Palladium-catalyzed reactions of 4-(Trifluoromethylsulfonyloxy)coumarins with amides and NH-heterocycles

Article abstract of DOI:10.1055/s-0029-1217018

Palladium-catalyzed reactions of 4-(trifluoromethylsulfonyloxy)coumarins with amides and NH-heterocycles afforded 4amido- and 4-(N-hetaryl)coumarins in 60-96% yield.

Full text of DOI:10.1055/s-0029-1217018

PAPER
3689
Palladium-Catalyzed Reactions of 4-(Trifluoromethylsulfonyloxy)coumarins
with Amides and NH-Heterocycles
R
eactions of 4-(T
r
l
ifluorom
g
ethylsulfon
a
yloxy)coumarinsG. Ganina,a Alexey Yu. Fedorov,b Irina P. Beletskaya*a
a
Department of Chemistry, Moscow State Lomonosov University, Vorobyevy Gory, 119991 Moscow, Russian Federation
Fax +7(495)9393618.; E-mail: beletska@org.chem.msu.ru
b
Department of Organic Chemistry, Nizhny Novgorod State University, 23 Gagarin Avenue, 603950 Nizhny Novgorod,
Russian Federation
E-mail: afnn@rambler.ru
Received 18 June 2009
larin sulfate effectively inhibits HIV-1 integrase.5 On the
other hand, amide- and heterocycle-containing coumarin
dyes are used as laser media in the blue-green region6 or
as coumarin dopants for light-emitting devices7 and for
selective detection of various biological molecules,8 for
example, in the case of fluorescent imaging of saccharides
in cells or test tubes.9
Abstract: Palladium-catalyzed reactions of 4-(trifluoromethylsul-
fonyloxy)coumarins with amides and NH-heterocycles afforded 4-
amido- and 4-(N-hetaryl)coumarins in 60–96% yield.
Key words: coumarins, palladium catalysis, cross-coupling,
amides, NH-heterocycles
It should be noted that the electrooptical properties of cou-
marin compounds, as well as the biological activity of the
derivatives presented in Figure 1 are strongly dependent
on the number and position of the alkoxy and/or hydroxy
substituents on the coumarin nucleus.1–9
Amide- and N-heterocycle-containing coumarins make
up an important class of flavonoid compounds, widely
distributed in nature as individual compounds, as well as
being constituents of the structures of more complex nat-
ural molecules, and exhibit a broad range of biological ac-
tivities.1 Thus, the coumarins novobiocin and
chlorobiocin, produced by the actinobacteria Streptomy-
ces niveus and Streptomyces roseochromogenes, respec-
tively, as well as synthetic 4-amidocoumarin compounds
1, all containing amide or N-heterocyclic fragments in
their skeletons, are efficient antibiotics (Figure 1).2,3
Lamellarins I and K (Figure 1) isolated from marine
sponges demonstrate significant cytotoxic activity against
multidrug-resistant tumor cell lines,4 while a-20-lamel-
Herein we report the palladium-catalyzed reactions of
amides and N-hetarenes with polymethoxylated 4-triflates
of coumarins. Of particular interest is the incorporation of
indolyl or benzimidazolyl fragments at the 4-position of
the coumarin molecule, as the products thus obtained can
be regarded as structural analogues of 4-indolylcoumarins
2 (Figure 1),10 exhibiting potent cytotoxicity and antimi-
totic activity.
R2O
O
N
O
R1
O
O
O
O
MeO
O
MeO
N
H
O
HO
O
R3
OMe
OH
OH
R2
R1O
novobiocin R1 = H, R2 = NH2
chlorobiocin R1 = Cl, R2 =
MeO
MeO
lamellarin I R1 = R2 = H, R3 = OH
lamellarin K R1 = Me, R2 = H, R3 = OH
α-20 lamellarin sulfate R1 = R3 = H, R2 = SO3Na
N
H
R3
MeO
R
O
O
O
O
O
O
MeO
R
O
2
R O
R4
HO
MeO
HN
n
N
R4
NH
O
O
2a R = OMe
2b R = H
1 R1 = H, halo, alkyl, alkenyl, alkynyl; R2 = H, alkyl
3 = R4 = alkyl
N
R
Me
Figure 1
SYNTHESIS 2009, No. 21, pp 3689–3693
x
x.
x
x
.
