Synthesis of 8-aryl-substituted coumarins based on ring-closing metathesis and Suzuki-Miyaura coupling: Synthesis of a furyl coumarin natural product from Galipea panamensis

Article abstract of DOI:10.1021/jo2026564

The synthesis of 7-methoxy-8-(4-methyl-3-furyl)-2H-chromen-2-one, a natural product with antileishmanial activity recently isolated from the plant Galipea panamensis, is described. The key step is a Suzuki-Miyaura coupling of a furan-3-boronic acid and an

Full text of DOI:10.1021/jo2026564

Article
pubs.acs.org/joc
Synthesis of 8-Aryl-Substituted Coumarins Based on Ring-Closing
Metathesis and Suzuki−Miyaura Coupling: Synthesis of a Furyl
Coumarin Natural Product from Galipea panamensis
Bernd Schmidt,*,† Stefan Krehl,† Alexandra Kelling,‡ and Uwe Schilde‡
‡
†Institut fuer Chemie (Organische Synthesechemie) and Institut fuer Chemie (Anorganische Chemie), Universitaet Potsdam,
Karl-Liebknecht-Straße 24-25, D-14476 Potsdam-Golm, Germany
S
* Supporting Information
ABSTRACT: The synthesis of 7-methoxy-8-(4-methyl-3-furyl)-2H-chromen-2-one, a natural
product with antileishmanial activity recently isolated from the plant Galipea panamensis, is
described. The key step is a Suzuki−Miyaura coupling of a furan-3-boronic acid and an 8-
halocoumarin, which is advantageously synthesized using a ring-closing metathesis reaction. Several
non-natural analogues are also available along these lines.
moderately cytotoxic against different tumor cell lines.
Deoxymicromelin is a semisynthetic non-natural derivative,
which was found to be completely inactive against the same
tumor cell lines (Chart 1).17
INTRODUCTION
■
The various forms of leishmaniasis are among the most serious
tropical diseases with more than two million new infections per
year. Like malaria and trypanosomiasis, it is caused by
protozoan parasites which are transferred to humans by the
bites of vector insects.1−3 It is estimated that 350 million
people, mostly living in the poorest countries, are threatened by
infection with any form of leishmaniasis. This situation might
become even more problematic by a worryingly increasing
occurrence of leishmaniases and HIV coinfection which has
been observed over the past few years.4 Undesirable side effects
of the established antimony-based drugs and the development
of drug resistance have been driving forces for a more
systematic phytochemical investigation of numerous medicinal
plants which have traditionally been used for the treatment of
leishmaniases.1,3,5,6 Among these, various plants of the family
Rutaceae, genus Galipea, have been investigated and were
found to produce some structurally diverse metabolites such as
quinolines or chromones with promising antiprotozoal
Chart 1. Structures of Naturally Occurring 8-Furylcoumarins
We are aware of only two reports describing synthetic studies
directed at these compounds. Both describe syntheses of
microminutin (2), starting from allyl ethers of umbelliferone
which undergo a regioselective Claisen rearrangement to C-8-
allylated coumarins. The allyl substituents are subsequently
elaborated to the butenolide.19,20 Intrigued by the interesting
biological activities reported for coumarins in general21−23 and
for the novel natural product 1 in particular, we investigated
synthetic routes to 7-methoxy-8-(4-methyl-3-furyl)-2H-chro-
men-2-one (1) using a Suzuki−Miyaura-coupling24−26 reaction
of an 8-halo-7-methoxycoumarin and a 4-methylfuran-3-
boronic acid.
activity.7,8 Very recently, this observation prompted Sae
Otalvaro et al. to investigate the plant Galipea panamensis, a
́
z,
́
small tree found in central America.9 Although first described in
1970 by Elias,10 no phytochemical investigations on Galipea
panamensis had been reported previously. In their study, the
authors report the isolation and structural elucidation of five
coumarins, inter alia the novel 8-(3′-furyl)coumarin 1, which
was found to be active against the amastigote form of
Leishmania panamensis with an effective concentration of 10.5
μg/mL.9 Structurally related coumarins had earlier been
isolated from other plants of the family Rutaceae. For instance,
microminutin (2) with a butenolide substituent at the 8-
position occurs in Micromelum minutum11−13 and Murraya
paniculata.14 This compound was tested for its suppressive
effect on nitric oxide generation.15 A similar C-6-substituted
coumarin is micromelin,16 which has been isolated from
Micromelum integerrimum17 and Micromelum minutum18 and is
RESULTS AND DISCUSSION
■
Umbelliferone (3) undergoes a highly regioselective iodination
at C-8 using KI3 in aqueous ammonia, as previously reported in
the literature.27−29 Unfortunately, all attempts to improve the
unsatisfactory yield of 8-iodoumbelliferone and to separate the
product from unreacted starting material failed. Therefore, the
Received: December 23, 2011
Published: February 5, 2012
© 2012 American Chemical Society
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Scheme 1. Syntheses of 8-Halocoumarins
Table 1. Regioselective Halogenation of Aldehyde 5
a
b
b
entry
solvent
additive (equiv)
reagent
conversion (%)
ratio 6:7
products (yield, %)
1
2
3
4
CH2Cl2
CH2Cl2
H3CCN
H3CCN
Br2
>98
90
>19:1
<1:19
2:3
6a (98)
7a (83)
nd
AlCl3 (1.0)
Br2
NIS
NIS
94
p-TosOH (0.5)
80
5:1
6b (67)
7b (13)
nd
5
6
7
H3CCN
CH2Cl2
CH2Cl2
AlCl3 (1.0)
NEt3 (2.0)
AlCl3 (1.0)
NIS
NIS
NIS
55
83
1:10
2:1
nd
90
<1:19
7b (90)
a
b
1
NIS: N-iodosuccinimide. Conversion and ratio of products were determined from H NMR spectra of the crude reaction mixture.
crude reaction mixture obtained after iodination was treated
with methyl iodide in the presence of a base. At this stage, the
isolation of pure 8-iodo-7-methoxycoumarin (4b) was possible,
albeit in only 32% yield based on 3, along with 7-
methoxycoumarin (Scheme 1). Unfortunately, this compound
could not be halogenated regioselectively and had to be
discarded. For these reasons, we thought that a synthesis
involving the construction of the heterocycle after halogenation
of the aromatic core might be overall more efficient. The
commercially available aldehyde 5 was identified as a suitable
starting material, and its regioselective halogenation was
investigated using a variety of different conditions (Table 1).
