Rapid access to 3-(N-substituted)-aminoquinolin-2(1H)-ones using palladium-catalyzed C-N bond coupling reaction

Article abstract of DOI:10.1016/j.tet.2007.07.085

A series of 3-(N-substituted)-aminoquinolin-2(1H)-ones have been synthesized by the palladium-catalyzed C-N coupling reaction starting from 3-bromoquinolin-2-(1H)-ones. Various nucleophiles including amines, amides, sulfonamides, carbamates and ureas have been used successfully. In all the cases, the reactions take place rapidly in 1,4-dioxane and proceed in good to excellent yield using palladium acetate as a catalyst, Xantphos as a ligand and Cs₂CO₃ as a base.

Full text of DOI:10.1016/j.tet.2007.07.085

Tetrahedron 63 (2007) 10202–10210
Rapid access to 3-(N-substituted)-aminoquinolin-2(1H)-ones using
palladium-catalyzed C–N bond coupling reaction
a,b,
Samir Messaoudi,a,b Davide Audisio,b Jean-Daniel Brionb,a and Mouad Alami
*
^
a
´
´
´
CNRS, BioCIS UMR 8076, Laboratoire de Chimie Therapeutique, Faculte de Pharmacie, rue J.B. Clement,
F-92296 Cha^tenay-Malabry, France
b
´
´
Univ Paris-Sud, BioCIS UMR 8076, Laboratoire de Chimie Therapeutique, Faculte de Pharmacie, rue J.B. Clement,
´
F-92296 Cha^tenay-Malabry, France
Received 27 June 2007; revised 20 July 2007; accepted 23 July 2007
Available online 29 July 2007
Abstract—A series of 3-(N-substituted)-aminoquinolin-2(1H)-ones have been synthesized by the palladium-catalyzed C–N coupling reac-
tion starting from 3-bromoquinolin-2-(1H)-ones. Various nucleophiles including amines, amides, sulfonamides, carbamates and ureas have
been used successfully. In all the cases, the reactions take place rapidly in 1,4-dioxane and proceed in good to excellent yield using palladium
acetate as a catalyst, Xantphos as a ligand and Cs2CO3 as a base.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
that target the hsp90, an exciting new target in cancer drug
discovery.8 As these compounds are not easily accessible
by current methodology, our goal was to explore the palla-
dium-catalyzed C–N bond coupling reaction starting from
3-haloquinolin-2(1H)-ones. The latter are of particular
interest, in that the coupling would offer a convergent and
straightforward approach to various 3-(N-substituted)-
aminoquinolin-2(1H)-ones.
Quinolin-2(1H)-ones are an important class of heteroaro-
matic compounds.1 As isosteres of coumarin, quinolinones
display a broad range of biological activities (e.g., anti-
viral,2 antitumoral3) and a number of analogues of this class
of heterocyclic structure have been reported as lead
compounds or are currently undergoing clinical trials.4
The growing importance of these pharmaceutical com-
pounds has led to the development of new methods for their
synthesis.5
Although significant advances have occurred in the metal-
catalyzed9 amination or amidation of aryl halides during
the last decade, application of this coupling to various het-
erocyclic structures is still a relatively unexplored process.10
To our knowledge, palladium-catalyzed C–N bond-forming
reactions between 3-haloquinolin-2(1H)-ones11 and nucleo-
philes including amines, amides, sulfonamides and carba-
mates are unknown. Herein we report our studies on these
useful reactions.
Although quinolin-2(1H)-ones exhibit a wide range of biolog-
ical activities, to date there have been a limited number of
methods to prepare 3-(N-substituted)-aminoquinolin-2(1H)-
ones. The main routes to these heterocyclic structures are re-
duction of 3-nitroquinolinones into 3-aminoquinolinones,6
or Hofmann rearrangement of quinolinone-3-carboxylic acid
derivatives followed by further N-functionalization.7 An alter-
native route consists of cyclization of a suitable N-chloro-
acetyl-o-aminobenzophenone precursor to form a-pyridinium
salt followed by hydrazinolysis.4d All these multi-step proce-
dures, however, are often moderate to low yielding, and the
variety of substrates is very limited.
2. Results and discussion
To optimize conditions for the preparation of aminoquino-
lin-2(1H)-one 3a, the coupling of 3-bromoquinolin-2(1H)-
one 1a with 4-methoxybenzamide 2a was initially selected
as a model reaction for investigating the effects of various
ligands (Fig. 1), palladium sources and bases. The results
are summarized in Table 1.
In an ongoing medicinal chemistry programme, we required
the synthesis of 3-(N-acyl)-, 3-(N-sulfonamyl)- and 3-(N-
aryl)-aminoquinolin-2(1H)-ones as analogues of novobiocin
As can seen from Table 1, the reaction of 1a with 2a was ini-
tially examined under the procedure developed by Buch-
wald12 for the amidation of aryl halides (Pd(OAc)2,
Xantphos,13 Cs2CO3 in 1,4-dioxane at 100 ꢀC). We were
Keywords: Palladium; C–N bond coupling reaction; Bromoquinolin-2-(1H)-
ones; 3-(N-Substituted)-aminoquinolin-2-(1H)-ones.
* Corresponding author. Tel.: +33 1 46835887; fax: +33 1 46835828;
e-mail: mouad.alami@u-psud.fr
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.085

S. Messaoudi et al. / Tetrahedron 63 (2007) 10202–10210
10203
Br
Br
O
Br
PPh2
PPh2
PPh2
PPh2
O
PCy2
i-Pr
1a: R = Me
O
N
N
R
O
PPh2
PPh2
1b: R = Bn
i-Pr
Me
1d
1c: R = CH2CO2Et
Figure 2. 3-Bromoquinolin-2(1H)-ones 1 used in this study.
i-Pr
Xantphos
Xphos
DPEphos
BINAP
of structurally diverse nucleophiles with some 3-bromo-
quinolin-2(1H)-ones 1 were studied (Fig. 2).
Figure 1. Supporting ligands used in this study.
Results summarized in Table 2 show that the optimized con-
ditions described above proved to be general for the coupling
with a large variety of nucleophiles. The coupling was found
to be compatible with primary aromatic and aliphatic amides
(entries 1–3) providing in excellent yields the corresponding
coupling products 3a–c.
Table 1. Optimization coupling reaction of 1a with 4-methoxybenzamide
2a under various conditionsa
OMe
H2N
O
OMe
2a
H
N
Br
O
O
[Pd] / L, base,
dioxane, 100 °C, 10 h
N
Me
N
Me
O
1a
3a
The reaction was also effective with cyclic amides (entry 4)
as well as with functionalized primary amides (entries 5 and
6), although the yields were slightly lower.
Entry [Pd]
Ligand
Base
Conversionb (%) Yieldc (%)
e
1
2
3
4
5
6
7
8
9
Pd(OAc)2 Xantphos Cs2CO3 100
Pd2(dba)3 Xantphos Cs2CO3 50
95d
ndf
85
Under our optimal conditions, the reaction selectivity was in-
vestigated with substrate 1d containing two carbon–bromine
atoms. The coupling proceeded at the more activated C-3 po-
sition and yielded the mono-substitution product 3g (44%,
entry 7) together with the bis-coupling one bis-3g (27%).
