The first synthesis of 2-amino-1,4-dihydroquinolines

Article abstract of DOI:10.1016/j.tet.2009.10.018

A versatile strategy is described for the synthesis of new 2-amino-1,4-dihydroquinolines. It involved a Knoevenagel condensation of N-protected-2-amino-5-bromobenzaldehyde with ethylcyanoacetate, followed by a cyclization and protection of the NH group to

Full text of DOI:10.1016/j.tet.2009.10.018

Tetrahedron 65 (2009) 10149–10154
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The first synthesis of 2-amino-1,4-dihydroquinolines
a
a
b
c
a,
*
´
´
´
Guillaume Viault , Danielle Gree , Thierry Roisnel , Srivari Chandrasekhar , Rene Gree
a Universite´ de Rennes 1, Laboratoire CPM, CNRS UMR 6510, Avenue du Ge´ne´ral Leclerc, 35042 Rennes Cedex, France
b Universite´ de Rennes 1, Sciences Chimiques de Rennes, CNRS UMR 6226, Campus de Beaulieu, 35042 Rennes-Cedex, France
c Indian Institute of Chemical Technology, 500607 Hyderabad, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 July 2009
Received in revised form 2 October 2009
Accepted 6 October 2009
Available online 13 October 2009
A versatile strategy is described for the synthesis of new 2-amino-1,4-dihydroquinolines. It involved
a Knoevenagel condensation of N-protected-2-amino-5-bromobenzaldehyde with ethylcyanoacetate,
followed by a cyclization and protection of the NH group to afford the key intermediates 7 or 19. Then
various 1,4 addition reactions have been performed to introduce substituents on the upper part of the
2-amino-1,4-dihydroquinolines.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
1,4-Dihydroquinolines
HA 14-1
Benzopyran
Anti-cancer
Bcl-2
1. Introduction
studied either by modification of the malonic type derivative, or by
introduction of halogen, aryl, or amino groups in the aromatic
The 2-amino-4H-chromenes belong to an important, and well
studied, group of heterocyclic compounds.1 During the last decade,
molecules with this skeleton have demonstrated potent biological
activity in various areas of medicinal chemistry. In particular, sev-
eral derivatives such as HA 14-1 and MX58151, which are known to
have proapoptotic activity, are under development as anti-cancer
agents (Fig. 1).2,3
aldehyde part.1–4
As a part of our programme on new anti-cancer agents active
through an apoptosis inducing mechanism,5,6 we became in-
terested in the ‘aza-analogues’ of these 2-amino-4H-chromenes, i.e,
the corresponding 2-amino-1,4-dihydroquinolines (Fig. 1).
The synthesis of 1,4-dihydroquinolines has been rarely de-
scribed in the literature.7 Several 2-methyl-1,4-dihydroquinolines
have been obtained by regioselective reduction of quinolinium salts
with sodium dithionite in the presence of sodium carbonate. These
1,4-dihydroquinolines are inhibitors of acetylcholine esterase and
therefore active against neurodegenerative diseases.8 The same
methodology was used for the synthesis of 1,2,4-trimethyl-1,4-
dihydroquinolines.9 Finally, a synthesis of N-substituted 1,4-dihy-
droquinolines, with an hydrogen on position 2, has been developed
starting from Baylis–Hillman adducts.10
N
R3
EtO2C
CN
CO2Et
EWG
NHZ
CN
Br
R4
N
R1
N
O
NH2
O
NH2
MX58151
2-amino-1,4-dihydroquinolines
HA 14-1
To the best of our knowledge, 2-amino-1,4-dihydroquinolines
have not been reported until now in the literature. Our strategy to
access such molecules was designed by analogy with the prepara-
tion of the corresponding 4H-chromenes.4,6 Our first target mole-
cules (type A) have been selected for Structure–Activity
Relationships in comparison with HA 14-1 derivatives, and there-
fore, we have kept the bromo substituent in para position to the
aromatic amine. These 1,4-dihydroquinolines could be obtained by
Michael addition reactions on the key imine (B), which should be
Figure 1. Representative 2-amino-4H-chromenes and general formula for targets
2-amino-1,4-dihydroquinolines.
These 2-amino-4H-chromenes are generally prepared by re-
action of a malonic derivative with substituted salicylaldehydes.
The molecular diversity around the skeleton was extensively
obtained by
a
Knoevenagel condensation between ethyl-
* Corresponding author. Tel.: þ33 2 23 23 57 15; fax: þ33 2 23 23 65 98.
´
cyanoacetate and the aldehyde (C). This latter derivative could be
E-mail address: rene.gree@univ-rennes1.fr (R. Gree).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.018

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G. Viault et al. / Tetrahedron 65 (2009) 10149–10154
prepared from anilino ester 1. In this strategy the amine function
must be protected with an appropriate R1 group. It has been
established earlier that, in the case of the primary amines obtained
for instance by reduction of a nitro group, the Knoevenagel con-
densation was followed by heterocyclization and aromatization
affording 2-aminoquinolines.11
The access to the key intermediate 7 should allow us to syn-
thesize a large variety of novel 2-amino-1,4-dihydroquinolines with
a molecular diversity in the upper position by 1,4 additions of nu-
cleophilic substrates. As a first example, the reaction with vinyl-
magnesiumbromide and copper iodide in THF at 0 ꢀC gave the
desired adduct 8 in 53% yield (Scheme 3). The structure of this
compound was established by NMR and unambiguously confirmed
by X-ray analysis (Fig. 2).14
2. Results and discussion
R
The reaction of the commercially available methyl-2-amino-5-
bromobenzoate 1 with benzoyl chloride and sodium bicarbonate in
CH2Cl2 at 0 ꢀC afforded 2 in 88% yield (Schemes 1 and 2). This amido
ester 2 was reduced by excess lithium aluminium hydride in THF at
ꢁ10 ꢀC to give, in 85% yield, the desired amino alcohol 3 which, on
further oxidation by 2-iodoxybenzoic acid (IBX) in a mixture of
CH2Cl2/DMSO, afforded the desired aldehyde intermediate 4 in 82%
yield.12 The next step of the synthesis was the Knoevenagel con-
Br
CO2Et
NHAc
Br
CO2Et
NHAc
MgBr
R
7
N
N
CuI, THF,
(53%)
DCM, Grubbs
catalyst 5 mol%
8
9a: R=CO2Et (74%)
9b: R=C6H5 (53%)
R
densation involving reaction of the aldehyde
4 with ethyl-
Br
CO2Et
NH2
cyanoacetate (1.1 equiv) and piperidine in ethanol. Under these
conditions the imine intermediate 6 was isolated in 86% yield. This
condensation gave only heterocylization on the nitrile group, in the
same way as for HA 14-1 and most of the analogues.13
N2H4.H2O
EtOH
8 and 9b
N
R3
Br
CO2Et
N-R2
10: R=H (26%)
Br
CO2Et
NH-R2
10b: R=C6H5 (48%)
N
R1
Scheme 3. Addition of vinyl cuprate on intermediate 7, followed by cross coupling
N
R1
metathesis reactions.