Upon treatment of 5 with bromine in CH2Cl2, the undesired
regioisomer 6a was obtained in nearly quantitative yield,30,31
which might be attributed to steric reasons (entry 1). In
contrast, addition of one equivalent of AlCl3 lead to a reversal
of the regioselectivity.32 Under these conditions, 7a was
observed exclusively and could be isolated in 83% yield
(entry 2). Presumably, the phenol forms a chelate complex with
the Lewis acid, which then directs the electrophile to the ortho
position. A previous synthesis of this regioisomer proceeded via
an organomercury compound which was subsequently cleaved
with bromine.33 For the synthesis of the iodo-analogue 7b, NIS
was used as a reagent. Initially, we tested acetonitrile as a
solvent, however, either conversion or regioselectivity were
unsatisfactory (entries 3−5). Synthetically useful results were
eventually obtained in CH2Cl2 with AlCl3 as a Lewis acid (entry
7).
For the conversion of 7a and 7b to the corresponding
coumarins 4a and 4b, respectively, a Perkin condensation
involving treatment with acetic anhydride and KOAc was first
investigated.34 Unfortunately, high reaction temperatures of
150 °C were necessary, resulting in modest yields of 47% in the
case of bromo derivative 4a and 34% in the case of iodo
derivative 4b. For these reasons, an olefin metathesis based
route was investigated. Wittig olefination of 7a,b, followed by
treatment with acryloyl chloride gives acrylates 9a,b, which
undergo ring-closing metathesis in the presence of second-
generation Grubbs’ catalyst B. Excellent yields of 4a,b were
obtained with this catalyst if the initial substrate concentrations
did not exceed 0.1 M.35 Higher substrate concentrations, or the
use of the less active first generation catalyst A, results in
incomplete conversion, very low yields and occasionally in the
formation of Rauhut−Currier products.36 Therefore, the
synthesis proceeding via RCM of acrylates 9 appears to be
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Article
advantageous overall, with yields of 64% of 4a and 54% of 4b,
starting from aldehydes 7a or 7b, respectively (Scheme 1).
The synthesis of the hitherto unknown 4-methylfuran-3-
boronic acid (12a) was accomplished from 3-iodo-4-methyl-
furan (11), which is available from alkyne 10 in few steps
following a literature procedure.37 Iodofuran 11 was first
treated with 2 equiv of t-BuLi and then with trimethyl borate.
Acidic hydrolysis of the intermediate boronate yields the
required boronic acid 12a in nearly quantitative yield, based on
iodofuran 11. In the next step, the Suzuki−Miyaura coupling of
12a and coumarins 4a,b was optimized by testing different
precatalysts (Scheme 2 and Table 2).
All spectroscopical data of synthetic 7-methoxy-8-(4-methyl-
3-furyl)-2H-chromen-2-one (1) match those reported by Saez,
́
Otalvaro et al. for the natural product isolated from Galipea
panamensis perfectly well.9 While these authors obtained
compound 1 from the extraction as an amorphous powder,
we were able to obtain crystals suitable for single-crystal X-ray
structure analysis by recrystallization from MTBE−hexane
mixtures. Crystallographic analysis leads to the confirmation of
the molecular structure assigned to compound 1. The planes of
the coumarin and the 3-methylfuran are not perpendicular but
adopt an angle of approximately 60°, as can be seen from the
C2−C3−C11−C12 torsion angle of 62.0(3)° and the C4−
C3−C11−C14 torsion angle of 58.7(3)°. Nonclassical hydro-
gen bonds as well as π−π and C−H···π interactions contribute
to the solid structure.
Scheme 2. Synthesis of 4-Methylfuran-3-boronic Acid (12a)
and Suzuki−Miyaura Coupling with 8-Halocoumarins 4a
and 4b
We then applied the optimized conditions for the Suzuki−
Miyaura coupling of 8-halo-7-methoxycoumarins 4 to the
synthesis of several analogues (Table 3). The 7-methoxy-8-
phenylcoumarin 13a was synthesized from phenylboronic acid
12b and iodocoumarin 4b in a yield similar to that for
compound 1 under otherwise identical conditions (Table 3,
entry 1). This compound had previously been synthesized from
4b and iodobenzene in a mixed Ullmann-coupling mediated by
copper bronze; unfortunately, no yield was reported. Over the
past few years, potassium organotrifluoroborates have emerged
as valuable, highly reactive reagents in Suzuki−Miyaura
reactions.41,42 In particular, application of these reagents often
results in reduced amounts of byproducts originating from
oxidation of the organoboron compound, such as phenols or
homocoupling products. These beneficial properties have been
attributed to a slow hydrolysis of the organotrifluoroborates
under the reaction conditions, ensuring the presence of fluoride
ions (which promote the reduction of phosphine containing
Pd(II) precatalysts) and a low stationary concentration of
boronic acid, which has been proposed as a rationale for the
reduced amount of homocoupling products.43,44 As a
consequence, water is often used as a cosolvent, e.g., in
combination with dioxane or alcohols, for cross-coupling
reactions involving organotrifluoroborates.45 However, diox-
ane−water mixtures have, in some cases, also been used
advantageously for the coupling of aryl bromides and boronic
acids.46
We found that the Suzuki−Miyaura reaction of 4b and
phenylboronic acid (12b) in aqueous dioxane results in a
significantly decreased yield of 58% (Table 3, entry 2), whereas
a quantitative conversion to 13a was achieved in this solvent
system with the analogous organotrifluoroborate 12c (Table 3,
entry 3). Very similar results were obtained for the synthesis of
a benzodioxolane substituted coumarin 13b (Table 3, entries
4−6), which becomes available in quantitative yield if 12e is
used. Three further examples (Table 3, entries 7−9) proceed
with nearly quantitative yields of the corresponding 8-aryl
oumarins 13c,d,e.
Table 2. Optimization of Conditions for the Suzuki−miyaura
a
Coupling Reactions
entry
coumarin 4
X
precatalyst
Pd(PPh3)4
yield (%)
1
2
3
4
5
6
4a
4a
4b
4b
4b
4b
Br
Br
I
39
51
32
29
57
77
Pd(PPh3)2Cl2
Pd(PPh3)4
I
Pd/C
[Pd(η3-C3H5)Cl]2
I
I
Pd(PPh3)2Cl2
a
Experimental conditions: 8-halocoumarin 4 (1.0 equiv), boronic acid
12a (1.5 equiv), precatalyst (5 mol %), Cs2CO3 (2.0 equiv), toluene,
110 °C.
A successful Suzuki−Miyaura coupling reaction24,38 of an
electron-rich, sterically congested aryl bromide and an electron-
rich aryl boronic acid has recently been achieved using
Pd(PPh3)4 as a precatalyst and cesium carbonate as a base.39
Application of these conditions to the coupling of 4a and 12a,
however, resulted in only moderate yields of 1 below 40%
(Table 2, entry 1). Unfortunately, the presumably more
reactive iodide 4b gave an even lower yield of 32% with this
precatalyst (Table 2, entry 3), and a comparable result was
obtained with commercial Pd/C40 (Table 2, entry 4).