C–N bond-forming reaction was also studied with benzyl
carbamate (entry 8) as well as with the less nucleophilic
alkyl- or arylsulfonamides (entries 9–12). These substrates
also proved to be viable nucleophiles for the coupling reac-
tion and in most cases, good yields of coupling products 3h–l
were obtained. Finally, the C–N bond-forming reactions
were examined using acyclic urea and we found that this
amide analogue was doubly heteroarylated in good yields
(entry 13).
Pd(OAc)2 Xphos
Pd(OAc)2 DPEphos Cs2CO3 64
Pd(OAc)2 BINAP
Pd(OAc)2 Dppfg
Pd(OAc)2 Xantphos Na2CO3
Cs2CO3 100
ndf
ndf
ndf
0h
Cs2CO3 77
Cs2CO3 60
0
Pd(OAc)2 Xantphos K3PO4 100
Pd(OAc)2 Xantphos K2CO3 100
82
86
a
Reactions of 1a (1.0 mmol) with 4-methoxybenzamide 2a (1.5 mmol)
were performed in a sealed Schlenk tube at 100 ꢀC for 10 h in dioxane
(2 mL) by using [Pd] (5 mol %), ligand (5 mol %) and base (2 mmol).
Conversion was determined by 1H NMR in the crude reaction mixture and
was based on remaining 1a.
b
c
d
e
f
Isolated yields.
No reaction occurred at room temperature.
No reaction occurred without palladium catalyst.
Yield not determined.
dppf: diphenylphosphino-ferrocene.
Reproducible result after three runs and starting material was recovered
unchanged.
g
h
The reaction was next carried out with a series of primary and
secondary amines. As shown in Table 3, various 3-(N-alkyl)-
and 3-(N-aryl)-aminoquinolin-2(1H)-one derivatives 4 were
obtained in good yields by using Pd(OAc)2 as the palladium
source, Xantphos as the ligand, Cs2CO3 as the base and 1,4-
dioxane as the solvent. Under these conditions, anilines
proved to be suitable substrates for this C–N bond-forming
reaction affording the coupling products in good yields
(entries 1 and 2). We were pleased to observe that the ethoxy-
carbonyl group was tolerated in the presence of our catalyst
system (entry 2). Similarly, primary alkyl- and benzylamines
worked well in this coupling, although the amines containing
a secondary carbon atom in the a-position gave slightly lower
reaction yields (entries 4 and 5). Finally, secondary cyclic
amines showed similar reaction activity relative to the other
primary aliphatic and aromatic amines (entry 7). For sub-
strate 1d containing two C–Br substituents, the reaction se-
lectivity was examined with morpholine. A 1:1 ratio of 1d/
morpholine gave selectively the monocoupling product 4h
(39%, not shown in table), clearly indicating that the C-3 po-
sition is more electrophilic than the C-7 position. Increasing
the ratio to 1:1.5 enhanced the reaction yield (48%, entry 8),
although a notable amount of bis-coupling product bis-4h
was obtained (15%). Finally, carrying out the reaction in
the presence of an excess of morpholine (5 equiv) had no sig-
nificant change on the mono- (41%) and bis-coupling (21%)
products’ yields.
pleased to find that these conditions provided the most gen-
erally successful results. Complete conversion of 1a was ob-
served after 10 h using only a 1:1 ratio of Pd/L and the
expected coupling product was formed in 95% yield (Table
1, entry 1). It should be noted that no reaction occurred with-
out palladium catalyst. Changing the bidentate ligand phos-
phine to the sterically hindered monodentate ligand Xphos14
also led to total conversion although the yield of 3a was
slightly lower (entry 3). The use of other bidentate phos-
phine ligands such as DPEphos, BINAP or dppf, however,
induced a lowering of the conversion rate (entries 4–6). It
is interesting to note that in the coupling of 1a with 2a, the
source of palladium used has an important influence on the
reaction rate. Thus, a slow rate was observed when running
the reaction with Pd2(dba)3 instead of Pd(OAc)2 in combina-
tion with Xantphos ligand (entry 2). This result clearly indi-
cated that in the present reaction, the catalytic activity of
Pd(OAc)2 proved to be superior to Pd2(dba)3. Finally, use
of bases such as K3PO4 and K2CO3 was found to be highly
effective (entries 8 and 9), whereas Na2CO3 did not promote
the coupling reaction (entry 7).
With a viable coupling procedure in hand, attention was
turned to the generality of the process, and the couplings

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S. Messaoudi et al. / Tetrahedron 63 (2007) 10202–10210
Table 2. Palladium-catalyzed amidation of 3-bromoquinolin-2(1H)-ones 1: synthesis of functionalized 3-(N-substituted)-aminoquinolin-2(1H)-ones 3a
Entry
1
ArBr
Amide
Product 3
OMe
Yieldsb (%)
OMe
OMe
H
N
1a
H2N
3a
3b
95
O
O
N
Me
O
O
O
OMe
H
N
H2N
2
1c
87
N
O
CH2CO2Et
H
N
Me
H2N
Me
3
4
5
1a
1a
1a
3c
3d
3e
92
69
60
O
O
N
Me
O
N
HN
O
N
Me
O
O
OH
Me
H
N
OH
Me
H2N
O
N
Me
O
O
OTs
OTs
H
N
6
1a
H2N
3f
46c
O
N
Me
O
O
OMe
OMe
H
Br
N
7
1d
H2N
3g
44d
O
N
Me
O
O
NHCO2Bn
O
H2N
OBn
8
9
1b
1a
3h
3i
57
85
N
Bn
O
Me
NHSO2p-Tol
H2N
S
N
O
O
Me
O
H
N
S
H2N
O2
O
10
1b
3j
74
S
N
Bn
O
O
(continued)

S. Messaoudi et al. / Tetrahedron 63 (2007) 10202–10210
10205
Table 2. (continued)
Entry
ArBr
Amide
Product 3
Yieldsb (%)
NHSO2Me
Me
H2N
S
11
1a
1b
3k
3l
66
N
Me
O
O
O
NHSO2Me
O
Me
H2N
S
12
68
N
Bn
O
O
H
N
H
N
H2N
NH2
13
1a
3m
61
O
O
O
N
N
O
Bn
Bn
a
Reactions of 1 (1.0 mmol) with amide/sulfonamide/carbamate/urea (1.5 mmol) were performed in a sealed Schlenk tube at 100 ꢀC for 10 h in dioxane (2 mL)
by using Pd(OAc)2 (5 mol %), Xantphos (5 mol %) and Cs2CO3 (2 mmol).
Isolated yields.
No product resulting from the coupling of the C-OTs bond with 4-tosylbenzamide was detected.
A 27% yield of the corresponding bis-coupling compound was obtained.
b
c
d
3. Conclusion
Elmer 240 analyzer. Rf values refer to TLC on 0.25 mm
silica gel plates (60-F254). Flash chromatography was per-
formed on silica gel 60 (0.040–0.063 mm). Melting points
(mp) were determined on a capillary melting point appara-
tus and were uncorrected. Amides, sulfonamides, amines,
carbamates and ureas are commercially available com-
pounds except p-tosylbenzamide that was synthesized as
described. 3-Bromoquinolin-2-(1H)-one 1a was synthesized
as described.
