A convenient and expeditious synthesis of 3-(N-substituted) aminocoumarins via palladium-catalyzed Buchwald-Hartwig coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2007.07.166

A convenient protocol for the rapid and efficient synthesis of 3-(N-substituted) aminocoumarins is described. The synthetic route developed involves the Pd-catalyzed C-N coupling reaction from readily available 3-bromocoumarin derivatives in the presence of the catalytic system Pd(OAc)₂/Xantphos. Under these conditions, a series of nucleophiles including amides, sulfonamides, carbamates and functionalized amines, have been successfully reacted to afford the coupling products in fair to good yields.

Full text of DOI:10.1016/j.tetlet.2007.07.166

Tetrahedron Letters 48 (2007) 6928–6932
A convenient and expeditious synthesis of 3-(N-substituted)
aminocoumarins via palladium-catalyzed
Buchwald–Hartwig coupling reaction
Davide Audisio, Samir Messaoudi, Jean-Franc¸ois Peyrat,
Jean-Daniel Brion and Mouaˆd Alami*
Univ Paris-Sud XI, CNRS, BioCIS UMR 8076, Laboratoire de Chimie The´rapeutique, Faculte´ de Pharmacie, rue J.B. Cle´ment,
ˆ
F-92296 Chatenay-Malabry, France
Received 18 June 2007; revised 16 July 2007; accepted 25 July 2007
Available online 28 July 2007
Abstract—A convenient protocol for the rapid and efficient synthesis of 3-(N-substituted) aminocoumarins is described. The syn-
thetic route developed involves the Pd-catalyzed C–N coupling reaction from readily available 3-bromocoumarin derivatives in
the presence of the catalytic system Pd(OAc)2/Xantphos. Under these conditions, a series of nucleophiles including amides, sulfon-
amides, carbamates and functionalized amines, have been successfully reacted to afford the coupling products in fair to good yields.
Ó 2007 Elsevier Ltd. All rights reserved.
The diverse biological activities of natural and synthetic
coumarins as anticoagulants and antithrombotics are
well known.1 Some of the coumarin derivatives are re-
ported as anti-HIV agents2 and antioxidants.3 They
have also been found to possess vasorelaxant,4 anti-
inflammatory5 antitumoral activity6 and many couma-
rin derivatives are known as free radical scavengers.7
Recent works demonstrated that novobiocin, a 3-amido-
coumarin-containing DNA gyrase inhibitor, binds to
the C-terminal nucleotide-binding region8 of heat shock
protein 90, an exciting new target in cancer drug discov-
ery,9 leading to decrease in hsp90 client proteins in var-
ious cancer cell lines.10
The literature reports a short number of synthetic routes
to these compounds and the most common route is
undoubtedly the reduction of 3-nitrocoumarins into
3-aminocoumarins followed by N-functionalization.11
While this multi-step procedure is a suitable method
the variety of substrates, however, is very limited. There-
fore, our approach to the synthesis of 3-(N-acyl)- or
3-(N-sulfonamyl) coumarins and related compounds fo-
cused on the well-documented palladium-catalyzed C–N
bond coupling reaction starting from 3-halocoumarins.
The latter are of particular interest, in that the coupling
would offer a convergent and straightforward approach
to various 3-(N-substituted) aminocoumarins.
Unfortunately, the ability of novobiocin to induce deg-
radation of hsp90 client proteins (e.g., ErbB2 in SkBr3
breast cancer cells)6 is relatively weak (ꢀ700 lM) and
requires further investigation. In an effort to identify
more potent inhibitors of hsp90, we became interested
in the synthesis of a combinatorial library based on
the scaffold of 3-(N-substituted) aminocoumarin of type
A, which includes two centres for introduction of diver-
sity into coumarin molecule (Scheme 1).
Although, significant advances have occurred in the
metal-catalyzed12 amination or amidation of aryl halides
during the last decade, application of this coupling to
various heterocyclic structures is still a relatively unex-
plored process.13 Very recently, Wu and co-workers14
reported the synthesis of 3-amino-4-sulfanyl-coumarins
starting from 3-bromo-4-sulfanyl-coumarin compounds.
