Synthesis and biological activities of new di-and trimeric quinoline derivatives

Article abstract of DOI:10.1016/j.bmc.2010.07.029

The synthesis of non-peptidic helix mimetics based on a trimeric quinoline scaffold is described. The ability of these new compounds, as well as their synthetic dimeric intermediates, to bind to various members of the Bcl-2 protein anti-apoptotic group is also evaluated. The most interesting derivative of this new series (compound A) inhibited Bcl-x_L/Bak, Bcl-x_L/Bax and Bcl-x_L/Bid interactions with IC₅₀ values around 25 μM.

Full text of DOI:10.1016/j.bmc.2010.07.029

Bioorganic & Medicinal Chemistry 18 (2010) 7132–7143
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and biological activities of new di- and trimeric quinoline derivatives
Sidonie Broch a,b, Hélène Hénon a,b, Anne-Laure Debaud c,d,e, Marie-Laure Fogeron c,d,e
,
Nathalie Bonnefoy-Bérard c,d,e, Fabrice Anizon a,b, Pascale Moreau a,b,
*
a Clermont Université, Université Blaise Pascal, SEESIB, BP 10448, F-63000 Clermont-Ferrand, France
b CNRS, UMR 6504, SEESIB, F-63177 Aubière, France
c Université de Lyon, France
d Inserm, U851, 21 Avenue Tony Garnier, Lyon F-69007, France
e Université Lyon 1, IFR128, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of non-peptidic helix mimetics based on a trimeric quinoline scaffold is described. The abil-
ity of these new compounds, as well as their synthetic dimeric intermediates, to bind to various members
of the Bcl-2 protein anti-apoptotic group is also evaluated. The most interesting derivative of this new
series (compound A) inhibited Bcl-xL/Bak, Bcl-xL/Bax and Bcl-xL/Bid interactions with IC50 values around
Received 1 April 2010
Revised 12 July 2010
Accepted 13 July 2010
Available online 16 July 2010
25 lM.
Ó 2010 Published by Elsevier Ltd.
Keywords:
Helix mimetic
Quinoline
Bcl-2 protein
Apoptosis
1. Introduction
small molecule drugs that fit into the groove of the pro-survival
members (BH3 mimetics), prevent these protein–protein interac-
tions, and reinstate the ability of the cells to self-destruct in re-
sponse to stress stimuli. Based on such strategy, several non-
peptidic small molecule inhibitors of anti-apoptotic Bcl-2 proteins
have already been reported in the literature4–17 (Fig. 1). One of
them, the ABT-737, a synthetic inhibitor that target Bcl-xL, Bcl-w
and Bcl-2 anti-apoptotic members, has recently entered clinical
development.18,19
The design of the compounds described in this paper is based on
the structure of known inhibitors and the analysis of the Protein
Data Bank (PDB) 1BXL structure that shows the binding interac-
tions between Bcl-xL and Bak BH3 peptide.20 Thus, we decided to
target poly-aromatic systems that can mimic the helical BH3 do-
main of pro-apoptotic protein, and more particularly, new trimeric
quinoline derivatives (Fig. 2). As illustrated in a previous paper,
molecular modelling studies have shown that, due to atropoisom-
erism, these compounds could adopt a helical structure.21 The first
aim of the present paper was to report the synthesis of new tri-
meric quinoline derivative A, bearing alkyl groups that are identi-
cal to the side chains of the aminoacid residues directly implicated
Altered apoptosis is a central step in cancer development that
leads to resistance of tumour cells to conventional cytotoxic therapy.
Consequently, an attractive approach for anticancer therapeutics is to
overcome this resistance to apoptosis by directly activating the
normal cell death machinery.
B-cell lymphoma-2 (Bcl-2) family members are important regu-
lators of apoptosis.1,2 Anti-apoptotic proteins such as Bcl-xL, Bcl-w,
Mcl-1, Bcl-2 and Bfl-1 can form heterodimers with pro-apoptotic
members such as Bax, Bak, Bad, Bid, Bim and PUMA sequestering
them and preventing them from inducing apoptosis by disrupting
outer mitochondrial membrane integrity and enabling cytochrome
c release. Heterodimer formation relies on the capacity of the a-he-
lix of Bcl-2 Homology-3 (BH3) pro-apoptotic proteins to interact
with the hydrophobic groove formed by BH1, 2 and 3 domains of
anti-apoptotic proteins.3 Increased expression of pro-survival
members is a hallmark of many cancers, and drugs that can pre-
vent their action are very valuable.
In cancer cells, balance between pro- and anti-apoptotic pro-
teins is often abolished, and increased expression of anti-apoptotic
members is a characteristic of many cancers. One strategy for the
development of new therapeutics for cancer therapy is to identify
in the interaction between Bcl-xL and the Bak BH3 a-helix (Fig. 2).
Moreover, to start a structure–activity relationship study in this
series, another analogue (compound 37, Scheme 4) was also pre-
pared. Finally, the ability of these compounds to bind to various
members of the Bcl-2 protein anti-apoptotic group was also
evaluated.
* Corresponding author. Tel.: +33 4 73 40 79 63; fax: +33 4 73 40 77 17.
E-mail address: Pascale.MOREAU@univbpclermont.fr (P. Moreau).
0968-0896/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.bmc.2010.07.029

S. Broch et al. / Bioorg. Med. Chem. 18 (2010) 7132–7143
7133
Cl
O
O
O
2S
HN
N
+
N
NH
OH
MeO
NH
Cl
Z
OMe
Chelerythrine
O
OMe
BH3I-2 :Y = Cl, I
Z = Br, I
Obatoclax
Y
HO2C
CHMe2
EtOOC
CN
O
H
N
N
O
OHCHN
S
O
O
Br
COOEt
S
OR
O
O
O
NH2
Antimycine derivatives
R = H, Me
O
HA14-1
O
CH2CHMe2
R
BH3I-1 : R = Br, Cl, H, NMe
2
NO2
H
N
CH2NMe2
H
N
OCH2COOH
O
CH2SPh
SO2
CH2CHMe2
N
N
CH2CHMe2
(CH2
)2COOH
ABT-737
Terphenyle derivatives
Cl
Figure 1. Few examples of Bcl-2 family non-peptidic inhibitors.
ture of the major isomers 7 and 9 were determined by HMBC
1H–15N, HMBC 1H–13C and HSQC 1H–13C analysis.
2. Chemistry
Compound 15 was prepared in 37% overall yield in five steps
from 9. The 2-chloroquinoline 11 was obtained by treatment of 9
with thionyl chloride. The displacement of the chlorine atom in
the presence of sodium methylate afforded compound 12. The cor-
responding Weinreb amide 13 was obtained from 12 by reaction
with iPrMgCl and Me(OMe)NHꢀHCl.24 The acetylated analogue 14
was obtained by treatment of 13 with methyl magnesium bromide.
Finally, compound 15 was prepared by a Wittig reaction between
14 and ethyltriphenylphosphonium bromide.
Compound 18 was obtained in three steps from 12. The reduc-
tion of the methylic ester was performed in the presence of DIBAL-
H to give 16 in 73% yield. The corresponding aldehyde 17 was
prepared in 75% yield by oxidation of 16 using Dess–Martin Period-
inane (DMP). Compound 18 was finally obtained in 93% yield by a
Wittig reaction between 17 and isopropyltriphenylphosphonium
iodide.
The key steps in the synthetic approach reported here are Suzu-
ki cross-coupling reactions between quinoline-3-boronic acids and
7-bromo-quinoline derivatives. The synthesis of compound A was
performed from the 2-methoxyquinolines 15, 18 and 23 bearing
the suitable substituents (Scheme 1).
These compounds were prepared by a convergent approach
from 3-aminobenzoic acid 1 or 3-amino-5-bromobenzoic acid 2
(Scheme 2). The methylic esters 3 and 4 prepared in good yields
by reacting the corresponding carboxylic acid 1 and 2 with thionyl
chloride in methanol were reacted with (E)-3-ethoxyprop-2-enoyl
chloride to give anilides 5 and 6 in good yields. The cyclisation of
anilides 5 or 6 in an acidic medium afforded the expected quino-
lones as a mixture of regioisomers 7/8 and 9/10 in 89% and 86%
yields, respectively.22,23 In both cases the major isomer was the
one bearing the methoxycarbonyl group in the 5-position. The reg-
ioisomeric ratio (10:1 for 7/8 and 9.5:1 for 9/10) was determined
from the 1H NMR spectrum on the signals of the H3 and H4 protons.
Major isomers were isolated by recrystallisation from ethanol,
leading to 7 and 9 in 47% and 50% yields, respectively. The struc-
Compound 23 was prepared in 54% overall yield in five steps
from 7. The tertiary alcohol 19 obtained from 7 by a Grignard reac-
tion using methyl magnesium bromide was dehydrated in the

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S. Broch et al. / Bioorg. Med. Chem. 18 (2010) 7132–7143
N
OR'
N
OR
R, R' = Me, Et or Bu
N
OR
Trimeric quinolines previously described
R = R’ = Et
N
O
N
O
N
O
Structure of BakBH3 peptide
Compound A
Figure 2. Structure of trimeric quinoline derivatives.
15
Br
N
OMe
N
O
N
O
18
23
N
O
Br
N
OMe
A
N
OMe
Scheme 1. Retrosynthetic approach.
presence of p-toluene sulphonic acid (PTSA) to give the corre-
sponding alkene 20. Compound 22 was obtained using the classical
two-step procedure to convert the quinolin-2-one moiety into the
corresponding 2-methoxyquinoline analogue. The catalytic hydro-
genation of compound 22 unsaturated side chain provided com-
pound 23.
The dimeric moiety 25 required for the preparation of com-
pound A was obtained by Suzuki coupling between 18 and boronic
acid 24 that was produced by reaction of 23 with triisopropyl
borate in the presence of lithium diisopropylamide (LDA)21
(Scheme 3). Due to the degradation of boronic acid 24 when we
tried to purify the corresponding reaction mixture, we decided to
use the crude reaction mixture of 24 to undertake the following
Suzuki coupling. After reduction of the double bond, compound
25 was obtained in 78% yield from 18.
Finally, compound A was obtained, as described for 25, by Suzu-
ki coupling between 15 and boronic acid 27 that was produced by
reaction of 25 with triisopropyl borate in the presence of LDA
(Scheme 3). As mentioned above for 25, the coupling reaction
was performed directly on the crude boronic acid 27, and the dou-
ble bond of the trimeric intermediate was subsequently reduced.
To get an insight into the influence of the alkoxy group in the 2-po-
sition of the quinoline moieties, compound A was deprotected in
the presence of HCl to give compound 28 in 89% yield. Moreover,
in order to compare the biological activities of compound 28 with
the one of its dimeric analogue, compound 25 was treated in the
presence of HCl to give 26 in 80% yield.
Finally, to evaluate the substitution profile of the heteroaro-
matic moiety on the biological activities of this series, compound
37 was also prepared (Scheme 4).

