Palladium-catalyzed coupling of 3-halo-substituted coumarins, chromenes, and quinolones with various nitrogen-containing nucleophiles

Article abstract of DOI:10.1002/ejoc.201100480

An efficient and general palladium-catalyzed coupling reaction between 3-bromocoumarins, 3-bromoquinolin-2(1H)-ones, and 3-iodo-2H-chromenes with a variety of nitrogen-containing nucleophiles (azole, amide, lactam, sulfonamide, aniline, amine, and urea) is described. The reaction proceeded rapidly and cleanly in dioxane providing the coupling products in good to excellent yields. The chemoselectivity of this reaction was also studied with polyhalocoumarins. Under optimized conditions, these underwent a site-selective amination at the C-3-Br bond, regardless of the nature of the nitrogen-containing nucleophile used. The coupling of 3-bromocoumarins, 3-iodochromenes, and 3-bromoquinolones with nitrogen-containing nucleophiles was effectively catalyzed by Pd(OAc) ₂/Xantphos. The process was efficient and selective with a broad range of nucleophiles including alkylamines, anilines, amides, lactams, sulfonamides, urea, and azole derivatives to give the 3-N-substituted heterocycles in good yields. Copyright

Full text of DOI:10.1002/ejoc.201100480

FULL PAPER
DOI: 10.1002/ejoc.201100480
Palladium-Catalyzed Coupling of 3-Halo-Substituted Coumarins, Chromenes,
and Quinolones with Various Nitrogen-Containing Nucleophiles
Mohamed Ali Soussi,[a] Davide Audisio,[a] Samir Messaoudi,*[a] Olivier Provot,[a]
Jean-Daniel Brion,[a] and Mouâd Alami*[a]
Keywords: Palladium / Heterocycles / C–N coupling / Amination
An efficient and general palladium-catalyzed coupling reac-
tion between 3-bromocoumarins, 3-bromoquinolin-2(1H)-
ones, and 3-iodo-2H-chromenes with a variety of nitrogen-
containing nucleophiles (azole, amide, lactam, sulfonamide,
aniline, amine, and urea) is described. The reaction pro-
ceeded rapidly and cleanly in dioxane providing the cou-
pling products in good to excellent yields. The chemoselec-
tivity of this reaction was also studied with polyhalocoumar-
ins. Under optimized conditions, these underwent a site-se-
lective amination at the C-3–Br bond, regardless of the na-
ture of the nitrogen-containing nucleophile used.
der copper catalysis.[11] An alternate route includes the con-
densation of salicylaldehydes with glycine derivatives.[12,9a]
Although these multistep procedures are useful to prepare
3-N-substituted coumarins, most of them require an extra
step for the N-functionalization, and thus have somewhat
limited applications in library synthesis. Therefore, the se-
arch for simple and selective procedures as well as diversity-
oriented reactions, such as metal-catalyzed couplings, pres-
ents an interesting challenge.
Introduction
Heterocyclic compounds are indispensable structural
units that are useful in medicinal chemistry and valuable as
synthetic organic building blocks. Among the various
classes of heterocyclic compounds, the coumarin ring is
present in a broad range of natural and nonnatural prod-
ucts of biological interest.[1] Over the past decades, synthe-
sis and screening of coumarin compounds for drug discov-
ery have been a subject of constant interest in medicinal
chemistry. Because of their noticeable biological activities,
including antimicrobial,[2] antiviral,[3] antiallergic,[4] and an-
ticancer[5] properties, 3-N-substituted coumarins represent
a promising class of synthetic compounds. Recent work
demonstrated that novobiocin[5a,5b] and its denoviose ana-
log 4TCNA,[6] two 3-amidocoumarin derivatives, have been
shown to bind to the C-terminal domain of heat shock pro-
tein 90 (hsp90), an exciting new target in cancer drug dis-
covery,[7] leading to a decrease in hsp90 client proteins in
various cancer cell lines.[8]
In 2007, Wu reported the preparation of 3-aminocoum-
arins by coupling 3-bromocoumarins with anilines[13] using
the Pd2(dba)3/Xantphos (dba = dibenzylideneacetone) cou-
ple in the presence of K2CO3 in toluene. In the same year,
we reported a general approach to a wide range of 3-N-
substituted aminocoumarins by the palladium-catalyzed
coupling of 3-bromocoumarins with a wider variety of ni-
trogen-containing nucleophiles,[14] including amides, sulfon-
amides, carbamates, ureas, and functionalized amines. We
demonstrated that using Pd(OAc)2/Xantphos as the cata-
lytic system in the presence of Cs2CO3 in dioxane proved
to be a versatile protocol for the preparation of various 3-
N-substituted coumarins[14] as well as related heterocyclic
structures, including 3-N-substituted quinolin-2(1H)-
ones.[15] From a synthetic viewpoint, these C–N bond cou-
plings represent the shortest and most efficient route to 3-
N-substituted coumarins and quinolin-2(1H)-ones for the
purpose of our medicinal chemistry screening programs.[16]
As part of our continuing effort with regard to the func-
tionalization of heterocycles through transition-metal-cata-
lyzed reactions,[17] in combination with our interest in dis-
covering new hsp90 inhibitors,[6,8,16a] we decided to expand
the scope of this reaction and to study the palladium-cata-
lyzed coupling of a series of heterocyclic substrates, such as
3-halo-substituted coumarin, quinolin-2(1H)-one, and 2H-
In contrast to the numerous applications of 3-aminocou-
marin derivatives, there are very few synthetic approaches
to these compounds. To introduce a variety of amine substi-
tutions at the 3-position, the most common route is un-
doubtedly the N-functionalization of 3-aminocoumarins,[9]
readily obtained from the reduction of 3-nitrocoumarins [10]
or by reaction of 3-bromocoumarins with sodium azide un-
[a] Université Paris-Sud, CNRS, BioCIS UMR 8076, Laboratoire
de Chimie Thérapeutique, Faculté de Pharmacie,
Rue J.-B. Clément, Châtenay-Malabry, 92296, France
Fax: +33-1-46835828
E-mail: samir.messaoudi@u-psud.fr
mouad.alami@u-psud.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100480.
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chromene derivatives with a wider variety of nitrogen-con- protocol.[18] Initially, we studied the reaction of a 3-bromo-
taining nucleophiles including amide, sulfonamide, lactam, coumarin (1 equiv.) with 4-methoxybenzamide (1.2 equiv.).
urea, aniline, benzylamine, and azole derivatives. In this pa- The optimum conditions for the palladium-catalyzed cou-
per, we wish to detail our progress with respect to this reac- pling were determined through a series of experiments in
tion, which allows for the high yielding synthesis of a wide which sequential changes were made to the catalyst, the li-
range of 3-N-substituted aminocoumarins and related het- gand, the base, and the solvent used for the reaction. The
erocyclic structures of biological interest.
best conditions required the use of a sealed tube with
Pd(OAc)2 (4 mol-%) as the catalyst, Xantphos (4 mol-%) as
the ligand, Cs2CO3 (1.5 equiv.) as the base, and dioxane as
the solvent at 100 °C.
Results and Discussion
The functionalized 3-bromocoumarins 1 were prepared
Accordingly, the expected 3-amidocoumarin 2a (Table 1)
from substituted salicylaldehydes by using a one-pot bromi- was obtained in a good yield (87%) after only 0.5 h. A com-
nation/Wittig/cyclization reaction according to our previous parative reaction under copper catalysis gave a lower yield
Table 1. Synthesis of functionalized 3-N-substituted aminocoumarins 2 and aminoquinolin-2(1H)-ones 3.[a]
[a] Reagents and conditions: substrate 1 (1 equiv.), nitrogen-containing nucleophile (1.2 equiv.), Pd(OAc)2 (4 mol-%), Xantphos (4 mol-
%), Cs2CO3 (1.5 equiv.), dioxane (0.2 m), 100 °C (for time, see Exp. Section). [b] Isolated yield. [c] The reaction was performed at 130 °C.
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Palladium-Catalyzed Heterocyclic C–N Coupling
(41%), as we previously reported.[19] It is worthy to note although a longer reaction time was needed (12 h), we were
that the reaction did not seem to be sensitive to steric hin- pleased to observe that the ethoxycarbonyl functionality in
drance, as the presence of a methyl (Table 1, Entry 2) or a glycine ester was well tolerated under the coupling condi-
phenyl (Table 1, Entry 3) substituent at the C-4 position of tions, as 2o was obtained in a satisfactory 57% yield
3-bromocoumarins did not alter the course of the coupling. (Table 1, Entry 15).
The reaction also worked well in the presence of a variety
As molecules containing heteroaryl-azole linkages are
of nucleophiles including aromatic, heteroaromatic, and ali- prevalent in biological and pharmaceutical sciences, azole
phatic amides (Table 1, Entries 1–5). The selectivity of this nuclei (e.g., indole, 1H-indazole, 1H-benzimidazole, 1H-
reaction with respect to nucleophile coupling partners must [2,3-b]pyrrolopyridine, 1H-pyrrole, and 1H-pyrrazole) were
be pointed out. The amidation reaction of 3-bromocoum- then evaluated as coupling partners with 3-bromocoum-
arin occurred rather than the etherification process[20] with arins. As previously observed for lactams, reactions of
2-hydroxypropanamide as the nucleophile, giving exclu- azoles with 3-bromocoumarins occurred at 130 °C, and the
sively amide 2e (60%; Table 1, Entry 5). Next, the condi- coupling products 2p–v were isolated in yields ranging from
tions employed for Entries 1–5 were applied to the prepara- 36 to 95% (Table 1, Entries 16–22). The efficiency of this
tion of compounds 2f–h. At 100 °C, no reaction occurred protocol was also demonstrated in the coupling of indole
when 3-bromocoumarin was treated with lactams even if with 3-bromoquinolin-2(1H)-one as the electrophilic part-
other ligands and palladium sources were used (data not ner. As shown in Entries 23 and 24, the reaction of indole
shown). Nevertheless, by performing the reaction at a and 5-methoxyindole with 3-bromo-1-methylquinolin-2-
higher temperature (130 °C), we were pleased to observe the (1H)-one, under optimal conditions, gave the desired cou-
formation of lactam-containing coumarins, regardless of pling products 3a and 3b in excellent yields (84% and 98%,
the size of the lactam ring. Thus, 2f, 2g, and 2h were ob- respectively).
tained in satisfactory to good yields (86%, 65%, and 41%,
To expand the scope of this protocol to other heterocy-
respectively; Table 1, Entries 6–8). Next, arylsulfonamides, clic substrates, we focused our attention to coupling these
which are poor nucleophilic partners, were examined nitrogen-containing nucleophiles with 4-substituted-3-iodo-
(Table 1, Entries 9 and 10). Although the desired products 2H-chromenes 4.[21] A variety of nucleophiles including
2i and 2j were obtained, the yields were moderate (53% and amide, amine, sulfonamide, lactam, and urea derivatives
42%, respectively). Anilines and benzylamines also reacted were examined to establish the scope and generality of the
efficiently to produce the corresponding coupling products present transformation, and the results are summarized in
2k–n in good yields (Table 1, Entries 11–14). In addition, Table 2. First, several functionalized aromatic amides were
Table 2. Synthesis of functionalized 3-N-substituted aminochromenes 5.[a]
[a] Reagents and Conditions: substrate 4 (1 equiv.), nitrogen-containing nucleophile (1.2 equiv.), Pd(OAc)2 (4 mol-%), Xantphos (4 mol-
%), Cs2CO3 (1.5 equiv.), dioxane (0.2 m), 100 °C (for time, see Exp. Section). [b] Isolated yield. [c] Reaction was performed using 1 equiv.
of nitrogen-containing nucleophile and 2 equiv. of 3-iodo-4-phenyl-2H-chromene derivative (4). [d] The reaction was performed at 130 °C.