Significantly improved yields were eventually observed with
Pd(II) precatalysts: starting from iodo coumarin 4b and using
[Pd(η3-C3H5)Cl]2 as a precatalyst, the desired coupling product
1 was isolated in 57% yield. The best precatalyst for this
particular cross coupling reaction is Pd(PPh3)2Cl2, with isolated
yields of 51% from 4a (Table 2, entry 2) and 77% from 4b
(Table 2, entry 6).
CONCLUSIONS
■
In summary, we report the first synthesis and single-crystal X-
ray structure analysis of a naturally occurring 8-furylcoumarin
recently isolated from Galipea panamensis using a Suzuki−
Miyaura cross-coupling reaction of an 8-halocoumarin and a
furylboronic acid. Conventional syntheses of the required 8-
halo coumarins turned out to be unsatisfactory due to low
overall yields and harsh reaction conditions, and we therefore
devised an olefin metathesis-based synthesis as a viable
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Table 3. Synthesis of 8-Arylcoumarin Analogues of Compound 1
mp 118−120 °C; 1H NMR (300 MHz, CDCl3) δ 11.93 (s, 1H), 9.71
(s, 1H), 7.51 (d, 1H, J = 8.7), 6.63 (d, 1H, J = 8.7), 4.00 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 194.2, 162.7, 160.1, 134.5, 116.0, 103.7,
99.6, 56.8; IR (neat) ν 2955 (w), 2850 (w), 1633 (s), 1496 (s), 1289
(s), 1240 (s), 1144 (s), 1096 (s); HRMS (EI) calcd for C8H7O3[79]Br
[M]+ 229.9579, found 229.9559; MS (EI) m/z 232 (M+, 82), 231
(100), 230 (M+, 86), 229 (100). Anal. Calcd for C8H7O3Br (231.04):
C, 41.6; H, 3.1. Found: C, 41.9; H, 2.8.
5-Iodo-2-hydroxy-4-methoxybenzaldehyde (6b). To a sol-
ution of aldehyde 5 (152 mg, 1.0 mmol) in acetonitrile (3 mL) was
added p-TosOH (95 mg, 0.5 mmol). The solution was stirred for 15
min before N-iodosuccinimide (225 mg, 1.0 mmol) was added. It was
stirred overnight at room temperature. Then all volatiles were
removed in vacuo. After column chromatography, aldehyde 6b was
isolated as a colorless solid (186 mg, 0.67 mmol, 67%). Additionally,
aldehyde 7b was isolated as a colorless solid (37 mg, 0.13 mmol, 13%):
mp 110−112 °C; 1H NMR (300 MHz, CDCl3) δ 11.44 (s, 1H), 9.68
(s, 1H), 7.88 (s, 1H), 6.42 (s, 1H), 3.93 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 193.5, 164.6, 164.5, 143.7, 117.0, 99.6, 73.9, 56.9; IR (neat)
ν 1636 (s), 1614 (s), 1484 (m), 1441 (m), 1360 (m), 1270 (s);
HRMS (EI) calcd for C8H7O3[127]I [M]+ 277.9440, found 277.9425;
MS (EI) m/z 278 (M+, 100), 277 (59). Anal. Calcd for C8H7O3I
(278.04): C, 34.6; H, 2.5. Found: C, 34.4; H, 2.2.
alternative. Excellent yields of other 8-arylcoumarins were
obtained using potassium organotrifluoroborates as coupling
reagents.
EXPERIMENTAL SECTION
■
5-Bromo-2-hydroxy-4-methoxybenzaldehyde (6a). A solu-
tion of aldehyde 5 (912 mg, 6.0 mmol) in dichloromethane (24 mL)
was cooled to −20 °C. Then a solution of bromine (957 mg, 309 μL,
6.0 mmol) in dichloromethane (10 mL) was added over 20 min. It was
stirred overnight while warming to room temperature. Then a
saturated solution of Na2SO3 (5 mL) was added. The aqueous layer
was extracted three times with dichloromethane (in each case 25 mL).
It was dried over magnesium sulfate, filtered, and concentrated in
vacuo. After column chromatography, aldehyde 6a was isolated as a
colorless solid (1352 mg, 5.9 mmol, 98%): mp 118−120 °C; 1H NMR
(300 MHz, CDCl3) δ 11.42 (s, 1H), 9.67 (s, 1H), 7.66 (s, 1H), 6.46
(s, 1H), 3.94 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 193.6, 163.7,
162.5, 137.2, 115.7, 102.1, 100.4, 56.7; IR (neat) ν 2923 (w), 1638 (s),
1619 (s), 1490 (m), 1442 (m), 1365 (s), 1273 (s), 1207 (s); HRMS
(EI) calcd for C8H7O3[79]Br [M]+ 229.9579, found 229.9579; MS
(EI) m/z 232 (M+, 91), 231 (85), 230 (M+, 100), 229 (85). Anal.
Calcd for C8H7O3Br (231.04): C, 41.6; H, 3.1. Found: C, 41.3; H, 2.7.
3-Bromo-2-hydroxy-4-methoxybenzaldehyde (7a). A solu-
tion of aldehyde 5 (608 mg, 4.0 mmol) in dichloromethane (24 mL)
was cooled to −20 °C. Then aluminum chloride (532 mg, 4.0 mmol)
was added in three portions. The suspension was stirred for 15 min
before a solution of bromine (638 mg, 206 μL, 4.0 mmol) in
dichloromethane (10 mL) was added over 20 min. It was stirred
overnight while warming to room temperature. Then a saturated
solution of Na2SO3 (5 mL) and hydrochloric acid (4 M, 10 mL) was
added in order. The aqueous layer was extracted two times with
dichloromethane (15 mL each). It was dried over magnesium sulfate,
filtered, and concentrated in vacuo. After column chromatography,
aldehyde 7a was isolated as a colorless solid (730 mg, 3.2 mmol, 79%):
2-Hydroxy-3-iodo-4-methoxybenzaldehyde (7b). A solution
of aldehyde 5 (608 mg, 4.0 mmol) in dichloromethane (24 mL) was
cooled to −20 °C. Then aluminum chloride (532 mg, 4.0 mmol) was
added in three portions. The solution was stirred for 15 min before N-
iodosuccinimide (990 mg, 4.4 mmol) was added in three portions. It
was stirred overnight while warming to room temperature. Then
hydrochloric acid (4 M, 10 mL) was added, and the aqueous layer was
extracted two times with dichloromethane (15 mL each). It was dried
with magnesium sulfate, filtered, and concentrated in vacuo. After
column chromatography, aldehyde 7b was isolated as a colorless solid
1
(1000 mg, 3.6 mmol, 90%): mp 106−108 °C; H NMR (300 MHz,
CDCl3) δ 12.18 (s, 1H), 9.64 (s, 1H), 7.54 (d, 1H, J = 8.6), 6.57 (d,
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1H, J = 8.6), 3.99 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 193.9, 165.0,