A
B
Br
CHO
Br
CO2Me
NH2
NH
R1
1
C
Scheme 1. Retrosynthetic analysis for the preparation of our target 1,4-dihydro-
quinolines.
Acetylation of the imine function was performed to give the
desired intermediate 7 in 95% yield. This protection should not only
stabilize imine 6 but also increase its reactivity towards the pro-
grammed Michael additions.
Figure 2. X-ray crystal structure of 1,4-dihydroquinoline 8.
O
O
Br
Br
Then, cross coupling metathesis reactions of 8 with ethylacrylate
or styrene in CH2Cl2 and in the presence of second generation
Grubbs catalyst15 at 5 mol %, gave the desired products 9a and 9b
with 37% and 53% yields, respectively. The yield of 9a could be in-
creased to 74%, when taking into account the recovery of starting
material. The amine function of 8 and 9b were deprotected by re-
action with hydrazine monohydrate to give the desired 2-amino-1,4-
dihydroquinolines 10 and 10b with 26% and 48% yields, respectively.
In the same way, the reaction of 7 with phenyllithium and
copper iodide in THF at 0 ꢀC gave the desired adduct 11 in 42% yield.
Deprotection with hydrazine afforded the targeted amine 12
(Scheme 4).
OH
NH
O
Br
LAH, THF,
(85%)
PhCOCl, NaHCO3
DCM, (88%)
O
NH
NH2
O
1
3
2
Br
Br
CO2Et
CN
O
EtO2C
CN
IBX, DMSO,
DCM, (82%)
NH
NH
EtOH, Piperidine,
4Å MS, (86%)
5
4
Br
CO2Et
NH
Br
CO2Et
NAc
Br
CO2Et
NHAc
Br
CO2Et
NH2
Ac2O,
N2H4.H2O
Phenyllithium
7
N
N
N
4Å MS, (95%)
CuI, THF,
(42%)
EtOH, (40%)
N
6
7
11
12
Scheme 4. Addition of phenyl cuprate on intermediate 7.
Scheme 2. Synthesis of the key intermediate 7.

G. Viault et al. / Tetrahedron 65 (2009) 10149–10154
10151
Another series of new 2-amino-1,4-dihydroquinolines was
obtained from 7 by addition of nitromethane in the presence of
tetramethylguanidine to give the adduct 13 in 95% yield. The nitro
group could be reduced by hydrogen with Raney Nickel, affording
the desired amine 14 in 74% yield (Scheme 5).
previous intermediate 2, the reaction with lithium aluminium hy-
dride (1.0 equiv) reduced selectively the ester function to give the
amido alcohol 16 in 98% yield. The oxidation of 16 by IBX afforded
the aldehyde 17 in 89% yield. The heterocyclization was accom-
plished after the Knoevenagel condensation with ethyl-
cyanoacetate in ethanol at 60 ꢀC to give the imine 18 in 95% yield.
This compound was again activated by acetylation of the
imine function with acetic anhydride and pyridine to afford the
key intermediate 19 in 72% yield. This derivative appears to be
less reactive than 7 as a Michael acceptor. However, the reaction
of 19 with phenyllithium and copper iodide in THF at 0 ꢀC oc-
curred with concommittent deprotection of the amine, affording
the target molecule 20 in 30% yield. The structure of this com-
pound was established by spectral and analytical data. In par-
ticular, the 1H NMR spectrum of 20 indicated two different
chemical shifts at 13.29 ppm and 11.04 ppm for the protons of
the amine, due to the presence of two intramolecular hydrogen
bonds (Scheme 7).
NH2
CO2Et
NO2
CO2Et
Br
Br
H2, Raney Ni
EtOH, (74%)
CH3NO2
7
N
NHAc
N
NHAc
TMG, (95%)
14
Scheme 5. Addition of nitromethane anion on intermediate 7.
13
The anions of ethylcyanoacetate, diethylmalonate or malononi-
trile did not react in EtOH with piperidine with our intermediate 7,
affording only recovery of starting materials and/or decomposition
products (Scheme 6). This unexpected result shows that 7 has
a lower reactivity than its oxygen counterpart, the benzopyran-2-
imine used for the synthesis of HA 14-1 and analogues.6
3. Conclusions
We have synthesized the first series of novel 2-amino-1,4-
dihydroquinolines in six to seven steps from commercial methyl-
2-amino-5-bromobenzoate. The key intermediate 7, obtained in
five steps and 50% yield, allowed us to introduce various sub-
stituents in the upper position of the skeleton. Furthermore, it
was also possible to modulate the protective group on the
intracyclic nitrogen. Exploration of the reactivity of these Mi-
chael acceptors 7 and 19 as well as extension of these syntheses
is under active study in our group. The biological activity of these
new 2-amino-1,4-dihydroquinolines is under evaluation and
particularly their interaction with the anti apoptotic family of
proteins such as Bcl-2 or BcL-xL. Results of these studies will be
reported in due course.
R2
R1
Br
CO2Et
NAc
Br
CO2Et
NHAc
X
N
N
7
15
15a:R1 = CN, R2 = CO2Et
15b:R1= R2 = CO2Et
15c:R1 = R2 = CN
Scheme 6. Tentative additions of malonic derivatives on intermediate 7.
4. Experimental section
4.1. General
O
Br
Br
Br
OH
O
O
IBX, DMSO,
DCM, (89%)
LAH, THF,
(98%)
NH
NH
NH
4.1.1. Methyl 2-benzamido-5-bromobenzoate (2)12. To a mixture of
methyl-2-amino-5-bromobenzoate (1 g, 4.35 mmol, 1.0 equiv),
NaHCO3 (0.73 g, 8.70 mmol, 2.0 equiv) and anhydrous CH2Cl2
(8 mL), benzoyl chloride (0.56 mL, 4.80 mmol, 1.1 equiv) was added
dropwise at 0 ꢀC. The solution was stirred under argon at room
temperature for 5 h. After adding water, the mixture was extracted
with CH2Cl2. The combined CH2Cl2 fractions were washed with
water, brine, dried over MgSO4, and concentrated under vacuum.