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Table 3. Site selective amination of polyhalogenated coumarins with various nucleophiles.[a]
[a] Reagents and conditions: substrate 6 (1 equiv.), nitrogen-containing nucleophile (1.2 equiv.), Pd(OAc)2 (4 mol-%), Xantphos (4 mol-
%), Cs2CO3 (1.5 equiv.), dioxane (0.2 m), 100 °C (for time, see Exp. Section). [b] Isolated yield.
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Palladium-Catalyzed Heterocyclic C–N Coupling
evaluated, and the expected 3-N-substituted amido- Table 4. Synthesis of polysubstituted coumarins 11.
chromenes 5a–d were isolated in excellent yields within 1–
2 h at 100 °C (Table 2, Entries 1–4). One can note that the
presence of a substituent at the C-4 position of the
chromene nucleus did not interfere with the general scope
of this reaction. Interestingly, products 5c and 5d revealed
excellent chemical selectivities, as the C–Cl and C–OTs
bonds, which could undergo further metal-catalyzed func-
tionalization processes, were preserved.[22] Aliphatic amides
were also coupled successfully with 3-iodo-4-phenyl-
chromene to provide the desired chromenes 5e and 5f in
acceptable yields (Table 2, Entries 5 and 6). Furthermore,
as shown in Entries 7–9, the coupling protocol was quite
effective with arylsulfonamide, urea, and aniline derivatives
to prepare the corresponding 3-N-substituted chromenes
5g–i. Finally, as it was previously observed with 3-bromo-
coumarins (Table 1, Entries 6–8), by achieving the coupling
reaction with lactams at 130 °C, we were pleased to observe
the total conversion of the starting materials, and
chromenes 5j and 5k were isolated in excellent yields
(Table 2, Entries 10–11).
Next, we investigated the reactivity of various nitrogen-
containing nucleophiles (1.2 equiv.) towards a variety of po-
lyhalogenated coumarins[18] (1 equiv.). The results of this
study are summarized in Table 3. Under the above experi-
mental conditions, amination of coumarins 6a–e with 4-
methoxyaniline as well as with nBuNH2 furnished 3-amino-
coumarins 7a–e and 8a–e with total chemoselectivity and
in good isolated yields. In each case, amination occurred at
the more reactive C-3–Br bond, and the other bromo and
chloro substituents remained unchanged. It is noteworthy
that in the case of 3,5-dibromo-2H-chromen-2-one (6a), the
coupling reaction yielded monosubstituted products 7a and
8a both in 74% yield (Table 3, Entries 1 and 6) together
with coupling byproducts 7aa and 5-butylaminocoumarin
8aa in 20% and 21% yields, respectively. This result clearly
indicates that the C-5–Br bond is more reactive than C-6–
Br, C-7–Br, and C-8–Br bonds when comparing 6a to 6b, c,
and d. When using others nucleophiles such as morpholine
or 4-methoxybenzamide, the coupling reaction with 6d, a,
and b also occurred at the C-3–Br bond, providing the de-
sired compounds 9, 10a, and 10b, respectively, in good
yields (Table 3, Entries 11–13).
Thus, the 3-N-substituted bromocoumarins 7–10 ob-
tained are useful synthetic intermediates for the introduc-
tion of various substituents to the surviving C–Br bond.
Examples reported in Table 4 illustrate some metal-cata-
[a] The reactions were performed with substrates 7a, 7c, or 9
(1 equiv.), ArB(OH)2 (1.2 equiv.), Pd(PPh3)4 (5 mol-%), K2CO3
(2 equiv.), in toluene/EtOH (2:1) at 100 °C for 2–3 h. [b] Isolated
yield. [c] The reaction was performed with substrate 7a (1 equiv.),
3,4,5-trimethoxyaniline (2 equiv.), Pd(OAc)2 (10 mol-%), Xantphos
(10 mol-%), Cs2CO3 (1.5 equiv.), in dioxane at 100 °C for 24 h.
[d] The reaction was performed with substrate 7a (1 equiv.), NaN3
(2 equiv.), Cu (10 mol-%), pepicolinic acid (30 mol-%), ascorbic
lyzed coupling reactions of these substrates with boronic acid (20 mol-%), in EtOH at 100 °C for 12 h. [e] The reaction was
performed with 7b (1 equiv.), 4-methoxyphenyl-N-tosylhydrazone
acids, anilines, sodium azide, and N-tosylhydrazones.
(1.2 equiv.), Pd2(dba)3 (10 mol-%), Xantphos (20 mol-%), tBuOLi
(2.5 equiv.), in dioxane at 80 °C for 3 h.
As observed in Entries 1–3, Suzuki couplings using
Pd(PPh3)4 and K2CO3 (2 equiv.) in toluene/EtOH (2:1) at
100 °C[23] furnished the required coupling products 11a–c
in good to excellent yields. Amination of 7a was achieved
by using 3,4,5-trimethoxyaniline as the nucleophile in the 7a with sodium azide as the amino source, according to our
presence of Pd(OAc)2 as the catalyst and Xantphos as the previously reported conditions.[11] The reaction occurred
ligand to give 11d in 60% yield (Table 4, Entry 4). The syn- rapidly in the presence of inexpensive copper powder as the
thesis of the 5-aminocoumarin derivative 11e was achieved catalyst and environmentally benign EtOH as the solvent,
by the copper-catalyzed C–N coupling reaction of substrate providing amino derivative 11e in a moderate yield (45%;
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ganic salts were removed. The filtrate was concentrated, and purifi-
cation of the residue by silica gel column chromatography gave the
desired product.
Table 4, Entry 5). Finally, the Pd-catalyzed coupling of 7b
with a 4-methoxyphenyl-N-tosylhydrazone[24] furnished the
1,1-diarylethylene derivative 11f which will be evaluated in
our group as an isoCA-4 analog of biological inter-
est.[16b–16e]
4-Methoxy-N-(7-methoxy-4,8-dimethyl-2-oxo-2H-chromen-3-yl)-
benzamide (2b). The reaction mixture was stirred for 1 h at 130 °C.
White solid (76%); m.p. 239–241 °C. Rf = 0.20 (Et2O). 1H NMR
(300 MHz): δ = 7.92 (s, 1 H), 7.82 (d, J = 9.0 Hz, 2 H), 7.44 (d, J
= 8.1 Hz, 1 H), 6.88 (d, J = 9.0 Hz, 2 H), 6.82 (d, J = 8.1 Hz, 1
Conclusions
H), 3.86 (s, 3 H), 3.80 (s, 3 H), 2.31 (s, 3 H), 2.24 (s, 3 H) ppm. 13
NMR (75 MHz): δ = 165.6, 162.8, 160.5, 159.7, 150.2, 143.7, 129.6
C
In summary, we demonstrated that the Pd(OAc)2/
Xantphos couple is a versatile and efficient catalytic system (2), 126.0, 123.0, 118.1, 114.4, 114.0, 113.9 (2), 107.3, 56.0, 55.5,
16.0, 8.2 ppm. MS (ESI+): m/z = 376.0 [M + Na]+. IR: ν = 3322,
2922, 1672, 1595, 1488, 1373, 1352, 1318, 1290, 1252, 1171, 1154,
1115, 1026, 967, 898, 835, 807, 772, 759, 702, 637, 610, 592,
561 cm–1.
˜
for the coupling of a wide range of nitrogen-containing nu-
cleophiles with 3-halo-substituted coumarins, quinolinones,
and chromenes. Various amide, lactam, amine, sulfonamide,
urea, and azole derivatives were successfully used to give
the coupling products in high yields. We also showed that
amination of various polyhalogenated coumarins selectively
provided 3-aminocoumarins 7, 8, 9, and 10 in good yields.
A subsequent coupling on the remaining C–Br bond fur-
nished various disubstituted coumarins in excellent yields.
The exploitation of this procedure will allow us to quickly
synthesize a library of polysubstituted coumarins as potent
inhibitors of hsp90.
N-(7-Benzyloxy-8-methyl-2-oxo-4-phenyl-2H-chromen-3-yl)-4-
methoxybenzamide (2c): The reaction mixture was stirred for 1 h at
130 °C. White solid (84%); m.p. 200 °C. Rf = 0.27 [EtOAc/c-hexane
1
(cyclohexane), 3:7]. H NMR (300 MHz): δ = 7.62–7.60 (m, 2 H),
7.46–7.33 (m, 11 H), 7.06 (d, J = 8.9 Hz, 1 H), 6.85–6.78 (m, 3 H),
5.15 (s, 2 H), 3.80 (s, 3 H), 2.42 (s, 3 H) ppm. 13C NMR (75 MHz):
δ = 165.8, 162.6, 160.5, 159.2, 151.5, 148.9, 136.5, 133.7, 129.4 (2),
128.9, 128.8 (2), 128.5 (4), 128.2, 127.2 (2), 126.1, 125.6, 117.9,
114.7, 114.2, 113.8 (2), 108.7, 70.6, 55.5, 8.6, (1 C missing) ppm.
MS [APCI+ (atmospheric pressure chemical ionization)]: m/z =
492.2 [M + H]+. IR: ν = 2925, 1988, 1731, 1604, 1479, 1260, 1177,
˜
1111, 1029, 845, 699 cm–1.
Experimental Section
N-(6-Methoxy-2-oxo-2H-chromen-3-yl)thiophene-2-carboxamide
(2d): The reaction mixture was stirred for 2 h at 130 °C. Yellow
solid (93 %); m.p. 195 °C. Rf = 0.72 (CH2 Cl2). 1 H NMR
(300 MHz): δ = 8.73 (s, 1 H), 8.69 (br. s, 1 H), 7.71 (d, J = 3.7 Hz,
1 H), 7.64 (d, J = 5.0 Hz, 1 H), 7.30 (d, J = 8.8 Hz, 1 H), 7.26–
7.18 (m, 1 H), 7.06 (dd, J = 8.8 Hz, J = 2.8 Hz, 1 H); 7.00 (d, J =
2.8 Hz, 1 H), 3.87 (s, 3 H) ppm. 13C NMR (75 MHz): δ = 160.5,
158.9, 156.8, 144.4, 138.3, 132.1, 129.2, 128.2, 124.3, 123.2, 120.4,
118.0 (2), 109.9, 55.9 ppm. MS (APCI–): m/z = 299.7 [M – H]+.
General: All glassware was oven-dried at 140 °C, and all reactions
were conducted under an argon atmosphere. The solvents Ϫ Et2O,
cyclohexane, and ethyl acetate (EtOAc) Ϫ for chromatography were
technical grade. All new compounds were characterized by using
1H and 13C NMR and IR spectroscopy. The 1H and 13C NMR
spectroscopic data were measured in CDCl3 with a Bruker Avance
1
300. The H NMR chemical shifts are reported in ppm with TMS
or residual chloroform (δ =7.27 ppm) as the internal standard. The
following abbreviations are used: (1) m [multiplet], (2) s [singlet],
(3) br. s [broad singlet], (4) d [doublet], (5) t [triplet], (6) dd [doublet
of doublets], (7) dt [doublet of triplets], and (8) td [triplet of dou-
blets]. The 13C chemical shifts are reported in ppm from the central
peak of deuteriochloroform (77.14 ppm). IR spectra were measured
with a Bruker Vector 22 spectrophotometer [neat (cm–1)]. Analyti-
cal TLC was performed with Merck precoated silica gel 60 F-254
plates. Merck silica gel 60 (230–400 mesh) was used for column
chromatography. The plates were visualized by either UV light
(254 nm) or by a solution of phosphomolybdic acid in ethanol.
Melting points (m.p.) were recorded with a Büchi B-450 apparatus.
IR: ν = 1711, 1695, 1650, 1581, 1529, 1513, 1493, 1417, 1261,
˜
1033 cm–1.