162.7, 136.0, 115.8, 103.3, 76.2, 56.9; IR (neat) ν 2848 (w), 1635 (s),
1489 (m), 1285 (s), 1237 (s), 1141 (s), 1064 (s); HRMS (EI) calcd
for C8H7O3[127]I [M]+ 277.9440, found 277.9437; MS (EI) m/z 278
(M+, 100), 277 (59). Anal. Calcd for C8H7O3I (278.04): C, 34.6; H,
2.5. Found: C, 34.5 H, 2.2.
was washed three times with diluted hydrochloric acid (0.5 M, in each
case 15 mL). The organic layer was dried over magnesium sulfate,
filtered, and concentrated in vacuo. After column chromatography,
acrylate 9b was isolated as a colorless oil (496 mg, 1.5 mmol, 65%): 1H
NMR (300 MHz, CDCl3) δ 7.52 (d, 1H, J = 8.7), 6.73 (d, 1H, J = 8.5),
6.71 (dd, 1H, J = 17.3, 1.1), 6.61 (dd, 1H, J = 17.3, 11.1), 6.40 (dd,
1H, J = 17.3, 10.5), 6.10 (dd, 1H, J = 10.4, 1.2), 5.63 (dd, 1H, J = 17.5,
0.8), 5.21 (dd, 1H, J = 11.0, 0.8), 3.90 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 163.0, 159.2, 149.7, 133.4, 130.3, 127.5, 127.1, 125.1, 115.4,
108.9, 84.3, 56.5; IR (neat) ν 2937 (w), 2840 (w), 1743 (s), 1626 (m),
1595 (m), 1478 (s), 1393 (s); HRMS (EI) calcd for C12H11O3[127]I
[M]+ 329.9753, found 329.9767; MS (EI) m/z 330 (M+, 10), 276
(32), 142 (100), 128 (30), 127 (62), 91 (15), 77 (22), 55 (30), 44
(14). Anal. Calcd for C12H11O3I (330.12): C, 43.7; H, 3.4. Found: C,
44.1; H, 3.3.
2-Bromo-3-methoxy-6-vinylphenol (8a). Sodium hydride (60%
in mineral oil, 0.42 g, 10.5 mmol) was suspended in THF (30 mL).
Then PPh3MeBr (4.12 g, 11.6 mmol) was added to the suspension,
which was heated to reflux for 1.5 h. After the suspension was cooled
to 0 °C, a solution of aldehyde 7a (767 mg, 3.3 mmol) in THF (10
mL) was added to the reaction mixture over 20 min. It was stirred
overnight, diluted with ethyl acetate (100 mL), and washed with water
(30 mL). The organic layer was dried over magnesium sulfate, filtered,
and concentrated in vacuo. After column chromatography, styrene 8a
was isolated as a colorless solid (706 mg, 3.1 mmol, 94%): mp 70−72
8-Bromo-7-methoxy-2H-chromen-2-one (4a). Method A.
Acrylate 9a (425 mg, 1.5 mmol) was dissolved in dry and degassed
toluene (15 mL). After addition of catalyst B (64 mg, 0.075 mmol, 5
mol %), the solution was heated to 80 °C. After 2.5 h, all volatiles were
removed in vacuo and the title compound was purified by column
chromatography. Compound 4a was isolated as a yellowish solid (374
mg, 1.47 mmol, 98%). Method B. Aldehyde 7a (462 mg, 2.0 mmol)
was dissolved in acetic anhydride (1.6 mL). Then potassium acetate
(116 mg, 1.2 mmol) was added, and the mixture was heated to 160 °C
for 5 h. After cooling, the mixture was diluted with ethyl acetate (100
mL). The organic layer was washed with brine (20 mL) and dried over
MgSO4. After filtration, all volatiles were removed in vacuo. The
residue was purified by column chromatography, and the title
compound was isolated as a yellowish solid (238 mg, 0.94 mmol,
47%): mp 166−168 °C; 1H NMR (300 MHz, CDCl3) δ 7.63 (d, 1H, J
= 9.5), 7.41 (d, 1H, J = 8.7), 6.88 (d, 1H, J = 8.6), 6.28 (d, 1H, J =
9.5), 4.00 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.1, 159.1, 152.3,
143.1, 127.5, 113.7, 113.7, 107.9, 99.7, 56.8; IR (neat) ν 2946 (w),
1730 (s), 1600 (s), 1542 (m), 1296 (s); HRMS (EI) calcd for
C10H7O3[79]Br [M]+ 253.9579, found 253.9569; MS (EI) m/z 256
(M+, 94), 254 (M+,100), 228 (59), 226 (61), 213 (77), 211 (82), 185
(10), 183 (11), 157 (15), 155 (18), 76 (20). Anal. Calcd for
C10H7O3Br (255.06): C, 47.1; H, 2.8. Found: C, 46.8; H, 2.6.
8-Iodo-7-methoxy-2H-chromen-2-one (4b). Method A. Acryl-
ate 9b (495 mg, 1.5 mmol) was dissolved in dry and degassed toluene
(15 mL). After addition of catalyst B (64 mg, 0.075 mmol, 5 mol %),
the solution was heated to 80 °C. After 2.5 h, all volatiles were
removed in vacuo and the title compound was purified by column
chromatography. Compound 4b was isolated as a yellowish solid (439
mg, 1.46 mmol, 97%). Method B. Aldehyde 7b (278 mg, 1.0 mmol)
was dissolved in acetic anhydride (0.8 mL). Then potassium acetate
(58 mg, 0.6 mmol) was added, and the mixture was heated to 160 °C
for 5 h. After cooling, the mixture was diluted with ethyl acetate (50
mL). The organic layer was washed with brine (10 mL) and dried with
magnesium sulfate. After filtration all volatiles were removed in vacuo.
The residue was purified by column chromatography, and the title
compound was isolated as a yellowish solid (102 mg, 0.34 mmol,
34%). Method C. Umbelliferone (3) (8.00 g, 49.4 mmol) was dissolved
in 20% ammonium hydroxide solution (200 mL). Then a solution of
potassium iodide (20.00 g, 120 mmol) and iodine (12.50 g, 89.4
mmol) in water (400 mL) was added over 75 min. The mixture was
stirred for 24 h at room temperature before 4 M sulfuric acid (200
mL) was added carefully. A precipitate was formed which was filtered.