2
0
0
9
Advanced online publication: 23.09.2009
DOI: 10.1055/s-0029-1217018; Art ID: Z12709SS
© Georg Thieme Verlag Stuttgart · New York

3690
O. G. Ganina et al.
PAPER
It was shown recently that reactions of 4-halocoumarins
as well as 4-triflates of coumarins with aliphatic and aro-
matic amines lead to 4-aminocoumarins in good to high
yields by an addition–elimination mechanism.11 How-
ever, since less nucleophilic amides are not capable of re-
acting under these conditions, we used palladium-
catalyzed amidation for the synthesis of 4-amidocou-
marins. Amidation of coumarins is very scarcely docu-
mented in the literature. In a recent precedent, amidation
of 3-bromocoumarins12 was reported for the synthesis of
analogues of novobiocin (Figure 1). On the other hand,
there are no examples of catalytic amidation or the intro-
duction of NH-heterocycles into position 4 of the cou-
marin skeleton. Moreover, it is known13 that triflates of
polymethoxylated coumarins can hamper oxidative addi-
tion due to the highly donating nature of the substituents.
PPh2
PPh2
O
PPh2
PPh2
BINAP
Xantphos
PPh2
PCy2
P(t-Bu)2
Fe
PPh2
dppf
Cy-JohnPhos
JohnPhos
Figure 2
H2N
Vinyl triflates and tosylates can undergo palladium-cata-
lyzed amidation reactions in the presence of biphe-
nylphosphine-derived,14 dppf-derived,15 or Xantphos-
type16 ligands (Figure 2). Variations of the reaction condi-
tions were tried to carry out the reaction between 5,6,7-tri-
methoxy-4-(trifluoromethylsulfonyloxy)coumarin (3a)
and acetamide (Scheme 1, Table 1). It was shown that ap-
plication of the conventional catalytic system Pd(dba)2/
BINAP does not afford the desired product 4a (Table 1,
entries 1 and 2). The use of Pd(dppf)Cl2 as the catalyst
leads to the product forming in poor yield (Table 1, entry
3). Xantphos was found to be the most efficient ligand
(Table 1, entries 4–6) and employment of the catalytic
system Pd(dba)2/Xantphos/K3PO4 (Table 1, entries 4 and
6) and increasing the reaction temperature by using diox-
ane instead of tetrahydrofuran as the solvent afforded the
desired product in high yield (Table 1, entry 6).
MeO
MeO
O
O
MeO
O
O
O
[Pd]/L
base
MeO
MeO
OTf
MeO
HN
3a
4a
O
Scheme 1
H
N
R2
R3
MeO
R1
O
N
O
MeO
O
O
O
Pd(dba)2/Xantphos
R1
K3PO4, dioxane
100 °C, 12 h
MeO
R2
MeO
OTf
R3
4–9
3a R1 = OMe
3b R1 = H
O
Scheme 2
The optimized catalytic system was applied to the amida-
tion reactions of triflates 3a and 3b with amides and lac-
tams (Scheme 2, Table 2). In all cases, the cross-coupling
products 4–8 were isolated in good to excellent yields
(60–96%).
The same catalytic system Pd(dba)2/Xantphos/K3PO4/di-
oxane afforded 4-imidazolylcoumarin 10b (Scheme 3,
Table 3, entry 1) in moderate yield. The use of the catalyt-
ic system Pd2(dba)3/BINAP18/Cs2CO3 led to the product
forming in poor yield only (Table 3, entry 2). Application
of the dppf ligand was also found to be ineffective
(Table 3, entry 3). In contrast, the monodentate JohnPhos
and Cy-JohnPhos ligands19 (Figure 2) used with cesium
No reaction of triflate 3b with phthalimide was observed;
this is due to the low nucleophilicity of the imide and, as
a result, the difficulty of reductive elimination from the
arylimidate–palladium complex.17
Table 1 Influence of the Catalyst, Base, and Solvent on the Reaction of 5,6,7-Trimethoxy-4-(trifluoromethylsulfonyloxy)coumarin (3a) with
Acetamidea
Entry
[Pd]/L (mol%)
Base
Solvent
dioxane
dioxane
THF
Reaction conditions
100 °C, 24 h
100 °C, 12 h
66 °C, 24 h
Yield 4a (%)
1
2
3
4
5
6
Pd(dba)2/BINAP (5/7.5)
Pd(dba)2/BINAP (5/5)
Pd(dppf)Cl2 (5)
Cs2CO3
t-BuOK
K3PO4
K3PO4
Cs2CO3
K3PO4
trace
trace
17
Pd(dba)2/Xantphos (5/7.5)
Pd(dba)2/Xantphos (5/7.5)
Pd(dba)2/Xantphos (5/7.5)
THF
66 °C, 24 h
68
dioxane
dioxane
100 °C, 24 h
100 °C, 12 h
55
90
a Reaction conditions: 3a (1 equiv), AcNH2 (1.2 equiv), base (2 equiv), Pd cat. (5 mol%)/L (5 or 7.5 mol%), solvent, heat.