S. Broch et al. / Bioorg. Med. Chem. 18 (2010) 7132–7143
7135
CO2H
CO2Me
CO2Me
OEt
O
O
SOCl
2
EtO
Cl
MeOH
R
NH2
R
NH2
R
N
H
5 R = H, 80%
6 R = Br, 81%
1 R = H
2 R = Br
3 R = H, 99%
4 R = Br, 94%
H SO
2
4
MeO2C
H4
R
H4
H3
O
H3
O
+
R
N
H
MeO2C
N
H
7 R = H, 47%
9 R = Br, 50%
8 R = H
10 R = Br
HO
COOMe
R = Br
R = H
CH MgBr
3
SOCl /DMF
2
THF
CH Cl
2
2
N
H
O
Br
N
Cl
19, 90%
11, 99%
NaOMe, MeOH
PTSA
Toluene
HO
COOMe
DIBAL-H
CH Cl
2
2
Br
N
H
OMe
N
H
O
Br
N
OMe
20, 72%
16, 73%
12, 75%
iPrMgCl
Me(OMe)NH.HCl
DMP
POCl
3
CH Cl
2
2
O
N
CHO
OMe
N
Cl
Br
N
H
OMe
Br
N
OMe
21, 95%
NaOMe, MeOH
17, 75%
13, 79%
iPr-PPh , I
3
MeMgBr
THF
n-BuLi, THF
O
N
OMe
Br
N
H
OMe
Br
N
OMe
18, 93%
22, 98%
H /PtO
14, 83%
Et-PPh , Br
3
2
2
n-Buli
AcOEt
N
OMe
Br
N
OMe
23, 90%
15, 76%
Scheme 2. Preparation of the monomeric quinoline derivatives.
Compound 33 was obtained in five steps with 56% overall yield
from 9 using the same synthetic approach as the one described for
the preparation of the non-brominated analogue 23. Dimeric deriv-
ative 35 was obtained in 88% yield by Suzuki coupling between 33
and boronic acid 34 which was prepared as previously described.
Compound 37 was prepared, as described for compound A, by

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S. Broch et al. / Bioorg. Med. Chem. 18 (2010) 7132–7143
1) 18, PdCl2(PPh3)2
1) B(OiPr)3,
B(OH)2
THF, aq. Na2CO3, µW
LDA, THF
N
OMe
2) Pd/C, HCO2NH4 , MeOH
2) sat. aq. NH4Cl
N
OMe
N
OMe
23
24
N
OMe
25, 78% from 18
1) B(OiPr)3,
HCl
LDA, THF
2) sat. aq. NH4Cl
N
H
O
N
H
O
B(OH)2
OMe
26, 80%
N
N
OMe
27
1) 15, PdCl2(PPh3)2
THF, aq. Na2CO3, µW
2) Pd/C, HCO2NH4, MeOH
N
OMe
N
H
O
HCl
N
OMe
N
H
O
N
H
O
N
OMe
28, 89%
Compound A, 81% from 15
Scheme 3. Synthesis of compounds 25, 26, A and 28.
Suzuki coupling between 33 and boronic acid 36 that was pro-
duced by reaction of 35 with triisopropyl borate in the presence
of LDA (Scheme 4). Unfortunately, the deprotection reaction car-
ried out on derivative 37 led to an insoluble compound 38 for
which we never manage to get NMR spectra. The only data we ob-
tained was the high-resolution mass spectrometry (HRMS) (ESI+)
analysis (calcd for C33H30N3O3 (M+H)+ 516.2287, found 516.2286
and calcd for C33H29N3NaO3 (M+Na)+ 538.2107, found 538.2088).
compound A which inhibited the interaction between Bcl-xL/Bak,
Bcl-xL/Bax and Bcl-xL/Bid with IC50 values of 25 M, 26 M and
27 M, respectively. Compound 37 most efficiently inhibited the
interaction between Bcl-xL/Bid with IC50 value of 21 M. Com-
pound 25 was the less active derivative, inhibiting only the Bcl-
xL/Bim interaction with an IC50 value of 29 M. Values observed
with these compounds are however one log higher than values ob-
served with the ABT-737 Bcl-xL inhibitor identified by Abbott
laboratories.
l
l
l
l
l
In addition to Bcl-xL, other members of the Bcl-2 family are
known to play critical roles in tumour cell survival. Therefore, the
capacity of compound A, that is, the most potent compound, was
also evaluated for its capacity to disrupt interaction between Bax
BH3 peptide and Bcl-2, Bfl-1 or Mcl-1. As shown in Table 1C, com-
pound A also disrupted Bax BH3 binding to other anti-apoptotic
Bcl-2 family members although IC50 values are slightly higher than
the one obtained against Bcl-xL.
3. Results and discussion
The binding properties of di- and trimeric quinoline new deriva-
tives towards Bcl-xL were evaluated by competitive fluorescence
polarisation assays. As a first step we first determined binding capac-
ity of Bcl-2 anti-apoptotic members towards different pro-apoptotic
BH3 peptides (Table 1A). Results obtained under our experimental
conditions are in agreement with data already published.25,26
These preliminary results have shown that the diversely substi-
tuted trimeric derivatives A and 37, bearing either methoxy or eth-
oxy group on the quinoline moiety inhibit the interaction between
Bcl-xL and Bak, Bax, Bid, Bim and PUMA pro-apoptotic BH3 peptides
with IC50 values in the micromolar range. Moreover, the dimeric
derivative 25 also decreased the binding between Bcl-xL/Bim with
Then, the binding properties of compounds 25, 26, 28, A and 37
against Bcl-xL were evaluated. Compounds 26 and 28 having quin-
olin-2-one moieties were found to be inefficient to disrupt these
interactions (data not shown). Oppositely, compounds 25, 37 and
A, showing 2-alkoxyquinoline units, exhibited inhibition potencies
towards Bcl-xL interactions with pro-apoptotic peptides in the
micromolar range (Table 1B). The most potent compound was
an IC50 value of 29 lM.

S. Broch et al. / Bioorg. Med. Chem. 18 (2010) 7132–7143
7137
OH
COOMe
CH MgBr, THF
3
PTSA
Toluene
Br
N
H
O
Br
N
H
O
Br
N
H
O
9
29, 80%
30, 88%
SOCl /DMF
2
CH Cl
2
2
H /PtO
NaOMe
MeOH
2
2
EtOAc
Br
N
OMe
Br
N
OMe
Br
N
Cl
33, 87%
32, 93%
31, 99%
33, PdCl (PPh )
B(OH)2
OEt
2
3 2
THF, aq. Na CO µW
2
3,
N
OMe
N
N
OEt
35, 88%
34
1) B(OiPr) , LDA
3
THF
2) sat. aq. NH Cl
4
B(OH)2
OMe
33, PdCl (PPh )
2
3 2
THF, aq. Na CO µW
N
OMe
2
3,
N
N
OMe
N
OEt
N
OEt
36
37, 75% from 33
HCl 6 N
N
H
O
N
H
O
N
H
O
38
Scheme 4. Synthesis of compound 37.
moieties. The preliminary structure–activity relationship study
has shown that, compared to their quinolin-2-one analogues, the
2-alkoxyquinoline derivatives are more potent modulators of the
Bcl-2 family protein interactions. This could be due to the better
solubility of 2-alkoxyderivatives compared to their quinolin-2-
one counterparts. Especially, compound A, that was designed to
4. Conclusion
The versatile synthetic approach reported here allows the
preparation of diversely substituted di- and trimeric quinoline
derivatives bearing different alkoxy groups in the 2-position as
well as various alkyl chains in the 5-position of the quinoline