In Wu study, the C–N bond coupling reaction was only
described with aniline derivatives. These results
prompted us to report our general approach to provide
a variety of 3-(N-substituted)-coumarins from various
low-nitrogen nucleophiles including amides, sulfona-
mides, carbamates and functionalized alkylamines. We
found that the use of Pd(OAc)2/Xantphos couple in
Keywords: Palladium; C–N bond coupling reaction; 3-Bromocouma-
rins; 3-(N-substituted) aminocoumarins.
*
Corresponding author. Tel.: +33 1 46 83 58 87; fax: +33 1 46 83 58
28; e-mail: mouad.alami@u-psud.fr
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.166

D. Audisio et al. / Tetrahedron Letters 48 (2007) 6928–6932
6929
OH
OH
H
N
R1
NH
O
O
O
O
O
MeO
H2N
O
O
Novobiocin
A
O
R1 = COR2, COOR2, SO2R2
R2 = alkyl, aryl
OH
O
Scheme 1.
the presence of Cs2CO3 in dioxane is an efficient
catalytic system to provide a general route to a range of
unkown 3-(N-acyl)-, 3-(N-sulfonamyl)-coumarins and
related compounds.
NaOtBu or K2CO3. In spite of this difficulty, the amida-
tion proceeded reasonably well, as can be seen in Table
1.
To check the validity of the coupling reaction of 1a with
2a, we set up a test under the Buchwald conditions15 for
the amidation of aryl halides (Pd(OAc)2, Xantphos,16
Cs2CO3 in 1,4-dioxane at 100°C). We were delighted
to observe complete conversion of 1a after only 30 min
using a 1:1 ratio of Pd:L (2 mol %) and the expected
coupling product 3a was formed in 87% yield (Table 1,
entry 1). As the ligand nature has been previously shown
to affect the C–N bond coupling reactions, we examined
the process in the presence others phosphine ligands. As
expected, no reaction occurred in the absence of any
In our initial screening experiments, 3-bromocoumarin
1a and 4-methoxyphenyl-acetamide 2a were used as
the model substrates for investigating the effects of
various ligands, palladium sources, solvents and bases.
Because coumarins are sensitive substrates in alkaline
media and may result in the cleavage of the lactone ring,
we carefully examined the alkaline conditions for the
coupling of 1a with 2a. In fact, 3-bromocoumarin 1a
completely disappeared within a few hours when heated
with 4-methoxyphenyl-acetamide 2a in the presence of
Table 1. Coupling reaction of 1a with amide 2a under various conditions:a synthesis of 3-amidocoumarin 3a
OMe
H
N
Br
O
Pd:L (1:1), base
solvent, 100 °C
H2N
O
OMe
O
O
O
O
1a
2a
3a
Entry
[Pd]
Ligand
Base
Solvent
Convb (%)
Yieldc (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Xantphos
—
Xphos
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
NaOtBu
KOtBu
Na2CO3
K3PO4
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Toluene
THF
100
0
100
7
<5
0
0
13
45
0
0
0
87d
0
85
ndf
ndf
0
0
8
36
0g
0g
0
DPEphos
BINAP
dppfe
dipfe
h
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
0
0
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
83
100
33
30
65
76
ndf
ndf
tAmOH
tBuOH
a All reactions of 1a (1.0 mmol) with 2a (1.2 mmol) were performed at 100 °C for 30 min in 3 mL of solvent by using a 1:1 ratio of Pd:L (2 mol %),
and base (1.5 equiv).
b Conversion was determined by 1H NMR in the crude reaction mixture and is based on remaining 1a.
c Isolated yields.
d No reaction occurred at room temperature and only 42% conversion was observed when performing the reaction at 80 °C for 30 min.
e dppf: diphenylphosphinoferrocene. dipf: 1,1-bis(di-isopropylphosphino)ferrocene.
f Yield not determined.
g No starting material was recovered.
h Performing the coupling reaction of 1a with 2a under Wu conditions14 (5 mol % Pd2(dba)3, 10 mol % Xantphos and 2 equiv of K2CO3 in toluene at
80 °C for 30 min) resulted in incomplete conversion (<10%) even after extended heating (12 h).