Synthesis 2009, No. 21, 3689–3693 © Thieme Stuttgart · New York

PAPER
Reactions of 4-(Trifluoromethylsulfonyloxy)coumarins
3691
Table 3 Influence of the Catalyst and Base on the Reaction of
5,7-Dimethoxy-4-(trifluoromethylsulfonyloxy)coumarin (3b) with
Imidazolea
Table 2 Palladium-Catalyzed Reaction between Triflates 3a and 3b
and Amides, Lactams, or an Imidea
Amide/lactam/imide
Triflate R1
Product Yieldb (%)
Entry Pd source
(mol%)
L
Base
Time Yieldb
(h) 10b (%)
H2N
3a
3b
OMe
H
4a
4b
90
94
(mol%)
O
1
2
3
4
5
6
7
Pd2(dba)3 (2.5) Xantphos (5)
PdCl2 (5) BINAP (7.5)
K3PO4 24 59
Cs2CO3 48 10
K3PO4 48 ndc
Cs2CO3 24 65
H2N
3a
OMe
5
79
O
Pd2(dba)3 (2.5) dppf (5)
H2N
3a
3b
OMe
H
6a
6b
96
95
Pd2(dba)3 (2.5) JohnPhos (7.5)
O
H
Pd2(dba)3 (2.5) Cy-JohnPhos (7.5) Cs2CO3 24 68
Pd2(dba)3 (2.5) JohnPhos (7.5) K3PO4 24 76
Pd2(dba)3 (2.5) Cy-JohnPhos (7.5) K3PO4 24 80
N
O
3a
3a
OMe
OMe
7
8
78
H
O
N
60c
a Reaction conditions: 3b (1 equiv), imidazole (1.05 equiv), base (2
equiv), toluene, 100 °C.
b Yield of isolated product.
c nd = not detected.
O
3b
H
9
ndd
NH
O
MeO
R
O
O
a Reaction conditions: 3a or 3b (1 equiv), amide (1.2 equiv), K3PO4
(2 equiv), Pd(dba)2 (5 mol%), Xantphos (7.5 mol%), dioxane, 100 °C,
12 h.
MeO
R
O
N
O
MeO
OTf
Pd2(dba)3
3a,b
Cy-JohnPhos
b Yield of isolated product.
+
H
N
K3PO4
toluene, 100 °C
24 h
c Decreased isolated yield is due to the poor separation of 8 from dba;
conversion of 3a according to 1H NMR is >99%.
d nd = not detected.
MeO
X
X
Y
Y
10–13
X, Y = CH, N
R = OMe (a), H (b)
H
MeO
O
O
MeO
O
N
O
N
Scheme 4
N
[Pd]/L, base
toluene, 100 °C
MeO
3b
OTf
MeO
10b
Table 4 Palladium-Catalyzed Reaction between Triflates 3a and 3b
N
and NH-Heterocyclesa
Scheme 3
NH-heterocycle
Triflate
R1
Product
Yieldb (%)
H
N
carbonate delivered the required imidazolylcoumarin in
65% and 68% yield, respectively (Table 3, entries 4 and
5). Use of the same ligands with potassium phosphate as
the base increased the yields to 76% and 80%, respective-
ly (Table 3, entries 6 and 7).
3a
3b
OMe
H
10a
10b
96
80
N
H
N
3a
3a
3b
OMe
OMe
H
11
12
13
96
The last catalytic system (Table 3, entry 7) was used for
the reactions of triflates 3a and 3b with NH-heterocycles
(Scheme 4, Table 4), and allowed the isolation of 4-N-im-
idazolyl-, 4-N-indolyl-, and 4-N-benzimidazolylcou-
marins 10–12 in good to excellent yields (74–96%). In the
case of the less nucleophilic benzotriazole, the product 13
was not detected.