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S. Broch et al. / Bioorg. Med. Chem. 18 (2010) 7132–7143
Table 1
Fluorescence polarisation assay evaluating compounds inhibiting capacities
A
Bak
15
2700 100
216 42
25 20
Bax
Bid
Bim
PUMA
65
287 100
336 22
Bcl-xl
Bcl-2
Bfl-1
6
47 16
148
68 17
124
Bax
71 16
3000 100
17
118 85
6
2
4
3
12
22
14
6
5
9
3
Mcl-1
5
1083 217
B
Peptide
Bak
Molecule
Bid
Bim
PUMA
25
A
37
ABT737
>1 mM
>1 mM
26
243 187
>1 mM
27 23
21 4.5
48.5 0.5 nM
29 10
92.5 4.5
47 19
2 nM
l
M
l
>1 mM
25
9
l
M
l
4
l
M
l
l
M
M
M
42
54
1
1
l
l
M
M
74 11.5
10 2 nM
M
lM
lM
23 3 nM
2
0.3 0.2 nM
C
Bax
Bcl-xl
Bcl-2
Bfl-1
26
43 12
68 10
4
Mcl-1
45.5 7.5
(A) Interactions between anti-apoptotic Bcl-2 family members and pro apoptotic BH3 peptides. IC50 values are in nM (+/- standard deviation).
(B) Bcl-xL xl/BH3 peptides interaction inhibition by synthesized compounds and ABT737 as positive control. IC50 values are in M or nM as indicated (+/- standard deviation).
(C) Anti apoptotic protein/Bax peptide interaction inhibition by compound A. IC50 values are in M as indicated (+/- standard deviation).
l
l
interact with Bcl-xL, inhibited Bcl-xL/Bak, Bcl-xL/Bax and Bcl-xL/Bid
interactions with IC50 values around 25 M.
Melting points were measured on a Reichert microscope and are
uncorrected.
l
Therefore, these new scaffolds could be of potential interest for
the development of new Bcl-2 anti-apoptotic group inhibitors. In
order to increase the affinity of these poly-quinoline derivatives to-
ward Bcl-2 anti-apoptotic members, the preparation of additional
diversely substituted trimeric 2-alkoxyquinolines with an im-
proved solubility is currently under investigation in our group.
5.2.1. Methyl 3-aminobenzoate (3)
A solution of 3-aminobenzoic acid 1 (5.00 g, 36.5 mmol) in meth-
anol (100 mL) was cooled to 0 °C before dropwise addition of SOCl2
(6.6 mL, 10.8 g, 91 mmol). The mixture was stirred at room temper-
ature for 24 h, evaporated and neutralised by addition of a saturated
aqueous NaHCO3 solution. After extraction with EtOAc, the assem-
bled organic fractions were dried over MgSO4 and evaporated to give
3 (5.48 g, 36.3 mmol, 99%) as a brown solid. This compound was par-
tially described by Gaudreault.27 In this reference the signal of the
methyl group was incorrectly given at 2.52 ppm.
5. Experimental
5.1. Fluorescence polarisation assays
Mp = 44 °C; IR (KBr): 3459, 3372, 3229, 1710, 1626, 1604, 1319,
Fluorescence polarisation assays were done using recombinant
GST-Bcl-xl, -Bcl-2, -Bfl-1 or -Mcl-1 without their C-terminal tail
1295, 1243 cmꢁ1 1H NMR (400 MHz, DMSO-d6): 3.79 (3H, s),
;
5.33ꢁ5.39 (2H, br s, NH2), 6.79 (1H, ddd, J1 = 7.5 Hz, J2 = 2.5 Hz,
J3 = 1.5 Hz), 7.08 (1H, dt, J1 = 7.5 Hz, J2 = 1.5 Hz), 7.13 (1H, t,
J = 7.5 Hz), 7.19 (1H, t, J = 2.0 Hz); 13C NMR (100 MHz, DMSO-d6):
51.8 (CH3), 114.1, 116.3, 118.3, 129.1 (CHarom), 130.2, 149.0 (Carom),
166.7 (C@O); HRMS (ESI+) calcd for C8H10NO2 (M+H)+ 152.0712,
found 152.0696.
and
N-terminal
FITC-conjugated
BH3
peptides
(Bim:
DMRPEIWIAQELRRIGDEFNAYYAR; Bid: EDIIRNIARHLAQVGDSMDR;
Bak: KGGGQVGRQLAIIGDDINRRYDS; Bax: VPQDASTKKLSECLKRIG-
DELDSNMELQR; PUMA: EQWAREIGAQLRRMADDLNA). 100 nM of
recombinant proteins were incubated with 15 nM FITC-conjugated
peptide (or 120 nM in the case of PUMA) in the dark in the presence
of various concentrations of the molecule (from 100 lM to 1 lM).
Fluorescence polarisation was measured using a Mithras LB940
equipment. IC50 determinations were performed using GraphPad
Prism software (GraphPad, Inc., San Diego, CA).
5.2.2. Methyl 3-amino-5-bromobenzoate (4)
The same procedure as described above for the preparation of
compound 3 (3-amino-5-bromobenzoic acid 2 (2.25 g, 10.4 mmol),
methanol (25 mL) and SOCl2 (1.5 mL, 2.46 g, 20.7 mmol)) yielded
compound 4 (2.25 g, 9.8 mmol, 94%) as a beige solid.
5.2. Chemistry
Mp = 96 °C (Lit. 83–88 °C)28; IR (KBr): 3413, 3325, 3218, 1714,
1644, 1605, 1574, 1311, 1245 cmꢁ1 1H NMR (400 MHz, DMSO-
;
IR spectra were recorded on Shimadzu FTIR-8400S or Perkin–El-
in cmꢁ1). NMR spectra were per-
ꢀ
m
mer Paragon 500 spectrometers (
d6): 3.81 (3H, s), 5.68ꢁ5.78 (2H, br s, NH2), 6.96 (1H, t,
J = 2.0 Hz), 7.12 (1H, t, J = 1.5 Hz), 7.16 (1H, dd, J1 = 2.0 Hz,
J2 = 1.5 Hz); 13C NMR (100 MHz, DMSO-d6): 52.2 (CH3), 113.3,
118.0, 119.8 (CHarom), 122.0, 132.0, 150.6 (Carom), 165.5 (C@O);
HRMS (ESI+) calcd for C8H979BrNO2 (M+H)+ 229.9817, found
229.9821.
formed on a Bruker AVANCE 400 (1H: 400 MHz, 13C: 100 MHz) or
Bruker AVANCE 500 (1H: 500 MHz, 13C: 125 MHz), chemical shifts
d in ppm, the following abbreviations are used: singlet (s), doublet
(d), triplet (t), quadruplet(q), sext (sextuplet), hept (heptuplet), dou-
blet of doublet (dd), doublet of triplet (dt), doublet of doublet of dou-
blet (ddd), multiplet (m), broad signal (br s). Mass spectra (ESI+)
were determined on a high-resolution Micro Q-Tof apparatus
(CRMP, Université Blaise Pascal, Clermont-Ferrand, France) or on a
Waters Q-Tof 2 apparatus (CRMPO, Université de Rennes, France).
Chromatographic purifications were performed by flash silica gel
Geduran SI 60 (Merck) 0.040–0.063 mm column chromatography.
Reactions were monitored by TLC using fluorescent silica gel plates
(60 F254 from Merck). Experiments under microwave irradiation
were performed using a CEM Discover Benchmate apparatus.
5.2.3. Methyl 3-[(E)-3-ethoxyprop-2-enoylamino]benzoate (5)
To a solution of 3 (7.47 g, 49.4 mmol) in CH2Cl2 (700 mL) were
added pyridine (6.6 mL, 6.5 g, 82 mmol) and a solution of (E)-3-
ethoxyprop-2-enoyl chloride (10.9 g, 81 mmol) in CH2Cl2 (40 mL).
The mixture was stirred at room temperature for 2.5 h and care-
fully poured into water, acidified with concentrated hydrochloric
acid and extracted with EtOAc. The assembled organic fractions
were dried over MgSO4 and evaporated. The residue was purified