We have demonstrated that the catalytic system used allows
the first general C–N bond-forming reaction between
3-bromoquinolin-2(1H)-ones and various nucleophiles in-
cluding amines, amides, sulfonamides, carbamates and
ureas. Consequently, various 3-(N-substituted)-aminoquino-
lin-2(1H)-ones were prepared in good to excellent yields. In-
vestigations on further expanding the scope of the method to
other related heterocycles are in progress in our laboratory.
4.3. Synthetic details for 3-bromoquinolin-2(1H)-one
compounds 1b–d
4. Experimental
4.1. Materials
4.3.1. Compound 1b. To a solution of 3-bromo-1-quinolin-
2-one (0.5 g, 2.23 mmol) in DMF (2 mL) were added NaH
(275 mg of a 65% oil dispersion, 7.44 mmol) and benzyl
bromide (533 mL, 4.46 mmol). The reaction mixture was
stirred for 3 h at room temperature before being diluted
with water and extracted with ethyl acetate. The combined
organic layers were washed with brine, dried over sodium
sulfate and concentrated in vacuo. Purification of the residue
by silica gel column chromatography (CH2Cl2/c-hexane:
6/4) yielded 644 mg of the desired product 1b.
All reactions were conducted under an argon atmosphere.
Solvents: cyclohexane, ethyl acetate (EtOAc), methylene
chloride (CH2Cl2) and methanol (MeOH) for extraction
and chromatography were of technical grade. Diethylether
(Et2O) and tetrahydrofuran (THF) were distilled under argon
from sodium–benzophenone ketyl, and piperidine, n-butyl-
amine, aniline and morpholine from potassium hydroxide.
4.2. Instrumentation
Yield: 92%; mp: 150–151 ꢀC; TLC: Rf 0.5 (CH2Cl2/c-
hexane: 9/1); IR (neat): 1646, 1591, 1557, 1494, 1436,
1363, 1289, 1214, 1149, 1069, 1028, 958, 932, 911, 799,
The compounds were all identified by usual physical
methods, i.e., H NMR, 13C NMR, IR, elemental analysis.
1
761, 726, 692, 622, 579 cmꢁ1 1H NMR (300 MHz,
;
1H and 13C NMR spectra were measured in CDCl3 or
DMSO-d6 on a 300 MHz spectrometer. H chemical shifts
CDCl3): d 8.2 (s, 1H), 7.53 (dd, 1H, J1¼7.8, J2¼1.5 Hz),
7.47 (td, 1H, J1¼8.7, J2¼1.5 Hz), 7.4–7.1 (m, 7H), 5.62 (s,
2H); 13C NMR (75 MHz, CDCl3): d 158.7 (CO), 141.1,
138.8, 135.8, 130.9, 128.9 (2CH), 128.2, 127.5, 126.8
(2CH), 122.8, 120.8, 117.4, 115.2, 47.6 (CH2); m/z MS
(ES+) 336.0 (M+Na+, 79Br), 338.0 (M+Na+, 81Br); Anal.
Calcd for C16H12BrNO (313.01): C 61.17, H 3.85, N 4.46;
found: C 61.01, H 3.73, N 4.34.
1
are reported in parts per million from an internal standard
TMS or of residual chloroform (7.27 ppm). The following
abbreviations are used: m (multiplet), s (singlet), br s (broad
singlet), d (doublet), t (triplet) dd (doublet of doublet), td
(triplet of doublet), q (quadruplet), quint (quintuplet).
13C chemical shifts are reported in parts per million from
the central peak of deuteriochloroform (77.14). IR spectra
were acquired on a FTIR and are reported in wave numbers
(cmꢁ1). Elemental analyzes were performed with a Perkin–
4.3.2. Compound 1c. A 100 mL round bottom flask was se-
quentially charged with NaH (65% oil dispersion, 447 mg,

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S. Messaoudi et al. / Tetrahedron 63 (2007) 10202–10210
Table 3. Pd-catalyzed amination of 3-bromoquinolin-2(1H)-ones 1: synthesis of functionalized 3-(N-substituted)-aminoquinolin-2(1H)-ones 4a
R"
N
R1
R1
Br
O
HN(R')R"
Pd(OAc)2
R'
/
N
R
N
R
O
Xantphos, Cs2CO3,
dioxane
1
4
100 °C, 10 h
Entry
1
ArBr
Amine
Product 4
Yieldsb (%)
H
N
1a
4a
4b
4c
93
N
Me
O
H2N
H2N
H
N
2
3
1c
1a
89
88
N
O
CH2COOEt
H
N
H2N
N
O
Me
H
N
H2N
4
5
6
7
1a
1a
1a
1b
4d
4e
4f
74
60
83
76
Me
N
Me
O
Me
H
N
H2N
N
Me
O
H
N
nBu
H2NBu
N
Me
O
N
O
4g
HN
N
Bn
O
N
Br
8
1d
4h
48c
HN
O
N
O
Me
a
Reactions of 1 (1.0 mmol) with amine (1.5 mmol) were performed in a sealed Schlenk tube at 100 ꢀC for 10 h in dioxane (2 mL) by using Pd(OAc)2 (5 mol %),
Xantphos (5 mol %) and Cs2CO3 (2 mmol).
Isolated yield.
A 15% yield of the corresponding bis-coupling compound was obtained.
b
c
12.1 mmol) and dry DMF (5 mL). The resulting suspension
temperature, the reaction mixture was poured into a solution
of brine (150 mL) and extracted with EtOAc (3ꢂ40 mL).
The combined organic layers were then washed with brine
(50 mL), dried over Na2SO4 and concentrated in vacuo.
Purification of the crude product by silica gel column chro-
matography (CH2Cl2) yielded 3.12 mmol of the desired
product 1c.
was cooled to 0 ꢀC with an ice/water bath and a solution of
3-bromo-1-quinolin-2-one (1.0 g, 4.46 mmol) in dry DMF
(25 mL) was slowly added over 10 min. The reaction mix-
ture was allowed to stir for 30 min at 0 ꢀC. Next, a solution
of ethyl bromoacetate (1.49 g, 8.92 mmol) in dry DMF
(5 mL) was added over 5 min. After 4 h of stirring at room

S. Messaoudi et al. / Tetrahedron 63 (2007) 10202–10210
10207
Yield: 70%; mp: 151–152 ꢀC; TLC: Rf 0.5 (CH2Cl2); IR
(neat): 2964, 1736, 1645, 1593, 1558, 1497, 1448, 1417,
1373, 1348, 1298, 1210, 1192, 1084, 1053, 1023, 939,
NMR (300 MHz, CDCl3): d 9.24 (s, 1H), 8.78 (s, 1H), 7.85
(d, 2H, J¼9.0 Hz), 7.55 (dd, 1H, J1¼7.8, J2¼1.5 Hz), 7.40
(td, 1H, J1¼8.7, J2¼1.5 Hz), 7.27 (d, 1H, J¼8.4 Hz), 7.19
(td, 1H, J1¼8.1, J2¼1.2 Hz), 6.69 (d, 2H, J¼9.0 Hz),
3.79 (s, 3H), 3.74 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 165.3 (CO), 162.7, 158.2 (CO), 135.5, 129.1 (2CH),
128.9, 128.8, 127.9, 126.5, 123.1, 121.2, 120.1, 114.5
(2CH), 114.0, 55.5 (OCH3), 30.3 (CH3); m/z MS (ES+)
331.0 (M+Na+); Anal. Calcd for C18H16N2O3 (308.12): C
70.12, H 5.23, N 9.09; found: C 69.98, H 5.02, N 8.97.