H
N
74
N
H
N
ndc
N
N
In conclusion, we have accomplished a convenient syn-
thesis of methoxy-substituted 4-amidocoumarins 4–8 and
4-N-hetarylcoumarins 10–13 by palladium-catalyzed re-
actions of triflates of 4-hydroxycoumarins 3 with linear
and cyclic amides and NH-heterocycles. The products
were obtained in 74–96% yields for all substrates except
the poor nucleophiles phthalimide and benzotriazole.
a Reaction conditions: 3a or 3b (1 equiv), NH-heterocycle (1.05
equiv), K3PO4 (2 equiv), Pd2(dba)3 (5 mol%), Cy-JohnPhos (7.5
mol%), toluene, 100 °C, 24 h.
b Yield of isolated product.
c nd = not detected.
Synthesis 2009, No. 21, 3689–3693 © Thieme Stuttgart · New York

3692
O. G. Ganina et al.
PAPER
All products were isolated by column chromatography on silica gel
and identified by 1H and 13C NMR spectroscopy and elemental anal-
ysis. NMR spectra of the compounds prepared as solns in CDCl3
with TMS as internal reference were obtained on a Bruker Avance
400 spectrometer. Elemental analyses were performed on a Perkin-
Elmer Series II CHN/O Analysis 2400 instrument. Separation by
column chromatography was performed on Merck Kieselgel 60
(70–230 mesh). PE refers to the fraction in the distillation range 40–
65 °C. All solvents were purified by standard techniques. All the
palladium sources, ligands, bases, amides, and NH-heterocycles
were commercially available. 4-(Trifluoromethylsulfonyloxy)cou-
marins 3a,b were prepared as previously reported.20
13C NMR (100.57 MHz, CDCl3): d = 21.48, 56.24, 61.29, 62.59,
96.35, 97.40, 100.78, 126.94, 129.70, 138.53, 143.23, 143.49,
147.44, 149.51, 151.31, 156.38, 161.98, 165.94.
Anal. Calcd for C20H19NO6: C, 65.03; H, 5.18; N, 3.79. Found: C,
65.22; H, 5.27; N, 3.85.
4-Methyl-N-(5,7-dimethoxycoumarin-4-yl)benzamide (6b)
Solid; yield: 88%; mp 221 °C.
1H NMR (400 MHz, CDCl3): d = 2.44 (s, 3 H), 3.85 (s, 3 H), 4.05
(s, 3 H), 6.39 (s, 1 H), 6.48 (s, 1 H), 7.32 (d, J = 7.77 Hz, 2 H), 7.60
(s, 1 H), 7.75 (d, J = 7.77 Hz, 2 H), 11.04 (br s, 1 H, NH).
13C NMR (100.57 MHz, CDCl3): d = 21.55, 55.85, 57.02, 94.85,
95.34, 95.41, 96.11, 127.02, 129.70, 131.70, 143.41, 147.95,
149.62, 153.47, 156.95, 162.59, 166.02.
Palladium-Catalyzed Amidation Reaction; General Procedure
Coumarin triflate 3a (50 mg, 0.13 mmol) or 3b (46 mg, 0.13 mmol),
the appropriate amide (0.16 mmol), K3PO4 (55 mg, 0.26 mmol),
Pd(dba)2 (3.7 mg, 0.0065 mmol), and Xantphos (3.8 mg, 0.0065
mmol) were loaded into a dry 10-mL round-bottom flask. The flask
was filled with argon. Anhyd dioxane (2 mL) was added and the re-
action mixture was stirred at 100 °C for 12 h. The crude reaction
mixture was poured into H2O (10 mL) and extracted with CH2Cl2
(3 × 5 mL). The combined organic extracts were dried (Na2SO4),
filtered, and concentrated. The crude product was purified by col-
umn chromatography (silica gel, PE–EtOAc, 1:0, then 1:4).
Anal. Calcd for C19H17NO5: C, 67.25; H, 5.05; N, 4.13. Found: C,
67.21; H, 5.11; N, 4.12.
1-(5,6,7-Trimethoxycoumarin-4-yl)pyrrolidin-2-one (7)
Solid; yield: 78%; mp 146 °C.