S. Broch et al. / Bioorg. Med. Chem. 18 (2010) 7132–7143
7139
by flash chromatography (CH2Cl2 then CH2Cl2/EtOAc 95:5) to give
5 (9.90 g, 39.7 mmol, 80%) as a white solid.
Mp = 126 °C; IR (KBr): 1717, 1592, 1255, 1122 cmꢁ1
;
1H NMR
(400 MHz, DMSO-d6): 3.95 (3H, s), 7.75 (1H, d, J = 9.0 Hz), 8.26
(1H, d, J = 2.0 Hz), 8.41 (1H, dd, J1 = 2.0 Hz, J2 = 0.5 Hz), 9.10 (1H,
dd, J1 = 9.0 Hz, J2 = 0.5 Hz); 13C NMR (100 MHz, DMSO-d6): 53.0
(CH3), 124.3, 133.3, 134.8, 137.7 (CHarom), 122.9, 123.8, 128.6,
148.0, 151.5 (Carom), 164.8 (C@O); HRMS (ESI+) calcd for
Mp = 105 °C; IR (KBr): 3245, 1728, 1656, 1617, 1602, 1296
cmꢁ1 1H NMR (400 MHz, DMSO-d6): 1.27 (3H, t, J = 7.0 Hz), 3.84
;
(3H, s), 3.96 (2H, q, J = 7.0 Hz), 5.51 (1H, d, J = 12.5 Hz), 7.43 (1H,
t, J = 8.0 Hz), 7.51 (1H, d, J = 12.5 Hz), 7.60 (1H, ddd, J1 = 7.5 Hz,
J2 = 1.5 Hz, J3 = 1.0 Hz), 7.86 (1H, ddd, J1 = 8.0 Hz, J2 = 2.0 Hz,
J3 = 1.0 Hz), 8.28 (1H, t, J = 2.0 Hz), 9.95 (1H, s, NH); 13C NMR
(100 MHz, DMSO-d6): 14.5, 52.1 (CH3), 66.6 (CH2), 99.6, 119.4,
123.3 (2C), 129.2, 159.9 (CH), 130.1, 140.0 (Carom), 164.9, 166.2
(C@O); HRMS (ESI+) calcd for C13H15NNaO4 (M+Na)+ 272.0899,
found 272.0888.
C
11H879Br35ClNO2 (M+H)+ 299.9427, found 299.9432.
5.2.8. Methyl 7-bromo-2-methoxyquinoline-5-carboxylate (12)
A solution of 11 (700 mg, 2.33 mmol) and NaOMe (10.5 mmol,
prepared from 241 mg of Na) in MeOH (8.7 mL) was heated in an
oil bath at 65 °C for 2 h. The mixture was poured into a saturated
aqueous NH4Cl solution cooled to 0 °C. After extraction with
CH2Cl2, the assembled organic fractions were dried over MgSO4,
evaporated and the residue was purified by flash chromatography
(cyclohexane/EtOAc 9:1) to give 12 (518 mg, 1.75 mmol, 75%) as a
white solid.
5.2.4. Methyl 3-bromo-5-[(E)-3-ethoxyprop-2-enoylamino]
benzoate (6)
The same procedure as described above for the preparation of
compound 5 (compound 4 (5.14 g, 22.3 mmol) in CH2Cl2 (40 mL),
pyridine (3.8 mL, 3.7 g, 47 mmol) and (E)-3-ethoxyprop-2-enoyl
chloride (6.40 g, 47.6 mmol) in CH2Cl2 (20 mL), for 2 h) yielded, after
flash chromatography (cyclohexane/EtOAc 9:1 then 8:2), compound
6 (5.93 g, 18.1 mmol, 81%) as an orange solid.
Mp = 95ꢁ97 °C; IR (ATR): 1721, 1613, 1240, 1126 cmꢁ1
;
1H NMR (400 MHz, CDCl3): 3.98 (3H, s), 4.05 (3H, s), 7.00 (1H, d,
J = 9.5 Hz), 8.15 (1H, d, J = 2.0 Hz), 8.20 (1H, dd, J1 = 2.0 Hz,
J2 = 0.5 Hz), 9.07 (1H, dd, J1 = 9.5 Hz, J2 = 0.5 Hz); 13C NMR
(100 MHz, CDCl3): 52.6, 53.6 (CH3), 114.9, 131.0, 134.7, 136.8
(CHarom), 122.1, 122.7, 127.9, 148.0, 162.8, 166.1 (Carom, C@O);
HRMS (ESI+) calcd for C12H1179BrNO3 (M+H)+ 295.9922, found
295.9932.
Mp = 121 °C; IR (KBr): 3361, 1715, 1682, 1602, 1290, 1140
cmꢁ1 1H NMR (400 MHz, DMSO-d6): 1.27 (3H, t, J = 7.0 Hz), 3.86
;
(3H, s), 3.97 (2H, q, J = 7.0 Hz), 5.47 (1H, d, J = 12.5 Hz), 7.54 (1H,
d, J = 12.5 Hz), 7.68 (1H, t, J = 1.5 Hz), 8.14 (1H, t, J = 1.5 Hz), 8.22
(1H, t, J = 2.0 Hz), 10.13 (1H, s, NH); 13C NMR (100 MHz, DMSO-
d6): 14.5, 52.6 (CH3), 66.8 (CH2), 99.2, 118.3, 125.1, 125.3, 160.5
(CH), 121.7, 131.9, 141.5 (Carom), 164.8, 165.1 (C@O); HRMS
(ESI+) calcd for C13H1579BrNO4 (M+H)+ 328.0184, found 328.0187.
5.2.9. 7-Bromo-N,2-dimethoxy-N-methylquinoline-5-
carboxamide (13)
A solution of 12 (495 mg, 1.67 mmol) and N,O-dimethylhydr-
oxylamine (1.5 equiv) in THF (8.5 mL) was cooled to ꢁ15 °C before
dropwise addition of a solution of iPrMgCl in THF (1 M, 3 equiv).
The mixture was stirred at ꢁ15 °C for 30 min and a saturated aque-
ous NH4Cl solution was added. After extraction with EtOAc, the
assembled organic fractions were dried over MgSO4, evaporated
and the residue was purified by flash chromatography (cyclohex-
ane/EtOAc 4:1) to give 13 (427 mg, 1.31 mmol, 79%) as a white
solid.
5.2.5. Methyl 2-oxo-1,2-dihydroquinoline-5-carboxylate (7)
A solution of 5 (3.00 g, 12.0 mmol) in concentrated sulphuric
acid (95ꢁ97%, 30 mL) was stirred at room temperature for 6 h
and then poured into ice-water. The precipitate was filtered off
and washed with Et2O. The solid was recrystallized from 96% eth-
anol to give 7 (1.15 g, 5.7 mmol, 47%) as a beige solid.
Mp = 259 °C; IR (KBr): 3415, 1716, 1668, 1606, 1142 cmꢁ1 1H
;
NMR (400 MHz, DMSO-d6): 3.90 (3H, s), 6.64 (1H, dd,
J1 = 10.0 Hz, J2 = 2.0 Hz), 7.55 (1H, d, J = 7.5 Hz), 7.60 (1H, t,
J = 7.5 Hz), 7.71 (1H, dd, J1 = 7.5 Hz, J2 = 1.5 Hz), 8.62 (1H, d,
J = 10.0 Hz), 11.95ꢁ12.01 (1H, br s, NH); 13C NMR (100 MHz,
DMSO-d6): 52.5 (CH3), 119.8, 123.7, 124.4, 129.8, 137.0 (CH),
117.3, 127.4, 139.8 (Carom), 161.1, 166.6 (C@O); HRMS (ESI+) calcd
for C11H10NO3 (M+H)+ 204.0661, found 204.0654.
Mp = 106ꢁ108 °C; IR (ATR): 1645, 1613, 1505, 1379, 1265
cmꢁ1
;
1H NMR (400 MHz, CDCl3): 3.30ꢁ3.48 (3H, br s),
3.36ꢁ3.58 (3H, br s), 4.05 (3H, s), 6.94 (1H, d, J = 9.0 Hz), 7.52
(1H, d, J = 2.0 Hz), 8.00 (1H, d, J1 = 9.0 Hz, J2 = 0.5 Hz), 8.09 (1H,
13
*
dd, J1 = 2.0 Hz, J2 = 1.0 Hz); C NMR (100 MHz, CDCl3): 33.4 ,
53.7, 61.6 (CH3), 114.3, 125.8, 131.2, 136.0 (CHarom), 120.8, 122.4,
134.3, 147.4, 163.1 (Carom). The chemical shift of the indicated car-
bon ( ) was determined for the HSQC 1H–13C spectrum. The car-
*
5.2.6. Methyl 7-bromo-2-oxo-1,2-dihydroquinoline-5-
carboxylate (9)
The same procedure as described above for the preparation of
compound 7 (compound 6 (6.35 g, 19.4 mmol) in concentrated sul-
phuric acid (95–97%, 40 mL)) yielded 9 (2.74 g, 9.7 mmol, 50%) as a
beige solid.
bonyl carbon was not detected; HRMS (ESI+) calcd for
C
13H1479BrN2O3 (M+H)+ 325.0188, found 325.0204.
5.2.10. 1-(7-Bromo-2-methoxyquinolin-5-yl)ethan-1-one (14)
A solution of 13 (357 mg, 1.10 mmol) in THF (8.5 mL) was cooled
to 0 °C before dropwise addition of a solution of MeMgBr in Et2O
(3 M, 3 equiv). The mixture was stirred at room temperature for
3 h and then poured into a saturated aqueous NH4Cl solution cooled
to 0 °C. After extraction with EtOAc, the assembled organic fractions
were dried over MgSO4, evaporated and the residue was purified by
flash chromatography (cyclohexane/EtOAc 9:1) to give 14 (256 mg,
0.91 mmol, 83%) as a white solid.
Mp = 263 °C; IR (KBr): 3434, 1729, 1668, 1591, 1239, 1140 cm
ꢁ1
;
1H NMR (400 MHz, DMSO-d6): 3.91 (3H, s), 6.68 (1H, d,
J = 10.0 Hz), 7.71 (1H, d, J = 1.5 Hz), 7.78 (1H, d, J = 2.0 Hz), 8.55
(1H, d, J = 10.0 Hz), 11.99ꢁ12.06 (1H, br s, NH); 13C NMR
(100 MHz, DMSO-d6): 52.8 (CH3), 121.5, 124.1, 126.5, 136.6 (CH),
116.5, 122.3, 129.1, 140.8 (Carom), 160.9, 165.2 (C@O); HRMS
(ESI+) calcd for C11H979BrNO3 (M+H)+ 281.9766, found 281.9771.
Mp = 102ꢁ105 °C; IR (ATR): 1684, 1614, 1501, 1316, 1242 cm
ꢁ1
;
1H NMR (400 MHz, CDCl3): 2.72 (3H, s), 4.06 (3H, s), 7.00 (1H,
5.2.7. Methyl 7-bromo-2-chloroquinoline-5-carboxylate (11)
To a solution of 9 (1.33 g, 4.71 mmol) in CH2Cl2 (40 mL) were
added SOCl2 (0.45 mL, 0.74 g, 6.2 mmol) and DMF (0.39 mL,
0.37 g, 5.1 mmol). The mixture was refluxed for 3 h, cooled and
poured into water. After extraction with EtOAc, the assembled or-
ganic fractions were dried over MgSO4 and evaporated to give 11
(1.40 g, 4.66 mmol, 99%) as a white solid.
d, J = 9.5 Hz), 7.92 (1H, d, J = 2.0 Hz), 8.21 (1H, dd, J1 = 2.0 Hz,
J2 = 0.5 Hz), 8.90 (1H, dd, J1 = 9.5 Hz, J2 = 0.5 Hz); 13C NMR
(100 MHz, CDCl3): 29.6, 53.6 (CH3), 115.2, 129.8, 134.4, 137.1
(CHarom), 121.4, 121.9, 136.1, 148.3, 163.0 (Carom), 199.8 (C@O);
HRMS (ESI+) calcd for C12H1179BrNO2 (M+H)+ 279.9973, found
279.9979.