The ester (2) was obtained after purification of the crude solid by
washing with diethyl ether (1.15 g, yield 88%); mp 130–132 ꢀC. 1H
O
O
O
2
16
17
Br
CO2Et
Br
CO2Et
NAc
EtO2C
CN
Ac2O, Py
N
NH
N
4Å MS, (72%)
EtOH, Piperidine,
4Å MS, (95%)
O
O
18
19
NMR
d ppm (CDCl3, 300 MHz): 3.97 (s, 3H), 7.45–7.60 (m, 3H), 7.68
(dd, J¼2.4, 9.0 Hz,1H), 8.00–8.10 (m, 2H), 8.19 (d, J¼2.4 Hz,1H), 8.87
(d, J¼9.0 Hz, 1H), 11.95 (br s, 1H). 13C NMR
d ppm (CDCl3, 75 MHz):
OEt
52.8, 115.0, 116.6, 122.1, 127.4 (2Car), 128.9 (2Car), 132.2, 133.5, 134.5,
137.5, 140.9, 165.6, 167.9. EI-HRMS: calcd for [C15H12BrNO3]þ:
333.0000, found: 332.9982.
Br
O
Phenyllithium
H
N
N
H
CuI, THF,
(42%)
4.1.2. (2-(benzylamino)-5-bromophenyl)methanol (3)12. To a sus-
pension of LiAlH4 (3,13 g, 83 mmol, 5.5 equiv) in anhydrous THF
(90 mL) at ꢁ10 ꢀC was added a solution of compound (2) (5 g,
15 mmol, 1.0 equiv) in anhydrous THF (40 mL) at ꢁ10 ꢀC. The so-
lution was stirred under argon at room temperature for 12 h. The
mixture was quenched successively with a 2 M NaOH aqueous so-
lution (4 mL) and water (4 mL). The mixture was dried over MgSO4,
filtered and concentrated under vacuum. The alcohol (3) was
obtained as a colourless oil (3.7 g, yield 85%) after purification by
flash column chromatography on silica gel (P/ EA: 8/2). 1H NMR
O
20
Scheme 7. Synthesis and reaction of benzoyl protected intermediate 19.
These series of novel 2-amino-1,4-dihydroquinolines were
obtained with the benzyl group to protect the intracyclic nitrogen.
In order to extend this synthesis, we changed this protecting group
with a benzoyl substituent, as shown in Scheme 7. Starting from the

10152
G. Viault et al. / Tetrahedron 65 (2009) 10149–10154
d
ppm (CDCl3, 300 MHz): 4.36 (s, 2H), 4.62 (s, 2H), 6.51 (d, J¼8.4 Hz,
water, brine, dried over MgSO4 and concentrated under vacuum.
Compound (8) was obtained as a white solid (120 mg, yield 53%) after
1H), 7.15–7.40 (m, 7H). 13C NMR
d
ppm (CDCl3, 75 MHz): 47.7, 64.1,
108.3, 112.7, 126.3, 127.3 (3Car), 128.7 (2Car), 131.4, 132.0, 138.8,
146.3.
purification by flash column chromatography on silica gel (P/EA: 9/1);
mp 134–136 ꢀC. 1H NMR
d
ppm (CDCl3, 500 MHz): 1.35 (t, J¼7.1 Hz,
3H), 2.24 (s, 3H), 4.15–4.35 (m, 2H), 4.67 (d, J¼5.5 Hz, 1H), 4.74 (m,
1H), 4.84 (d, J¼16.2 Hz, 1H), 4.99 (m, 1H), 5.07 (d, J¼16.2 Hz, 1H), 5.76
(m, 1H), 6.88 (d, J¼8.8 Hz, 1H), 7.10–7.40 (m, 7H), 10.15 (s, 1H). 13C
4.1.3. 2-(Benzylamino)-5-bromobenzaldehyde (4). To a mixture of
IBX (10.6 g, 38.0 mmol, 3.0 equiv), DMSO (55 mL) and CH2Cl2
(40 mL), a solution of compound (3) (3.7 g, 12.7 mmol, 1.0 equiv) in
CH2Cl2 (40 mL) was added dropwise. The solution was stirred un-
der argon at reflux for 1 h. The reaction was quenched with water
(20 mL) at 0 ꢀC and the residue of IBX was filtered on a pad of Celite.
The mixture was extracted with CH2Cl2 and the organic layers were
washed three times with water, brine, dried over MgSO4, and
concentrated under vacuum. The aldehyde (4) was obtained as
a yellow solid (3.0 g, yield 82%) after purification by flash column
chromatography on silica gel (P/EA): (9/1); mp 72–74 ꢀC. 1H NMR
NMR d ppm (CDCl3, 125 MHz): 14.5, 24.7, 40.8, 50.2, 60.2, 89.5, 113.8,
116.4, 118.4 127.5, 127.6 (2Car), 128.5 (2Car), 129.3, 129.9, 131.4, 136.8,
137.4, 140.0, 147.1, 168.7, 170.7. ES-HRMS: calcd for
79
[C23
H
BrN2O3þNa]þ: 477.0790, found: 477.0793.
23
4.1.7. (E)-Ethyl
2-(acetamido)-1-benzyl-6-bromo-4-(3-ethoxy-3-
oxoprop-1-enyl)-1,4-dihydroquinoline-3-carboxylate (9a). A mix-
ture of compound (8) (320 mg, 0.71 mmol, 1.0 equiv), anhydrous
CH2Cl2 (5 mL), ethylacrylate (0.76 mL, 7.14 mmol, 10.0 equiv) and
second generation Grubbs catalyst (30 mg, 0.035 mmol, 0.05 equiv)
was stirred under argon at reflux for 48 h. The solution was con-
centrated under vacuum and ester (9a) was obtained as a brown
solid (140 mg, yield 37%) after purification by flash column chro-
matography on silica gel (P/EA: 9/1). During this process 150 mg of
d
ppm (CDCl3, 300 MHz): 4.47 (s, 2H), 6.55 (d, J¼9.0 Hz, 1H), 7.25–
7.45 (m, 6H), 7.59 (d, J¼2.4 Hz, 1H), 8.75 (br s, 1H), 9.79 (s, 1H). 13C
NMR
d ppm (CDCl3, 75 MHz): 46.7, 106.3, 113.9, 119.9, 126.9 (2Car),
127.5, 128.8 (2Car), 137.7, 138.2, 138.5, 149.3, 192.9. EI-HRMS: calcd
for [C14H12BrNO]þ: 289.0102, found: 289.0086.
starting material were also recovered. For (9a): 1H NMR
d ppm
4.1.4. Ethyl 1-benzyl-6-bromo-2-imino-1,2-dihydroquinoline-3-carb-
oxylate (6). A mixture of aldehyde (4) (3 g, 10.3 mmol, 1.0 equiv),
molecular sieves 4 Å (3 g), absolute ethanol (55 mL), ethyl-
cyanoacetate (1.22 mL, 11.4 mmol, 1.1 equiv) and piperidine in cat-
alytic amount was stirred under argon at room temperature for
12 h. The solution was diluted with CH2Cl2 and molecular sieves
were filtered on a pad of Celite. The mixture was concentrated
under vacuum and the intermediate (6) was obtained as a yellow
solid (3.8 g, yield 86%) after purification by washing with a mixture
of pentane and diethyl ether (P/E: 6/4); mp 206–208 ꢀC. 1H NMR
(CDCl3, 500 MHz): 1.20–1.40 (m, 6H), 2.24 (s, 3H), 4.10–4.30 (m,
4H), 4.75–4.90 (m, 2H), 4.99–5.05 (m, 1H), 5.33 (dd, J¼1.4, 15.6 Hz,
1H), 6.80 (dd, J¼5.5, 15.6 Hz, 1H), 6.92 (d, J¼8.4 Hz, 1H), 7.10–7.35
(m, 7H), 10.13 (s, 1H). 13C NMR
d ppm (CDCl3, 125.77 MHz): 14.3,
14.4, 24.7, 39.5, 50.4, 60.4, 60.5, 87.8, 116.8, 118.7, 120.6, 127.7 (3Car),
128.1, 128.6 (2Car), 130.3, 131.4, 136.5, 137.5, 147.47, 148.8, 166.6,
79
168.1, 170.6. ES-HRMS: calcd for [C26H BrN2O2þNa]þ: 549.1001,
27
found: 549.1001.