1H NMR (400 MHz, CDCl3): d = 2.27 (q, J = 7.51 Hz, 2 H), 2.59 (t,
J = 8.12 Hz, 2 H), 3.70–3.81 (m, 2 H), 3.83 (s, 3 H), 3.89 (s, 3 H),
3.91 (s, 3 H), 6.10 (s, 1 H), 6.67 (s, 1 H).
13C NMR (100.57 MHz, CDCl3): d = 19.23, 31.26, 50.75, 56.29,
61.18, 62.30, 96.42, 104.48, 111.45, 139.27, 149.96, 150.12,
152.09, 157.19, 160.93, 174.68.
N-(5,6,7-Trimethoxycoumarin-4-yl)acetamide (4a)
Solid; yield: 90%; mp 196 °C.
1H NMR (400 MHz, CDCl3): d = 2.23 (s, 3 H), 3.85 (s, 3 H), 3.90
(s, 3 H), 4.08 (s, 3 H), 6.64 (s, 1 H), 7.42 (s, 1 H), 10.46 (br s, 1 H,
NH).
Anal. Calcd for C16H17NO6: C, 60.18; H, 5.37; N, 4.39. Found: C,
60.23; H, 5.41; N, 4.36.
13C NMR (100.57 MHz, CDCl3): d = 25.59, 56.25, 61.22, 62.41,
96.32, 97.36, 100.47, 138.55, 143.23, 149.48, 151.31, 156.37,
161.93, 169.13.
1-(5,6,7-Trimethoxycoumarin-4-yl)azepan-2-one (8)
Solid; yield: 60%; mp 173 °C.
1H NMR (400 MHz, CDCl3): d = 1.51–1.75 (m, 6 H), 2.40–2.45 (m,
2 H), 3.15–3.19 (m, 2 H), 3.80 (s, 3 H), 3.88 (s, 3 H), 3.89 (s, 3 H),
6.05 (s, 1 H), 6.65 (s, 1 H).
Anal. Calcd for C14H15NO6: C, 57.34; H, 5.16; N, 4.78. Found: C,
57.41; H, 4.90; N, 4.71.
Anal. Calcd for C18H21NO6: C, 62.24; H, 6.09; N, 4.03. Found: C,
61.43; H, 5.61; N, 4.26.
N-(5,7-Dimethoxycoumarin-4-yl)acetamide (4b)
Solid; yield: 94%; mp 203 °C.
1H NMR (400 MHz, CDCl3): d = 2.21 (s, 3 H), 3.84 (s, 3 H), 4.00
(s, 3 H), 6.34 (d, J = 2.16 Hz, 1 H), 6.44 (d, J = 2.16 Hz, 1 H), 7.39
(s, 1 H), 10.18 (br s, 1 H, NH).
13C NMR (100.57 MHz, CDCl3): d = 25.74, 55.80, 56.87, 94.75,
95.17, 95.24, 95.98, 147.58, 156.98, 157.07, 162.06, 162.57,
169.06.
Palladium-Catalyzed Reaction between Coumarin Triflates
3a,b and NH-Heterocycles; General Procedure
Coumarin triflate 3a (50 mg, 0.13 mmol) or 3b (46 mg, 0.13
mmol)], the appropriate NH-heterocycle (0.16 mmol), K3PO4 (55
mg, 0.26 mmol), Pd2(dba)3 (3.4 mg, 0.0033 mmol), and Cy-
JohnPhos (2.9 mg, 0.0098 mmol) were loaded into a dry 10-mL
round-bottom flask. The flask was charged with argon. Anhyd tol-
uene (2 mL) was added and the reaction mixture was stirred at
100 °C for 24 h. The crude reaction mixture was poured into H2O
(10 mL) and extracted with CH2Cl2 (3 × 5 mL). The combined or-
ganic extracts were dried (Na2SO4), filtered, and concentrated. The
crude product was purified by column chromatography (silica gel,
PE–EtOAc, 2:3).
Anal. Calcd for C13H13NO5: C, 59.31; H, 4.98; N, 5.32. Found: C,
59.48; H, 4.82; N, 5.23.
2-Phenyl-N-(5,6,7-trimethoxycoumarin-4-yl)acetamide (5)
Solid; yield: 79%; mp 204 °C.
1H NMR (400 MHz, CDCl3): d = 3.44 (s, 3 H), 3.77 (s, 3 H), 3.80
(s, 2 H), 3.87 (s, 3 H), 6.60 (s, 1 H), 7.32–7.44 (m, 5 H), 7.54 (s, 1
H), 10.34 (br s, 1 H, NH).