7140
S. Broch et al. / Bioorg. Med. Chem. 18 (2010) 7132–7143
5.2.11. (Z,E)-7-Bromo-5-(but-2-en-2-yl)-2-methoxyquinoline
(15)
J1 = 9.0 Hz, J2 = 0.5 Hz); 13C NMR (100 MHz, DMSO-d6): 19.4, 25.8,
53.3 (CH3), 113.1, 120.4, 127.1, 127.3, 136.7 (CH), 122.2, 122.4,
137.9, 139.1, 147.1, 162.4 (C); HRMS (ESI+) calcd for C14H1579BrNO
(M+H)+ 292.0337, found 292.0350.
A solution of ethylphosphonium bromide (5 equiv) in THF
(2.14 mL/mmol) was cooled to 0 °C before dropwise addition of a
solution of n-BuLi in hexane (2.4 M, 0.9 equiv/ethylphosphonium
bromide). The mixture was stirred at 0 °C for 30 min and a solution
of 14 (256 mg, 0.91 mmol) in THF (10 mL) was added dropwise.
The mixture was stirred at room temperature for 20 h and a 1 M
aqueous NH4Cl solution was added. After extraction with EtOAc,
the assembled organic fractions were dried over MgSO4, evapo-
rated and the residue was purified by flash chromatography (cyclo-
hexane/EtOAc 99:1) to give 15 (203 mg, 0.69 mg, 76%) as a mixture
of diastereoisomers which was directly used for the preparation of
compound 28.
5.2.15. 5-(2-Hydroxypropan-2-yl)quinolin-2(1H)-one (19)
A solution of 7 (1.16 g, 5.71 mmol) in THF (50 mL) was cooled to
0 °C before dropwise addition of MeMgBr (3.0 M in Et2O, 11.5 mL,
34.5 mmol). The mixture was stirred at room temperature for 15 h
and poured into a saturated aqueous NH4Cl solution. After extrac-
tion with EtOAc, the assembled organic fractions were dried over
MgSO4, evaporated and the residue was purified by flash chromatog-
raphy (cyclohexane/EtOAc 8:2) to give 19 (1.04 g, 5.12 mmol, 90%)
as a beige solid.
Mp = 238 °C; IR (ATR): 3397, 1638, 1611, 1549, 1425, 1134 cm
5.2.12. 7-Bromo-2-methoxyquinolin-5-ylmethanol (16)
A solution of DIBAL in CH2Cl2 (1 M, 5.7 mL, 5.70 mmol) was
added dropwise to a solution of 12 (562 mg, 1.90 mmol) in CH2Cl2
(20 mL). After stirring for 30 min at room temperature, a saturated
aqueous NH4Cl solution was added. The mixture was poured into a
1 M aqueous Rochelle salt solution. After stirring for 30 min, the
mixture was extracted with EtOAc and the assembled organic frac-
tions were washed with a 0.1 M aqueous HCl solution, water, brine
and then dried over MgSO4 and evaporated. The residue was puri-
fied by flash chromatography (cyclohexane/EtOAc 8:2) to give 16
(372 mg, 1.39 mmol, 73%) as a white solid.
ꢁ1
;
1H NMR (400 MHz, DMSO-d6): 1.59 (6H, s), 5.39 (1H, s, OH),
6.46 (1H, d, J = 10.0 Hz), 7.17 (1H, dd, J1 = 7.5 Hz, J2 = 1.0 Hz), 7.24
(1H, d, J = 8.0 Hz), 7.38 (1H, t, J = 8.0 Hz), 11.69 (1H, br s, NH); 13C
NMR (100 MHz, DMSO-d6): 31.8 (2CH3), 71.9 (C), 114.8, 118.6,
120.0, 129.4, 139.9 (CH), 116.8, 140.4, 146.4 (Carom), 161.2 (C@O);
HRMS (ESI+) calcd for C12H14NO2 (M+H)+ 204.1025, found
204.1037.
5.2.16. 5-(Propen-2-yl)quinolin-2(1H)-one (20)
PTSA monohydrate (852 mg, 4.48 mmol) was added to a solu-
tion of 19 (1.14 g, 5.61 mmol) in toluene (80 mL). The mixture
was refluxed for 15 h using a Dean-Stark apparatus. After cooling,
the mixture was poured into a saturated aqueous NaHCO3 solution
and extracted with EtOAc. The assembled organic fractions were
dried over MgSO4, evaporated and the residue was purified by flash
chromatography (cyclohexane/EtOAc 1:1) to give 20 (747 mg,
4.03 mmol, 72%) as a white solid.
Mp = 148 °C; IR (ATR): 3327, 1616, 1593, 1574, 1504, 1314,
1261 cmꢁ1 1H NMR (400 MHz, DMSO-d6): 3.98 (3H, s), 4.91 (2H,
;
d, J = 5.5 Hz), 5.50 (1H, t, J = 5.5 Hz), 7.07 (1H, d, J = 9.0 Hz), 7.58
(1H, m), 7.87 (1H, d, J = 1.5 Hz), 8.36 (1H, d, J = 9.0 Hz); 13C NMR
(100 MHz, DMSO-d6): 53.3 (CH3), 60.1 (CH2), 113.0, 125.1, 127.8,
135.7 (CHarom), 121.3, 122.7, 141.3, 147.2, 162.3 (Carom); HRMS
(ESI+) calcd for C11H1179BrNO2 (M+H)+ 267.9973, found 267.9988.
Mp = 184 °C; IR (ATR): 1682, 1655, 1641, 1611, 1557, 1445 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6): 2.09 (3H, s), 4.92 (1H, m), 5.40 (1H,
m), 6.49 (1H, d, J = 10.0 Hz), 7.02 (1H, dd, J1 = 7.5 Hz, J2 = 1.0 Hz),
7.23 (1H, d, J = 8.5 Hz), 7.45 (1H, dd, J1 = 8.5 Hz, J2 = 7.5 Hz), 7.92
(1H, d, J = 10.0 Hz), 11.77 (1H, br s, NH); 13C NMR (100 MHz,
DMSO-d6): 24.8 (CH3), 114.2, 120.5, 121.7, 130.0, 137.5 (CH),
115.9, 117.0, 139.4, 142.2, 142.5 (@CH2, C), 161.6 (C@O); HRMS
(ESI+) calcd for C12H12NO (M+H)+ 186.0919, found 186.0925.
5.2.13. 7-Bromo-2-methoxyquinoline-5-carbaldehyde (17)
A solution of Dess–Martin periodinane in CH2Cl2 (15 wt %,
4.0 mL, 1.93 mmol) was added to a solution of 16 (340 mg,
1.27 mmol) in CH2Cl2 (8 mL). The mixture was stirred at room tem-
perature for 10 min, poured into a 1 M aqueous NaOH solution and
extracted with Et2O. The assembled organic fractions were dried
over MgSO4, evaporated and the residue was purified by flash chro-
matography (cyclohexane/EtOAc 9:1) to give 17 (254 mg,
0.95 mmol, 75%) as a white solid.
5.2.17. 2-Chloro-5-(propen-2-yl)quinoline (21)
Mp = 143 °C; IR (ATR): 1692, 1611, 1586, 1503, 1265 cmꢁ1 1H
;
A solution of 20 (790 mg, 4.27 mmol) in POCl3 (20 mL) was re-
fluxed for 2 h. After cooling, the mixture was poured into water
and extracted with EtOAc. The assembled organic fractions were
dried over MgSO4, evaporated and the residue was purified by flash
chromatography to give 21 (827 mg, 4.06 mmol, 95%) as a colourless
oil.
NMR (400 MHz, DMSO-d6): 4.00 (3H, s), 7.22 (1H, d, J = 9.5 Hz),
8.19 (1H, d, J = 2.0 Hz), 8.21 (1H, d, J = 2.0 Hz), 9.19 (1H, d,
J = 9.5 Hz), 10.29 (1H, s); 13C NMR (100 MHz, DMSO-d6): 53.4
(CH3), 115.7, 134.7, 135.0, 135.5 (CHarom), 121.0, 122.2, 132.5,
147.4, 162.6 (Carom), 193.0 (CHO); HRMS (ESI+) calcd for
C11H979BrNO2 (M+H)+ 265.9817, found 265.9833.
IR (ATR): 1601, 1584, 1568, 1489, 1111 cmꢁ1; 1H NMR (400 MHz,
DMSO-d6): 2.18 (3H, dd, J1 = 1.5 Hz, J2 = 1.0 Hz), 5.03 (1H, m), 5.51
(1H, m), 7.52 (1H, dd, J1 = 7.0 Hz, J2 = 1.5 Hz), 7.58 (1H, d,
J = 9.0 Hz), 7.79 (1H, dd, J1 = 8.5 Hz, J2 = 7.0 Hz), 7.89 (1H, dt,
J1 = 8.0 Hz, J2 = 1.0 Hz), 8.45 (1H, dd, J1 = 9.0 Hz, J2 = 1.0 Hz); 13C
NMR (100 MHz, DMSO-d6): 24.8 (CH3), 122.3, 125.4, 127.0, 130.5,
137.7 (CHarom), 117.7, 124.1, 142.1, 142.2, 147.6, 149.7 (@CH2, C);
5.2.14. 7-Bromo-2-methoxy-5-(2-methylpropen-1-yl)quinoline
(18)
n-BuLi (2.5 M in hexane, 0.60 mL, 1.50 mmol) was added to a
suspension, cooled to 0 °C, of isopropyltriphenylphosphonium
iodide (715 mg, 1.65 mmol) in THF (8 mL). The mixture was stirred
at 0 °C for 30 min and a solution of 17 (220 mg, 0.83 mmol) in THF
(5 mL) was added. After stirring for 2 h at 0 °C, the mixture was
poured into water and extracted with EtOAc. The assembled organ-
ic fractions were dried over MgSO4, evaporated and the residue
was purified by flash chromatography (cyclohexane/EtOAc 98:2)
to give 18 (225 mg, 0.77 mmol, 93%) as a white solid.
HRMS (ESI+) calcd for
204.0585.
C
12H1135ClN (M+H)+ 204.0580, found
5.2.18. 2-Methoxy-5-(propen-2-yl)quinoline (22)
A solution of NaOMe (2.35 mmol, prepared from 54 mg of Na) in
methanol (5 mL) was added to compound 21 (95 mg, 0.47 mmol)
and the mixture was refluxed for 15 h. After evaporation, water
was added and the mixture was extracted with EtOAc. The assem-
bled organic fractions were dried over MgSO4 and evaporated to
give 22 (91 mg, 0.46 mmol, 98%) as a colourless oil.
Mp = 63 °C; IR (ATR): 1611, 1582, 1497, 1312 cmꢁ1 1H NMR
;
(400 MHz, DMSO-d6): 1.66 (3H, d, J = 1.0 Hz), 1.98 (3H, d,
J = 1.5 Hz), 3.98 (3H, s), 6.60 (1H, m), 7.03 (1H, d, J = 9.0 Hz), 7.32
(1H, dd, J1 = 2.0 Hz, J2 = 1.0 Hz), 7.85 (1H, m), 8.20 (1H, dd,