6930
D. Audisio et al. / Tetrahedron Letters 48 (2007) 6928–6932
Table 2. Synthesis of functionalized 3-(N-substitued) aminocoumarins 3a
Entry
1
Bromocoumarin 1
Nucleophile
Time (h)
0.5
Product 3
Yieldsb (%)
87
OMe
OMe
OMe
Br
H
N
1a
1b
H2N
O
3a
3b
O
O
O
O
O
OMe
OMe
H
N
Br
O
2
3
H2N
O
6
76
51
O
MeO
MeO
O
O
O
O
MeO
OMe
Br
O
H
N
1c
H2N
O
0.5
3c
O
O
O
MeO
Br
Br
H
Br
H2N
Me
N
Me
4
5
6
1a
1b
1a
4
12
30
3d
3e
3f
60
45
60
O
O
O
O
O
O
O
H
N
Br
O
Me
H2N
Me
OH
O
O
MeO
MeO
O
O
OH
H
N
Br
O
H2N
HN
Me
Me
O
O
O
O
O
O
O
Br
O
N
O
7
8
1a
1b
12
12
3g
3h
0
O
O
Me
H
Br
O
N
S
H2N
53
S
S
O
O
O
MeO
O
O
MeO
O
O
O
H
N
Br
O
H2N
9
1a
1a
12
12
3i
3j
42
S
O
O
O
O
O
O
O
O
H
N
Br
O
Me
H2N
Me
12c
S
S
O
10
O
O
O
O
H
N
Br
O
H2N
OBn
OBn
11
12
1a
1a
12
2
3k
3l
26d
78
O
O
O
O
O
O
O
H
N
Br
O
H2N
H2N
O
H
N
O
O
OBn
NH2
Br
O
13
1d
2
3m
60e
BnO
O
BnO
O
O
N
H
H
N
Br
O
14
15
16
1a
1c
1d
2
2
3n
3o
3p
65
59
57
H2N
H2N
O
O
O
H
N
Br
O
O
MeO
BnO
Me
O
O
MeO
Br
Br
Me
O
H
N
Br
O
O
O
12
ClH.H2N
O
O
BnO
O
O
a Unless otherwise stated, all coupling reactions of 1 (1.0 mmol) with nucleophile (1.2 mmol) were performed at 100 °C for 30 min in 3 mL of 1,4-
dioxane by using a 1:1 ratio of Pd:L (2 mol %), and Cs2CO3 (1.5 equiv). For a general procedure; see Ref. 18.
b Isolated yields.
c Starting material was recovered.
d 40% of the reduced coumarin was obtained.
e 15% of monocoupling product was obtained.

D. Audisio et al. / Tetrahedron Letters 48 (2007) 6928–6932
6931
ligands (entry 2). Changing the bidentate ligand phop-
shine Xantphos to sterically hindered monodentate
ligand Xphos also led to total conversion of 1a after 1 h
(entry 3). The use of other bidentate phosphine ligands
such as DPEphos, BINAP, dppf or dipf however, did
not promote the C–N bond coupling reaction (entries
4–7).
after extended heating or if other ligands and palladium
sources were used. In this case, the majority of the mass
balance is made up of unreacted starting material. Final-
ly, primary benzyl carbamate, also reacted slowly to give
only 26% yield of the desired product 3k (entry 11)
together with a notable amount (40%) of a side couma-
rin compound formed from a carbon–bromine bond
reduction.
The palladium source was also examined and in the
present reaction, in contrast to Wu conditions,13 the cat-
alytic activity of Pd(OAc)2 proved to be superior to
Pd2(dba)3 as the use of Pd2(dba)3 in combination with
Xantphos ligand induced a lowering of the conversion
rate and gave 3a in only 8% yield (entry 8). The effect
of bases and solvents were then explored. Of the bases
screened, the highest yield was achieved by using
Cs2CO3 (entries 1 and 3). In contrast to Wu condi-
tions,13 replacing Cs2CO3 by K2CO3 was found less
effective and gave much lower yield of 3a (entry 9).