Then acetone (200 mL) was added to the solid, and the suspension
was heated to reflux for 20 min. It was filtered, and the procedure was
repeated once. The filtrates were combined, and the solvent was
removed in vacuo. 8-Iodoumbelliferone was obtained together with
umbelliferone (3) as a brown solid (6.80 g). The ratio of 8-
iodoumbelliferone to 3 was determined to be approximately 1:1 via
integration in the 1H NMR spectrum of the crude product. The crude
mixture of umbelliferone (3) and 8-iodoumbelliferone was dissolved in
acetone (60 mL). Then potassium carbonate (7.76 g, 55.2 mmol) and
MeI (3.46 mL, 7.84 g, 55.2 mmol) were added, and the reaction
mixture was heated to 40 °C for 24 h. It was diluted with ethyl acetate
(100 mL) and filtered. All volatiles were removed in vacuo, and the
1
°C; H NMR (300 MHz, CDCl3) δ 7.35 (d, 1H, J = 8.7), 6.93 (dd,
1H, J = 17.7, 11.2), 6.48 (d, 1H, J = 8.6), 5.86 (s, 1H), 5.68 (dd, 1H, J
= 17.7, 1.4), 5.22 (dd, 1H, J = 11.2, 1.4), 3.88 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 155.8, 150.6, 131.0, 126.1, 118.9, 113.7, 103.7, 100.5,
56.3; IR (neat) ν 3455 (m), 3017 (w), 2940 (w), 2838 (w), 1599 (s),
1494 (s), 1415 (s), 1288 (s); HRMS (EI) calcd for C9H9O2[79]Br
[M]+ 227.9786, found 227.9792; MS (EI) m/z 230 (M+, 50), 228 (M+,
59), 134 (100), 83 (24), 57 (26). Anal. Calcd for C9H9O2Br (229.07):
C, 47.2; H, 4.0. Found: C, 47.4; H, 3.8.
2-Iodo-3-methoxy-6-vinylphenol (8b). Sodium hydride (60% in
mineral oil, 0.51 g, 12.7 mmol) was suspended in THF (40 mL). Then
PPh3MeBr (5.00 g, 14.0 mmol) was added to the suspension, and it
was heated to reflux for 1.5 h. After the suspension was cooled to 0 °C,
a solution of aldehyde 7b (1.12 g, 4.0 mmol) in THF (10 mL) was
added to the reaction mixture over 20 min. It was stirred overnight,
diluted with ethyl acetate (100 mL), and washed with water (30 mL).
The organic layer was dried with magnesium sulfate, filtered, and
concentrated in vacuo. After column chromatography, styrene 8b was
isolated as a colorless solid (0.95 mg, 3.44 mmol, 86%): mp 70−72
1
°C; H NMR (300 MHz, CDCl3) δ 7.36 (d, 1H, J = 8.5), 6.94 (dd,
1H, J = 17.7, 11.1), 6.39 (d, 1H, J = 8.6), 5.66 (s, 1H), 5.66 (dd, 1H, J
= 17.7, 1.2), 5.20 (dd, 1H, J = 11.2, 1.2), 3.87 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 155.8, 150.6, 131.0, 126.1, 118.9, 113.7, 103.7, 100.5,
56.3; IR (neat) ν 3463 (m), 3006 (w), 2937 (m), 2838 (w), 1601 (s),
1484 (s), 1417 (m), 1285 (m); HRMS (EI) calcd for C9H9O2[127]I
[M]+ 275.9647, found 275.9628; MS (EI) m/z 276 (M+, 100), 134
(59).
2-Bromo-3-methoxy-6-vinylphenyl Acrylate (9a). A solution
of styrene 8a (606 mg, 2.7 mmol) and NEt3 (803 mg, 1.1 mL, 7.9
mmol) in dichloromethane (20 mL) was cooled to 0 °C. Then
acryloyl chloride (719 mg, 0.64 mL, 7.9 mmol) was added dropwise to
the reaction mixture, which was stirred overnight while warming to
room temperature. After the mixture was diluted with MTBE (100
mL), it was washed three times with diluted hydrochloric acid (0.5 M,
in each case 15 mL). The organic layer was dried over magnesium
sulfate, filtered, and concentrated in vacuo. After column chromatog-
raphy, acrylate 9a was isolated as a colorless oil (523 mg, 1.9 mmol,
1
70%): H NMR (300 MHz, CDCl3) δ 7.49 (d, 1H, J = 8.8), 6.81 (d,
1H, J = 8.8), 6.70 (dd, 1H, J = 17.4, 1.1), 6.62 (dd, 1H, J = 17.6, 11.1),
6.39 (dd, 1H, J = 17.3, 10.5), 6.09 (dd, 1H, J = 10.4, 1.0), 5.65 (dd,
1H, J = 17.6, 0.7), 5.24 (dd, 1H, J = 11.1, 0.7), 3.90 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 163.0, 156.6, 146.6, 133.5, 129.8, 127.0, 125.5,
125.1, 115.4, 109.6, 106.9, 56.5; IR (neat) ν 3088 (w), 2941 (w), 2841
(w), 1745 (s), 1599 (m), 1485 (s), 1397 (s); HRMS (EI) calcd for
C12H11O3[79]Br [M]+ 281.9892, found 281.9899; MS (EI) m/z 284
(M+, 19), 282 (M+, 20), 230 (72), 228 (79), 203 (17), 148 (14), 134
(24), 133 (28), 77 (18), 55 (100). Anal. Calcd for C12H11O3Br
(283.12): C, 50.9; H, 3.9. Found: C, 50.9; H, 3.9.
2-Iodo-3-methoxy-6-vinylphenyl Acrylate (9b). A solution of
styrene 8b (636 mg, 2.3 mmol) and NEt3 (698 mg, 956 μL, 6.9 mmol)
in dichloromethane (20 mL) was cooled to 0 °C. Then acryloyl
chloride (719 mg, 642 μL, 6.9 mmol) was added dropwise to the
reaction mixture. It was stirred overnight while warming to room
temperature. After the mixture was diluted with MTBE (100 mL), it
2364
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The Journal of Organic Chemistry
Article
residue was purified by column chromatography. Coumarin 4b was
obtained as a yellowish solid (4.77 g, 15.8 mmol, 32% over two steps):
mp 160−162 °C; 1H NMR (300 MHz, CDCl3) δ 7.63 (d, 1H, J = 9.5),
7.44 (d, 1H, J = 8.6), 6.81 (d, 1H, J = 8.6), 6.25 (d, 1H, J = 9.5) 3.99
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.6, 160.4, 154.9, 143.0,
129.1, 113.8, 113.6, 107.4, 75.9, 56.9; IR (neat) ν 3438 (w), 2942 (w),
2843 (w), 2249 (w), 1721 (s), 1644 (m), 1594 (s), 1538 (m); HRMS
(EI) calcd for C10H7O3[127]I [M]+ 301.9440, found 301.9424; MS
(EI) m/z 302 (M+, 100), 274 (34), 259 (49), 203 (9), 132 (20), 76
(30). Anal. Calcd for C10H7O3I (302.07): C, 39.8; H, 2.3. Found: C,
40.0; H: 2.3.