S. Broch et al. / Bioorg. Med. Chem. 18 (2010) 7132–7143
7141
IR (ATR): 1611, 1578, 1503, 1485, 1397, 1316, 1263 cmꢁ1
;
1H
146.5, 147.0, 159.3, 162.3 (Carom); HRMS (ESI+) calcd for
27H31N2O2 (M+H)+ 415.2386, found 415.2382.
NMR (400 MHz, DMSO-d6): 2.15 (3H, dd, J1 = 1.5 Hz, J2 = 1.0 Hz),
3.98 (3H, s), 4.97 (1H, m), 5.45 (1H, m), 7.01 (1H, d, J = 9.0 Hz),
7.28 (1H, dd, J1 = 7.0 Hz, J2 = 1.5 Hz), 7.62 (1H, dd, J1 = 8.5 Hz,
J2 = 7.0 Hz), 7.70 (1H, ddd, J1 = 8.5 Hz, J2 = 1.5 Hz, J3 = 1.0 Hz), 8.26
(1H, dd, J1 = 9.0 Hz, J2 = 1.0 Hz); 13C NMR (100 MHz, DMSO-d6):
24.9, 53.1 (CH3), 112.7, 122.5, 125.9, 129.2, 136.8 (CHarom), 116.9,
121.9, 141.8, 143.0, 146.3, 161.6 (@CH2, C); HRMS (ESI+) calcd for
C
5.2.21. 50-Isobutyl-5-isopropyl-3,70-biquinoline-2,20(1H,10H)-
dione (26)
A suspension of 25 (16 mg, 39 lmol) in a 6 M aqueous HCl solu-
tion (1.5 mL) was refluxed for 4 h. The mixture was poured into
water and extracted with CH2Cl2. The assembled organic fractions
C
13H14NO (M+H)+ 200.1075, found 200.1081.
were dried over MgSO4 and evaporated to give 26 (12 mg, 31
lmol,
80%) as a beige solid.
Mp = 246 °C; IR (ATR): 1655, 1616, 1549, 1439, 1225 cmꢁ1
;
1H
5.2.19. 5-Isopropyl-2-methoxyquinoline (23)
mixture of 22 (300 mg, 1.51 mmol) and PtO2 (68 mg,
NMR (400 MHz, CDCl3): 1.02 (6H, d, J = 6.5 Hz), 1.41 (6H, d,
J = 7.0 Hz), 1.98 (1H, m), 2.90 (2H, d, J = 7.0 Hz), 3.63 (1H, hept,
J = 7.0 Hz), 6.82 (1H, d, J = 9.5 Hz), 7.20 (1H, d, J = 7.0 Hz), 7.27
(1H, s), 7.47 (1H, d, J = 8.0 Hz), 7.52 (1H, t, J = 7.5 Hz), 8.11 (1H, d,
J = 9.5 Hz), 8.44 (1H, s), 8.71 (1H, s), 13.50 (1H, br s, NH), 13.95
(1H, br s, NH); 13C NMR (100 MHz, CDCl3): 22.7 (2C), 23.7 (2C),
28.8, 30.5 (CH3, CH), 42.0 (CH2), 114.4, 116.2, 119.3, 120.7, 123.8,
131.0, 135.3, 137.6 (CHarom), 117.9, 118.6, 129.1, 137.9, 138.9,
139.3, 139.4, 146.2 (Carom), 163.4, 165.2 (C@O); HRMS (ESI+) calcd
for C25H27N2O2 (M+H)+ 387.2073, found 387.2086.
A
0.30 mmol) in EtOAc (10 mL) was hydrogenated for 15 h before fil-
tration on Celite. After evaporation, the residue was purified by
flash chromatography (cyclohexane/EtOAc 98:2) to give 23
(272 g, 1.35 mmol, 90%) as a colourless oil.
IR (ATR): 1611, 1578, 1508, 1487, 1400, 1308, 1265 cmꢁ1 1H
;
NMR (400 MHz, DMSO-d6): 1.30 (6H, d, J = 7.0 Hz), 3.67 (1H, hept,
J = 7.0 Hz), 3.98 (3H, s), 7.02 (1H, d, J = 9.0 Hz), 7.31–7.38 (1H, m),
7.58–7.65 (2H, m), 8.47 (1H, d, J = 9.0 Hz); 13C NMR (100 MHz,
DMSO-d6): 23.5 (2C), 27.8, 53.0 (CH3, CH), 112.3, 120.0, 125.0,
129.5, 135.1 (CHarom), 122.5, 145.1, 146.4, 161.3 (Carom); HRMS
(ESI+) calcd for C13H16NO (M+H)+ 202.1232, found 202.1231.
5.2.22. (R,S)-500-(Butan-2-yl)-50-isobutyl-5-isopropyl-2,20,200-
trimethoxy-3,70:3,700-terquinoline (A)
Step A. A solution of diisopropylamine (0.14 mL, 0.99 mmol) in
THF (1 mL) was cooled to 0 °C before dropwise addition of n-BuLi
(2.5 M in hexane, 0.36 mL, 0.90 mmol). The mixture was stirred
for 1 h at 0 °C and was added dropwise to a solution, cooled to
ꢁ78 °C, of 25 (100 mg, 0.24 mmol) and triisopropylborate
(0.22 mL, 0.95 mmol) in THF (2 mL). After stirring for 4 h at
ꢁ78 °C, the mixture was allowed to reach room temperature and
was stirred for 15 h. After addition of a saturated aqueous NH4Cl
solution, the mixture was extracted with EtOAc and the assembled
organic fractions were dried over MgSO4 and evaporated to give 27
(112 mg) as a pale yellow solid.
5.2.20. 2,20-Dimethoxy-50-isobutyl-5-isopropyl-3,70-biquinoline
(25)
Step A. A solution of diisopropylamine (0.31 mL, 2.19 mmol) in
THF (2 mL) was cooled to 0 °C before dropwise addition of n-BuLi
(2.5 M in hexane, 0.80 mL, 2.00 mmol). The mixture was stirred
at 0 °C for 1 h and was added dropwise to a solution, cooled to
ꢁ78 °C, of 23 (109 mg, 0.54 mmol) and triisopropylborate
(0.50 mL, 2.16 mmol) in THF (5 mL). After stirring for 4 h at
ꢁ78 °C, the mixture was allowed to reach room temperature and
was stirred for 15 h. After addition of a saturated aqueous NH4Cl
solution, the mixture was extracted with EtOAc and the assembled
organic fractions were dried over MgSO4 and evaporated to give 24
(132 mg) as a pale yellow solid.
Step B. To a solution of 15 (24 mg, 82
lmol) in THF (2 mL) were
added PdCl2(PPh3)2 (2.9 mg, 4 mol), a 2 M aqueous Na2CO3 solu-
l
tion (0.21 mL, 0.42 mmol) and boronic acid 27 from step A
(112 mg). The mixture was stirred under microwave irradiation
(65 °C, 50 W, Patm) for 20 min, poured into water and extracted
with EtOAc. The assembled organic fractions were dried over
MgSO4, evaporated and the residue was purified by flash chroma-
tography (cyclohexane/EtOAc 99:1) to give the intermediate trimer
Step B. To a solution of 18 (132 mg, 0.45 mmol) in THF (4 mL)
were added PdCl2(PPh3)2 (15.9 mg, 23 lmol), a 2 M aqueous
Na2CO3 solution (1.1 mL, 2.2 mmol) and boronic acid 24 from step
A (221 mg). The mixture was stirred under microwave irradiation
(65 °C, 50 W, Patm) for 20 min, poured into water and extracted
with EtOAc. The assembled organic fractions were dried over
MgSO4, evaporated and the residue was purified by flash chroma-
tography (cyclohexane/EtOAc 99:1) to give the intermediate dimer
(169 mg, 0.41 mmol) as a white solid.
(47 mg, 75
Step C. To a solution of the intermediate trimer from step B
(47 mg, 75 mol) in MeOH (1 mL) were added ammonium formate
lmol) as a white solid.
l
(95 mg, 1.5 mmol) and 10% Pd/C (7.5 mg). The mixture was re-
fluxed for 6 days before filtration on Celite. Water was added and
the mixture was extracted with EtOAc. The assembled organic frac-
tions were dried over MgSO4, evaporated and the residue was puri-
fied by flash chromatography (cyclohexane/EtOAc 98:2) to give A
Step C. To a solution of the intermediate dimer from step B
(169 mg, 0.41 mmol) in MeOH (2 mL) were added ammonium for-
mate (258 mg, 4.10 mmol) and 10% Pd/C (41 mg). The mixture was
refluxed for 15 h before filtration on Celite. Water was added and
the mixture was extracted with EtOAc. The assembled organic frac-
tions were dried over MgSO4, evaporated and the residue was puri-
fied by flash chromatography (cyclohexane/EtOAc 98:2) to give 25
(146 mg, 0.35 mmol, 78% from 18) as a white solid.
(42 mg, 67
lmol, 81% from 15) as a white solid.
Mp = 131 °C; IR (ATR): 1609, 1570, 1261 cmꢁ1
;
1H NMR
(400 MHz, CDCl3): 0.99 (3H, t, J = 7.5 Hz), 1.04 (6H, d, J = 6.5 Hz),
1.42 (9H, d, J = 7.0 Hz), 1.71ꢁ1.96 (2H, m), 2.10 (1H, m), 2.99 (2H,
d, J = 7.0 Hz), 3.46 (1H, sext, J = 7.0 Hz), 3.74 (1H, hept, J = 7.0 Hz),
4.13 (3H, s), 4.15 (3H, s), 4.16 (3H, s), 6.96 (1H, d, J = 9.0 Hz), 7.36
(1H, d, J = 7.5 Hz), 7.53 (1H, d, J = 1.5 Hz), 7.59 (1H, d, J = 1.5 Hz),
7.62 (1H, t, J = 8.0 Hz), 7.80 (1H, d, J = 8.5 Hz), 8.00 (1H, s), 8.02
(1H, s), 8.34 (1H, d, J = 9.0 Hz), 8.34 (1H, s), 8.45 (1H, s); 13C NMR
(100 MHz, CDCl3): 12.2, 21.5, 22.8 (2C), 23.9 (2C), 28.7, 30.1,
35.6, 53.6, 53.8, 53.9 (CH3, CH), 30.7, 42.2 (CH2), 112.7, 120.3,
122.9, 125.1, 125.7 (2C), 127.3, 129.5, 134.4, 134.6, 134.9 (CHarom),
123.0, 123.5, 123.9, 125.8, 126.1, 137.9, 138.2, 138.4, 143.7, 145.4,
Mp = 141 °C; IR (ATR): 1611, 1570, 1458, 1263 cmꢁ1 1H NMR
;
(400 MHz, CDCl3): 1.02 (6H, d, J = 6.5 Hz), 1.40 (6H, d, J = 7.0 Hz),
2.01 (1H, m), 2.93 (2H, d, J = 7.0 Hz), 3.71 (1H, hept, J = 7.0 Hz),
4.13 (2 ꢂ 3H, 2s), 6.95 (1H, d, J = 9.0 Hz), 7.35 (1H, d, J = 7.0 Hz),
7.50 (1H, d, J = 1.5 Hz), 7.62 (1H, t, J = 8.0 Hz), 7.80 (1H, d,
J = 8.5 Hz), 8.00 (1H, s), 8.24 (1H, d, J = 9.0 Hz), 8.42 (1H, s); 13C
NMR (100 MHz, CDCl3): 22.8 (2C), 23.9 (2C), 28.7, 30.2, 53.8, 53.9
(CH3, CH), 42.1 (CH2), 112.6, 120.3, 125.0, 125.8, 127.2, 129.6,
134.6, 135.5 (CHarom), 123.3, 123.4, 125.6, 137.8, 138.4, 145.5,