NaOtBu and KOtBu cleaved the lactone ring and were
thus ineffective (entries 10 and 11) whereas, the use of
other bases including, Na2CO3 and K3PO4 did not pro-
mote any coupling reaction and starting material was
recovered unchanged (entries 12 and 13). Finally, in
the presence of other solvents such as THF and toluene,
two common solvents used for the aryl amination, the
C–N bond coupling reaction proved also to be effective
providing 3a but in slightly lower yields (entries 14 and
15). Use of tert-butyl or tert-amyl alcohol as previously
was reported17 induced a lowering of the conversion rate
(entries 16 and 17).
Under the optimized conditions, we then explored the
coupling of 3-bromocoumarin derivatives with amines
as nucleophiles. The results outlined in Table 2 show
that the reactions performed with aniline and benzyl-
amine derivatives (entries 12–15) were generally com-
plete within 2 h, with fair to good yields. For substrate
1c containing two C–Br substituents, the reaction selec-
tivity was examined with R(+)-1-(1-naphtyl)ethylamine.
A 1:1.2 ratio of 1c:amine gave selectively the mono-cou-
pling product 3o in 59% yield (entry 15). Performing the
C–N bond forming reactions with para-phenylenedi-
amine (ratio 1d:diamine = 2:1) provides the bis-coupling
compound 3m in 60% yield together with a small
amount (15%) of mono-coupling product (entry 13).
Amination of 3-bromocoumarins using chlorohydrate
of ethyl ester glycine expectedly turned out to be a slow
reaction (12 h); giving 3p in 57% yield (entry 16). Under
these conditions, we were pleased to observe that the
ethoxycarbonyl group was tolerated in the presence of
our catalytic system.
In conclusion, we have succeeded in developing an effi-
cient and selective Pd-mediated C–N coupling reactions
of 3-bromocoumarins with various nucleophiles includ-
ing amides, sulfonamides and amines using palladium
acetate as a catalyst, Xantphos as a ligand and Cs2CO3
as a base. Under this synthetic way, a series of 3-(N-
substituted) aminocoumarin derivatives was obtained
in sufficiently good yields and isolation of the products
is easily achieved by column chromatography. The
application of this C–N coupling methodology to syn-
thesize a small 3-aminocoumarin library related to
novobiocin is currently under investigation in our
laboratory.
With optimized conditions in hand, we subsequently ex-
plored the substrate scope of the reaction with a series of
3-bromocoumarin derivatives and various nucleophiles
including amides, sulfonamides as well as functionalized
alkylamines. Considering its high activity in all cases,
ligand Xantphos was our choice for further experimen-
tation. As summarized in Table 2, various 3-bro-
mocoumarins undergo smoothly the C–N coupling
reaction with amides over the catalytic system
Pd(OAc)2/Xantphos. The representative examples in
Table 2 illustrate the generality of this reaction. As
shown, various types of amides underwent coupling
reactions efficiently under the optimized conditions.
Both primary aromatic and aliphatic amides reacted to
provide 3-amidocoumarin derivatives 3a–f in fair to
good isolated yields (Table 2, entries 1–6). It is worthy
to note that the chemoselectivity of the reaction must
be especially underlined as the amidation of substrate
1c containing two carbon–bromine atoms provide exclu-
sively the coupling product at the more activated C-3
position (entry 3). The reaction was also effective with
functionalized primary amides (entry 6) whereas, with
cyclic amides, the reaction turned out to be less effective
even if other ligands and palladium sources were used
(entry 7). Unlike the amidations with primary aromatic
amides, however, the catalytic system Pd(OAc)2/xant-
phos was less effective in the couplings with the less
nucleophilic primary arylsulfonamides, providing only
a moderate yield of the desired products (entries 8 and
9). Primary aliphatic sulfonamides were more sluggish
to react (entry 10), with incomplete conversion even
Acknowledgements
The CNRS is gratefully acknowledged for financial sup-
port of this research and the European Community for
the financial support and a doctoral fellowship to D.A.