927, 906, 861, 802, 767, 753, 732, 632, 574 cmꢁ1 1H
;
NMR (300 MHz, CDCl3): d 8.08 (s, 1H), 7.52–7.42 (m,
2H), 7.18 (td, 1H, J1¼8.0, J2¼0.7 Hz), 7.00 (d, 1H,
J¼9.4 Hz), 5.05 (s, 2H), 4.15 (m, 2H), 1.19 (t, 3H,
J¼7.1 Hz); 13C NMR (75 MHz, DMSO-d6): d 167.6 (CO),
158.2 (CO), 141.4, 138.7, 131.1, 128.4, 123.0, 120.6,
116.9, 113.8, 61.9, 45.2, 14.1 (CH2CH3); m/z MS (ES+)
332.0 (M+Na+, 79Br), 334.0 (M+Na+, 81Br); Anal. Calcd
for C13H12BrNO3 (309.00): C 50.34, H 3.90, N 4.52; found:
C 49.90, H 3.70, N 4.37.
4.4.2. Compound 3b. Yield: 87%; mp: 153–155 ꢀC; TLC:
Rf 0.39 (CH2Cl2); IR (neat): 3390, 1736, 1676, 1636,
1600, 1530, 1507, 1489, 1377, 1247, 1206, 1033, 843,
4.3.3. Compound 1d. To a solution of 1a (0.5 g, 2.1 mmol)
in acetic acid (6 mL) was added a solution of bromine
(1.27 g, 8.2 mmol, 4 equiv) in acetic acid (30 mL) and the
resulting solution was stirred at room temperature for 20 h.
A white precipitate was filtered off, and the filtrate was con-
centrated. Purification of the residue by silica gel column
chromatography (Et2O) yielded 480 mg of compound 1d
as a white solid.
758, 759, 637, 624, 600 cmꢁ1 1H NMR (300 MHz,
;
CDCl3): d 9.17 (s, 1H), 8.86 (s, 1H), 7.85 (d, 2H, J¼
8.8 Hz), 7.59 (dd, 1H, J1¼7.7, J2¼1.1 Hz), 7.39 (td, 1H,
J1¼8.5, J2¼1.4 Hz), 7.23 (d, 1H, J¼7.3 Hz), 7.06 (d, 1H,
J¼8.4 Hz), 6.91 (d, 2H, J¼8.8 Hz), 5.03 (s, 2H), 4.18 (q,
2H, J¼7.1 Hz), 3.80 (s, 3H), 1.2 (t, 3H, J¼7.2 Hz); 13C
NMR (75 MHz, CDCl3): d 165.6 (CO), 165.4 (CO), 162.8,
158.2, 134.9, 129.1 (2CH), 128.9, 128.8, 127.6, 126.3,
123.5, 121.3, 121.1, 114.0 (2CH), 113.3, 61.9, 55.5, 44.7,
14.4; m/z MS (ES+) 404.0 (M+H++Na+); Anal. Calcd for
C21H20N2O5 (380.14): C 66.31, H 5.30, N 7.36; found: C
65.89, 5.19, N 7.28.
Yield: 72%; mp: 186–188 ꢀC; TLC: Rf 0.42 (Et2O); IR
(neat): 3050, 1641, 1587, 1553, 1514, 1486, 1454, 1412,
1356, 1315, 1290, 1260, 1213, 1159, 1124, 1091, 1059,
1002, 946, 910, 896, 810, 796, 755, 742, 647, 619, 592,
1
561 cmꢁ1; H NMR (300 MHz, CDCl3): d 8.20 (s, 1H),
4.4.3. Compound 3c. Yield: 92%; mp: 177–179 ꢀC; TLC: Rf
0.28 (CH2Cl2/EtOAc: 9/1); IR (neat): 3300, 1679, 1676,
1628, 1613, 1590, 1521, 1494, 1457, 1419, 1374, 1285,
1229, 1178, 1115, 1039, 1013, 943, 903, 847, 774, 751,
7.78 (d, 1H, J¼2.4 Hz), 7.65 (dd, 1H, J1¼9.0, J2¼2.4 Hz),
7.4 (d, 1H, J¼9.0 Hz), 3.63 (s, 3H); 13C NMR (75 MHz,
DMSO-d6): d 157.0 (CO), 139.6, 138.1, 133.3, 129.9,
121.5, 117.8, 117.3, 114.3, 31.0; m/z MS (ES+) 338.0
(M+Na+, 79Br), 340.0 (M+Na+, 81Br); Anal. Calcd for
C10H7Br2NO (314.88): C 37.89, H 2.23, N 4.42; found: C
37.03, H 2.09, N 4.10.
1
713, 641, 602, 581 cmꢁ1; H NMR (300 MHz, CDCl3):
d 8.62 (s, 1H), 8.50 (s, 1H), 7.51 (dd, 1H, J1¼7.7, J2¼
1.3 Hz), 7.40 (td, 1H, J1¼8.6, J2¼1.5 Hz), 7.25 (d, 1H, J¼
8.3 Hz), 7.18 (td, 1H, J1¼8.1, J2¼1.0 Hz), 3.70 (s, 3H,
CH3),), 2.17 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3):
d 169.2 (CO), 157.8 (CO), 135.5, 128.6, 128.5, 127.6,
123.1, 121.0, 120.3, 113.9, 30.3 (CH3), 24.8 (CH3); m/z
MS (ES+) 239 (M+Na+); Anal. Calcd for C12H12N2O2
(216.08): C 66.65, H 5.59, N 12.96; found: C 66.31, H
5.21, N 12.14.
4.4. General procedure for Pd-catalyzed couplings of
3-bromoquinolin-2(1H)-ones with various nucleophiles:
amines, amides, sulfonamides, carbamates and ureas
A flame-dried resealable Schlenk tube was charged with
Pd(OAc)2 (7.5 mg, 0.05 mmol, 5 mol %), Xantphos
(29 mg, 0.05 mmol, 5 mol %), the solid reactant(s)
(1.0 mmol of the bromoquinolin-2(1H)-one, 1.5 mmol of the
amide/amines/carbamate/sulfonamide/urea) and Cs2CO3
(651 mg, 2 mmol). The Schlenk tube was capped with
a rubber septum, evacuated and backfilled with argon; this
evacuation/backfill sequence was repeated one additional
time. The liquid reactant(s) and 1,4-dioxane (2 mL) were
added through the septum. The septum was replaced with
a Teflon screwcap. The Schlenk tube was sealed, and the
mixture was stirred at 100 ꢀC for 10 h. The resulting suspen-
sion was cooled to room temperature and filtred through
Celite eluting with ethyl acetate, and the inorganic salts
were removed. The filtrate was concentrated and purification
of the residue by silica gel column chromatography gave the
desired product.