7-Methoxy-8-(4-methylfuran-3-yl)-2H-chromen-2-one (1).
Coumarin 4b (91 mg, 0.30 mmol) was dissolved in toluene (5 mL).
Then Cs2CO3 (201 mg, 0.61 mmol), Pd(PPh3)2Cl2 (11.0 mg, 0.015
mmol), and boronic acid 11a (56 mg, 0.45 mmol) were added. This
suspension was heated to 110 °C for 16 h. After the suspension was
cooled to room temperature, water (5 mL) was added. After phase
separation, the aqueous phase was extracted three times with
dichloromethane (20 mL each). The combined organic extracts
were dried over magnesium sulfate and filtered, and all volatiles were
removed in vacuo. After column chromatography, coumarin 1 was
isolated as a slightly yellow solid (59 mg, 0.23 mmol, 77%): mp 145−
147 °C; 1H NMR (300 MHz, CDCl3) δ 7.68 (d, 1H, J = 9.5), 7.48 (d,
1H, J = 1.5), 7.46 (d, 1H, J = 8.6), 7.34 (m, 1H), 6.95 (d, 1H, J = 8.7),
6.25 (d, 1H, J = 9.5), 3.88 (s, 3H), 1.90 (d, 3H, J = 1.0); 13C NMR (75
MHz, CDCl3) δ 160.9, 160.3, 152.9, 143.5, 142.1, 139.6, 128.0, 121.0,
115.8, 113.2, 113.1, 109.9, 107.6, 56.1, 8.8; IR (neat) ν 3087 (w), 2926
(w), 2848 (w), 1723 (s), 1597 (s), 1541 (m), 1493 (m), 1460 (m),
1402 (m), 1283 (s), 1245 (s); HRMS (EI) calcd for C15H12O4 [M]+
256.0736, found 256.0732; MS (EI) m/z 256 (M+, 39), 213 (21), 128
(24), 127 (27), 111 (29), 98 (47), 97 (51), 95 (26), 85 (38), 84 (28),
83 (37), 71 (100), 70 (44), 69 (96), 57 (81), 56 (25), 55 (51), 43
(79), 41 (36).
7-Methoxy-8-phenyl-2H-chromen-2-one (13a). Method A:
Coumarin 4b (91 mg, 0.30 mmol) was dissolved in toluene (5 mL).
Then Cs2CO3 (201 mg, 0.61 mmol), Pd(PPh3)2Cl2 (11.0 mg, 0.015
mmol), and boronic acid 12b (56 mg, 0.45 mmol) were added. This
suspension was heated to 110 °C for 16 h. After the suspension was
cooled to room temperature, water (5 mL) was added. After phase
separation the aqueous phase was extracted three times with
dichloromethane (20 mL each). The combined organic extracts
were dried with magnesium sulfate and filtered, and all volatiles were
removed in vacuo. After column chromatography, coumarin 13a was
isolated as a slightly yellow solid (57 mg, 0.23 mmol, 75%). Method B:
Coumarin 4b (91 mg, 0.30 mmol) was dissolved in a mixture of
dioxane (4 mL) and water (1 mL). Then Cs2CO3 (201 mg, 0.61
mmol), Pd(PPh3)2Cl2 (11.0 mg, 0.015 mmol), and boronic acid 12b
(56 mg, 0.45 mmol) were added. This solution was heated to 110 °C
for 16 h. After the solution was cooled to room temperature, water (5
mL) was added. After phase separation, the aqueous phase was
extracted three times with ethyl acetate (20 mL in each case). The
combined organic extracts were dried with magnesium sulfate and
filtered, and all volatiles were removed in vacuo. After column
chromatography, coumarin 13a was isolated as a slightly yellow solid
(44 mg, 0.17 mmol, 58%). Method C: Coumarin 4b (91 mg, 0.30
mmol) was dissolved in a mixture of dioxane (4 mL) and water (1
mL). Then Cs2CO3 (201 mg, 0.61 mmol), Pd(PPh3)2Cl2 (11.0 mg,
0.015 mmol), and organotrifluoroborate 12c (83 mg, 0.45 mmol) were
added. This solution was heated to 110 °C for 16 h. After the solution
was cooled to room temperature, water (5 mL) was added. After phase
separation, the aqueous phase was extracted three times with ethyl
acetate (20 mL each). The combined organic extracts were dried over
magnesium sulfate and filtered, and all volatiles were removed in
vacuo. After column chromatography, coumarin 13a was isolated as a
slightly yellow solid (76 mg, 0.30 mmol, quantitative): mp 124−126
°C; 1H NMR (300 MHz, CDCl3) δ 7.67 (d, 1H, J = 9.5), 7.49 − 7.33
(6H), 6.96 (d, 1H, J = 8.6), 6.24 (d, 1H, J = 9.4), 3.83 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 160.9, 159.7, 152.3, 143.5, 131.1, 130.7,
128.0, 127.9, 127.7, 119.0, 113.3, 113.2, 107.8, 56.2; IR (neat) ν 3056
(w), 2943 (w), 2841 (w), 1720 (s), 1597 (s), 1535 (m), 1401 (m);
HRMS (EI) calcd for C16H12O3 [M]+ 252.0786, found 252.0773; MS
(EI) m/z 252 (M+, 100), 224 (65), 209 (20), 181 (85), 152 (35).
8-(Benzo[d][1,3]dioxol-5-yl)-7-methoxy-2H-chromen-2-one
(13b). Method A: Coumarin 4b (91 mg, 0.30 mmol) was dissolved in
toluene (5 mL). Then Cs2CO3 (201 mg, 0.61 mmol), Pd(PPh3)2Cl2
(11.0 mg, 0.015 mmol), and boronic acid 12d (74 mg, 0.45 mmol)
were added. This suspension was heated to 110 °C for 16 h. After the
suspension was cooled to room temperature, water (5 mL) was added.