References and notes
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mp = 177–179 °C; IR (neat): 3401, 1712, 1667, 1604, 1578,
1507, 1446, 1359, 1296, 1246, 1190, 1112, 1063, 925, 910,
859, 842, 754, 691, 643, 606, 568 cmÀ1; 1H NMR (CDCl3,
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J = 8.8 Hz), 7.47 (dd, 1H, J = 7.7 Hz, J = 1.3 Hz), 7.38
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127.9, 125.7, 125.2, 124.3, 123.0, 120.0, 116.4, 114.2 (2C),
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18. General procedure for Pd-catalyzed couplings of 3-bro-
mocoumarins with various nucleophiles (amines, amides,
sulfonamides and carbamates): A flame-dried resealable
Schlenk tube was charged with Pd(OAc)2 (0.025 mmol,
2.0 mol %), Xantphos (0.025 mmol, 2.0 mol %), the solid
reactant(s) (1.0 mmol of the bromocoumarin, 1.2 mmol of
the amide/amine/carbamate/sulfonamide) and Cs2CO3
(1.5 mmol). The Schlenk tube was capped with a rubber
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1
590,573 cmÀ1; H NMR (CDCl3, 300 MHz): d 7.85–7.81
(m, 2H), 7.72 (s, 1H), 7.54 (m, 1H), 7.46–7.30 (m, 5H),
7.26–7.18 (m, 2H); 13C NMR (CDCl3, 75 MHz): d 158.3,
150.3, 138.7, 133.8, 130.2, 129.4 (2C), 127.6, 127.2 (2C),
125.3, 123.2, 123.0, 119.0, 116.5; m/z MS (ES+) 324.0
(M+Na+). Compound 3l: Yield: 78%; TLC: Rf 0.76
(CH2Cl2); mp = 108–110 °C; IR (neat): 3328, 3054, 1702,
1626, 1589, 1572, 1531, 1494, 1456, 1444, 1362, 1322, 1281,
1243, 1215, 1139, 1114, 1027, 926, 867, 837, 750, 740, 705,
1
656, 639, 592 cmÀ1; H NMR (CDCl3, 300 MHz): d 7.22
(d, 1H, J = 7.5 Hz), 7.19 (d, 1H, J = 7.5), 7.14–7.00 (m,
8H), 6.95 (s, 1H), 6.89 (t, 1H, J = 7.4), 6.63 (br s, 1H); 13
C
NMR (CDCl3, 75 MHz): d 159.8, 148.5, 139.8, 129.6 (2C),
129.3, 126.8, 125.6, 124.8, 123.5, 121.0, 120.6 (2C), 116.1,
108.5; m/z MS (ES+) 260.0 (M+Na+). Compound 3p:
Yield: 57%; TLC: Rf 0.44 (CH2Cl2); mp = 105–107 °C; IR
(neat): 3402, 2923, 1730, 1698, 1610, 1500, 1453, 1372,
1334, 1275, 1209, 1167, 1122, 1018, 860, 801, 767, 732, 696,
1
591 cmÀ1; H NMR (CDCl3, 300 MHz): d 7.38–7.26 (m,
5H), 6.79 (d, 1H, J = 9.0 Hz), 5.06 (s, 2H), 4.10 (q, 2H,
J = 14.3 Hz), 3.88 (s, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 1.17
(t, 3H, J = 7.1 Hz); 13C NMR (CDCl3, 75 MHz): d 170.4,
159.1, 158.4, 155.9, 150.5, 147.8, 135.5, 128.2, 127.6 (2C),
127.0, 126.0 (2C), 120.0, 113.2, 107.5, 69.5, 60.2, 48.3,
15.3, 12.4, 7.4; m/z MS (ES+) 408.0 (M+Na+).