4.4.4. Compound 3d. Yield: 69%; mp: 100–102 ꢀC; TLC:
Rf 0.21 (CH2Cl2/EtOAc: 7/3); IR (neat): 3524, 3423, 1674,
1624, 1592, 1461, 1411, 1303, 1267, 1225, 1200, 1147,
1128, 905, 858, 838, 793, 762, 739, 716, 692, 621, 598,
1
559 cmꢁ1; H NMR (300 MHz, CDCl3): d 7.81 (s, 1H),
7.52–7.45 (m, 2H), 7.27 (d, 1H, J1¼8.4 Hz), 7.18 (dt, 1H,
J1¼8.4, J2¼1.0 Hz), 3.91 (t, 2H, J¼7.2 Hz), 3.67 (s, 3H,
CH3), 2.50 (t, 2H, J¼8.2 Hz), 2.15–2.00 (m, 2H); 13C
NMR (75 MHz, CDCl3): d 175.7 (CO), 159.1 (CO), 138.7,
135.2, 130.4, 129.0, 128.5, 122.5, 119.8, 114, 48.9, 31.3,
29.9, 18.9; m/z MS (ES+) 243.0 (M+H+), 265.0 (M+Na+),
507.0 (2M+Na+); Anal. Calcd for C14H14N2O2 (242.10): C
69.41, H 5.82, N 11.56; found: C 68.87, H 5.17, N 11.19.
4.4.5. Compound 3e. Yield: 60%; mp: 188–189 ꢀC; TLC: Rf
0.4 (CH2Cl2/EtOAc: 7/3); IR (neat): 3386, 3348, 1679, 1633,
1614, 1592, 1527, 1499, 1463, 1423, 1375, 1321, 1275,
1231, 1209, 1181, 1122, 1041, 1018, 945, 902, 853, 777,
4.4.1. Compound 3a. Yield: 95%; mp: 181–183 ꢀC; TLC: Rf
0.74 (CH2Cl2/EtOAc: 8/2); IR (neat): 3375, 1669, 1638,
1619, 1598, 1576, 1527, 1494, 1465, 1421, 1377, 1327,
1296, 1255, 1217, 1177, 1115, 1023, 965, 947, 907, 858,
838, 800, 777, 752, 739, 716, 692, 621, 598, 559 cmꢁ1; 1H
1
743, 720, 703, 638 cmꢁ1; H NMR (300 MHz, CDCl3):
d 9.5 (s, 1H), 8.6 (s, 1H), 7.49–7.36 (m, 2H), 7.25 (d, 1H,
J¼8.3 Hz), 7.18 (td, 1H, J1¼7.6, J2¼0.9 Hz), 4.37 (m,

10208
S. Messaoudi et al. / Tetrahedron 63 (2007) 10202–10210
1H), 3.66 (s, 3H, CH3), 3.57 (d, 1H, J¼4.2 Hz), 1.41 (d, 3H,
J¼6.8 Hz, CH3); 13C NMR (75 MHz, CDCl3): d 174.1 (CO),
157.9 (CO), 135.7, 128.8, 128.7, 127.0, 123.1, 120.9, 120.8,
113.9, 69.0, 30.2 (CH3), 21.0 (CH3); m/z MS (ES+) 269
(M+Na+); Anal. Calcd for C13H14N2O3 (246.10): C 63.40,
H 5.73, N 11.38, found: C 62.89, H 5.32, N 11.08.
134.8, 128.8 (2C), 128.6 (2C), 128.4 (2C), 128.3 (2C),
128.2, 127.7, 127.5 (2C), 126.5, 123.1, 121.3, 118.9,
114.7, 67.2 (CH2Bn), 46.8 (CH2Bn); m/z MS (ES+) 407.0
(M+Na+); Anal. Calcd for C24H20N2O3 (384.14): C 74.98,
H 5.24, N 7.29; found: C 74.09, H 5.07, N 7.11.
4.4.10. Compound 3i. Yield: 85%; mp: 167–169 ꢀC; TLC:
Rf 0.56 (CH2Cl2/EtOAc: 7/3); IR (neat): 3167, 1640, 1618,
1595, 1541, 1507, 1465, 1435, 1418, 1366, 1338, 1308,
1275, 1231, 1189, 1157, 1112, 1090, 1036, 909, 947, 888,
4.4.6. Compound 3f. Yield: 46%; mp: 144–146 ꢀC; TLC: Rf
0.71 (CH2Cl2/EtOAc: 9/1); IR (neat): 3371, 1669, 1636,
1619, 1596, 1489, 1365, 1202, 1178, 1151, 1091, 1013,
1
905, 866, 766, 747, 680, 570 cmꢁ1; H NMR (300 MHz,
866, 816, 772, 749, 735, 724, 663, 638, 556 cmꢁ1 1H
;
CDCl3): d 9.28 (s, 1H), 8.77 (s, 1H), 7.81 (d, 2H, J¼
8.7 Hz), 7.64 (d, 2H, J¼8.3 Hz), 7.57 (dd, 1H, J1¼8.7,
J2¼1.0 Hz), 7.44 (td, 1H, J1¼8.4, J2¼1.3 Hz), 7.33–7.18
(m, 4H), 7.04 (d, 2H, J¼8.7 Hz), 3.57 (s, 3H), 2.39 (s,
3H). 13C NMR (75 MHz, CDCl3): d 164.6 (CO), 158.1,
152.3, 145.8, 135.7, 132.9, 131.9, 129.9 (2C), 128.9 (3C),
128.8, 128.5 (2C), 127.5, 123.3, 122.8 (2C), 120.9, 120.8,
114.0, 30.4 (OCH3), 21.8 (CH3); m/z MS (ES+) 449.0
(M+H+), 471 (M+Na+); Anal. Calcd for C24H20N2O5S
(448.10): C 64.27, H 4.49, N 6.25; found: C 63.98, H 4.01,
N 5.87.
NMR (300 MHz, CDCl3): d 7.99 (s, 1H), 7.74–7.70 (m,
3H), 7.47 (d, 1H, J1¼7.8, J2¼1.2 Hz), 7.39 (td, 1H, J1¼
8.4, J2¼1.2 Hz), 7.38–7.13 (m, 3H), 4.94 (s, 1H), 3.62 (s,
3H, CH3), 2.26 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3):
d 157.6 (CO), 144.2, 136.0, 135.9, 129.8 (2CH), 128.9,
128.3, 127.2 (2C), 126.9, 123.2, 120.3, 118.9, 114.0,
30.4 (CH3), 21.5 (CH3); m/z MS (ES+) 329.0 (M+H+),
351 (M+Na+); Anal. Calcd for C17H16N2O3S (328.08):
C 62.18, H 4.91, N 8.53; found: C 61.83, H 4.59, N 8.27.