13C NMR (100.57 MHz, CDCl3): d = 46.03, 56.23, 61.09, 62.10,
96.60, 97.12, 100.55, 127.91, 129.29, 129.71, 133.24, 145.56,
147.17, 147.46, 149.64, 156.28, 162.02, 170.61.
4-(1H-Imidazol-1-yl)-5,6,7-trimethoxycoumarin (10a)
Yellow oil; yield: 96%.
1H NMR (400 MHz, CDCl3): d = 3.47 (s, 3 H), 3.78 (s, 3 H), 3.96
(s, 3 H), 6.28 (s, 1 H), 6.92 (s, 1 H), 7.17 (d, J = 2.4 Hz, 1 H), 7.45
(d, J = 2.4 Hz, 1 H), 8.02 (s, 1 H).
13C NMR (100.57 MHz, CDCl3): d = 57.11, 65.51, 62.48, 97.73,
97.80, 111.83, 122.69, 128.59, 139.28, 145.89, 149.28, 151.34,
153.28, 159.73, 162.01.
Anal. Calcd for C20H19NO6: C, 65.03; H, 5.18; N, 3.79. Found: C,
65.41; H, 4.97; N, 3.73.
4-Methyl-N-(5,6,7-trimethoxycoumarin-4-yl)benzamide (6a)
Solid; yield: 96%; mp 154 °C.
Anal. Calcd for C15H14N2O5: C, 59.60; H, 4.67; N, 9.27. Found: C,
59.42; H, 4.80; N, 9.43.
1H NMR (400 MHz, CDCl3): d = 2.43 (s, 3 H), 3.90 (s, 3 H), 3.91
(s, 3 H), 4.07 (s, 3 H), 6.67 (s, 1 H), 7.32 (d, J = 8.05 Hz, 2 H), 7.62
(s, 1 H), 7.78 (d, J = 8.05 Hz, 2 H), 11.29 (br s, 1 H, NH).
4-(1H-Imidazol-1-yl)-5,7-dimethoxycoumarin (10b)
Solid; yield: 80%; mp 183 °C.
Synthesis 2009, No. 21, 3689–3693 © Thieme Stuttgart · New York

PAPER
Reactions of 4-(Trifluoromethylsulfonyloxy)coumarins
3693
1H NMR (400 MHz, CDCl3): d = 3.59 (s, 3 H), 3.88 (s, 3 H), 6.06
(s, 1 H), 6.28 (d, J = 2.4 Hz, 1 H), 6.53 (d, J = 2.4 Hz, 1 H), 7.07 (s,
1 H), 7.14 (s, 1 H), 7.61 (s, 1 H).
(6) (a) Azim, S. A.; Al-Hazmy, S. M.; Ebeid, E. M.; El-Daly,
S. A. Opt. Laser Tech. 2005, 37, 245. (b) Dahiya, P.;
Kumbhakar, M.; Mukherjee, T.; Pal, H. Chem. Phys. Lett.
2005, 414, 148. (c) Sivakumar, K.; Xie, F.; Cash, B. M.;
Long, S.; Barnhill, H. N.; Wang, Q. Org. Lett. 2004, 6,
4603. (d) Trenor, S. R.; Shultz, A. R.; Love, B. J.; Long,
T. E. Chem. Rev. 2004, 104, 3059.
(7) (a) Traven, V. F.; Bochkov, A. Y.; Krayushkin, M. M.;
Yarovenko, V. N.; Nabatov, B. V.; Dolotov, S. M.;
Barachevsky, V. A.; Beletskaya, I. P. Org. Lett. 2008, 10,
1319. (b) Lee, M.-T.; Yen, C.-K.; Yang, W.-P.; Chen, H.-H.;
Liao, C.-H.; Tsai, C.-H.; Chen, C. H. Org. Lett. 2004, 6,
1241.
Anal. Calcd for C14H12N2O4: C, 61.76; H, 4.44; N, 10.29. Found: C,
61.48; H, 4.63; N, 10.02.
4-(1H-Indol-1-yl)-5,6,7-trimethoxycoumarin (11)
Orange oil; yield: 96%.