7142
S. Broch et al. / Bioorg. Med. Chem. 18 (2010) 7132–7143
146.6, 146.7, 147.2, 159.3, 159.8, 162.3 (Carom); HRMS (ESI+) calcd
for C41H46N3O3 (M+H)+ 628.3539, found 628.3552.
into water. After extraction with EtOAc, the assembled organic
fractions were dried over MgSO4 and evaporated to give 31
(195 mg, 0.69 mmol, 99%) as a beige solid.
5.2.23. (R,S)-500-(Butan-2-yl)-50-isobutyl-5-isopropyl-3,70:3,700-
terquinoline-2,20,200(1H,10H,100H)-trione (28)
A suspension of A (29 mg, 46 lmol) in a 6 M aqueous HCl solu-
tion (1.5 mL) was refluxed for 7 days. The mixture was poured into
Mp = 108 °C; IR (ATR): 1591, 1582,1560, 1113 cmꢁ1 1H NMR
;
(400 MHz, DMSO-d6): 2.17 (3H, dd, J1 = 1.5 Hz, J2 = 1.0 Hz), 5.07
(1H, m), 5.54 (1H, m), 7.63 (1H, d, J = 9.0 Hz), 7.68 (1H, d,
J = 2.0 Hz), 8.13 (1H, dd, J1 = 2.0 Hz, J2 = 1.0 Hz), 8.43 (1H, dd,
J1 = 9.0 Hz, J2 = 1.0 Hz); 13C NMR (100 MHz, DMSO-d6): 24.5
(CH3), 122.9, 128.3, 128.9, 138.0 (CHarom), 118.7, 123.2, 123.8,
141.0, 144.1, 148.2, 151.0 (@CH2, C); HRMS (ESI+) calcd for
water and extracted with CH2Cl2. The assembled organic fractions
were dried over MgSO4 and evaporated to give 28 (24 mg, 41
lmol,
89%) as a yellow solid.
Mp = 281 °C; IR (ATR): 1653, 1616, 1551 cmꢁ1
;
1H NMR
C
12H1079Br35ClN (M+H)+ 281.9685, found 281.9700.
(400 MHz, CDCl3): 0.99 (3H, t, J = 7.0 Hz), 1.07 (6H, d, J = 6.5 Hz),
1.43 (9H, d, J = 7.0 Hz), 1.73ꢁ1.94 (2H, m), 2.05 (1H, m), 2.98 (2H,
d, J = 7.0 Hz), 3.39 (1H, sext, J = 7.0 Hz), 3.65 (1H, hept, J = 7.0 Hz),
6.82 (1H, dd, J1 = 10.0 Hz, J2 = 1.5 Hz), 7.21 (1H, d, J = 7.0 Hz), 7.29
(1H, s), 7.36 (1H, s), 7.47 (1H, d, J = 8.0 Hz), 7.53 (1H, t,
J = 7.5 Hz), 8.21 (1H, d, J = 10.0 Hz), 8.35 (1H, s), 8.45 (1H, s), 8.73
(1H, s), 8.75 (1H, s), 13.60 (1H, br s), 13.99 (1H, br s), 14.14 (1H,
br s); 13C NMR (100 MHz, CDCl3): 12.2, 21.6, 22.8 (2C), 23.8 (2C),
28.8, 30.8, 35.6 (CH3, CH), 30.9, 42.2 (CH2), 114.4, 115.8, 116.0,
119.3, 119.6, 120.6, 123.9, 131.1, 135.2, 135.8, 136.8 (CH), 117.9,
118.1, 118.8, 129.1, 129.6, 138.0, 138.2, 138.9, 139.0, 139.3,
139.6, 145.1, 146.1, 163.4, 163.8, 165.1 (C); HRMS (ESI+) calcd for
5.2.27. 7-Bromo-2-methoxy-5-(propen-2-yl)quinoline (32)
Compound 31 (180 mg, 0.64 mmol) was added to a solution of
NaOMe (2.87 mmol, prepared from 66 mg of Na) in MeOH (5 mL)
and the mixture was refluxed form 15 h. After evaporation, water
was added and the mixture was extracted with EtOAc. The assem-
bled organic fractions were dried over MgSO4 and evaporated to
give 32 (164 mg, 0.59 mmol, 93%) as a colourless oil.
IR (ATR): 1611, 1580, 1570, 1497, 1316 cmꢁ1
;
1H NMR
(400 MHz, DMSO-d6): 2.15 (3H, dd, J1 = 1.5 Hz, J2 = 1.0 Hz), 3.98
(3H, s), 5.01 (1H, m), 5.48 (1H, m), 7.05 (1H, d, J = 9.0 Hz), 7.43
(1H, d, J = 2.0 Hz), 7.89 (1H, dd, J1 = 2.0 Hz, J2 = 1.0 Hz), 8.24 (1H,
dd, J1 = 9.0 Hz, J2 = 1.0 Hz); 13C NMR (100 MHz, DMSO-d6): 24.6,
53.4 (CH3), 113.4, 125.3, 127.8, 137.0 (CHarom), 117.9, 121.0,
122.5, 141.7, 143.9, 147.3, 162.5 (@CH2, C); HRMS (ESI+) calcd
for C13H1379BrNO (M+H)+ 278.0181, found 278.0185.
C
38H40N3O3 (M+H)+ 586.3070, found 586.3070.
5.2.24. 7-Bromo-5-(2-hydroxypropan-2-yl)quinolin-2(1H)-one
(29)
A solution of 9 (250 mg, 0.89 mmol) in THF (15 mL) was cooled
to 0 °C before dropwise addition of MeMgBr (3.0 M in Et2O, 1.8 mL,
5.4 mmol). The mixture was stirred at room temperature for 15 h,
poured into a saturated aqueous NH4Cl solution and extracted with
EtOAc. The assembled organic fractions were dried over MgSO4,
evaporated and the residue was purified by flash chromatography
(cyclohexane/EtOAc 8:2) to give 29 (201 mg, 0.71 mmol, 80%) as a
pale yellow solid.
5.2.28. 7-Bromo-5-isopropyl-2-methoxyquinoline (33)
A
mixture of 32 (83 mg, 0.30 mmol) and PtO2 (13.4 mg,
59
lmol) in EtOAc (5 mL) was hydrogenated for 15 h before filtra-
tion on Celite. After evaporation, the residue was purified by flash
chromatography (cyclohexane/EtOAc 98:2) to give 33 (73.1 mg,
0.26 mmol, 87%) as a colourless oil.
IR (ATR): 1609, 1591, 1574, 1501, 1464, 1400, 1306, 1256 cmꢁ1
;
Mp = 258 °C; IR (ATR): 3372, 3322, 1647, 1595, 1549 cmꢁ1 1H
;
1H NMR (400 MHz, CDCl3): 1.33 (6H, d, J = 7.0 Hz), 3.51 (1H, hept,
J = 7.0 Hz), 4.04 (3H, s), 6.88 (1H, d, J = 9.0 Hz), 7.38 (1H, d,
J = 1.5 Hz), 7.91 (1H, d, J = 1.5 Hz), 8.14 (1H, d, J = 9.0 Hz); 13C
NMR (100 MHz, CDCl3): 23.4 (2C), 28.6, 53.3 (CH3, CH), 112.7,
123.5, 127.9, 134.3 (CHarom), 121.6, 123.7, 146.8, 148.0, 162.4 (Car-
om); HRMS (ESI+) calcd for C13H1579BrNO (M+H)+ 280.0337, found
280.0353.
NMR (400 MHz, DMSO-d6): 1.58 (6H, s), 5.51 (1H, s, OH), 6.51
(1H, dd, J1 = 10.0 Hz, J2 = 2.0 Hz), 7.30 (1H, d, J = 2.0 Hz), 7.43 (1H,
d, J = 1.5 Hz), 8.79 (1H, d, J1 = 10.0 Hz, J2 = 0.5 Hz), 11.77 (1H, s,
NH); 13C NMR (100 MHz, DMSO-d6): 31.5 (2CH3), 71.7 (C), 116.9,
120.7, 121.6, 139.2 (CH), 115.7, 122.7, 141.4 (Carom), 148.9, 161.0
(C@O); HRMS (ESI+) calcd for C12H1379BrNO2 (M+H)+ 282.0130,
found 282.0139.
5.2.29. 2-Ethoxy-50-isopropyl-20-methoxy-3,70-biquinoline (35)
To a solution of 33 (100 mg, 0.36 mmol) in THF (3 mL) were
added PdCl2(PPh3)2 (12.5 mg, 18 lmol), a 2 M aqueous Na2CO3
5.2.25. 7-Bromo-5-(propen-2-yl)quinolin-2(1H)-one (30)
PTSA monohydrate (133 mg, 0.70 mmol) was added to a solu-
tion of 29 (246 mg, 0.87 mmol) in toluene (15 mL). The mixture
was refluxed for 15 h using a Dean-Stark apparatus. After cooling,
the mixture was poured into a saturated aqueous NaHCO3 solution
and extracted with EtOAc. The assembled organic fractions were
dried over MgSO4, evaporated and the residue was purified by flash
chromatography (cyclohexane/EtOAc 1:1) to give 30 (202 mg,
0.76 mmol, 88%) as a white solid.
solution (0.89 mL, 1.78 mmol) and boronic acid 34 (155 mg,
0.71 mmol). The mixture was stirred under microwave irradiation
(65 °C, 50 W, Patm) for 20 min, poured into water and extracted
with EtOAc. The assembled organic fractions were dried over
MgSO4, evaporated and the residue was purified by flash chroma-
tography (cyclohexane/EtOAc 99:1) to give 35 (117 mg, 0.31 mmol,
88%) as a white solid.
Mp = 225 °C; IR (ATR): 1665, 1653, 1597, 1549 cmꢁ1 1H NMR
;
Mp = 157 °C; IR (ATR): 1609, 1570, 1258 cmꢁ1
;
1H NMR
(400 MHz, DMSO-d6): 2.09 (3H, dd, J1 = 1.5 Hz, J2 = 1.0 Hz), 4.96
(1H, m), 5.43 (1H, m), 6.53 (1H, d, J = 10.0 Hz), 7.19 (1H, d,
J = 2.0 Hz), 7.42 (1H, dd, J1 = 2.0 Hz, J2 = 0.5 Hz), 7.88 (1H, dd,
J1 = 10.0 Hz, J2 = 0.5 Hz), 11.85 (1H, br s, NH); 13C NMR (100 MHz,
DMSO-d6): 24.4 (CH3), 116.4, 122.3, 123.1, 137.2 (CH), 115.1,
117.9, 123.0, 140.5, 141.3, 144.2 (@CH2, C), 161.4 (C@O); HRMS
(ESI+) calcd for C12H1179BrNO (M+H)+ 264.0024, found 264.0042.
(400 MHz, CDCl3): 1.43 (6H, d, J = 7.0 Hz), 1.46 (3H, t, J = 7.0 Hz),
3.68 (1H, hept, J = 7.0 Hz), 4.11 (3H, s), 4.64 (2H, q, J = 7.0 Hz),
6.95 (1H, d, J = 9.0 Hz), 7.40 (1H, ddd, J1 = 8.0 Hz, J2 = 7.0 Hz,
J3 = 1.0 Hz), 7.64 (1H, ddd, J1 = 8.5 Hz, J2 = 7.0 Hz, J3 = 1.5 Hz), 7.72
(1H, d, J = 1.5 Hz), 7.78 (1H, dd, J1 = 8.0 Hz, J2 = 1.0 Hz), 7.90 (1H,
d, J = 8.5 Hz), 7.98 (1H, s), 8.17 (1H, s), 8.32 (1H, d, J = 9.0 Hz); 13C
NMR (100 MHz, CDCl3): 14.7, 23.8 (2C), 28.7, 53.5 (CH3, CH), 62.2
(CH2), 112.6, 122.1, 124.2, 125.7, 126.9, 127.6, 129.5, 134.4, 138.4
(CHarom), 122.4, 125.6, 126.5, 138.3, 144.3, 146.1, 147.2, 159.5,
162.2 (Carom); HRMS (ESI+) calcd for C24H25N2O2 (M+H)+
373.1916, found 373.1933.
5.2.26. 7-Bromo-2-chloro-5-(propen-2-yl)quinoline (31)
To a solution of 30 (185 mg, 0.70 mmol) in CH2Cl2 (8 mL) were
added SOCl2 (66
lL, 108 mg, 0.91 mmol) and DMF (70 lL, 67 mg,
0.91 mmol). The mixture was refluxed for 3 h, cooled and poured