2-Hydroxy-N-(2-oxo-2H-chromen-3-yl)propanamide (2e): The reac-
tion mixture was stirred for 0.5 h at 100 °C. White solid (60%);
m.p. 131–133 °C. Rf = 0.51 (CH2Cl2/EtOAc, 7:3). 1H NMR
(300 MHz): δ = 9.18 (br. s, 1 H), 8.62 (s, 1 H), 7.50–7.30 (m, 2 H),
7.26–7.19 (m, 2 H), 4.38 (q, J = 7.1 Hz, 1 H), 2.85 (br. s, 1 H), 1.50
(d, J = 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz): δ = 173.8, 158.6,
150.1, 129.8, 127.8, 125.1, 123.7, 123.5, 119.7, 116.3, 69.0,
21.0 ppm. MS (ESI+): m/z = 256.0 [M + Na]+. IR: ν = 3350, 1721,
˜
General Procedure for the Synthesis of Coumarins 2b–i, 2k–n, and
2p–v; Quinolones 3a and b; Chromenes 5a–k; and Coumarins 7a–e,
8a–e, 9, and 10a–b (for experimental data of the known compounds
2a, 2j, and 2o, see the Supporting Information): A flame-dried re-
sealable Schlenk tube was charged with Pd(OAc)2 (0.04 mmol,
4 mol-%), Xantphos (0.04 mmol, 4 mol-%), the heterocyclic halide
(1.0 mmol), the nitrogen nucleophile (1.2 mmol), and Cs2CO3
(1.5 mmol). The Schlenk tube was capped with a rubber septum,
evacuated, and backfilled with argon. This evacuation/backfill se-
quence was repeated one additional time. The liquid reactant(s)
and 1,4-dioxane (2 mL per mmol) were added through the septum.
The septum was replaced with a Teflon® screw cap. The Schlenk
tube was sealed, and the mixture was stirred at 100 °C or 130 °C
(for temperature and reaction time, see Tables 1 and 2). The re-
sulting suspension was cooled to room temperature and filtered
through a pad of Celite, eluting with ethyl acetate, and the inor-
1661, 1628, 1606, 1517, 1485, 1450, 1366, 1315, 1294, 1180, 1141,
1111, 1069, 1030, 949, 912, 868, 757, 650, 599, 579 cm–1.
1-(2-Oxo-2H-chromen-3-yl)azetidin-2-one (2f): The reaction mix-
ture was stirred for 1 h at 130 °C. Yellow solid (86%); m.p. 169 °C.
Rf = 0.50 (EtOAc/c-hexane, 4:6). 1H NMR (300 MHz): δ = 8.22 (s,
1 H), 7.40–7.35 (m, 2 H), 7.29–7.20 (m, 2 H), 4.12 (t, J = 4.7 Hz,
2 H), 3.14 (t, J = 7.7 Hz, 2 H) ppm. 13C NMR (75 MHz): δ =
166.9, 156.7, 150.7, 129.9, 127.4, 125.4, 125.0, 123.8, 119.4, 116.3,
42.9, 38.3 ppm. MS (ESI+): m/z = 238.0 [M + Na]+. IR: ν = 2964,
˜
2163, 1719, 1616, 1460, 1360, 1166, 757 cm–1.
1-(2-Oxo-2H-chromen-3-yl)pyrrolidin-2-one (2g): The reaction mix-
ture was stirred for 1 h at 130 °C. White solid (65%); m.p. 137 °C.
1
Rf = 0.52 (EtOAc). H NMR (300 MHz): δ = 7.96 (s, 1 H), 7.50–
7.47 (m, 2 H), 7.32–7.25 (m, 2 H), 3.98 (t, J = 8.2 Hz, 2 H), 2.56
(t, J = 8.2 Hz, 2 H), 2.24–2.09 (m, 2 H) ppm. 13C NMR (75 MHz):
5082
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 5077–5088

Palladium-Catalyzed Heterocyclic C–N Coupling
δ = 175.8, 158.0, 152.4, 137.4, 131.3, 128.1, 124.8, 124.5, 118.9,
116.4, 48.7, 31.4, 18.8 ppm. MS (APCI+): m/z = 230.0 [M + H]+.
IR: ν = 3309, 2928, 1647, 1598, 1524, 1495, 1447, 1425, 1350, 1317,
˜
1298, 1258, 1231, 1175, 1078, 1028, 927, 884, 835, 800, 743, 694,
IR: ν = 2989, 1721, 1692, 1608, 1492, 1389, 1123, 923, 755,
614 cm–1.
˜
629 cm–1.
3-(1H-Indol-1-yl)-2H-chromen-2-one (2p): The reaction mixture was
stirred for 1 h at 130 °C. Yellow solid (95%); m.p. 160 °C. Rf = 0.34
(CH2Cl2/c-hexane, 3:7). 1H NMR (300 MHz): δ = 7.87 (s, 1 H),
7.68 (d, J = 8.1 Hz, 1 H), 7.59–7.01 (m, 8 H), 6.72 (d, J = 3.1 Hz,
1 H) ppm. 13C NMR (75 MHz): δ = 158.5, 152.7, 136.4, 134.7,
131.8, 129.7, 128.6, 128.1, 126.0, 125.3, 123.1, 121.7, 121.4, 119.1,
117.0, 110.8, 105.0 ppm. MS (ESI+): m/z = 284.0 [M + Na]+. IR:
1-(2-Oxo-2H-chromen-3-yl)piperidin-2-one (2h): The reaction mix-
ture was stirred for 1 h at 130 °C. White solid (41%); m.p. 164 °C.
1
Rf = 0.30 (EtOAc). H NMR (300 MHz): δ = 7.70 (s, 1 H), 7.55–
7.45 (m, 2 H), 7.35–7.25 (m, 2 H), 3.61 (t, J = 6 Hz, 2 H), 2.56 (t,
J = 6.0 Hz, 2 H), 1.94–1.98 (m, 4 H) ppm. 13C NMR (75 MHz): δ
= 170.8, 158.1, 153.1, 140.5, 131.8, 129.1, 128.2, 124.7, 118.9, 116.7,
50.1, 32.6, 23.2, 21.3 ppm. MS (APCI+): m/z = 244.0 [M +
ν = 2918, 1722, 1632, 1604, 1463, 1335, 1157, 923, 910, 753,
˜
720 cm–1.
H]+. IR: ν = 2947, 2034, 1722, 1651, 1630, 1607, 1458, 1412, 982,
˜
756 cm–1.
3-(3-Methyl-1H-indol-1-yl)-2H-chromen-2-one (2q): The reaction
mixture was stirred for 2 h at 130 °C. Yellow solid (71 %); m.p.
130 °C. Rf = 0.59 (Et2O/c-hexane, 3:7). H NMR (300 MHz): δ =
N-(7-Methoxy-4,8-dimethyl-2-oxo-2H-chromen-3-yl)-4-methyl-
benzenesulfonamide (2i): The reaction mixture was stirred for 0.5 h
at 100 °C. Orange solid (53 %); m.p. 185–187 °C. Rf = 0.42
(CH2Cl2). 1H NMR (300 MHz): δ = 8.97 (s, 1 H), 8.06 (d, J =
8.3 Hz, 2 H), 7.37–7.34 (m, 3 H), 6.93 (d, J = 8.6 Hz, 1 H), 3.91
(s, 3 H), 2.50 (s, 3 H), 2.44 (s, 3 H), 2.35 (s, 3 H) ppm. 13C NMR
(75 MHz): δ = 158.5, 156.5, 153.9, 145.1, 139.6, 135.9, 129.7 (2),
128.6 (2), 128.3, 122.7, 118.4, 110.0, 108.5, 56.5, 21.7, 9.3, 8.6 ppm.
1
7.82 (s, 1 H), 7.65–7.50 (m, 3 H), 7.47–7.40 (m, 2 H), 7.38–7.18 (m,
4 H), 2.38 (s, 3 H) ppm. 13C NMR (75 MHz): δ = 158.4, 152.2,
136.4, 133.4, 131.3, 130.2, 127.8, 125.9, 125.7, 125.1, 122.8, 120.8,
119.5, 119.0, 116.7, 114.0, 110.6, 9.7 ppm. MS (APCI+): m/z (%)
= 276.0 [M + H]+. IR: ν = 2920, 1718, 1608, 1449, 1373, 1142,
˜
1054, 928, 757, 733, 642, 623 cm–1.
MS (ESI+): m/z = 396.0 [M + Na]+. IR: ν = 3265, 2920, 2852,
˜
3-(1H-Indazol-1-yl)-2H-chromen-2-one (2r): The reaction mixture
was stirred for 2 h at 130 °C. White solid (36%); m.p. 166 °C. Rf =
1695, 1602, 1503, 1385, 1342, 1285, 1254, 1189, 1163, 1127, 1109,
1094, 1036, 880, 850, 816, 795, 778, 748, 708, 664, 616 cm–1.
1
0.34 (Et2O/c-hexane, 3:7). H NMR (300 MHz): δ = 8.37 (s, 1 H),
8.12 (dd, J = 8.1 Hz, J = 1.1 Hz, 1 H), 7.87 (d, J = 8.1 Hz, 1 H),
7.70 (dd, J = 8.1 Hz, J = 1.1 Hz, 1 H), 7.67 (td, J = 8.5 Hz, J =
1.5 Hz, 1 H), 7.54 (td, J = 8.5 Hz, J = 1.5 Hz, 1 H), 7.46 (dd, J =
8.1 Hz, J = 8.1 Hz, 1 H), 7.38–7.29 (m, 2 H), 6.63 (s, 1 H) ppm.
13C NMR (75 MHz): δ = 161.2, 154.8, 149.5, 140.1, 138.5, 132.9,
128.5, 127.1, 125.9, 124.5, 123.4, 121.9, 117.5, 116.0, 111.4,
3,3Ј-[1,4-Phenylenebis(azanediyl)]bis[7-(benzyloxy)-4,8-dimethyl-
2H-chromen-2-one] (2k): The reaction mixture was stirred for 0.5 h
at 100 °C. Yellow solid (60%); m.p. 238–240 °C. Rf = 0.44 (CH2Cl2/
c-hexane, 9:1). 1H NMR {300 MHz, [D6]DMSO (dimethyl
sulfoxide)}: δ = 7.54–7.31 (m, 12 H), 7.14 (d, J = 9.1 Hz, 2 H), 7.07
(s, 2 H), 6.54 (s, 4 H), 5.27 (s, 4 H), 2.27 (s, 6 H), 2.18 (s, 6 H) ppm.
107.9 ppm. MS (APCI+): m/z = 263.1 [M + H]+. IR: ν = 2927,
˜
MS (APCI+): m/z = 665.0 [M + H]+. IR: ν = 3360, 2922, 1698,
˜
1724, 1607, 1427, 1256, 1104, 938, 736 cm–1.
1599, 1515, 1454, 1373, 1347, 1326, 1278, 1159, 1120, 843, 805,
766, 739, 698 cm–1.
3-(1H-Benzo[d]imidazol-1-yl)-6-methyl-2H-chromen-2-one (2s): The
reaction mixture was stirred for 3.5 h at 130 °C. Yellow solid (56%);
m.p. 157 °C. Rf = 0.26 (EtOAc/c-hexane, 4:6). 1 H NMR
(300 MHz): δ = 8.26 (br. s, 1 H), 7.94 (d, J = 6.0 Hz, 1 H), 7.49–
7.41 (m, 5 H), 6.56 (s, 1 H), 2.33 (s, 3 H) ppm. 13C NMR (75 MHz):
δ = 160.3, 152.6, 147.2, 143.5, 141.7, 135.1, 134.8, 133.5, 125.0,
124.2, 124.1, 121.0, 117.7, 115.5, 111.9, 111.2, 21.0 ppm. MS
7-Benzyloxy-8-methyl-4-phenyl-3-(3,4,5-trimethoxyphenylamino)-
chromen-2-one (2l): The reaction mixture was stirred for 1 h at
100 °C. Yellow solid (71%); m.p. 162 °C. Rf = 0.61 (EtOAc/c-hex-
1
ane, 4:6). H NMR (300 MHz): δ = 7.45–7.20 (m, 10 H), 7.01 (d,
J = 9.0 Hz, 1 H), 6.78 (d, J = 9.0 Hz, 1 H), 5.89 (s, 2 H), 5.81 (s,
1 H), 5.15 (s, 2 H), 3.70 (s, 9 H), 2.46 (s, 3 H) ppm. 13C NMR
(75 MHz): δ = 160.8, 157.5, 153.0 (2), 149.5, 138.8, 136.8, 134.6,
133.7, 133.4, 129.4 (2), 128.8 (2), 128.7 (3), 128.2, 127.2 (2), 123.9,
123.6, 115.0, 114.7, 108.7, 97.9 (2), 70.7, 61.0 (2), 56.1, 8.7 ppm.