4.4.11. Compound 3j. Yield: 74%; mp: 216–218 ꢀC; TLC:
Rf 0.64 (CH2Cl2); IR (neat): 3174, 2923, 2854, 1630, 1616,
1597, 1502, 1448, 1432, 1371, 1341, 1319, 1279, 1261,
1216, 1185, 1163, 1119, 1090, 1015, 941, 917, 865, 804,
4.4.7. Compound 3g. Yield: 44%; mp: 191–193 ꢀC; TLC: Rf
0.6 (CH2Cl2); IR (neat): 3343, 1631, 1619, 1526, 1505,
1461, 1425, 1359, 1334, 1250, 1218, 1173, 1029, 874,
773, 752, 729, 719, 690, 648, 627 cmꢁ1
;
1H NMR
1
838, 800, 596, 564 cmꢁ1; H NMR (300 MHz, CDCl3):
(300 MHz, DMSO-d6): d 9.88 (s, 1H), 7.95–7.90 (m, 3H),
7.78 (d, 1H, J¼7.7 Hz), 7.66 (t, 1H, J¼7.4 Hz), 7.59–7.52
(m, 2H), 7.41 (t, 1H, J¼7.3 Hz), 7.32 (d, 1H, J¼8.5 Hz),
7.28–7.19 (m, 4H), 6.97 (d, 2H, J¼6.8 Hz), 5.47 (s, 2H,
CH2Bn); 13C NMR (75 MHz, DMSO-d6): d 157.5 (CO),
139.4, 136.2, 135.6, 133.1, 129.4, 129.1 (2C), 128.6 (3C),
127.1, 126.9 (2C), 126.7 (2C), 126.4, 124.2, 122.8, 119.7,
114.9, 45.4 (CH2Bn); m/z MS (ES+) 413.0 (M+Na+); Anal.
Calcd for C22H18N2O3S (390.10): C 67.67, H 4.65,
N 7.17; found: C 67.39, H 4.16, N 6.92.
d 9.31 (s, 1H), 8.77 (s, 1H), 7.91 (d, 2H, J¼8.8 Hz), 7. 47
(d, 1H, J¼2.2 Hz), 7.55 (dd, 1H, J1¼8.9, J2¼2.2 Hz), 7.22
(d, 1H, J¼8.9 Hz), 6.98 (d, 2H, J¼8.8 Hz), 3.88 (s, 3H),
3.80 (s, 3H); 13C NMR (75 MHz, CDCl3): d 165.4 (CO),
162.9, 157.9 (CO), 134.4, 131.1, 130.6, 129.2 (2CH),
128.8, 126.2, 122.9, 118.6, 116.1, 115.6, 114.1 (2CH),
55.5 (OCH3), 30.5 (CH3); m/z MS (ES+) 409.0 (M+Na+,
79Br), 411.0 (M+Na+, 81Br); Anal. Calcd for C18H15BrN2O3
(386.02): C 55.83, H 3.90, N 7.23; found: C 55.28, H 3.66,
N 7.08.
4.4.12. Compound 3k. Yield: 66%; mp: 198–199 ꢀC; TLC:
Rf 0.24 (c-hexane/EtOAc: 6/4); IR (neat): 3156, 2926, 2854,
1729, 1642, 1621, 1598, 1507, 1447, 1417, 1419, 1361,
1335, 1317, 1280, 1219, 1184, 1146, 1110, 1073, 1040,
981, 968, 921, 894, 869, 858, 780, 755, 712, 658, 634,
4.4.8. Compound bis-3g. Yield: 27%; mp: 256–258 ꢀC;
TLC: Rf 0.15 (Et2O); IR (neat): 3387, 3274, 2924, 1734,
1672, 1638, 1603, 1578, 1524, 1490, 1364, 1251, 1180,
1052, 858, 841, 804, 756, 732, 677, 610, 596, 559 cmꢁ1
;
1H NMR (300 MHz, CDCl3): d 10.24 (s, 1H), 9.41 (s, 1H),
8.64 (s, 1H), 8.14 (d, 1H, J¼2.2 Hz), 7.99 (d, 2H, J¼
8.7 Hz), 7.93–7.89 (m, 3H), 7.56 (d, 1H, J¼8.2 Hz), 7.11–
7.06 (m, 4H), 3.85 (s, 6H), 3.76 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 164.8 (CO), 164.4 (CO), 162.3,
161.9, 156.9 (CO), 134.6, 131.7, 129.5 (2CH), 129.1
(2CH), 127.8, 126.7, 125.8, 121.8, 120.1, 119.7, 118.4,
114.9, 114.1 (2CH), 113.6 (2CH), 55.5 (OCH3), 55.4
(OCH3), 30.1 (CH3); m/z MS (ES+) 480.0 (M+Na+); Anal.
Calcd for C26H23N3O5 (457.16): C 68.26, H 5.07, N 9.19;
found: C 67.79, H 4.88, N 8.88.
556 cmꢁ1; H NMR (300 MHz, CDCl3): d 7.76 (s, 1H),
1
7.72 (s, 1H), 7.53 (dd, 1H, J1¼7.8, J2¼1.1 Hz), 7.47 (td,
1H, J1¼8.6, J2¼1.4 Hz), 7.31 (d, 1H, J¼8.4 Hz), 7.24 (td,
1H, J1¼7.8, J2¼0.6 Hz), 3.75 (s, 3H, CH3), 2.99 (s, 3H,
CH3); 13C NMR (75 MHz, CDCl3): d 157.8 (CO), 136.1,
129.2, 128.5, 127.2, 123.4, 120.3, 119.5, 114.2, 39.4, 30.5.
m/z MS (ES+) 275.0 (M+Na+); Anal. Calcd for
C11H12N2O3S (252.05): C 52.37, H 4.79, N 11.10; found:
C 51.82, H 4.33, N 10.86.
4.4.13. Compound 3l. Yield: 68%; mp: 180–182 ꢀC; TLC:
Rf 0.50 (CH2Cl2); IR (neat): 3179, 1615, 1599, 1583,
1499, 1441, 1367, 1353, 1315, 1278, 1223, 1148, 1119,
1041, 1015, 974, 943, 899, 870, 776, 749, 724, 692, 661,
4.4.9. Compound 3h. Yield: 57%; mp: 136–138 ꢀC; TLC:
Rf 0.71 (CH2Cl2); IR (neat): 3266, 1717, 1633, 1622,
1601, 1532, 1490, 1455, 1388, 1364, 1342, 1316, 1256,
1217, 1197, 1129, 1086, 1052, 1027, 993, 974, 940, 926,
1
628 cmꢁ1; H NMR (300 MHz, CDCl3): d 7.81 (s, 1H),
7.71 (br s, 1H), 7.54 (dd, 1H, J1¼7.8, J2¼1.1 Hz), 7.33
(td, 1H, J1¼8.4, J2¼1.3 Hz), 7.27–7.11 (m, 7H), 5.55 (s,
2H), 3.04 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3):
d 158.0 (CO), 135.5 (2C), 129.2, 128.9 (2C), 128.6, 127.6,
127.2, 126.5 (2C), 123.4, 120.5, 119.7, 115.0, 47.1, 39.5;
m/z MS (ES+) 351.0 (M+Na+); Anal. Calcd for
1
906, 887, 847, 772, 744, 730, 637, 563 cmꢁ1; H NMR
(300 MHz, DMSO-d6): d 8.46 (s, 1H), 8.16 (s, 1H), 7.61
(dd, 1H, J1¼7.7, J2¼0.9 Hz), 7.48–7.18 (m, 13H), 5.63 (s,
2H, CH2Bn), 5.28 (s, 2H, CH2Bn); 13C NMR (75 MHz,
DMSO-d6): d 157.9 (CO), 153.4 (CO), 135.9, 135.8,

S. Messaoudi et al. / Tetrahedron 63 (2007) 10202–10210
10209
C17H16N2O3S (328.08): C 62.18, H 4.91, N 8.53; found: C
61.83, H 4.67, N 8.10.