1H NMR (400 MHz, CDCl3): d = 3.17 (s, 3 H), 3.83 (s, 3 H), 3.97
(s, 3 H), 6.37 (s, 1 H), 6.77 (s, 1 H), 7.16 (t, J = 7.6 Hz, 1 H), 7.26
(t, J = 7.6 Hz, 1 H), 7.44 (d, J = 2.3 Hz, 1 H), 7.48 (d, J = 8.1 Hz, 1
H), 7.57 (d, J = 8.0 Hz, 1 H), 8.83–8.91 (m, 1 H).
13C NMR (100.57 MHz, CDCl3): d = 56.20, 61.28, 61.60, 96.31,
96.90, 107.57, 111.46, 113.34, 113.99, 119.70, 120.46, 122.45,
124.55, 126.79, 135.56, 148.89, 151.39, 152.01, 156.48, 161.36.
(8) (a) Bennett, F. A.; Barlow, D. J.; Dodoo, N. O.; Hider, R. C.;
Lansley, A. B.; Lawrence, M. J.; Marriott, C.; Bansal, S. S.
Anal. Biochem. 1999, 270, 15. (b) Lo, L.-C.; Liao, Y.-C.;
Kuo, C.-H.; Chen, C.-T. Org. Lett. 2000, 2, 683.
(c) Murata, C.; Masuda, T.; Kamochi, Y.; Todoroki, K.;
Yoshida, H.; Nohta, H.; Yamaguchi, M.; Takadate, A.
Chem. Pharm. Bull. 2005, 53, 750. (d) Coleman, R. S.;
Berg, M. A.; Murphy, C. J. Tetrahedron 2007, 63, 3450.
(9) Nakata, E.; Koshi, Y.; Koga, E.; Katayama, Y.; Hamachi, I.
J. Am. Chem. Soc. 2005, 127, 13253.
(10) Ganina, O. G.; Daras, E.; Bourgarel-Rey, V.; Peyrot, V.;
Andresyuk, A. N.; Finet, J.-P.; Fedorov, A. Yu.; Beletskaya,
I. P.; Combes, S. Bioorg. Med. Chem. 2008, 16, 8806.
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A. Yu.; Beletskaya, I. P. Russ. Chem. Bull. 2006, 9, 1642.
(b) Griffin, R. J.; Fontana, G.; Golding, B. T.; Guiard, S.;
Hardcastle, I. R.; Leahy, J. J. J.; Martin, N.; Richardson, C.;
Rigoreau, L.; Stockley, M.; Smith, G. C. M. J. Med. Chem.
2005, 48, 569. (c) Stoyanov, E. V.; Ivanov, I. C. Molecules
2004, 9, 627. (d) Hishmat, O. H.; Gohar, A. M.; Wassef,
M. E.; Shalash, M. R.; Ismail, I. Pharm. Acta Helv. 1977, 52,
252. (e) Zagorevsky, V. A.; Savel’ev, V. L.; Mesheryakova,
L. M. Chem. Heterocycl. Compd. 1970, 947.
Anal. Calcd for C20H17NO5: C, 68.37; H, 4.88; N, 3.99. Found: C,
68.72; H, 4.80; N, 3.53.
4-(1H-Benzimidazol-1-yl)-5,6,7-trimethoxycoumarin (12)
Orange oil; yield: 74%.
1H NMR (400 MHz, CDCl3): d = 3.21 (s, 3 H), 3.75 (s, 3 H), 3.98
(s, 3 H), 6.43 (s, 1 H), 6.80 (s, 1 H), 7.40–7.57 (m, 3 H), 8.07 (d,
J = 8.1 Hz, 1 H), 8.85 (s, 1 H).
13C NMR (100.57 MHz, CDCl3): d = 56.61, 61.26, 61.87, 96.58,
96.77, 111.05, 112.36, 118.60, 125.61, 126.81, 127.91, 128.85,
139.32, 141.33, 144.82, 149.72, 149.94, 158.79, 159.37.
Anal. Calcd for C19H16N2O5: C, 64.77; H, 4.58; N, 7.95. Found: C,
64.52; H, 4.70; N, 7.73.
Acknowledgment
This work was supported by the Russian Foundation for Basic Re-
search (Grant No. 09-03-00647-a and 09-03-97038-r-povolj’e-a).
O. Ganina thanks INTAS for a YS-05-109-5412 fellowship.
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A. Yu.; Finet, J.-P. Synlett 2004, 2797.
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3229.
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Synthesis 2009, No. 21, 3689–3693 © Thieme Stuttgart · New York