(APCI+): m/z = 277.1 [M + H]+. IR: ν = 2920, 2204, 1979, 1721,
˜
1626, 1573, 1387, 1288, 939, 763, 606 cm–1.
3-(1H-Pyrrolo[2,3-b]pyridin-1-yl)-2H-chromen-2-one (2t): The reac-
MS (APCI+): m/z = 546.3 [M + Na]+. IR: ν = 3331, 1695, 1596,
tion mixture was stirred for 2.5 h at 130 °C. White solid (60%);
˜
1
1503, 1266, 1232, 1124, 731 cm–1.
m.p. 169 °C. Rf = 0.19 (Et2O/c-hexane, 3:7). H NMR (300 MHz):
δ = 8.53 (s, 1 H), 8.35 (dd, J = 4.7 Hz, J = 1.4 Hz, 1 H), 7.80 (dd,
J = 7.8 Hz, J = 1.5 Hz, 1 H), 7.88 (d, J = 3.8 Hz, 1 H), 7.62 (dd,
J = 7.8 Hz, J = 1.5 Hz, 1 H), 7.58–7.49 (m, 1 H), 7.42–7.37 (m, 1
H), 7.33 (td, J = 7.8 Hz, J = 1.1 Hz, 1 H), 7.16 (dd, J = 8.2 Hz, J
= 5.0 Hz, 1 H), 6.63 (d, J = 4 Hz, 1 H) ppm. 13C NMR (75 MHz):
δ = 158.4, 152.2, 148.2, 143.3, 135.3, 131.3, 129.3, 128.9, 128.4,
125.0, 123.4, 121.7, 119.1, 117.5, 116.5, 102.0 ppm. MS (ESI+): m/z
3-(Indolin-1-yl)-2H-chromen-2-one (2m): The reaction mixture was
stirred for 1 h at 130 °C. Yellow solid (99%); m.p. 130 °C. Rf = 0.68
(EtOAc/c-hexane, 3:7). 1H NMR (300 MHz): δ = 7.53 (s, 1 H),
7.42–7.32 (m, 3 H), 7.28–7.19 (m, 2 H), 7.12 (t, J = 8.0 Hz, 1 H),
6.86–6.81 (m, 2 H), 4.09 (t, J = 8.6 Hz, 2 H), 3.17 (t, J = 8.6 Hz,
2 H) ppm. 13C NMR (75 MHz): δ = 158.8, 151.0, 146.5, 131.8,
131.5, 128.9, 126.9, 126.4, 125.3, 124.7, 123.9, 120.4, 120.0, 116.3,
= 285.2 [M + Na]+. IR: ν = 2925, 1724, 1631, 1608, 1520, 1421,
˜
111.3, 53.1, 28.8 ppm. MS (APCI+): m/z = 264.0 [M + H]+. IR: ν
1271, 1070, 908, 747, 718 cm–1.
˜
= 2930, 1726, 1603, 1567, 1483, 1457, 1387, 1249, 1126, 747 cm–1.
3-(1H-Pyrrol-1-yl)-2H-chromen-2-one (2u): The reaction mixture
was stirred for 1 h at 130 °C. Brown solid (56%); m.p. 137 °C. Rf
= 0.52 (CH2Cl2/c-hexane, 3:7). 1H NMR (300 MHz): δ = 7.61 (s, 1
3-(Benzylamino)-2H-chromen-2-one (2n): The reaction mixture was
stirred for 0.5 h at 100 °C. White solid (65%); m.p. 95–97 °C. Rf =
0.21 (CH2Cl2). 1H NMR (300 MHz): δ = 7.59 (d, J = 7.5 Hz, 1 H), H), 7.55–7.50 (m, 2 H), 7.40–7.30 (m, 2 H), 7.25 (m, 2 H), 6.36 (m,
7.43 (s, 1 H), 7.40–7.17 (m, 8 H), 6.89 (br. s, 1 H), 4.61 (m, 2
2 H) ppm. 13C NMR (75 MHz): δ = 157.6, 151.9, 131.1, 129.8,
H) ppm. 13C NMR (75 MHz): δ = 158.8, 154.7, 148.6, 137.8, 128.8
128.9, 127.7, 126.9, 125.1, 121.1, 119.0, 116.5, 110.9 (2) ppm. MS
(2), 128.0 (2), 127.8, 127.6, 126.9, 123.7, 122.8, 111.7, 110.7, (APCI+): m/z = 212.0 [M + H]+. IR: ν = 2915, 2194, 1709, 1626,
˜
43.4 ppm. MS (ESI+): m/z = 274.0 [M + Na]+, 525.0 [2M + Na]+.
1607, 1480, 1342, 1260, 1100, 910, 756, 733, 637 cm–1.
Eur. J. Org. Chem. 2011, 5077–5088
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5083

S. Messaoudi, M. Alami et al.
FULL PAPER
3-(1H-Pyrazol-1-yl)-2H-chromen-2-one (2v): The reaction mixture
was stirred for 2 h at 130 °C. White solid (58%); m.p. 127 °C. Rf =
0.56 (EtOAc/c-hexane, 4:6). H NMR (300 MHz): δ = 8.25 (d, J =
4-[(4-Phenyl-2H-chromen-3-yl)carbamoyl]phenyl 4-Methyl-
benzenesulfonate (5d): The reaction mixture was stirred for 2 h at
100 °C. Yellow solid (97%); m.p. 121 °C. Rf = 0.50 (EtOAc/c-hex-
ane, 3:7). 1H NMR (300 MHz): δ = 7.68 (d, J = 8.5 Hz, 2 H), 7.54–
7.44 (m, 6 H), 7.31 (d, J = 7.0 Hz, 4 H), 7.15–7.09 (m, 1 H), 7.01
1
8.1 Hz, 1 H), 7.93–7.91 (m, 2 H), 7.61 (t, J = 8.1 Hz, 1 H), 7.42 (d,
J = 8.1 Hz, 1 H), 7.33 (t, J = 8.1 Hz, 1 H), 6.60 (m, 1 H), 6.44 (m,
1 H) ppm. 13C NMR (75 MHz): δ = 160.8, 154.6, 149.6, 143.6, (d, J = 8.5 Hz, 2 H), 6.93 (d, J = 8.1 Hz, 1 H), 6.87–6.80 (m, 1 H),
132.9, 130.8, 126.8, 124.6, 117.5, 115.1, 109.1, 107.2 ppm. MS
6.70 (dd, J = 8.1 Hz, J = 1.5 Hz, 1 H), 5.34 (s, 2 H), 2.49 (s, 3
H) ppm. 13C NMR (75 MHz): δ = 164.2, 153.0, 152.3, 145.9, 133.9,
132.2, 130.3 (2), 130.0 (2), 129.6 (2), 128.8 (3), 128.5 (2), 128.3,
126.5, 125.6, 124.3, 122.8 (2), 121.8, 120.8, 115.9, 65.3, 21.8, (1 C
(APCI+): m/z = 213.0 [M + H]+. IR: ν = 3113, 2926, 2172, 1727,
˜
1621, 1438, 1248, 1189, 1038, 753, 615 cm–1.
3-(1H-Indol-1-yl)-1-methylquinolin-2(1H)-one (3a): The reaction
mixture was stirred for 1 h at 130 °C. Orange solid (84%); m.p.
170 °C. Rf = 0.34 (EtOAc/c-hexane, 3:7). 1H NMR (300 MHz): δ
= 7.90 (s, 1 H), 7.71–7.55 (m, 4 H), 7.40–7.37 (m, 2 H), 7.32 (td, J
= 7.5 Hz, J = 1.0 Hz, 1 H), 7.28–7.15 (m, 2 H), 6.71 (m, 1 H), 3.85
(s, 3 H) ppm. 13C NMR (75 MHz): δ = 159.2, 138.7, 136.4, 132.1,
130.6, 129.5, 129.3, 129.0, 128.8, 122.9, 122.3, 121.2, 120.6, 119.7,
114.3, 110.7, 103.7, 30.4 ppm. MS (APCI+): m/z = 275.1
missing) ppm. MS (APCI+): m/z = 498.1 [M + H]+. IR: ν = 2919,
˜
1669, 1600, 1478, 1376, 1244, 1178, 1154, 1092, 1017, 863, 738,
665 cm–1.
N-(4-Phenyl-2H-chromen-3-yl)acetamide (5e): The reaction mixture
was stirred for 5 h at 100 °C. Brown solid (60%); m.p. 123 °C. Rf
1
= 0.30 (EtOAc/c-hexane, 3:7). H NMR (300 MHz): δ = 7.52–7.40
(m, 3 H), 7.28 (d, J = 2.1 Hz, 1 H), 7.09 (td, J = 8.0 Hz, J = 1.5 Hz,
1 H), 6.90 (d, J = 7.5 Hz, 1 H), 6.85–6.73 (m, 2 H), 6.63 (dd, J =
8.1 Hz, J = 1.5 Hz, 1 H), 5.22 (s, 2 H), 1.94 (s, 3 H, NH not
seen) ppm. 13C NMR (75 MHz): δ = 168.8, 152.9, 134.2, 130.3 (2),
129.48 (2), 128.5, 128.1, 126.8, 125.5, 124.5, 121.7, 119.6, 115.8,
[M + H]+. IR: ν = 3838, 2030, 1641, 1625, 1594, 1449, 1013, 778,
˜
649 cm–1.
3-(5-Methoxy-1H-indol-1-yl)-1-methylquinolin-2(1H)-one (3b): The
reaction mixture was stirred for 1 h at 130 °C. Brown solid (98%);
m.p. 104 °C. Rf = 0.23 (EtOAc/c-hexane, 3:7). 1 H NMR
(300 MHz): δ = 7.86 (s, 1 H), 7.66–7.57 (m, 2 H), 7.55 (d, J =
3.1 Hz, 1 H), 7.42 (d, J = 9.0 Hz, 1 H), 7.38–7.23 (m, 2 H), 7.13
(s, 1 H), 6.88 (m, 1 H), 6.62 (d, J = 3.2 Hz, 1 H), 3.87 (s, 3 H),
3.84 (s, 3 H) ppm. 13C NMR (75 MHz): δ = 159.2, 154.7, 138.5,
131.6, 131.4, 130.4, 129.9, 129.6, 128.7, 122.9, 119.8, 114.3, 112.2,
111.6, 103.4, 103.0, 55.9, 30.4, (1 C missing) ppm. MS (APCI+):
65.4, 23.8 ppm. MS (APCI+): m/z = 266.0 [M + H]+. IR: ν = 3279,
˜
2924, 1664, 1576, 1482, 1329, 1042, 757, 702, 631 cm–1.
2-Hydroxy-N-(4-phenyl-2H-chromen-3-yl)propanamide (5f): The re-
action mixture was stirred for 3 h at 100 °C. Brown solid (57%);
m.p. 151 °C. Rf = 0.20 (EtOAc/c-hexane, 3:7). 1 H NMR
(300 MHz): δ = 8.02 (br. s, 1 H), 7.51–7.38 (m, 3 H), 7.28–7.23 (m,
2 H), 7.10 (td, J = 7.7 Hz, J = 1.6 Hz, 1 H), 6.90 (dd, J = 7.7 Hz,
J = 1.1 Hz, 1 H), 6.81 (td, J = 8.0 Hz, J = 1.1 Hz, 1 H), 6.67 (dd,
J = 8.0 Hz, J = 2.0 Hz, 1 H), 5.31 (s, 2 H), 4.20–4.13 (m, 1 H), 1.61
(br. s, 1 H), 1.37 (d, J = 7.7 Hz, 3 H) ppm. 13C NMR (75 MHz): δ
= 172.6, 152.9, 133.9, 130.2 (2), 129.4 (2), 128.5, 128.2, 126.1, 125.5,
125.2, 124.5, 121.7, 115.8, 68.6, 65.1, 21.2 ppm. MS (APCI+): m/z
m/z = 305.1 [M + H]+. IR: ν = 1654, 1601, 1474, 1265, 1244, 1160,
˜
731 cm–1.