4.1.8. (E)-Ethyl
2-acetamido-1-benzyl-6-bromo-4-styryl-1,4-dihy-
d
ppm (CDCl3, 300 MHz,): 1.44 (t, J¼7.1 Hz, 3H), 4.41 (q, J¼7.1 Hz,
droquinoline-3-carboxylate (9b). A mixture of compound (8)
(0.36 g, 0.79 mmol, 1.0 equiv), anhydrous CH2Cl2 (5.5 mL), styrene
(0.91 mL, 7.90 mmol, 10.0 equiv) and second generation Grubbs
catalyst (34 mg, 0.039 mmol, 0.05 equiv) was stirred under argon at
reflux for 18 h. The solution was concentrated under vacuum and
(9b) was obtained as a white solid (220 mg, yield 53%) after puri-
fication by flash column chromatography on silica gel (P/EA: 95/
2H), 5.58 (br s, 2H), 6.86 (d, J¼9.0 Hz, 1H), 7.20–7.40 (m, 5H), 7.45
(dd, J¼2.3, 9.0 Hz, 1H), 7.58 (d, J¼2.3 Hz, 1H), 8.15 (s, 1H), 9.17 (br s,
1H). 13C NMR
d ppm (CDCl3, 75 MHz): 14.3, 47.0, 61.6, 113.0, 115.9,
119.0, 119.9, 126.3 (2Car), 127.1, 128.9 (2Car), 132.2, 135.9, 136.1, 139.9,
141.4, 155.4, 165.1. EI-HRMS: calcd for [C17H12BrN2O2 (M-C2H5)]þ:
355.0082, found: 355.0083.
0.5); mp 84–86 ꢀC. 1H NMR
d ppm (C6D6, 500 MHz): 1.05 (t,
4.1.5. (E)-ethyl 2-(acetylimino)-1-benzyl-6-bromo-1,2-dihydroquino-
line-3-carboxylate (7). A mixture of compound (6) (2 g, 5.2 mmol,
1.0 equiv), acetic anhydride (40 mL), acetic acid (3 mL) and 4 Å mo-
lecular sieves (0.5 g) was stirred under argon and heated at 40 ꢀC for
12 h. The solutionwas diluted with CH2Cl2 and molecular sieves were
filtered on a pad of Celite. The mixture was concentrated under vac-
uum and coevaporated withtoluene to give (7) asayellowsolid (2.1 g,
J¼7.1 Hz, 3H),1.79 (s, 3H), 4.00–4.20 (m, 2H), 4.76 (d, J¼16.4 Hz,1H),
4.78 (d, J¼5.5 Hz, 1H), 4.96 (d, J¼16.4 Hz, 1H), 6.09 (dd, J¼5.5,
15.9 Hz, 1H), 6.16 (d, J¼15.9 Hz, 1H), 6.60 (d, J¼8.8 Hz, 1H), 6.80–
6.90 (m, 3H), 6.94 (dd, J¼2.3, 8.8 Hz, 1H), 7.00–7.10 (m, 8H), 10.21
(br s, 1H). 13C NMR
d ppm (CDCl3, 75 MHz): 14.5, 24.7, 40.0, 50.4,
60.3, 89.5, 116.5, 118.4, 126.3 (2Car), 126.5, 127.3, 127.4, 127.6 (2Car),
128.4 (2Car), 128.6 (2Car), 128.8, 129.8, 130.2, 131.3, 136.7, 136.8,
79
yield 95%); mp 144–146 ꢀC. 1H NMR
d
ppm (CDCl3, 300 MHz): 1.43 (t,
137.4, 147.1, 168.1, 170.6. ES-HRMS: calcd for [C29
553.1103, found: 553.1104.
H
BrN2O3þNa]þ:
27
J¼7.1 Hz, 3H), 2.24 (s, 3H), 4.39 (q, J¼7.1 Hz, 2H), 5.70 (br s, 2H), 7.00–
7.10 (m, 6H), 7.52 (dd, J¼2.2, 9.1 Hz,1H), 7.71 (d, J¼2.2 Hz,1H), 8.04 (s,
1H).13C NMR
d
ppm (CDCl3, 75 MHz): 14.2, 26.8, 47.0, 62.0,116.0,117.5,
4.1.9. Ethyl 2-amino-1-benzyl-6-bromo-4-vinyl-1,4-dihydroquino-
line-3-carboxylate (10). A mixture of compound (8) (0.20 g,
0.44 mmol, 1.0 equiv), absolute ethanol (3.0 mL), and hydrazine
monohydrate (2.1 mL) was stirred at room temperature for 3 h. The
solution was concentrated under vacuum and the residue was
extracted with CH2Cl2. The organic layers were washed with water,
brine, dried over MgSO4 and concentrated under vacuum. Com-
pound (10) was obtained as a white solid (48 mg, yield 26%) after
purification by flash column chromatography on silica gel (P/EA: 8/
121.6, 123.8, 126.5 (2Car), 127.6, 129.0 (2Car), 131.9, 135.2, 135.6, 138.7,
140.1, 150.9, 165.2, 181.9. Anal. Calc for C21H19BrN2O3: C, 59.03; H,
4.48; N, 6.56. Found: C, 58.68; H, 4.43; N, 6.37. EI-HRMS: calcd for
[C21H19BrN2O3]þ: 426.0579, found: 426.0561.
