
1448, 1381, 1235, 1163, 1096 cm−1; HRMS (EI) m/z calcd for
C28H22O6, 454.1416; found, 454.1413.
3,3′-(1,3-Phenylene)-bis(7-hydroxy-4-methylcoumarin) (5a):
61% yield (78.0 mg), pale brown solid, melting point 367−369 °C; 1H
NMR (400 MHz, acetone-d6, 25 °C) δ 9.43 (s, 2H), 7.71 (d, J = 8.7
Hz, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 7.6 Hz, 2H), 7.32 (s,
1H), 6.90 (d, J = 8.7 Hz, 2H), 6.79 (s, 2H), 2.37 (s, 6H); 13C NMR
(100 MHz, acetone-d6, 25 °C) 161.6, 161.1, 155.4, 149.0, 136.0, 133.6,
130.7, 128.6, 127.9, 124.0, 114.2, 113.6, 103.1, 16.8; IR (KBr) 3254,
1612, 1588, 1542, 1509, 1350, 1241, 1164, 1142 cm−1; HRMS (EI) m/
z calcd for C26H18O6, 426.1103; found, 426.1104.
6.49 (d, J = 2.46 Hz, 1H), 6.33 (d, J = 2.43 Hz, 1H), 3.86 (d, J = 0.94
Hz, 6H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3, 25 °C) 162.9,
161.4, 159.8, 156.3, 150.8, 136.3, 135.2, 134.2, 132.3, 131.6, 130.4,
129.7, 127.9, 123.1, 105.8, 96.2, 93.6, 56.2, 56.1, 20.0; IR (film) 3056,
3003, 2924, 2851, 1715, 1615, 1590, 1158, 1113, 824 cm−1; HRMS
(EI) m/z calcd for C24H20O4S, 404.1082; found, 404.1083.
5,7-Dimethoxy-4-methyl-3-(4-phenylacetylenyl)-
phenylcoumarin (6c): 90% yield (107.0 mg), pale brown solid,
1
melting point 180−185 °C; H NMR (400 MHz, CDCl3, 25 °C) δ
7.59 (dt, J = 8.14, 1.78 Hz, 2H), 7.56−7.53 (m, 2H), 7.38−7.33 (m,
3H), 7.27 (d, J = 8.17 Hz, 2H), 6.48 (d, J = 2.37 Hz, 1H), 6.33 (d, J =
2.44 Hz, 1H), 3.85 (s, 6H), 2.41 (s, 3H); 13C NMR (100 MHz,
CDCl3, 25 °C) 163.0, 161.3, 159.9, 156.3, 150.8, 1358, 132.1, 132.0,
131.0, 128.8, 1287, 123.7, 123.2, 123.1, 105.8, 96.2, 93.6, 90.2, 89.7,
56.2, 56.1, 22.0; IR (film) 3054, 2986, 1714, 1616, 1594, 1265, 739,
704 cm−1; HRMS (EI) m/z calcd for C26H20O4, 396.1362; found,
396.1361.
5,7-Dimethoxy-4-methyl-3-(4-n-propylthio)benzylcoumarin
(6d): 87% yield (100.4 mg), pale yellow solid, melting point 95−100
°C; 1H NMR (400 MHz, CDCl3, 25 °C) δ 7.23 (dt, J = 8.32, 1.81 Hz,
2H), 7.16 (d, J = 8.23 Hz, 2H), 6.45 (d, J = 2.45 Hz, 1H), 6.31 (d, J =
2.43 Hz, 1H), 3.99 (s, 2H), 3.84 (s, 6H), 2.84 (t, J = 7.14 Hz, 2H),
2.56 (s, 3H), 1.63 (sextet, J = 7.45 Hz, 2H), 0.99 (t, J = 7.43 Hz, 3H);
13C NMR (100 MHz, CDCl3, 25 °C) 162.49, 162.42, 159.4, 155.9,
150.6, 137.8, 134.5, 130.1, 129.1, 121.0, 105.8, 96.1, 93.5, 56.14, 56.07,
365, 32.4, 23.0, 20.4, 13.8; IR (film) 2961, 2929, 2850, 1705, 1617,
1596, 1459, 1159, 823, 800 cm−1; HRMS (EI) m/z calcd for
C22H24O4S, 384.1395; found, 384.1396.