4-Methoxy-N-(4-methyl-2H-chromen-3-yl)benzamide (5a): The re-
action mixture was stirred for 1 h at 100 °C. Brown solid (82%);
m.p. 166 °C. Rf = 0.40 (EtOAc/c-hexane, 3:7). 1 H NMR
(300 MHz): δ = 7.81 (d, J = 9.0 Hz, 2 H), 7.52 (s, 1 H), 7.23–7.07
(m, 2 H), 7.02–6.92 (m, 3 H), 6.89 (dd, J = 8.0 Hz, J = 1.0 Hz, 1
H), 5.02 (s, 2 H), 3.86 (s, 3 H), 2.01 (s, 3 H) ppm. 13C NMR
(75 MHz): δ = 165.7, 162.9, 153.1, 129.2 (2), 128.2, 126.0, 125.7,
125.7, 123.6, 121.7, 116.9, 115.9, 114.2 (2), 66.1, 55.6, 12.0 ppm.
= 296.1 [M + H]+. IR: ν = 2922, 2022, 1659, 1504, 1483, 1227,
˜
1122, 1042, 756 cm–1.
4-Methyl-N-(4-phenyl-2H-chromen-3-yl)benzenesulfonamide (5g):
The reaction mixture was stirred for 2 h at 100 °C. Yellow solid
(61%); m.p. 110 °C. Rf = 0.58 (EtOAc/c-hexane, 3:7). 1H NMR
(300 MHz): δ = 7.59 (d, J = 8.0 Hz, 2 H), 7.37–7.24 (m, 5 H), 7.09
(td, J = 8.0 Hz, J = 2.0 Hz, 1 H), 6.90 (dd, J = 8.0 Hz, J = 1.0 Hz,
1 H), 6.75 (td, J = 8.0 Hz, J = 1.0 Hz, 1 H), 6.57 (m, 2 H), 6.45
(dd, J = 8.0 Hz, J = 1.5 Hz, 1 H), 6.10 (s, 1 H), 5.12 (s, 2 H), 2.48
(s, 3 H) ppm. 13C NMR (75 MHz): δ = 152.5, 144.5, 135.7, 132.7,
130.1 (2), 129.7 (2), 129.4 (2), 128.7 (2), 127.5 (2), 125.8, 124.2 (3),
121.7, 115.9, 65.5, 21.8 ppm. MS (APCI–): m/z = 376.1 [M – H]+.
MS (APCI+): m/z = 296.1 [M + H]+. IR: ν = 1732, 1265, 1045,
˜
733 cm–1.
4-Methoxy-N-(4-phenyl-2H-chromen-3-yl)benzamide (5b): The reac-
tion mixture was stirred for 1 h at 100 °C. Yellow solid (95%); m.p.
160 °C. Rf = 0.55 (EtOAc/c-hexane, 3:7). 1H NMR (300 MHz): δ
= 7.53–7.40 (m, 6 H), 7.35–7.32 (m, 2 H), 7.14–7.08 (m, 1 H), 6.94
(m, 1 H), 6.88–6.80 (m, 3 H), 6.71 (m, 1 H), 5.39 (s, 2 H), 3.88 (s,
3 H) ppm. 13C NMR (75 MHz): δ = 165.0, 162.8, 153.0, 134.2,
130.42 (2), 129.5 (2), 129.1 (2), 128.6, 128.0, 127.3, 125.7, 125.5,
124.6, 121.7, 119.6, 115.9, 114.1 (2), 65.5, 55.6 ppm. MS (APCI+):
IR: ν = 3636, 3253, 1597, 1574, 1482, 1456, 1339, 1164, 963, 758,
˜
671 cm–1.
1,3-Bis(4-phenyl-2H-chromen-3-yl)urea (5h): The reaction mixture
was stirred for 12 h at 100 °C. White solid (not stable, 50%); m.p.
m/z = 358.2 [M + H]+. IR: ν = 1605, 1575, 1476, 1247, 1174, 1115,
1
˜
94 °C. Rf = 0.36 (EtOAc/c-hexane, 1:9). H NMR (300 MHz): δ =
1209, 757 cm–1.
7.52 (br. s, 2 H), 7.45–7.30 (m, 6 H), 7.21–7.18 (m, 4 H), 7.12–7.00
(m, 2 H), 6.87 (dd, J = 8.0 Hz, J = 1.0 Hz, 2 H), 6.79 (td, J =
8.0 Hz, J = 1.0 Hz, 2 H), 6.54 (dd, J = 8.0 Hz, J = 1.0 Hz, 2 H),
5.14 (s, 4 H) ppm. 13C NMR (75 MHz): δ = 186.9, 152.2, 134.6,
130.4 (2), 129.0 (2), 127.9, 127.5, 127.2, 125.2, 124.8, 121.4, 117.3,
4-Chloro-N-(4-phenyl-2H-chromen-3-yl)benzamide (5c): The reac-
tion mixture was stirred for 2 h at 100 °C. Yellow solid (86%); m.p.
132 °C. Rf = 0.75 (EtOAc/c-hexane, 3:7). 1H NMR (300 MHz): δ
= 7.54–7.44 (m, 6 H), 7.38–7.31 (m, 4 H), 7.17–7.07 (m, 1 H), 6.94
(dd, J = 8.1 Hz, J = 1.1 Hz, 1 H), 6.84 (td, J = 7.5 Hz, J = 1.1 Hz,
1 H), 6.71 (dd, J = 7.7 Hz, J = 1.1 Hz, 1 H), 5.38 (s, 2 H) ppm.
13C NMR (75 MHz): δ = 164.4, 153.1, 138.7, 134.0, 131.8, 130.3
(2), 129.6 (2), 129.2 (2), 128.8, 128.5 (2), 128.4, 126.7, 125.6, 124.4,
121.8, 120.6, 115.9, 65.4 ppm. MS (APCI+): m/z = 384.1
115.3, 65.4 ppm. MS (APCI–): m/z = 471 [M – H]+. IR: ν = 2989,
˜
1713, 1373, 1324, 1044, 737 cm–1.
N-(4-Phenyl-2H-chromen-3-yl)-2-(4-phenyl-2H-chromen-3-yl-
amino)benzamide (5i): The reaction mixture was stirred for 12 h at
100 °C. Yellow solid (68%); m.p. 117 °C. Rf = 0.40 (EtOAc/c-hex-
ane, 1:9). 1H NMR (300 MHz): δ = 8.63 (s, 1 H), 7.55 (s, 1 H),
7.50–7.35 (m, 6 H), 7.31–7.26 (m, 5 H), 7.13–7.06 (m, 2 H), 7.02
[M + Na]+. IR: ν = 2925, 2197, 1675, 1478, 1243, 1042, 751, 702,
˜
616 cm–1.
5084
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 5077–5088

Palladium-Catalyzed Heterocyclic C–N Coupling
(dd, J = 8.0 Hz, J = 1.4 Hz, 1 H), 6.96–6.89 (m, 2 H), 6.87–6.79
H), 6.94 (d, J = 8.9 Hz, 2 H), 6.79 (s, 1 H), 6.59 (s, 1 H), 3.83 (s,
(m, 3 H), 6.72–6.65 (m, 3 H), 5.21 (s, 2 H), 4.80 (s, 2 H) ppm. 13C 3 H) ppm. 13C NMR (75 MHz): δ = 159.2, 156.9, 148.4, 132.1,
NMR (75 MHz): δ = 166.8, 153.0, 144.6, 135.0, 134.1, 133.1, 130.3
(2), 130.2 (2), 129.5 (2), 129.0 (2), 128.7, 128.2, 128.1, 127.9 (2),
127.2, 126.9, 125.8, 125.6, 125.5, 124.7, 122.0, 121.8, 121.7, 120.4,
119.0, 118.5, 118.1, 115.8, 115.7, 65.7, 65.4, (1 C missing) ppm. MS
131.2, 128.1, 126.3, 124.3 (2), 120.4, 119.3, 119.1, 115.0 (2), 106.0,
55.7 ppm. MS (APCI+): m/z = (for 79Br) 345.2 [M]+, (for 81Br)
347.2 [M]+. IR: ν = 3345, 1709, 1620, 1506, 1234, 1037, 871,
˜
738 cm–1.
(APCI+): m/z = 549.2 [M + H]+. IR: ν = 3340, 2253, 1642, 1622,
˜
8-Bromo-3-[(4-methoxyphenyl)amino]-2H-chromen-2-one (7d): The
reaction mixture was stirred for 4 h at 100 °C. Yellow solid (61%);
m.p. 147 °C. Rf = 0.65 (EtOAc/c-hexane, 3:7). 1 H NMR
(300 MHz): δ = 7.43 (d, J = 2.3 Hz, 1 H), 7.18–7.15 (m, 3 H), 6.98–
6.92 (m, 2 H), 6.70 (s, 1 H), 6.68 (s, 1 H), 3.83 (s, 3 H) ppm. 13C
NMR (75 MHz): δ = 158.6, 157.2, 143.3, 132.2, 131.5, 130.3, 129.1,
124.5 (2), 123.8, 123.7, 115.1 (2), 110.5, 104.6, 55.3 ppm. MS
1501, 1245, 1039, 755 cm–1.
1-(4-Phenyl-2H-chromen-3-yl)azetidin-2-one (5j): The reaction mix-
ture was stirred for 1 h at 130 °C. White solid (90%); m.p. 90 °C.
1
Rf = 0.51 (EtOAc/c-hexane, 3:7). H NMR (300 MHz): δ = 7.46–
7.39 (m, 3 H), 7.29–7.26 (m, 2 H), 7.14–6.99 (m, 1 H), 6.88 (dd, J
= 8 Hz, J = 1.5 Hz, 1 H), 6.78 (td, J = 7.5 Hz, J = 1.5 Hz, 1 H),
6.58 (dd, J = 8.0 Hz, J = 1.5 Hz, 1 H), 5.32 (s, 2 H), 2.81–2.72 (m,
4 H) ppm. 13C NMR (75 MHz): δ = 165.8, 152.2, 134.7, 131.2 (2),
128.5 (2), 128.2, 127.9, 127.0, 125.6, 125.0, 121.7, 116.9, 115.6, 64.4,
(APCI+): m/z = (for 79Br) 380 [M]+, (for 81Br) 382 [M]+. IR: ν =
˜
3345, 1709, 1620, 1506, 1234, 1037, 871, 738 cm–1.
6,8-Dibromo-7-methoxy-3-[(4-methoxyphenyl)amino]-2H-chromen-
2-one (7e): The reaction mixture was stirred for 2 h at 100 °C. Yel-
41.7, 36.7 ppm. MS (APCI+): m/z = 278.2 [M + H]+. IR: ν = 1745,
˜
1485, 1352, 1265, 1145, 1072, 732, 702 cm–1.