4.1.6. Ethyl 2-acetamido-1-benzyl-6-bromo-4-vinyl-1,4-dihydroquino-
line-3-carboxylate (8). To a suspension of copper iodide (95 mg,
0.5 mmol, 1.1 equiv) in anhydrous THF (1.5 mL), vinyl-
magnesiumbromide (1.0 M in THF, 1.1 mL, 1.1 mmol, 2.2 equiv) was
added dropwise under argon at 0 ꢀC. The mixture was stirred 30 min
at 0 ꢀC. The compound (7) (210 mg, 0.5 mmol,1.0 equiv) in anhydrous
THF (1.5 mL) solution was added to the mixture at ꢁ30 ꢀC. The so-
lution was warmed to room temperature and stirred for 2 h. The
black mixture was quenched with a NH4Cl saturated aqueous solu-
tion and extracted with AcOEt. The organic layers were washed with
2); mp 110–112 ꢀC. 1H NMR
d ppm (CDCl3, 500 MHz): 1.31 (t,
J¼7.1 Hz, 3H), 4.15–4.25 (m, 2H), 4.58 (d, J¼5.9 Hz, 1H), 4.74–4.94
(m, 3H), 5.12–5.18 (m, 1H), 5.78–5.87 (m, 1H), 6.27–6.32 (m, 2H),
6.56 (d, J¼8.7 Hz, 1H), 7.10–7.40 (m, 7H). 13C NMR
d ppm (CDCl3,
125.77 MHz): 14.7, 39.8, 49.3, 59.0, 78.4, 112.0, 115.4, 116.0, 125.5,
127.9 (2Car), 129.4 (2Car), 129.7, 129.9, 131.5, 135.6, 138.3, 141.2,
155.2, 169.5. Anal. Calc for C21H21BrN2O2: C, 61.03; H, 5.12; N, 6.78.

G. Viault et al. / Tetrahedron 65 (2009) 10149–10154
10153
Found: C, 60.17; H, 5.47; N, 6.33. EI-HRMS: calcd for
[C21H21BrN2O2]þ: 412.0786, found: 412.0793.
argon at room temperature for 18 h. The mixture was quenched
with NH4Cl saturated aqueous solution and extracted with CH2Cl2.
The organic layers were washed with water, brine, dried over
MgSO4 and concentrated under vacuum. Compound (13) was
obtained as a yellow solid (460 mg, yield 95%) after purification by
flash column chromatography on silica gel (P/EA: 8/2); mp 78–
4.1.10. (E)-Ethyl 2-amino-1-benzyl-6-bromo-4-styryl-1,4-dihydroqu-
inoline-3-carboxylate (10b). A mixture of compound (9b) (150 mg,
0.28 mmol, 1.0 equiv), absolute ethanol (1.5 mL), and hydrazine
monohydrate (1.4 mL) was stirred at room temperature for 3 h. The
solution was concentrated under vacuum and the residue was
extracted with CH2Cl2. The organic layers were washed with water,
brine, dried over MgSO4 and concentrated under vacuum. Com-
pound (10b) was obtained as a white solid (67 mg, yield 48%) after
purification by flash column chromatography on silica gel (P/EA: 9/
80 ꢀC. 1H NMR
d
ppm (CDCl3, 300 MHz): 1.24 (t, J¼8.0 Hz, 3H), 2.18
(s, 3H), 3.90 (d, J¼6.7 Hz, 2H), 4.11 (q, J¼8.0 Hz, 2H), 4.77 (t,
J¼6.7 Hz, 1H), 4.78–4.97 (m, 2H), 7.00–7.30 (m, 8H), 10.09 (s, 1H).
13C NMR
d ppm (CDCl3, 75 MHz): 14.2, 24.8, 37.0, 50.9, 60.7, 79.4,
89.5, 117.2, 118.9, 126.8, 127.8 (2Car), 128.2 (2Car), 128.9, 131.0, 131.1,
136.3, 137.4, 147.9, 167.8, 170.4. ES-HRMS: calcd for
79
1); mp 156–158 ꢀC. 1H NMR
d
ppm (C6D6, 500 MHz): 1.15 (t,
[C22
H
BrN3O5þNa]þ: 510.0641, found: 510.0644.
22
J¼7.1 Hz, 3H), 4.11 (d, J¼18.1 Hz, 1H), 4.20–4.30 (m, 2H), 4.37 (d,
J¼18.1 Hz, 1H), 4.92 (d, J¼5.7 Hz, 1H), 6.11 (d, J¼8.7 Hz, 1H), 6.20 (br
s, 2H), 6.29 (dd, J¼5.7, 15.7 Hz, 1H), 6.35 (d, J¼15.7 Hz, 1H), 6.69–
6.71 (m, 2H), 6.92 (dd, J¼2.3, 8.7 Hz, 1H), 7.00–7.14 (m, 8H), 7.27 (d,
4.1.14. Ethyl 2-acetamido-4-(aminomethyl)-1-benzyl-6-bromo-1,4-
dihydroquinoline-3-carboxylate (14). A mixture of compound (13)
(0.15 g, 0.28 mmol, 1.0 equiv), absolute ethanol (1.5 mL), and a cat-
alytic amount of Raney nickel (50% solution in water) was stirred
under a hydrogen atmosphere at room temperature for 18 h. The
solution was diluted with CH2Cl2, dried over MgSO4 and filtered on
a pad of Celite. The mixture was concentrated under vacuum and
compound (14) was obtained as a white solid (0.10 g, yield 74%)
after purification by flash column chromatography on silica gel (P/
J¼2.3 Hz,1H). 13C NMR
d ppm (CDCl3, 75 MHz): 14.7, 39.4, 49.3, 59.1,
77.2, 115.5, 116.2, 125.6 (2Car), 126.3 (2Car), 127.0, 127.3, 128.0, 128.4
(2Car), 129.4 (2Car), 129.8, 129.9, 131.6, 131.1, 135.6, 137.4, 138.3,
155.2, 169.6. Anal. calcd for C27H25BrN2O2: C, 66.26; H, 5.15; N,
5.72. Found: C, 66.22; H, 5.36; N, 5.43. ES-HRMS: calcd for
79
[C27
H
BrN2O2þH]þ: 489.1178, found: 489.1179.
26
EA: 9/1); mp 124–126 ꢀC. 1H NMR
d ppm (CDCl3, 500 MHz): 1.04 (t,
4.1.11. Ethyl 2-acetylimino-1-benzyl-6-bromo-4-phenyl-1,4-dihydro-
quinoline-3-carboxylate (11). To a suspension of copper iodide
(0.34 g,1.80 mmol,1.1 equiv) in anhydrous THF (8 mL), phenyllithium
(1.9 M in butyl ether, 1.9 mL, 3.61 mmol, 2.2 equiv) was added drop-
wise under argon at 0 ꢀC. The mixture was stirred 30 min at 0 ꢀC. The
compound (6) (0.70 g,1.64 mmol,1.0 equiv) in anhydrous THF (2 mL)
solution was added to the mixture at ꢁ30 ꢀC. The solution was
warmed to room temperature and stirred for 2 h. The black mixture
was quenched with NH4Cl saturated aqueous solution and extracted
with AcOEt. The organic layers were washed with water, brine, dried
over MgSO4 and concentrated under vacuum. Compound (11) was
obtained as a white solid (350 mg, yield 42%) after purification by
flash column chromatography on silica gel (P/EA: 95/05). 1H NMR
J¼6.8 Hz, 3H), 2.17 (s, 3H), 3.58 (m, 1H), 4.00 (m, 3H), 4.77 (t,
J¼6.7 Hz, 1H), 4.24 (m, 1H), 4.30 (s, 2H), 4.40 (br s, 1H), 6.50 (d,
J¼8.6 Hz, 1H), 7.15–7.35 (m, 7H), 10.68 (br s, 1H). 13C NMR
d ppm
(CDCl3, 75 MHz): 14.5, 24.5, 38.8, 48.4, 51.7, 58.8, 81.2, 109.7, 112.9,
127.3, 127.4 (2Car), 128.7 (2Car), 130.1, 131.0, 131.4, 139.0, 144.4, 157.3,
168.3, 170.5. Anal. Calcd for C20H22BrN3O2: C, 57.70; H, 5.33; N,
10.09. Found: C, 57.61; H, 5.16; N, 8.96. ES-HRMS: calcd for
79
[C22
H
BrN3O3þH]þ: 458.1079, found: 458.1079.