5,7-Dimethoxy-4-methyl-3-(4-phenylthio)benzylcoumarin
(6e): 84% yield (105.5 mg), pale brown solid, melting point 130−135
°C; 1H NMR (400 MHz, CDCl3, 25 °C) δ 7.28−7.23 (m, 6H), 7.20−
7.17 (m, 3H), 6.44 (d, J = 2.45 Hz, 1H), 6.30 (d, J = 2.44 Hz, 1H),
4.00 (s, 2H), 3.84 (s, 6H), 2.55 (s, 3H); 13C NMR (100 MHz, CDCl3,
25 °C) 162.49, 162.45, 159.4, 155.9, 150.7, 139.4, 136.9, 132.9, 132.3,
130.6, 129.52, 129.47, 127.0, 120.7, 105.8, 96.2, 93.5, 56.2, 56.1, 32.6,
20.4; IR (film) 3055, 3006, 2939, 2841, 1703, 1616, 1595, 1158, 1092,
743 cm−1; HRMS (EI) m/z calcd for C25H22O4S, 418.1239; found,
418.1242.
3,3′-(1,4-Phenylene)-bis(7-hydroxy-4-methylcoumarin) (5b):
1
65% yield (83.2 mg), brown solid, melting point above 400 °C; H
NMR (400 MHz, DMSO-d6, 25 °C) δ 10.6 (s, 2H), 7.71 (d, J = 8.8
Hz, 2H), 7.37 (s, 4H), 6.86 (d, J = 8.8 Hz, 2H), 6.77 (s, 2H), 2.28 (s,
6H); 13C NMR (100 MHz, DMSO-d6, 25 °C) 161.3, 160.6, 154.2,
148.9, 134.5, 130.4, 127.6, 122.4, 113.4, 112.8, 102.3, 16.9; IR (KBr)
3157, 1664, 1594, 1567, 1263, 1134, 992 cm−1; HRMS (EI) m/z calcd
for C26H18O6, 426.1103; found, 426.1106.
3,3′-(1,4-Phenylene-bis(methylene))-bis(7-hydroxy-4-meth-
ylcoumarin) (5d): 71% yield (96.8 mg), pale brown solid, melting
point above 400 °C; 1H NMR (400 MHz, DMSO-d6, 25 °C) δ 10.4 (s,
2H), 7.61 (d, J = 8.7 Hz, 2H), 7.10 (s, 4H), 6.79 (d, J = 8.7 Hz, 2H),
6.99 (d, J = 7.7 Hz, 2H), 6.69 (s, 2H), 3.87 (s, 4H), 2.37 (s, 6H); 13C
NMR (100 MHz, DMSO-d6, 25 °C) 161.7, 160.8, 153.8, 148.8, 137.5,
128.4, 127.1, 120.5, 113.3, 112.8, 102.3, 32.0, 15.5; IR (KBr) 3119,
1662, 1592, 1446, 1380, 1233, 1166, 1098, 856 cm−1; HRMS (FAB)
m/z calcd for C28H22O6Na, 477.1314; found, [M + Na]+ 477.1312.
Synthesis of 5,7-Dimethoxy-4-methyl-3-(4-n-propylthio)-
phenylcoumarin (6a). To a suspension of Pd(OAc)2 (2.7 mg,
0.012 mmol, 4 mol %) and Xantphos (7.3 mg, 0.013 mmol, 4.2 mol %)
in DMF (0.5 mL) was added 3-(4-iodophenyl)-5,7-dimethoxy-4-
methylcoumarin (126.7 mg, 0.3 mmol) in DMF (0.3 mL) at room
temperature under a nitrogen atmosphere. After the mixture was
stirred for 5 min, In(SnPr)3 (34.7 mg, 0.102 mmol) and DIPEA (52.3
μL, 0.3 mmol) in DMF (0.5 mL) were transferred via double-ended
needle, and the mixture was stirred at 100 °C for 1 h. The reaction
mixture was quenched with sat. NaHCO3 solution (10 mL). The
aqueous layer was extracted with ether (3 × 20 mL), and the
combined organic layers were washed with brine (10 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography to give 5,7-
dimethoxy-4-methyl-3-(4-n-propylthio)phenylcoumarin (6a) as a pale
brown solid (91.1 mg, 82%). Melting point 90−95 °C; 1H NMR (400
MHz, CDCl3, 25 °C) δ 7.37 (dt, J = 6.51, 1.70 Hz, 2H), 7.18 (dt, J =
8.32, 1.83 Hz, 2H), 6.48 (d, J = 2.47 Hz, 1H), 6.33 (d, J = 2.43 Hz,
1H), 3.86 (d, J = 0.9 Hz, 6H), 2.94 (t, J = 7.17 Hz, 2H), 2.40 (s, 3H),
1.72 (sextet, J = 7.31 Hz, 2H), 1.05 (t, J = 7.38 Hz, 3H); 13C NMR
(100 MHz, CDCl3, 25 °C) 162.8, 161.5, 159.24, 150.62, 137.17, 132.9,
131.3, 128.8, 123.3, 105.9, 96.2, 93.6, 56.2, 56.1, 35.8, 23.0, 22.0, 13.9;
IR (film) 3005, 2962, 2933, 2870, 1715, 1616, 1591, 1158, 824 cm−1;
HRMS (EI) m/z calcd for C21H22O4S, 370.1239; found, 370.1236.