1
low solid (73%); m.p. 165 °C. Rf = 0.45 (EtOAc/c-hexane, 3:7). H
1-(4-Phenyl-2H-chromen-3-yl)pyrrolidin-2-one (5k): The reaction
NMR (300 MHz): δ = 7.42 (s, 1 H), 7.15 (d, J = 9.0 Hz, 2 H), 6.95
(d, J = 9.0 Hz, 2 H), 6.70 (s, 1 H), 6.61 (s, 1 H), 3.92 (s, 3 H), 3.84
mixture was stirred for 2 h at 130 °C. Yellow solid (92%); Rf = 0.31
1
(EtOAc/c-hexane, 3:7). H NMR (300 MHz): δ = 7.44–7.35 (m, 3 (s, 3 H) ppm. 13C NMR (75 MHz): δ = 158.8, 157.0, 152.7, 131.8,
H), 7.30–7.22 (m, 2 H), 7.19–7.10 (m, 1 H), 6.92 (dd, J = 8.0 Hz, 131.0, 127.4, 124.4 (2), 119.8, 115.2 (2), 113.5, 106.5, 104.9, 61.2,
J = 1.1 Hz, 1 H), 6.83 (td, J = 7.5 Hz, J = 1.1 Hz, 1 H), 6.75 (dd, 55.3, (1 C missing) ppm. MS (APCI+): m/z = 455.9 [M]+. IR: ν =
˜
J = 8.0 Hz, J = 1.5 Hz, 1 H), 4.94 (s, 2 H), 2.97 (t, J = 7.1 Hz, 2
H), 2.30 (t, J = 8.1 Hz, 2 H), 1.98–1.70 (m, 2 H) ppm. 13C NMR
(75 MHz): δ = 176.4, 153.5, 135.4, 129.9 (2), 129.1, 128.7 (2), 128.3,
126.8, 126.3, 124.3, 121.6, 115.9, 66.8, 48.8, 30.8, 20.0, (1 C miss-
3361, 1712, 1621, 1345, 980 cm–1.
5-Bromo-3-(butylamino)-2H-chromen-2-one (8a): The reaction mix-
ture was stirred for 2 h at 100 °C. Yellow solid (74%); m.p. 75 °C.
Rf = 0.41 (EtOAc/c-hexane, 3:7). 1H NMR (300 MHz): δ = 7.49 (s,
1 H), 7.46–7.43 (m, 2 H), 7.30–7.27 (m, 1 H), 6.58 (br. s, 1 H), 3.49
(q, J = 7.0 Hz, 2 H), 1.67–1.62 (m, 2 H), 1.48–1.41 (m, 2 H), 0.98
(t, J = 7.0 Hz, 3 H) ppm. 13C NMR (75 MHz): δ = 158.4, 154.4,
149.2, 129.5, 127.6, 126.8, 115.8, 110.9, 110.2, 39.3, 31.8, 20.2,
13.9 ppm. MS (APCI+): m/z = (for 79Br) 296.1 [M]+, (for 81Br)
ing) ppm. MS (APCI+): m/z = 292.2 [M + H]+. IR: ν = 2921, 2851,
˜
1680, 1480, 1452, 1401, 1216, 1034, 760, 706, 622 cm–1.
5-Bromo-3-[(4-methoxyphenyl)amino]-2H-chromen-2-one (7a): The
reaction mixture was stirred for 2 h at 100 °C. Yellow solid (74%);
m.p. 154 °C. Rf = 0.54 (EtOAc/c-hexane, 3:7). 1 H NMR
(300 MHz): δ = 7.45 (d, J = 8.0 Hz, 1 H), 7.27–7.20 (m, 4 H), 7.10
(t, J = 8.0 Hz, 1 H), 6.97 (d, J = 8.8 Hz, 2 H), 6.72 (s, 1 H), 3.84
(s, 3 H) ppm. 13C NMR (75 MHz): δ = 159.3, 156.8, 148.5, 132.0,
131.5, 128.8, 126.5, 123.6 (2), 121.5, 119.3, 115.6, 115.1 (2), 105.4,
55.6 ppm. MS (APCI+): m/z = (for 79Br ) 346.1 [M + H]+, (for
298.1 [M]+. IR: ν = 2957, 1648, 1522, 1278, 912 cm–1.
˜
3-Bromo-5-(butylamino)-2H-chromen-2-one (8aa): The reaction
mixture was stirred for 2 h at 100 °C. Yellow solid (21 %); m.p.
1
87.2 °C. Rf = 0.80 (EtOAc/c-hexane, 3:7). H NMR (300 MHz): δ
= 7.44 (d, J = 8.0 Hz, 1 H), 7.22 (d, J = 8.0 Hz, 1 H), 7.05 (t, J =
8.0 Hz, 1 H), 6.57 (s, 1 H), 5.02 (br. s, 1 H), 3.22–3.15 (m, 2 H),
1.75–1.66 (m, 2 H), 1.52–1.43 (m, 2 H), 1.0 (t, J = 7 Hz, 3 H) ppm.
13C NMR (75 MHz): δ = 148.0, 134.5, 128.7, 125.6, 122.1, 118.9,
115.6, 102.8, 43.0, 30.6, 20.1, 13.9, (1 C missing) ppm. MS
81Br) 348.0 [M + H]+. IR: ν = 1737, 1373, 1234, 1044 cm–1.
˜
3,5-Bis[(4-methoxyphenyl)amino]-2H-chromen-2-one (7aa): Yellow
solid (20 %); m.p. 188 °C. Rf = 0.37 (EtOAc/c-hexane, 3:7). 1H
NMR (300 MHz): δ = 7.12 (t, J = 8.0 Hz, 1 H), 7.03–6.82 (m, 11
H), 6.54 (s, 1 H), 5.42 (s, 1 H), 3.80 (s, 6 H) ppm. 13C NMR (APCI+): m/z = (for 79Br) 296.1 [M]+, (for 81Br) 298.1 [M]+. IR: ν
˜
(75 MHz): δ = 159.9, 156.4, 155.4, 149.7, 139.9, 137.0, 132.6, 129.5,
= 3368, 1711, 1611, 1179, 944 cm–1.
126.8, 123.3 (2), 121.5 (2), 115.0 (2), 114.9 (2), 114.3, 112.9, 109.7,
6-Bromo-3-(butylamino)-2H-chromen-2-one (8b): The reaction mix-
ture was stirred for 1.5 h at 100 °C. Yellow solid (66%); m.p. 80 °C.
Rf = 0.43 (EtOAc/c-hexane, 3:7). 1H NMR (300 MHz): δ = 7.79 (s,
1 H), 7.49 (d, J = 8.6 Hz, 1 H), 7.38–7.34 (m, 2 H), 6.62 (br. s, 1
H), 3.48 (q, J = 6.3 Hz, 2 H), 1.67–1.58 (m, 2 H), 1.49–1.37 (m, 2
H), 0.96–0.94 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR (75 MHz): δ =
103.1, 55.7, 55.6 ppm. MS (APCI+): m/z = 389.2 [M + H]+. IR: ν
˜
= 3355, 1677, 1509, 1036 cm–1.
6-Bromo-3-[(4-methoxyphenyl)amino]-2H-chromen-2-one (7b): The
reaction mixture was stirred for 2 h at 100 °C. Yellow solid (88%);
m.p. 132 °C. Rf = 0.61 (EtOAc/c-hexane, 3:7). 1 H NMR
(300 MHz): δ = 7.38 (d, J = 1.8 Hz, 1 H), 7.31 (dd, J = 8.7 Hz, J 158.4, 153.4, 150.1, 129.8, 129.7, 125.3, 116.8, 113.3, 109.5, 39.3,
= 1.8 Hz, 1 H), 7.17–7.13 (m, 3 H), 6.95 (d, J = 8.7 Hz, 2 H), 6.73
(s, 1 H); 6.64 (s, 1 H), 3.83 (s, 3 H) ppm. 13C NMR (75 MHz): δ =
165.4, 157.0, 147.1, 131.9, 131.7, 129.0, 127.6, 124.3 (2), 123.2,
117.8, 117.6, 115.1 (2), 105.2, 55.7 ppm. MS (APCI+): m/z = (for
31.7, 20.2, 13.7 ppm. MS (APCI+): m/z = (for 79Br) 296
[M + H]+, (for 81Br) 298 [M + H]+. IR: ν = 2958, 1733, 1645, 1563,
˜
1312, 1186, 1049, 961, 797, 699 cm–1.
7-Bromo-3-(butylamino)-2H-chromen-2-one (8c): The reaction mix-
ture was stirred for 1.5 h at 100 °C. Yellow solid (66%); m.p. 90 °C.
Rf = 0.40 (EtOAc/c-hexane, 3:7). 1H NMR (300 MHz): δ = 7.66 (s,
79Br) 346 [M + H]+, (for 81Br) 348 [M + H]+. IR: ν = 3340, 1705,
˜
1619, 1509, 1237, 1205, 828 cm–1.
7-Bromo-3-[(4-methoxyphenyl)amino]-2H-chromen-2-one (7c): The 1 H), 7.52 (dd, J = 8.3 Hz, J = 0.9 Hz, 1 H), 7.42–7.39 (m, 2 H),
reaction mixture was stirred for 4 h at 100 °C. Brown solid (99%);
6.61 (br. s, 1 H), 3.48 (q, J = 6.1 Hz, 2 H), 1.68–1.58 (m, 2 H),
m.p. 138 °C. Rf = 0.57 (EtOAc/c-hexane, 3:7). 1 H NMR
1.49–1.37 (m, 2 H), 0.96–0.94 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR
(300 MHz): δ = 7.43 (d, J = 1.7 Hz, 1 H), 7.30 (dd, J = 8.3 Hz, J (75 MHz): δ = 158.5, 154.9, 149.8, 127.4, 126.8, 123.7, 120.2, 115.2,
= 1.8 Hz, 1 H), 7.16 (d, J = 8.9 Hz, 2 H), 7.11 (d, J = 8.3 Hz, 1 110.1, 39.3, 31.8, 20.2, 13.9 ppm. MS (APCI+): m/z = (for 79Br)
Eur. J. Org. Chem. 2011, 5077–5088
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5085

S. Messaoudi, M. Alami et al.
FULL PAPER
296 [M + H]+, (for 81Br) 298 [M + H]+. IR: ν = 2957, 1643, 1599, 5-(4-Methoxyphenyl)-3-[(4-methoxyphenyl)amino]-2H-chromen-2-
˜
1533, 1454, 1288, 1048, 846, 737 cm–1.
one (11a): The reaction mixture was stirred for 3 h at 100 °C. Yel-
low solid (90%); m.p. 207.7 °C. Rf = 0.56 (EtOAc/c-hexane, 3:7).
1H NMR (300 MHz, [D6]DMSO): δ = 8.10 (s, 1 H), 7.38–7.33 (m,
4 H), 7.21–7.19 (m, 3 H), 7.05 (d, J = 8.5 Hz, 2 H), 6.98 (s, 1 H),
6.90 (d, J = 8.5 Hz, 2 H), 3.79 (s, 3 H), 3.71 (s, 3 H) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 158.8, 158.2, 155.2, 148.5, 137.2,
132.7, 130.6 (2), 130.0, 126.0, 125.5, 123.0 (2), 118.5, 114.4, 114.3
(2), 114.0 (2), 105.0, 54.90 (2), (1 C missing) ppm. MS (APCI+):
8-Bromo-3-(butylamino)-6-chloro-2H-chromen-2-one (8d): The reac-
tion mixture was stirred for 2 h at 100 °C. Orange solid (76%); m.p.
1
98 °C. Rf = 0.50 (EtOAc/c-hexane, 3:7). H NMR (300 MHz): δ =
7.60 (d, J = 2.5 Hz, 1 H), 7.57 (d, J = 2.5 Hz, 1 H), 7.45 (s, 1 H),
6.68 (br. s, 1 H), 3.53–3.46 (q, J = 6.2 Hz, 2 H), 1.70–1.60 (m, 2
H), 1.50–1.38 (m, 2 H), 0.98 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR
(75 MHz): δ = 158.0, 150.8, 150.6, 129.7, 129.6, 129.4, 121.5, 110.5,
104.8, 39.4, 31.7, 20.3, 13.5 ppm. MS (APCI+): m/z = (for 79Br)
m/z = 374 [M + H]+. IR: ν = 1711, 1617, 1508, 1235 cm–1.