25
4.1.15. N-(4-Bromo-2-(hydroxymethyl)phenyl)benzamide
(16). To
a suspension of LiAlH4 (0.57 g, 15 mmol, 1.0 equiv) in anhydrous
THF (40 mL) at ꢁ10 ꢀC was added a solution of compound (2) (5 g,
15 mmol, 1.0 equiv) in anhydrous THF (40 mL) at ꢁ10 ꢀC. The so-
lution was stirred under argon at room temperature for 2 h. The
mixture was quenched successively with a 2 M NaOH aqueous so-
lution (4 mL) and water (4 mL). The organic phase was dried over
MgSO4, filtered and concentrated under vacuum. The amide (16)
was obtained as a white solid (4.5 g, yield 98%) after purification by
flash column chromatography on silica gel (P/EA: 8/2); mp 138–
d
ppm (CDCl3, 300 MHz): 1.38 (t, J¼7.1 Hz, 3H), 2.28 (s, 3H), 4.25–4.30
(m, 2H), 4.95 (m, 2H), 5.35 (s,1H), 6.89–7.41 (m,13H),10.08 (s,1H).13C
NMR ppm (CDCl3, 75 MHz): 14.4, 24.7, 41.5, 50.0, 60.3, 91.8, 116.5,
d
118.3, 126.5, 127.1 (2Car), 127.5, 127.7 (2Car), 128.3 (2Car), 128.5 (2Car),
129.8, 130.9, 131.8, 136.4, 137.5, 144.6, 147.0, 169.0, 170.9. EI-HRMS:
81
calcd for [C27
H
BrN2O3]þ: 506.1028, found: 506.1063.
25
140 ꢀC. 1H NMR
6.87–7.03 (m, 5H), 7.43–7.45 (m, 2H), 7.64–7.67 (m, 1H), 9.70 (br s,
1H). 13C NMR
d ppm (CDCl3, 300 MHz): 4.18 (s, 2H), 5.25 (br s,1H),
4.1.12. Ethyl 2-amino-1-benzyl-6-bromo-4-phenyl-1,4-dihydroquino-
line-3-carboxylate (12). A mixture of compound (11) (0.14 g,
0.28 mmol, 1.0 equiv), absolute ethanol (1.5 mL), and hydrazine
monohydrate (1.4 mL) was stirred at room temperature for 3 h. The
solution was concentrated under vacuum and the residue was
extracted with CH2Cl2. The organic layers were washed with water,
brine, dried over MgSO4 and concentrated under vacuum. Com-
pound (12) was obtained as a white solid (50 mg, yield 40%) after
purification by flash column chromatography on silica gel (P/EA:
d
ppm (CDCl3þDMSO d6, 75 MHz): 62.2, 115.5, 122.8,
126.3.0 (2Car), 127.8 (2Car), 130.0, 130.1, 131.0, 132.3, 133.6, 136.2,
164.4. EI-HRMS: calcd for [C14H12BrNO2]þ: 305.0051, found:
305.0039.
4.1.16. N-(4-bromo-2-formylphenyl)benzamide (17). To a mixture of
IBX (8.2 g, 29.4 mmol, 2.0 equiv), DMSO (60 mL) and CH2Cl2
(45 mL), a solution of compound (16) (4.5 g,14.7 mmol,1.0 equiv) in
CH2Cl2 (45 mL) was added dropwise. The solution was stirred un-
der argon at reflux for 1 h. The reaction was quenched with water
(20 mL) at 0 ꢀC and the residue of IBX was filtered on a pad of Celite.
The mixture was extracted with CH2Cl2 and the organic layers were
washed three times with water, brine, dried over MgSO4, and
concentrated under vacuum. The amide (17) was obtained as
a white solid (4.0 g, yield 89%) after purification by flash column
chromatography on silica gel (P/EA: 8/2); mp 118–120 ꢀC. 1H NMR
9/1); mp 82–84 ꢀC. 1H NMR
J¼8.0 Hz, 3H), 4.04 (q, J¼8.0 Hz, 2H), 5.00 (m, 2H), 5.10 (s,1H), 6.27 (s,
1H), 6.52 (d, 1H), 6.90–7.30 (m, 12H). 13C NMR
ppm (CDCl3,
d ppm (CDCl3, 300 MHz): 1.18 (t,
d
75 MHz): 14.6, 41.6, 49.5, 59.3, 79.7, 115.7, 116.4, 125.5 (2Car), 126.1,
126.9 (2Car), 127.9, 128.4 (2Car), 129.5 (2Car), 129.7, 131.4, 131.8, 135.7,
138.2, 147.3, 155.1, 169.6. Anal. Calc for C25H23BrN2O2: C, 64.80; H,
5.00; N, 6.05. Found: C, 65.56; H, 5.19; N, 5.74. EI-HRMS: calcd for
[C19H18BrN2O2 (M-C6H5)]þ: 385.0552, found: 385.0574.
4.1.13. Ethyl 2-acetamido-1-benzyl-6-bromo-4-(nitomethyl)-1,4-di-
hydroquinoline-3-carboxylate (13). A mixture of compound (7)
(430 mg, 1.00 mmol, 1.0 equiv), nitromethane (3 mL), and tetra-
methylguanidine (0.13 mL, 1.0 mmol, 1.0 equiv) was stirred under
d
ppm (CDCl3, 300 MHz): 7.50–7.70 (m, 3H), 7.78 (dd, J¼2.4, 9.0 Hz,
1H), 7.78 (d, J¼2.4 Hz, 1H), 8.05–8.10 (m, 2H), 8.92 (d, J¼9.0 Hz, 1H),
9.95 (s, 1H), 12.00 (br s, 1H). 13C NMR
ppm (CDCl3, 75 MHz): 115.2,
121.9, 123.3, 127.5 (2Car), 129.0 (2Car), 132.5, 134.0, 138.2, 139.1,
d

10154
G. Viault et al. / Tetrahedron 65 (2009) 10149–10154
140.2, 166.1, 194.6. EI-HRMS: calcd for [C13H10BrNO (M-C]O)]þ:
CNRS, MESR, and CSIR as well as the ‘Ligue contre le Cancer’
´
(Comite d’Ille et Vilaine) for support of this research. We thank the
274.9946, found: 274.9958.