5,7-Dimethoxy-4-methyl-3-(4-phenylthio)phenylcoumarin
(6b): 82% yield (99.5 mg), pale yellow solid, melting point 100−105
°C; 1H NMR (400 MHz, CDCl3, 25 °C) δ 7.46−7.42 (m, 2H), 7.36−
7.32 (m, 4H), 7.30−7.28 (m, 1H), 7.19 (dt, J = 8.34, 1.97 Hz, 2H),
5,7-Dimethoxy-4-methyl-3-(4-phenylacetylenyl)-
benzylcoumarin (6f): 84% yield (103.4 mg), pale brown solid,
1
melting point 150−155 °C; H NMR (400 MHz, CDCl3, 25 °C) δ
7.52−7.49 (m, 2H), 7.42 (d, J = 8.24, 2H), 7.34−7.30 (m, 3H), 7.22
(d, J = 8.15 Hz, 2H), 6.45 (d, J = 2.44 Hz, 1H), 6.30 (d, J = 2.44 Hz,
1H), 4.04 (s, 2H), 3.84 (d, J = 1.74 Hz, 6H), 2.54 (s, 3H); 13C NMR
(100 MHz, CDCl3, 25 °C) 162.5, 159.4, 155.9, 150.8, 140.4, 132.1,
132.0, 128.7, 128.6, 128.5, 123.8, 121.4, 120.7, 105.8, 96.2, 93.5, 89.9,
89.4, 56.2, 56.1, 32.9, 20.4; IR (film) 3053, 2987, 1699, 1617, 1598,
1264, 895, 748 cm−1; HRMS (EI) m/z calcd for C27H22O4, 410.1518;
found, 410.1519.
Synthesis of 3-(4-Allenylbenzyl)-5,7-dimethoxy-4-methyl-
coumarin (6g). To a suspension of Pd2dba3CHCl3 (6.2 mg, 0.006
mmol, 2 mol %), PPh3 (12.6 mg, 0.048 mmol, 16 mol %), and LiCl
(38.2 mg, 0.9 mmol) in DMF (0.5 mL) was added 5,7-dimethoxy-3-
(4-iodobenzyl)-4-methylcoumarin (130.9 mg, 0.3 mmol) at room
temperature under a nitrogen atmosphere. After being stirred for 10
min, an organoindium reagent generated in situ from indium (34.4 mg,
0.3 mmol) and propargyl bromide (20.0 μL, 0.45 mmol) in DMF (0.5
mL) was added, and the mixture was stirred at 100 °C for 3 h. The
reaction mixture was quenched with sat. NaHCO3 (10 mL). The
aqueous layer was extracted with diethyl ether (3 × 20 mL), and the
combined organic layers were washed with brine (10 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography to give 3-(4-
allenylbenzyl)-5,7-dimethoxy-4-methylcoumarin (6f) as a yellow solid
1
(87.8 mg, 84%). Melting point 100−105 °C; H NMR (400 MHz,
CDCl3, 25 °C) δ 7.18 (s, 4H), 6.44 (d, J = 2.37 Hz, 1H), 6.29 (d, J =
2.36 Hz, 1H), 6.11 (t, J = 6.71 Hz, 1H), 5.10 (d, J = 6.82 Hz, 2H), 4.00
(s, 2H), 3.83 (d, J = 2.85 Hz, 6H), 2.54 (s, 3H); 13C NMR (100 MHz,
CDCl3, 25 °C) 210.1, 162.5, 162.4, 159.4, 155.9, 150.5, 138.7, 132.1,
128.9, 127.2, 121.2, 105.9, 96.1, 94.1, 93.6, 79.0, 56.1, 56.0, 32.6, 20.3;
6535
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Article
IR (film) 3004, 2938, 2844, 1941, 1703, 1617, 1596, 1206, 1159, 823,
735 cm−1; HRMS (EI) m/z calcd for C22H20O4, 348.1362; found,
348.1359.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: phlee@kangwon.ac.kr.
■
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This paper is dedicated to Professor Yong-Kwang Park,
Kangwon National University, on the occasion of his honorable
retirement. We thank the CRI (2012-0001245) and BRL
program (2009-0087013) funded by the National Research
Foundation of Korea. We thank Dr. Sung Hong Kim at the
KBSI (Daegu) for obtaining the HRMS data.
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