After phase separation, the aqueous phase was extracted three times
with dichloromethane (20 mL in each case). The combined organic
extracts were dried with magnesium sulfate and filtered, and all
volatiles were removed in vacuo. After column chromatography,
coumarin 13b was isolated as a slightly yellow solid (70 mg, 0.23
mmol, 78%). Method B: Coumarin 4b (91 mg, 0.30 mmol) was
dissolved in a mixture of dioxane (4 mL) and water (1 mL). Then
Cs2CO3 (201 mg, 0.61 mmol), Pd(PPh3)2Cl2 (11.0 mg, 0.015 mmol),
and boronic acid 12d (74 mg, 0.45 mmol) were added. This solution
was heated to 110 °C for 16 h. After the solution was cooled to room
temperature, water (5 mL) was added. After phase separation, the
aqueous phase was extracted three times with ethyl acetate (20 mL in
each case). The combined organic extracts were dried with magnesium
sulfate and filtered, and all volatiles were removed in vacuo. After
column chromatography, coumarin 13b was isolated as a slightly
yellow solid (60 mg, 0.20 mmol, 67%). Method C: Coumarin 4b (91
mg, 0.30 mmol) was dissolved in a mixture of dioxane (4 mL) and
water (1 mL). Then Cs2CO3 (201 mg, 0.61 mmol), Pd(PPh3)2Cl2
(11.0 mg, 0.015 mmol), and organo trifluoroborate 12e (103 mg, 0.45
mmol) were added. This solution was heated to 110 °C for 16 h. After
the solution was cooled to room temperature, water (5 mL) was
added. After phase separation, the aqueous phase was extracted three
times with ethyl acetate (20 mL each). The combined organic extracts
were dried with magnesium sulfate and filtered, and all volatiles were
removed in vacuo. After column chromatography, coumarin 13b was
4-Methoxybut-2-yn-1-ol (10). To a solution of methyl propargyl
ether (4.9 g, 70 mmol) in THF was added n-butyllithium (1.7 M in
pentane, 3.53 mL, 6.0 mmol) at −78 °C within 20 min. The solution
was stirred for 1 h at this temperature before paraformaldehyde (3.46
g, 115 mmol) was added. The reaction was stirred overnight while
warming to room temperature. Then saturated ammonium chloride
solution (50 mL) was added. It was extracted three times with MTBE
(50 mL in each case), dried with magnesium sulfate, and filtered. The
solvent was removed in vacuo. The crude product was purified
through distillation (80−82 °C, 20 mbar), and the title compound was
1
obtained as a colorless liquid (5.5 g, 55 mmol, 79%): H NMR (300
MHz, CDCl3) δ 4.33 − 4.26 (2H), 4.15 − 4.11 (2H), 3.40 (s, 3H),
2.75 (s(br), 1H); 13C NMR (75 MHz, CDCl3) δ 84.9, 81.1, 59.8, 57.5,
50.7; IR (neat) ν 3375 (m), 2933 (m), 1450 (m), 1356 (m), 1091 (s),
1011 (s); HRMS (ESI) calcd for C5H8O2Na [M+Na]+ 123.0422,
found 123.0409; MS (EI) m/z 98 (14), 97 (13), 85 (46), 83 (75), 71
(31), 69 (33), 57 (35), 55 (28), 43 (31), 41 (28), 38 (33), 36 (100).
4-Methylfuran-3-ylboronic Acid (12a). Furan 11 (3.0 mmol)
was added dropwise to a solution of tert-butyllithium (1.7 M in
pentane, 3.53 mL, 6.0 mmol) in THF (20 mL) at −78 °C. The
mixture was stirred 30 min at this temperature before B(OMe)3 (920
μL, 8.2 mmol) was added dropwise. After complete addition, the
reaction mixture was allowed to warm to room temperature and stirred
for 1 h. The mixture was cooled to 0 °C, and 1 M hydrochloric acid
(10 mL) was added carefully. After complete addition, the reaction
mixture was allowed to warm to room temperature and stirred for 45
min. Then the mixture was neutralized by addition of saturated sodium
bicarbonate solution (approximately 6 mL). It was extracted three
times with MTBE (20 mL in each case), dried with MgSO4, and
filtered. All volatiles were removed in vacuo. The title compound was
isolated as a slight yellow solid (376 mg, quantitative) and used
1
without further purification: H NMR (300 MHz, CDCl3) δ 7.93 (d,
1H, J = 1.1), 7.28 (m), 2.27 (d, 1H, J = 0.6); 13C NMR (75 MHz,
CDCl3) δ 154.6, 140.5, 123.9, 10.0 (signal for C3 not observed due to
quadrupolar line broadening); IR (neat) ν 3210 (w), 2928 (w), 1589
(m), 1533 (s), 1383 (s), 1344 (s), 1294 (m); HRMS (EI) calcd for
C5H7O3[11]B [M]+ 126.0483, found 126.0448.
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The Journal of Organic Chemistry
Article
isolated as a slightly yellow solid (90 mg, 0.30 mmol, quantitative): mp
154−156 °C; H NMR (300 MHz, CDCl3) δ 7.67 (d, 1H, J = 9.5),
134.4, 133.2, 131.0, 128.4, 126.9, 117.9, 113.4, 113.2, 107.9, 67.0, 56.2,
signal for CH2N not observed due to hindered rotation and/or
quadrupole broadening; IR (neat) ν 2921 (w), 2954 (w), 2247 (w),
1722 (s), 1600 (s), 1459 (m), 1430 (m), 1267 (s); HRMS (EI) calcd
for C21H19O5N [M]+ 365.1263, found 365.1270; MS (EI) m/z 365
(M+, 15), 341 (10), 327 (12), 279 (46), 267 (36), 239 (25), 134 (46),
98 (52), 85 (75), 83 (100), 71 (35), 57 (44), 43 (48). Anal. Calcd for
C21H19O5N (365.38): C, 69.0; H, 5.2; N, 3.8. Found: C, 69.0; H, 5.4;
N, 3.8.
1
7.43 (d, 1H, J = 8.6), 6.95 (d, 1H, J = 8.7), 6.91 (d, 1H, J = 8.4), 6.85
(d, 1H, J = 1.6), 6.85 (dd, 1H, J = 8.4, 1.6), 6.25 (d, 1H, J = 9.4), 6.00
(s, 2H), 3.85 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.9, 159.8,
152.5, 147.4, 147.2, 143.5, 127.7, 124.4, 124.3, 118.6, 113.3, 113.2,
111.2, 108.2, 107.8, 101.0, 56.3; IR (neat) ν 2957 (m), 2253 (w), 1719
(s), 1597 (s), 1488 (m), 1447 (s), 1276 (s); HRMS (EI) calcd for
C17H12O5 [M]+ 296.0685, found 296.0675; MS (EI) m/z = 296 (M+,
6), 267 (10), 134 (18), 98 (30), 85 (19), 84 (24), 71 (35), 69 (28), 57
(72), 55 (40), 43 (100). Anal. Calcd for C17H12O5 (296.27): C, 68.9;
H, 4.1. Found: C, 69.0; H, 4.2.