´
´
‘Ligue contre le Cancer’ (Comite d’Ille et Vilaine) and Region Bre-
tagne for a fellowship to G.V. Fruitful discussions with Dr. Frederic
Caijo are gratefully acknowledged.
4.1.17. Ethyl
1-benzoyl-6-bromo-2-imino-1,2-dihydroquinoline-3-
carboxylate (18). A mixture of aldehyde (17) (4 g, 13.15 mmol,
1.0 equiv), molecular sieves 4 Å (4 g), absolute ethanol (80 mL),
ethylcyanoacetate (1.68 mL, 15.8 mmol, 1.2 equiv) and piperidine in
catalytic amount was stirred under argon at 60 ꢀC for 24 h. The
solution was diluted with CH2Cl2 and molecular sieves were filtered
on a pad of Celite. The mixture was concentrated under vacuum
and the compound (18) was obtained as a yellow solid (5.5 g, yield
95%) after purification by washing with a mixture of pentane and
References and notes
1. See for instance: (a) Khafagy, M. M.; El-Wahas, A. H. F. A.; Eid, F. A.; El-Agrody,
´
A. M. Il Farmaco 2002, 57, 715–722; (b) Kidwai, M.; Saxena, S.; Khan, M. K. R.;
Thukral, S. S. Bioorg. Med. Chem. Lett. 2005, 15, 4295–4298; (c) Makarem, S.;
Mohammadi, A. A.; Fakhari, A. R. Tetrahedron Lett. 2008, 49, 7194–7196; (d)
Elinson, M. N.; Dorofeev, A. S.; Miloserdov, F. M.; Ilovaisky, A. I.; Feducovich, S.
K.; Belyakov, P. A.; Nikishin, G. I. Adv. Synth. Catal. 2008, 350, 591–601 and
references cited therein.
2. (a) Wang, J.-L.; Liu, D.; Zhang, Z.-J.; Shan, S.; Han, X.; Srinivasula, S. M.; Croce, C.
M.; Alnemri, E. S.; Huang, Z. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 7124–7129; (b)
Skommer, J.; Wlodkowic, D.; Matto, M.; Eray, M.; Pelkonen, J. Leuk. Res. 2006,
30, 322–331; (c) Doshi, J. M.; Tian, D.; Xing, C. J. Med. Chem. 2006, 49, 7731–
7739; (d) Doshi, J. M.; Tian, D.; Xing, C. Mol. Pharm. 2007, 4, 919–928 and ref-
erences cited therein.
3. (a) Kemnitzer, W.; Drewe, J.; Jiang, S.; Zhang, H.; Wang, Y.; Zhao, J.; Jia, S.; Herich,
J.; Labreque, D.; Storer, R.; Meerovitch, K.; Bouffard, D.; Rej, R.; Denis, R.; Blais, C.;
Lamothe, S.; Attardo, G.; Gourdeau, H.; Tseng, B.; Kasibhatla, S.; Cai, S. X. J. Med.
Chem. 2004, 47, 6299–6310; (b) Kemnitzer, W.; Khasibhatla, S.; Jiang, S.; Zhang,
H.; Zhao, J.; Jia, S.; Xu, L.; Crogan-Grundy, C.; Denis, R.; Barriault, N.; Vaillancourt,
L.; Charron, S.; Dodd, J.; Attardo, G.; Labreque, D.; Lamothe, S.; Gourdeau, H.;
Tseng, B.; Drewe, J.; Cai, S. X. Bioorg. Med. Chem. Lett. 2005, 15, 4745–4751; (c)
Kemnitzer, W.; Drewe, J.; Jiang, S.; Zhang, H.; Wang, Y.; Zhao, J.; Crogan-Grundy,
C.; Xu, L.; Lamothe, S.; Gourdeau, H.; Denis, R.; Tseng, B.; Kasibhatla, S.; Cai, S. X.
J. Med. Chem. 2007, 50, 2858–2864; (d) Kemnitzer, W.; Drewe, J.; Jiang, S.;
Crogan-Grundy, C.; Labreque, D.; Bubenick, M.; Attardo, G.; Denis, R.; Lamothe, S.;
Gourdeau, H.; Tseng, B.; Kasibhatla, S.; Cai, S. X. J. Med. Chem. 2008, 51, 417–423.
4. (a) Fujimoto, A.; Sakurai, A. Synthesis 1977, 871–872; (b) Roudier, J.-F.; Foucaud, A.
Synthesis 1984, 159–160; (c) Yu, N.; Aramini, J. M.; Germann, M. W.; Huang, Z.
Tetrahedron Lett. 2000, 41, 6993–6996; (d) Ballini, R.; Bossica, G. B.; Conforti, M. L.;
Maggi, R.; Maccazani, A.; Righi, P.; Sartori, G. Tetrahedron 2001, 57, 1395–1398; (e)
Curini, M.; Epifano, F.; Chimichi, S.; Montanari, F.; Nocchetti, M.; Rosati, O. Tet-
rahedron Lett. 2005, 46, 3497–3499; (f) Curini, M.; Rosati, O.; Marcotullio, M. C.;
Montanari, F.; Campagna, V.; Pace, V.; Cravotto, G. Eur. J. Org. Chem. 2006, 3,
746–751.
diethyl ether (P/E: 6/4); mp 168–170 ꢀC. 1H NMR
d ppm (CDCl3,
500 MHz): 1.49 (t, J¼7.2 Hz, 3H), 4.51 (q, J¼7.2 Hz, 2H), 7.50–7.60
(m, 3H), 6.65 (dd, J¼2.2, 9.0 Hz, 1H); 7.97 (d, J¼2.2 Hz, 1H); 7.99 (d,
J¼9.0 Hz, 1H), 8.10–8.15 (m, 2H), 11.92 (s, 1H). 13C NMR
d ppm
(CDCl3, 125 MHz): 14.2, 62.6, 113.2, 119.5, 125.2, 127.6 (2Car), 128.9
(2Car), 130.4, 130.5, 132.3, 134.7, 136.0, 141.3, 147.6, 150.0, 164.5,
166.8. EI-HRMS: calcd for [C19H15BrN2O3]þ: 398.0266, found:
398.0265.