125.5, 124.7, 122.7, 122.5 (2C), 122.2, 113.7, 105.0, 49.3,
30.1, 23.5; m/z MS (ES+) 351.0 (M+Na+); Anal. Calcd for
C22H20N2O (328.15): C 80.46, H 6.14, N 8.53; found: C
89.88, H 6.09, N 8.33.
4.4.14. Compound 3m. Yield: 61%; mp: 164–165 ꢀC; TLC:
Rf 0.4 (Et2O/c-hexane: 1/1); IR (neat): 3465, 3225, 1702,
1633, 1616, 1525, 1492, 1386, 1237, 1207, 902, 755, 747,
4.4.19. Compound 4e. Yield: 60%; mp: 98–99 ꢀC; TLC: Rf
0.48 (CH2Cl2); IR (neat): 3334, 2941, 1633, 1597, 1510,
1485, 1460, 1414, 1370, 1336, 1252, 1193, 1040, 1022,
1
725, 695, 570 cmꢁ1; H NMR (300 MHz, CDCl3): d 10.03
(s, 2H, NH), 8.67(s, 2H), 7.72 (d, 2H, J¼2.2 Hz), 7.40–
7.22 (m, 16H), 5.65 (s, 4H); 13C NMR (75 MHz, CDCl3):
d 157.5 (2CO), 152.9 (CO), 136.5 (2C), 134.1 (2C), 128.9
(2C), 128.7 (4CH), 127.9 (2C), 127.8 (2C), 121.1 (2C),
126.5 (4CH), 122.8 (2C), 120.9 (2C), 118.2 (2C), 114.8
(2C), 45.6 (2ꢂCH2Bn); m/z MS (ES+) 549.0 (M+Na+);
Anal. Calcd for C33H26N4O3 (526.20): C 75.27, H 4.98, N
10.64; found: C 74.89, H 4.69, N 10.44.
1
979, 863, 824, 779, 741, 614 cmꢁ1; H NMR (300 MHz,
CDCl3): d 7.40 (d, 1H, J¼7.5 Hz), 7.24–7.09 (m, 3H),
6.77 (s, 1H), 5.36 (s, 1H), 3.71 (s, 3H), 2.40 (m, 1H),
0.75–0.72 (m, 2H), 0.54–0.51 (m, 2H); 13C NMR
(75 MHz, CDCl3): d 158.5 (CO), 137.6, 133.4, 128.8,
125.8, 122.9, 122.6, 113.8, 105.1, 30.0, 24.3, 6.9 (2C); m/z
MS (ES+) 215 (M+H+) 237.0 (M+Na+), 451.0 (2M+Na+);
Anal. Calcd for C13H14N2O (214.11): C 72.87, H 6.59, N
13.07; found: C 72.02, H 6.34, N 12.79.
4.4.15. Compound 4a. Yield: 93%; mp: 95–97 ꢀC; TLC: Rf
0.79 (CH2Cl2); IR (neat): 3304, 2925, 1599, 1581, 1521,
1490, 1462, 1444, 1415, 1369, 1110, 931, 902, 774, 734,
4.4.20. Compound 4f. Yield: 83%; mp: 89–90 ꢀC; TLC: Rf
0.45 (CH2Cl2); IR (neat): 3334, 2955, 2865, 1632, 1607,
1594, 1509, 1489, 1461, 1417, 1388, 1366, 1319, 1263,
1236, 1205, 1142, 1080, 1042, 918, 847, 824, 805, 778,
1
705, 623, 559 cmꢁ1; H NMR (300 MHz, CDCl3): d 7.34–
7.09 (m, 10H), 6.97 (t, 1H, J¼7.3 Hz), 3.74 (s, 3H); 13C
NMR (75 MHz, CDCl3): d 158.7, 140.7, 133.9, 132.7,
129.5 (2CH), 126.4, 125.9, 122.8, 122.6, 122.1, 120.1
(2CH), 113.8, 106.9, 30.4; m/z MS (ES+) 273.0 (M+Na+),
289.0 (M+K+); Anal. Calcd for C16H14N2O (250.11): C
76.78, H 5.64, N 11.19; found: C 76.49, H 5.47, N 11.09.
1
729, 645, 576 cmꢁ1; H NMR (300 MHz, CDCl3): d 7.34
(dd, 1H, J1¼8.3, J2¼1.1 Hz), 7.20–7.07 (m, 3H), 6.35 (s,
1H), 5.1 (br s, 1H, NH), 3.71 (s, 3H), 3.09 (q, 2H, J¼
6.8 Hz), 1.64–1.56 (m, 2H), 145–1.33 (m, 2H), 0.90 (t, 3H,
J¼7.3 Hz); 13C NMR (75 MHz, CDCl3): d 158.6, 137.1,
132.9, 125.5, 124.4, 123.1, 122.6, 113.7, 102.9, 42.8, 30.8,
30.1, 20.4, 13.9; m/z MS (ES+) 231.0 (M+H+), 253.0
(M+Na+); Anal. Calcd for C14H18N2O (230.14): C 73.01,
H 7.88, N 12.16; found: C 72.87, H 7.67, N 12.01.
4.4.16. Compound 4b. Yield: 89%; mp: 153–154 ꢀC; TLC:
Rf 0.45 (CH2Cl2); IR (neat): 3291, 1733, 1617, 1587, 1531,
1504, 1464, 1447, 1424, 1377, 1348, 1211, 1123, 1016, 865,
803, 740, 690, 594, 570 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d 7.37–6.96 (m, 11H), 5.10 (s, 2H), 4.18 (q, 2H, J¼7.1 Hz),
1.20 (t, 3H, J¼7.1 Hz); 13C NMR (75 MHz, CDCl3):
d 168.0, 158.7, 140.5, 133.2, 132.5, 129.5 (2CH), 126.7,
126.1, 123.2, 122.8, 122.2, 120.3 (2CH), 113.2, 107.7,
61.8, 44.8, 14.2; m/z MS (ES+) 345.0 (M+Na+); Anal. Calcd
for C19H18N2O3 (322.13): C 70.79, H 5.63, N 8.69; found: C
70.47, H 5.49, N 8.47.