˜
330 [M + H]+, (for 81Br) 332 [M + H]+. IR: ν = 2927, 1659, 1583,
7-(4-Methoxyphenyl)-3-[(4-methoxyphenyl)amino]-2H-chromen-2-
one (11b): The reaction mixture was stirred for 3 h at 100 °C. Yel-
low solid (90%); m.p. 155.3 °C. Rf = 0.54 (EtOAc/c-hexane, 3:7).
1H NMR (300 MHz): δ = 7.53 (d, J = 8.5 Hz, 2 H), 7.46 (s, 1 H),
7.40 (d, J = 8.5 Hz, 1 H), 7.28 (d, J = 8.5 Hz, 1 H), 7.17 (d, J =
8.5 Hz, 2 H), 7.00–6.91 (m, 4 H), 6.81 (s, 1 H), 6.60 (br. s, 1 H),
3.85 (s, 3 H), 3.83 (s, 3 H) ppm. 13C NMR (75 MHz): δ = 160.1,
159.6, 156.6, 148.8, 139.3, 132.6, 132.3, 130.5, 128.1 (2), 125.7,
123.9 (2), 123.3, 119.8, 115.0 (2), 114.5 (2), 113.8, 107.0, 55.48
˜
1178, 732 cm–1.
6,8-Dibromo-3-(butylamino)-7-methoxy-2H-chromen-2-one (8e):
The reaction mixture was stirred for 2 h at 100 °C. Brown oil
1
(82%); Rf = 0.39 (EtOAc/c-hexane, 3:7). H NMR (300 MHz): δ =
7.80 (s, 1 H), 7.42 (s, 1 H), 6.65 (br. s, 1 H), 3.90 (s, 3 H), 3.50 (q,
J = 6.1 Hz, 2 H), 1.7–1.60 (m, 2 H), 1.49–1.37 (m, 2 H), 0.98 (t, J
= 7.0 Hz, 3 H) ppm. 13C NMR (75 MHz): δ = 158.0, 153.2, 152.3,
150.8, 125.6, 125.0, 114.1, 110.1, 100.1, 61.4, 39.4, 31.8, 20.2,
13.9 ppm. MS (APCI+): m/z = (for 81Br79Br) 406.2 [M + H]+. IR:
(2) ppm. MS (APCI+): m/z = 374.1 [M + H]+. IR: ν = 3328, 1701,
˜
1520, 1267 cm–1.
ν = 1695, 1590, 1402, 1167, 1051 cm–1.
˜
6-Chloro-8-(4-methoxyphenyl)-3-morpholino-2H-chromen-2-one
(11c): The reaction mixture was stirred for 3 h at 100 °C. White
solid (99%); m.p. 135.3 °C. Rf = 0.20 (EtOAc/c-hexane, 3:7). 1H
NMR (300 MHz): δ = 7.73 (d, J = 8.9 Hz, 2 H), 7.55 (d, J = 2.0 Hz,
1 H), 7.49 (d, J = 2.0 Hz, 1 H), 7.35 (s, 1 H), 7.02 (d, J = 8.9 Hz,
2 H), 3.88 (3 H), 3.86–3.71 (m, 8 H) ppm. 13C NMR (75 MHz): δ
= 162.9, 160.1, 159.3, 150.3, 150.2, 129.9, 129.7 (2), 128.7, 127.0,
125.8, 120.1, 114.4 (2), 112.3, 67.1 (4), 55.2 ppm. MS (APCI+): m/z
8-Bromo-6-chloro-3-morpholino-2H-chromen-2-one (9): The reac-
tion mixture was stirred for 2 h at 100 °C. White solid (79%); m.p.
124 °C. Rf = 0.23 (EtOAc/c-hexane, 3:7). 1H NMR (300 MHz): δ
= 7.60–7.53 (m, 2 H), 7.35 (s, 1 H), 3.99–3.75 (m, 8 H) ppm. 13C
NMR (75 MHz): δ = 158.5, 150.9, 150.5, 129.9, 129.3, 128.7, 121.0,
112.7, 104.9, 66.9 (4) ppm. MS (APCI+): m/z = (for 79Br) 344.0 [M
+ H]+, (for 81Br) 346.0 [M + H]+. IR: ν = 3083, 1636, 1613, 1426,
˜
= 372.1 [M + H]+. IR: ν = 1629, 1516, 1426, 1248 cm–1.
1275, 1171, 1023, 852, 731 cm–1.
˜
3-[(4-Methoxyphenyl)amino]-5-[(3,4,5-trimethoxyphenyl)amino]-2H-
chromen-2-one (11d): Compound 11d was prepared just as com-
pounds 7, using 3,4,5-trimethoxyaniline (2 equiv.), Pd(OAc)2
(10 mol-%), Xantphos (10 mol-%), and Cs2CO3 (1.5 equiv.) in diox-
ane at 100 °C for 2 h. Yellow solid (60%); m.p. 176.6 °C. Rf = 0.25
(EtOAc/c-hexane, 3:7). 1H NMR (300 MHz): δ = 7.17 (t, J =
8.1 Hz, 1 H) 7.03–6.94 (m, 5 H), 6.84 (d, J = 8.8 Hz, 2 H), 6.55 (s,
1 H), 6.14 (s, 2 H), 5.33 (br. s, 1 H), 3.82 (s, 3 H), 3.78 (s, 3 H),
3.75 (s, 6 H) ppm. 13C NMR (75 MHz): δ = 159.7, 156.4, 154.0 (2),
149.5, 140.6, 138.5, 132.8, 132.3, 129.6, 126.6, 123.4 (2), 116.5,
114.9, 114.5, 110.8, 102.9, 96.0 (2), 61.2, 56.2, 55.6 ppm. MS
N-(5-Bromo-2-oxo-2H-chromen-3-yl)-4-methoxybenzamide (10a):
The reaction mixture was stirred for 2 h at 100 °C. White solid
(41%); m.p. 209 °C. Rf = 0.34 (EtOAc/c-hexane, 3:7). 1H NMR
(300 Mz): δ = 9.18 (s, 1 H), 8.79 (s, 1 H), 7.91 (d, J = 8.8 Hz, 2 H),
7.56 (m, 1 H), 7.32–7.28 (m, 2 H), 7.1 (d, J = 8.8 Hz, 2 H), 3.89
(s, 3 H) ppm. 13C NMR (75 Mz): δ = 165.5, 163.2, 158.7, 150.4,
129.9, 129.4, 129.35 (2 C), 125.7, 125.5, 122.1, 121.7, 120.4, 116.0,
114.4 (2 C), 55.7 ppm. MS (APCI+): m/z = (for 79Br) 373.9 [M]+,
(for 81Br) 375.8 [M]+. IR: ν = 1717, 1605, 1503, 1253, 771 cm–1.
˜
N-(6-Bromo-2-oxo-2H-chromen-3-yl)-4-methoxybenzamide (10b):
The reaction mixture was stirred for 2 h at 100 °C. Yellow solid
(78%); m.p. 187 °C. Rf = 0.51 (EtOAc/c-hexane: 3:7). 1H NMR
(300 Mz): δ = 8.76 (s, 1 H), 8.74 (s, 1 H), 7.88 (d, J = 8.9 Hz, 2 H),
7.66 (d, J = 2.2 Hz, 1 H), 7.53 (m, 1 H), 7.22 (d, J = 8.8 Hz, 1 H),
6.99 (d, J = 8.9 Hz, 2 H), 3.88 (s, 3 H) ppm. 13C NMR (75 Mz): δ
= 165.7, 163.3, 158.7, 148.7, 132.4, 130.1, 129.3 (2 C), 125.6,
125.30, 121.9, 121.40, 118.2, 118.1, 114.3 (2 C), 55.7 ppm. MS
(APCI–): m/z = (for 7 9 Br) 372 [M – H]+ , (for 8 1 Br) 374
(APCI+): m/z = 449 [M + H]+. IR: ν = 3317, 1696, 1502,
˜
1132 cm–1.
Synthesis of 11e: A flame-dried, resealable Schlenk tube was
charged with Cu powder (10 mol-%), ascorbic acid (20 mol-%), pi-
pecolinic acid (30 mol-%), sodium azide (2 equiv.), and 7a
(0.10 mmol). The Schlenk tube was capped with a rubber septum
and then evacuated and backfilled with argon. EtOH (2 mL) was
added through the septum that was then replaced with a Teflon®
screw cap. The Schlenk tube was sealed, and the mixture was stirred
at 100 °C. The resulting suspension was cooled to room tempera-
ture and filtered through Celite, eluting with ethyl acetate. The fil-
trate was concentrated, and purification of the residue by silica gel
column chromatography gave the desired product 11e.
[M – H]+. IR: ν = 2921, 1718, 1670, 1603, 1504, 1340, 1247, 1178,
˜
1024, 756 cm–1.
General Procedure for Suzuki Coupling Reactions: To a mixture of
bromocoumarin 7a–c, 9 (1 mmol) in toluene (4 mL) and EtOH
(2 mL) was successively added the desired boronic acid (1.2 mmol),
K2CO3 (2 mmol), and Pd(PPh3)4 (0.05 mmol). The reaction was
heated at 100 °C with vigorous stirring and monitored by TLC un-
til the starting material completely disappeared. The solvent was
evaporated in vacuo, and water (10 mL) was added. After extrac-
tion with CH2Cl2 (3ϫ10 mL), the combined organic layers were
dried with MgSO4, and the solvent was removed under reduced
pressure. The crude material was purified by column chromatog-
raphy to afford the expected compounds 11a–c.
5-Amino-3-(4-methoxyphenylamino)chromen-2-one (11e): Yellow oil
(45%); Rf = 0.4 (EtOAc/c-hexane, 3:7). 1H NMR (300 Mz, [D6]-
DMSO): δ = 7.73 (s, 1 H), 7.32–7.26 (m, 3 H), 7.0 (t, J = 8.1 Hz,
1 H), 6.93 (d, J = 9.0 Hz, 2 H), 6.50 (d, J1 = 7.9 Hz, 2 H), 5.66 (s,
2 H), 3.74 (s, 1 H) ppm. 13C NMR (75 Mz, [D6]DMSO): δ = 158.9,
154.5, 149.4, 144.5, 133.9, 127.3, 127.1, 121.7 (2 C), 114.5 (2 C),
109.5, 107.2, 106.0, 103.2, 55.2 ppm. MS (APCI+): m/z = 283 [M
+ H]+. IR: ν = 3331, 1701, 1461, 1234, 1025 cm–1.
˜
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Eur. J. Org. Chem. 2011, 5077–5088

Palladium-Catalyzed Heterocyclic C–N Coupling
HSP90inCancerTreatmentID20086.html; c) Y. L. Janin, Drug
Discov. Today 2010, 15, 342–353.
Synthesis of 11f: To a solution of N-tosylhydrazone (1.2 mmol),
tBuOLi (3 mmol), Pd2(dba)2 (0.12 mmol), and XPhos (0.24 mmol)
in dioxane (6 mL) was added 7b (0.5 mmol) in dioxane (2 mL). The
reaction vessel was sealed and then heated at 80 °C for 3 h. The
resulting suspension was cooled to room temperature and filtered
through a pad of Celite, eluting with EtOAc, to remove the inor-
ganic salts. The filtrate was concentrated, and purification of the
residue by silica gel column chromatography gave 11f.
[8]
[9]
a) C. Radanyi, G. Le Bras, V. Marsaud, J.-F. Peyrat, S. Messa-
oudi, M. G. Catelli, J.-D. Brion, M. Alami, J.-M. Renoir, Can-
cer Lett. 2009, 274, 88–94; b) C. Radanyi, G. Le Bras, C. Boucl-
ier, S. Messaoudi, J.-F. Peyrat, J.-D. Brion, M. Alami, J.-M.
Renoir, Biochem. Biophys. Res. Commun. 2009, 379, 514–518;
c) D. Audisio, S. Messaoudi, I. Ijjaali, E. Dubus, F. Petitet, J.-
F. Peyrat, J.-D. Brion, M. Alami, Eur. J. Med. Chem. 2010, 45,
2000–2009.
a) A. A. Kudale, J. Kendall, C. Warford, N. D. Wilkins, G. J.