4.1.18. (E)-Ethyl 2-(acetylimino)-1-benzoyl-6-bromo-1,2-dihydroq-
uinoline-3-carboxylate (19). A mixture of compound (18) (2.5 g,
6.3 mmol, 1.0 equiv), acetic anhydride (30 mL), pyridine (8 mL) and
molecular sieves 4 Å (0.5 g) was stirred under argon and heat at
90 ꢀC for 48 h. The solution was diluted with CH2Cl2 and molecular
sieves were filtered on a pad of Celite. The mixture was concen-
trated under vacuum and coevaporated with toluene to give the
compound (19) as a yellow solid (2 g, yield 72%); mp 108–110 ꢀC. 1H
NMR
4.47 (q, J¼7.1 Hz, 2H), 7.10–7.40 (m, 3H), 7.60–7.80 (m, 4H), 8.00–
8.01 (m, 1H), 8.69 (s, 1H). 13C NMR
ppm (CDCl3, 75 MHz): 14.2,
d
ppm (CDCl3, 300 MHz): 1.46 (t, J¼7.1 Hz, 3H), 2.59 (s, 3H),
d
25.7, 62.2, 121.9, 122.8, 127.3, 128.3 (2Car), 128.8 (2Car), 130.2, 130.4,
131.9, 135.4, 135.4, 140.3, 146.3, 150.1, 164.5, 172.2, 174.4. EI-HRMS:
calcd for [C21H17BrN2O4]þ: 440.0372, found: 440.0379.
5. (a) Manero, F.; Gautier, F.; Gallenne, T.; Cauquil, N.; Gre´e, D.; Cartron, P.-F.;
´
Geneste, O.; Gree, R.; Vallette, F. M.; Juin, P. Cancer Res. 2006, 66, 2757–2764; (b)
Oliver, L.; Mahe´, B.; Gre´e, R.; Vallette, F. M.; Juin, P. Leuk. Res. 2007, 31, 859–863.
6. Gre´e, D.; Vorin, S.; Manthati, V. L.; Caijo, F.; Viault, G.; Manero, F.; Juin, P.; Gre´e,
R. Tetrahedron Lett. 2008, 49, 3276–3278.
7. The addition of nucleophiles to quinolinium salts is a well established method
for the synthesis of substituted quinolines but it gives mainly the 1,2 dihy-
droderivatives. For representative examples see: (a) Mani, N. S.; Chen, P.; Jones,
T. K. J. Org. Chem. 1999, 64, 6911–6914; (b) Diaba; Le Houerou, C.; Grignon-
Dubois, M.; Gerval, P. J. Org. Chem. 2000, 65, 907–910 and references cited
therein.
8. (a) Bohn, P.; Le Fur, N.; Hagues, G.; Costentin, J.; Torquet, N.; Papamicae¨l, C.;
Marsais, F.; Levacher, V. Org. Biomol. Chem. 2009, 7, 2612–2618; (b) Marsais, F.;
Bohn, P.; Levacher, V.; Le Fur, N. PCT Int. Appl., WO, 103120, 2006.
9. Mikata, Y.; Mizukami, K.; Hayashi, K.; Matsumoto, S.; Yano, S.; Yamazaki, N.;
Ohno, A. J. Org. Chem. 2001, 66, 1590–1599.
10. Kim, J. N.; Kim, H. S.; Gong, J. H.; Chung, Y. M. Tetrahedron Lett. 2001, 42,
8341–8344.
11. (a) Zhou, L.; Zhang, Y. J. Chem. Soc., Perkin Trans. 1 1998, 2899–2902; (b) Zhou, L.;
Tu, S.; Shi, D.; Dai, G. J. Chem. Res., Synop. 1998, 398–399; (c) Sharma, U.; Ahmed,
S.; Boruah, R. C. Tetrahedron Lett. 2000, 41, 3493–3495; (d) Ukhin, L. Yu.; Belov,
E. G. Russ. Chem. Bull. 2008, 57, 418–421.
4.1.19. Ethyl 2-amino-1-benzoyl-6-bromo-4-phenyl-1,4-dihydroqui-
noline-3-carboxylate (20). To a solution of copper iodide (86 mg,
0.45 mmol, 1.0 equiv) and anhydrous THF (2 mL), phenyllithium
(1.9 M in butyl ether, 0.48 mL, 0.90 mmol, 2.0 equiv) was added
dropwise under argon at 0 ꢀC. The mixture was stirred 30 min at
0 ꢀC. A solution of compound (19) (0.20 g, 0.45 mmol, 1.0 equiv) in
anhydrous THF (0.5 mL) was added to the mixture at ꢁ30 ꢀC. The
solution was warmed to room temperature and stirred for 2 h. The
black mixture was quenched with a NH4Cl saturated aqueous so-
lution and extracted with AcOEt. The organic layers were washed
with water, brine, dried over MgSO4 and concentrated under vac-
uum. The compound (20) was obtained as a white solid (70 mg,
yield 30%) after purification by flash column chromatography on
silica gel (P/EA: 95/05). 1H NMR
d ppm (CDCl3, 500 MHz): 1.26 (t,
J¼7.0 Hz, 3H), 4.17 (q, J¼7.0 Hz, 2H), 5.16 (s, 1H), 6.81 (m, 1H), 7.20–
12. For a similar sequence see: He, Y.; Mahmud, H.; Moningka, R.; Lovely, C. J.;
Dias, H. V. R. Tetrahedron 2006, 62, 8755–8769.
13. In a few cases with some benzopyrans derivatives, cyclization occurs also on
the ester affording quinolones Volmajer, J.; Toplak, R.; Bittner, S.; Leban, I.;
Majcen Le Marechal, A. Tetrahedron Lett. 2003, 44, 2363–2366.
7.80 (m, 10H), 8.05 (m, 2H), 11.04 (br s, 1H), 13.29 (br s, 1H). 13C NMR
d
ppm (CDCl3, 125.77 MHz): 14.3, 42.2, 60.1, 82.6, 115.9, 117.5, 126.5,
127.3 (2Car),127.4,127.6,127.9 (2Car),128.5,129.1,130.2,132.2,132.8,
14. The crystal structure corresponding to 1,4-dihydroquinoline
8 has been
133.1, 133.6, 146.9, 148.1, 148.4, 168.4, 170.0. ES-HRMS: calcd for
79
deposited at the Cambridge Crystallographica Data Centre and allocated the
deposition number CCDC 739472. These data can be obtained free of charge
from www.ccdc.cam.ac.uk/conts/retrieving.html or from the Cambridge Crys-
tallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: þ441 223
336 033; email: deposit@cccdc.cam.ac.uk.
[C25
H
21
BrN2O3þNa]þ: 499.0633, found: 499.0636.
Acknowledgements
15. (a) Grubbs, R. H. Adv. Synth. Catal. 2007, 349, 34–40; (b) Chatterjee, A. K.; Choi,
T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360–11370 and
references cited therein.
This research has been performed as part of the Indo-French
‘Joint Laboratory for Sustainable Chemistry at Interfaces’. We thank