4.4.21. Compound 4g. Yield: 76%; mp: 125–127 ꢀC; TLC:
Rf 0.29 (CH2Cl2); IR (neat): 2941, 1630, 1593, 1495, 1455,
1382, 1338, 1301, 1279, 1238, 1185, 1120, 1029, 995, 1034,
885, 858, 736, 718, 696, 670, 620 cmꢁ1
;
1H NMR
(300 MHz, CDCl3): d 7.39 (dd, 1H, J1¼7.5, J2¼1.2 Hz),
7.22–7.10 (m, 7H), 7.05 (td, 1H, J1¼8.1, J2¼1.6 Hz), 6.93
(s, 1H), 5.50 (s, 2H), 3.13–3.08 (m, 4H), 1.75–1.68 (m,
4H), 158–1.51 (m, 2H); 13C NMR (75 MHz, CDCl3):
d 159.8, 143.0, 136.6, 135.6, 128.7 (2C), 127.2 (2C),
127.1, 126.7 (2C), 122.3, 121.7, 119.0, 114.5, 51.1 (2C),
46.6, 25.9 (2C), 24.5; m/z MS (ES+) 341.0 (M+Na+), 357.0
(M+K+); Anal. Calcd for C21H22N2O (318.17): C 79.21, H
6.96, N 8.80; found: C 78.88, H 6.77, N 8.69.
4.4.17. Compound 4c. Yield: 88%; mp: 133–135 ꢀC; TLC:
Rf 0.68 (CH2Cl2); IR (neat): 3355, 2928, 1615, 1598, 1509,
1488, 1453, 1418, 1377, 1355, 1324, 1295, 1025, 986, 822,
777, 745, 735, 720, 691, 620, 600 cmꢁ1
;
1H NMR
(300 MHz, CDCl3): d 7.31–7.17 (m, 8H), 7.05 (m, 1H),
6.34 (s, 1H), 5.60 (t, 1H, J¼5.2 Hz), 4.34 (d, 2H, J¼
5.8 Hz), 3.72 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 158.6, 138.2, 136.7, 133.2, 128.7 (2CH), 127.3, 127.2
(2CH), 125.8, 124.8, 122.8, 122.6, 113.6, 104.1, 47.3,
30.1; m/z MS (ES+) 287.0 (M+Na+), 303.0 (M+K+); Anal.
Calcd for C17H16N2O (264.12): C 77.25, H 6.10, N 10.60;
found: C 77.08, H 6.01, N 10.23.
4.4.22. Compound 4h. Yield: 48%; mp: 141–143 ꢀC; TLC:
Rf 0.1 (CH2Cl2); IR (neat): 2812, 1634, 1612, 1588, 1493,
1447, 1421, 1377, 1305, 1263, 1226, 1204, 1118, 1059,
1
1011, 910, 895, 803, 778, 759, 686, 665, 570 cmꢁ1; H
NMR (300 MHz, CDCl3): d 7.61 (d, 1H, J¼2.2 Hz), 7.48
(dd, 1H, J1¼8.9, J2¼2.2 Hz), 7.18 (d, 1H, J¼8.9 Hz), 6.82
(s, 1H), 3.94–3.90 (m, 4H), 3.72 (s, 3H), 3.27–3.23 (m,
4H); 13C NMR (75 MHz, CDCl3): d 158.9, 142.4, 135.0,
130.0, 129.2, 122.8, 116.8, 115.4, 115.2, 66.8 (2C), 49.8
(2C), 30.1; m/z MS (ES+) 345.0 (M+Na+, 79Br), 347.0
(M+Na+, 81Br); Anal. Calcd for C14H15BrN2O2 (322.03):
C 52.03, H 4.68, N 8.67; found: C 51.97, H 4.31, N 8.36.
4.4.18. Compound 4d. Yield: 74%; mp: 163–164 ꢀC; TLC:
Rf 0.6 (CH2Cl2); IR (neat): 3408, 2973, 1615, 1594, 1509,
1476, 1413, 1365, 1326, 1242, 1204, 1117, 1090, 1040,
1
852, 827, 804, 779, 754, 742, 647, 559 cmꢁ1; H NMR
(300 MHz, CDCl3): d 8.10 (d, 1H, J¼8.4 Hz), 7.83 (dd,
1H, J1¼7.9, J2¼1.4 Hz), 7.66 (d, 1H, J¼8.2 Hz), 7.53–
7.41 (m, 3H), 7.30 (t, 1H, J¼7.7 Hz), 7.16–7.08 (m, 2H),
6.99–6.89 (m, 2H), 5.96 (s, 1H), 5.70 (d, 1H, J¼5.3 Hz),
5.21 (m, 1H), 3.72 (s, 3H), 1.65 (d, 3H, J¼6.7 Hz); 13C
NMR (75 MHz, CDCl3): d 158.6 (CO), 138.7, 135.5,
134.1, 133.1, 130.7, 129.2, 127.7, 126.2 125.9, 125.8,
4.4.23. Compound bis-4h. The compound is not sufficiently
stable to be fully characterized. Yield: 15%; TLC: Rf 0.13
(CH2Cl2); IR (neat): 2922, 2853, 1637, 1618, 1597, 1568,
1436, 1372, 1321, 1260, 1236, 1203, 1113, 1064, 1009,

10210
S. Messaoudi et al. / Tetrahedron 63 (2007) 10202–10210
1
931, 898, 801, 781, 704, 659 cmꢁ1; H NMR (300 MHz,
CDCl3): d 7.19 (d, 1H, J¼9.1 Hz), 7.02 (dd, 1H, J1¼9.1,
J2¼2.6 Hz), 6.88 (d, 1H, J¼2.6 Hz), 6.82 (s, 1H), 3.85–
3.80 (m, 8H), 3.66 (s, 3H), 3.19–3.14 (m, 4H), 3.13–3.06
(m, 4H); m/z MS (ES+) 352.0 (M+Na+).
Org. Chem. 2004, 479–486; (e) Andresen, B. M.; Couturier,
M.; Cronin, B.; D’Occhio, M.; Ewing, M. D.; Guinn, M.;
Hawkins, J. M.; Jasys, V. J.; LaGreca, S. D.; Lyssikatos, J. P.;
Moraski, G.; Ng, K.; Raggon, J. W.; Stewart, A. M.; Tickner,
D. L.; Tucker, J. L.; Urban, F. J.; Vazquez, E.; Wei, L. Org.
Process Res. Dev. 2004, 8, 643–650.
5. (a) Williams, A. C.; Camp, N. Science of Synthesis: Houben–
Weyl Methods of Molecular Transformations; Bellus, D., Ley,
S. V., Noyori, R., Regitz, M., Schaumann, E., Shinkai, E.,
Thomas, E. J., Trost, B. M., Reider, P. J., Series Eds.;
Thomas, E. J., Volume Ed.; Thieme: Stuttgart, Germany,
2004; Vol. 14, pp 347–438; (b) Kadnikov, D. V.; Larock,
R. C. J. Org. Chem. 2004, 69, 6772–6780; (c) Manley, P. J.;
Bilodeau, M. T. Org. Lett. 2004, 6, 2433–2435; (d) Glasnov,
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Acknowledgements
The CNRS is gratefully acknowledged for support of
this research and the European Community for a doctoral
fellowship to D.A.
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