Bodwell, Tetrahedron Lett. 2007, 48, 5077–5080; b) H. W. Lee,
J. B. Ahn, J. H. Lee, S. K. Kang, S. K. Ahn, S. J. Lee, Heterocy-
cles 2005, 65, 1843–1856; c) S. Lee, K. Sivakumar, W. S. Shin,
F. Xiea, Q. Wang, Bioorg. Med. Chem. Lett. 2006, 16, 4596–
4599; d) K. Sivakumar, F. Xie, B. M. Cash, S. Long, H. N.
Barnhill, Q. Wang, Org. Lett. 2004, 6, 4603–4606; e) A. R. Das,
A. Medda, R. Singha, Tetrahedron Lett. 2010, 51, 1099–1102.
D. W. Gammon, R. Hunter, S. A. Wilson, Tetrahedron 2005,
61, 10683–10688.
S. Messaoudi, J.-D. Brion, M. Alami, Adv. Synth. Catal. 2010,
352, 1677–1687.
L. Santana, E. Uriarte, H. Gonzalez-Diaz, G. Zagotto, R.
Soto-Otero, E. Mendez-Alvarez, J. Med. Chem. 2006, 49, 1149–
1156.
a) W. Wang, Q. Ding, R. Fan, J. Wu, Tetrahedron Lett. 2007,
48, 3647–3649; b) L. Zhang, T. Meng, R. Fan, J. Wu, J. Org.
Chem. 2007, 72, 7279–7286.
3-[(4-Methoxyphenyl)amino]-6-[1-(4-methoxyphenyl)vinyl]-2H-
chromen-2-one (11f): Yellow oil (55%); Rf = 0.58 (EtOAc/c-hexane,
1
3:7). H NMR (300 MHz): δ = 7.30–7.00 (m, 6 H), 6.90–6.81 (m,
6 H), 6.61 (br. s, 1 H), 5.32–5.27 (m, 2 H), 3.84 (s, 6 H) ppm. 13C
NMR (75 MHz): δ = 159.9, 159.6, 156.7, 148.6, 147.9, 138.7, 133.8,
132.3, 131.1, 129.5 (2), 126.7, 125.1, 124.1 (2), 121.0, 116.0, 115.0
(2), 113.7 (2), 113.4, 107.1, 55.3 (2) ppm. MS (APCI+): m/z = 400
[M + H]+. IR: ν = 3335, 1705, 1425, 1027 cm–1.
˜
[10]
[11]
[12]
Acknowledgments
The Centre National de la Recherche Scientifique (CNRS) is grate-
fully acknowledged for financial support of this research. We wish
to thank also l’Association pour la Recherche sur le Cancer (ARC)
for the doctoral position to M. A. S. and the European Union (EU)
within the EST network BIOMED-CHEM (MEST-CT-2005–
020580) for the Ph.D. grant to D. A. and for its financial support.
Région Ile-de-France is also acknowledged for its support.
[13]
[14]
[15]
[16]
D. Audisio, S. Messaoudi, J.-F. Peyrat, J.-D. Brion, M. Alami,
Tetrahedron Lett. 2007, 48, 6928–6932.
S. Messaoudi, D. Audisio, J.-D. Brion, M. Alami, Tetrahedron
2007, 63, 10202–10210.
a) D. Audisio, S. Messaoudi, L. Cegielkowski, J.-F. Peyrat, J.-D.
Brion, D. Methy-Gonnot, C. Radanyi, J.-M. Renoir, M. Alami,
ChemMedChem 2011, 6, 804–815; b) M. Alami, J.-D. Brion, O.
Provot, J.-F. Peyrat, S. Messaoudi, A. Hamze, A. Giraud, J.
Bignon, J. Bakala, J.-M. Liu, WO 122620 A1, 2008; c) S. Mes-
saoudi, B. Tréguier, A. Hamze, O. Provot, J.-F. Peyrat, J. R.
Rodrigo De Losada, J.-M. Liu, J. Bignon, J. Wdzieczak-Bakala,
S. Thoret, J. Dubois, J.-D. Brion, M. Alami, J. Med. Chem.
2009, 52, 4538–4542; d) A. Hamze, A. Giraud, S. Messaoudi,
O. Provot, J.-F. Peyrat, J. Bignon, J.-M. Liu, J. Wdzieczak-Bak-
ala, S. Thoret, J. Dubois, J.-D. Brion, M. Alami, ChemMed-
Chem 2009, 4, 1912–1924; e) S. Messaoudi, A. Hamze, O. Pro-
vot, B. Tréguier, J. R. Rodrigo De Losada, J. Bignon, J.-M. Liu,
J. Wdzieczak-Bakala, S. Thoret, J. Dubois, J.-D. Brion, M. Al-
ami, ChemMedChem 2011, 6, 488–497; f) E. Rasolofonjatovo,
O. Provot, A. Hamze, J. Bignon, S. Thoret, J.-D. Brion, M.
Alami, Eur. J. Med. Chem. 2010, 45, 3617–3626; g) C. Mousset,
A. Giraud, O. Provot, A. Hamze, J. Bignon, J.-M. Liu, S. Tho-
ret, J. Dubois, J.-D. Brion, M. Alami, Bioorg. Med. Chem. Lett.
2008, 18, 3266–3271; h) A. Giraud, O. Provot, A. Hamze, J.-
D. Brion, M. Alami, Tetrahedron Lett. 2008, 49, 1107–1110;
i) O. Provot, A. Giraud, J.-F. Peyrat, M. Alami, J.-D. Brion,
Tetrahedron Lett. 2005, 46, 8547–8550.
a) S. Sahnoun, S. Messaoudi, J.-F. Peyrat, J.-D. Brion, M. Al-
ami, Tetrahedron Lett. 2008, 49, 7279–7283; b) S. Sahnoun, S.
Messaoudi, J.-D. Brion, M. Alami, Org. Biomol. Chem. 2009,
7, 4271–4278; c) S. Sahnoun, S. Messaoudi, J.-D. Brion, M.
Alami, Eur. J. Org. Chem. 2010, 6097–6102; d) S. Sahnoun, S.
Messaoudi, J.-D. Brion, M. Alami, ChemCatChem 2011, 3,
893–897; e) S. Messaoudi, J.-D. Brion, M. Alami, Eur. J. Org.
Chem. 2010, 6495–6516; f) C. Mousset, O. Provot, A. Hamze,
J. Bignon, J.-D. Brion, M. Alami, Tetrahedron 2008, 64, 4287–
4294; g) M. Jacubert, A. Tikad, O. Provot, A. Hamze, J.-D.
Brion, M. Alami, Eur. J. Org. Chem. 2010, 4492–4500.
D. Audisio, S. Messaoudi, J.-D. Brion, M. Alami, Eur. J. Org.
Chem. 2010, 1046–1051.
[1] a) R. O’Kennedy, R. D. Thornes, Coumarins: Biology, Applica-
tions, and Mode of Action, Wiley, Chichester, 1997; b) For re-
views, see: D. L. Yu, M. Suzuki, L. Xie, S. L. Morris-Natschke,
K. H. Lee, Med. Res. Rev. 2003, 23, 322–345; c) K. C. Fylak-
takidou, D. J. Hadjipavlou-Litina, K. E. Litines, D. N. Nico-
laides, Curr. Pharm. Des. 2004, 10, 3813–3833; d) F. Borges, F.
Roleira, N. Mihazes, L. Santana, E. Uriarte, Curr. Med. Chem.
2005, 12, 887–916; e) M. V. Kulkarni, G. M. Kulkarni, C.-H.
Lin, C.-M. Sun, Curr. Med. Chem. 2006, 13, 2795–2818; f) L.
Wu, X. Wang, W. Xu, F. Farzaneh, R. Xu, Curr. Med. Chem.
2009, 16, 4236–4260.
[2] a) A. Kumar, M. Verma, A. K. Saxena, K. Shanker, Indian J.
Chem. B 1987, 26, 378; b) L. Santana, E. Uriarte, H. Gonzalez-
Diaz, G. Zagotto, R. Soto-Otero, E. Mendez-Alvarez, J. Med.
Chem. 2006, 49, 1149–1156.
[3] a) M. Gellert, M. H. O’Dea, T. Itoh, J. I. Tomizawa, Proc. Natl.
Acad. Sci. USA 1976, 73, 4474–4478; b) T. Yamaguchi, T. Fu-
kuda, F. Ishibashi, M. Iwao, Tetrahedron Lett. 2006, 47, 3755–
3757, and references cited therein.
[4] D. T. Connor, U. S. Patent, 126, 1981 [Chem. Abstr. 1981, 287,
4].
[5] a) M. G. Marcu, A. Chadli, I. Bouhouche, M. Catelli, L. M.
Neckers, J. Biol. Chem. 2000, 275, 37181–37186; b) M. G.
Marcu, T. W. Schulte, L. Neckers, J. Natl. Cancer Inst. 2000,
92, 242–248; c) M. A. Ferrar, J. Alberola-Ila, R. M. Perlmutter,
Nature 1996, 383, 178–181; d) J. A. Burlison, L. Neckers, A. B.
Smith, A. Maxwell, B. S. J. Blagg, J. Am. Chem. Soc. 2006, 128,
15529–15536.
[6] a) G. Le Bras, C. Radanyi, J.-F. Peyrat, J.-D. Brion, M. Alami,
V. Marsaud, B. Stella, J.-M. Renoir, J. Med. Chem. 2007, 50,
6189–6200; b) C. Radanyi, G. Le Bras, S. Messaoudi, C. Boucl-
ier, J.-F. Peyrat, J.-D. Brion, V. Marsaud, J.-M. Renoir, M. Al-
ami, Bioorg. Med. Chem. Lett. 2008, 18, 2495–2498.
[7] a) S. Messaoudi, J.-F. Peyrat, J.-D. Brion, M. Alami, Anti-Can-
cer Agents Med. Chem. 2008, 8, 761–782; b) J.-F. Peyrat,
S. Messaoudi, J.-D. Brion, M. Alami, Atlas Genet Cytogenet
[17]
[18]
[19]
D. Audisio, S. Messaoudi, J.-F. Peyrat, J.-D. Brion, M. Alami,
J. Org. Chem. 2011, 76, 4995–5005.
Oncol
Haematol.
http://atlasgeneticsoncology.org/Deep/
Eur. J. Org. Chem. 2011, 5077–5088
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5087

S. Messaoudi, M. Alami et al.
FULL PAPER
[20] D. Maiti, S. L. Buchwald, J. Am. Chem. Soc. 2009, 131, 17423–
17429.
[21] S. A. Worlikar, T. Kesharwani, T. Yao, R. C. Larock, J. Org.
Chem. 2007, 72, 1347–1353.
[22] a) A. F. Littke, G. C. Fu, Angew. Chem. 2002, 114, 4350–4386;
Angew. Chem. Int. Ed. 2002, 41, 4176–4211; b) E. Brachet, A.
Hamze, J.-F. Peyrat, J.-D. Brion, M. Alami, Org. Lett. 2010,
12, 4042–4045.
[23] A. Tikad, A. Hamze, O. Provot, J.-D. Brion, M. Alami, Eur. J.
Org. Chem. 2010, 725–731.
[24]
a) J. Barluenga, P. Moriel, C. Valdes, F. Aznar, Angew. Chem.
2007, 119, 5683–5686; Angew. Chem. Int. Ed. 2007, 46, 5587–
5590; b) J. Barluenga, M. Escribano, F. Aznar, C. Valdes, An-
gew. Chem. 2010, 122, 7008–7011; Angew. Chem. Int. Ed. 2010,
49, 6856–6859; c) J. Barluenga, L. Florentino, F. Aznar, C.
Valdes, Org. Lett. 2011, 13, 510–513.
Received: April 5, 2011
Published Online: July 21, 2011
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Eur. J. Org. Chem. 2011, 5077–5088