ASSOCIATED CONTENT
■
S
* Supporting Information
8-(4-Fluorophenyl)-7-methoxy-2H-chromen-2-one (13c).
Coumarin 4b (121 mg, 0.40 mmol) was dissolved in a mixture of
dioxane (5.3 mL) and water (1.3 mL). Then Cs2CO3 (268 mg, 0.81
mmol), Pd(PPh3)2Cl2 (15.0 mg, 0.020 mmol) and organo
trifluoroborate 12f (121 mg, 0.60 mmol) were added. This solution
was heated to 110 °C for 16 h. After the solution was cooled to room
temperature, water (10 mL) was added. After phase separation, the
aqueous phase was extracted three times with ethyl acetate (20 mL in
each case). The combined organic extracts were dried with magnesium
sulfate and filtered, and all volatiles were removed in vacuo. After
column chromatography, coumarin 13c was isolated as a slightly
Experimental details, analytical data, and copies of H and 13C
1
NMR spectra for all new compounds. Crystallographic details
for compound 1 (CCDC-859533) (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bernd.schmidt@uni-potsdam.de.
1
Notes
yellow solid (106 mg, 0.39 mmol, 98%): mp 262−264 °C; H NMR
The authors declare no competing financial interest.
(300 MHz, CDCl3) δ 7.69 (d, 1H, J = 9.5), 7.48 (d, 1H, J = 8.6), 7.37
(d, 2H, J = 8.9, 5.4), 7.48 (dd, 2H, J = 8.8, 8.8), 6.99 (d, 1H, J = 8.7),
1
6.27 (d, 1H, J = 9.5); 13C NMR (75 MHz, CDCl3) δ 162.4 (d, J =
ACKNOWLEDGMENTS
246.6), 160.9, 159.7, 152.3, 143.6, 132.5 (d, 3J = 8.1), 128.1, 127.0 (d,
■
2
4J = 3.5), 117.8, 115.1 (d, J = 21.6), 113.3, 113.2, 107.8, 56.3; IR
This work was generously supported by the Deutsche
Forschungsgemeinschaft. We thank Evonik Oxeno for generous
donations of solvents and Umicore (Hanau, Germany) for a
generous donation of palladium catalysts.
(neat) ν 2930 (w), 2849 (w), 1708 (s), 1598 (s), 1515 (m), 1489 (w),
1428 (w), 1400 (w), 1269 (s); HRMS (EI) calcd for C16H11O3F [M]+
270.0692, found 270.0681; MS (EI) m/z = 270 (M+, 94), (242 (12),
227 (12), 199 (60), 170 (12), 134 (48), 112 (32), 98 (75), 97 (30), 85
(45), 84 (50), 74 (42), 71 (53), 69 (46), 57 (94), 55 (56), 43 (100).
7-Methoxy-8-(pyridin-3-yl)-2H-chromen-2-one (13d). Cou-
marin 4b (121 mg, 0.40 mmol) was dissolved in a mixture of dioxane
(5.3 mL) and water (1.3 mL). Then Cs2CO3 (268 mg, 0.81 mmol),
Pd(PPh3)2Cl2 (15.0 mg, 0.020 mmol), and organo trifluoroborate 12g
(111 mg, 0.60 mmol) were added. This solution was heated to 110 °C
for 16 h. After the solution was cooled to room temperature, water (10
mL) was added. After phase separation, the aqueous phase was
extracted three times with ethyl acetate (20 mL in each case). The
combined organic extracts were dried with magnesium sulfate and
filtered, and all volatiles were removed in vacuo. After column
chromatography, coumarin 13d was isolated as a slightly yellow solid
REFERENCES
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(1) Chan-Bacab, M. J.; Pena-Rodriguez, L. M. Nat. Prod. Rep. 2001,
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(96 mg, 0.38 mmol, 95%): mp 165−167 °C; H NMR (300 MHz,
(6) Fournet, A.; Munoz, V. Curr. Top. Med. Chem. 2002, 2, 1215−
CDCl3) δ 8.65 (dd, 1H, J = 2.1, 0.6), 8.60 (dd, 1H, J = 4.9, 1.6), 7.77
(ddd, 1H, J = 7.8, 2.0, 1.8), 7.70 (d, 1H, J = 9.5), 7.51 (d, 1H, J = 8.8),
7.40 (ddd, 1H, J = 7.9, 4.9, 0.7), 6.99 (d, 1H, J = 8.7), 6.27 (d, 1H, J =
9.5), 3.86 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.5, 159.6, 152.4,
151.3, 148.5, 143.4, 138.2, 128.8, 127.4, 123.1, 115.2, 113.5, 113.2,
107.8, 56.2; IR (neat) ν 3373 (m), 2847 (w), 1731 (m), 1705 (m),
1603 (s), 1499 (m), 1406 (m); HRMS (EI) calcd for C15H11O3N
[M]+ 253.0739, found 253.0734; MS (EI) m/z = 253 (M+, 100).
7-Methoxy-8-(4-(morpholine-4-carbonyl)phenyl)-2H-chro-
men-2-one (13e). Coumarin 4b (121 mg, 0.40 mmol) was dissolved
in a mixture of dioxane (5.3 mL) and water (1.3 mL). Then Cs2CO3
(268 mg, 0.81 mmol), Pd(PPh3)2Cl2 (15.0 mg, 0.020 mmol), and
organo trifluoroborate 12h (134 mg, 0.60 mmol) were added. This
solution was heated to 110 °C for 16 h. After the solution was cooled
to room temperature, water (10 mL) was added. After phase
separation, the aqueous phase was extracted three times with ethyl
acetate (20 mL in each case). The combined organic extracts were
dried with magnesium sulfate and filtered, and all volatiles were
removed in vacuo. After column chromatography, coumarin 13e was
isolated as a slightly yellow solid (103 mg, 0.38 mmol, 94%): mp 198−
200 °C; 1H NMR (300 MHz, CDCl3) δ 7.70 (d, 1H, J = 9.5), 7.52 −
7.42 (5H), 6.97 (d, 1H, J = 8.7), 6.26 (d, 1H, J = 9.5), 3.83 (s, 3H),
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8H); 13C NMR (75 MHz, CDCl3) δ 170.3, 160.8, 159.7, 152.2, 143.6,
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