S. Broch et al. / Bioorg. Med. Chem. 18 (2010) 7132–7143
7143
5.2.30. 2-Ethoxy-50,500-diisopropyl-20,200-dimethoxy-3,70:3,700-
References and notes
terquinoline (37)
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2. Adams, J. M.; Cory, S. Science 1998, 281, 1322.
3. Szegezdi, E.; MacDonald, D. C.; Chonghaile, T. N.; Gupta, S.; Samali, A. Am. J.
Physiol. Cell Physiol. 2009, 296, 941.
4. Yu, N.; Aramini, J. M.; Germann, M. W.; Huang, Z. Tetrahedron Lett. 2000, 41,
6993.
5. 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. 2000, 97, 7124.
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X.; Huang, Y.; Long, Y.-Q.; Roller, P. P.; Yang, D.; Wang, S. J. Med. Chem. 2001, 44,
4313.
Step A. A solution of diisopropylamine (0.12 mL, 0.85 mmol) in
THF (1 mL) was cooled to 0 °C before dropwise addition of n-BuLi
(2.5 M in hexane, 0.32 mL, 0.80 mmol). The mixture was stirred
for 1 h at 0 °C and was added dropwise to a solution, cooled to
ꢁ78 °C, of 35 (80 mg, 0.21 mmol) and triisopropylborate
(0.20 mL, 0.87 mmol) in THF (2 mL). After stirring for 4 h at
ꢁ78 °C, the mixture was allowed to reach room temperature and
was stirred for 15 h. After addition of a saturated aqueous NH4Cl
solution, the mixture was extracted with EtOAc and the assembled
organic fractions were dried over MgSO4 and evaporated to give 36
(89 mg) as a pale yellow solid.
7. Degterev, A.; Lugovskoy, A.; Cardone, M.; Mulley, B.; Wagner, G.; Mitchison, T.;
Yuan, J. Nat. Cell Biol. 2001, 3, 173.
8. Tzung, S.-P.; Kim, K. M.; Basañez, G.; Giedt, C. D.; Simon, J.; Zimmerberg, J.;
Zhang, K. Y. J.; Hockenbery, D. M. Nat. Cell Biol. 2001, 3, 183.
9. Kim, K. M.; Giedt, C. D.; Basañez, G.; O’Neill, J. W.; Hill, J. J.; Han, Y.-H.; Tzung, S.-P.;
Zimmerberg, J.; Hockenbery, D. M.; Zhang, K. Y. J. Biochemistry 2001, 40, 4911.
10. Kaneko, M.; Nakashima, T.; Uosaki, Y.; Hara, M.; Ikeda, S.-I.; Kanda, Y. Bioorg.
Med. Chem. Lett. 2001, 11, 887.
11. Vogler, M.; Dinsdale, D.; Dyer, M. J. S.; Cohen, G. M. Cell Death Differ. 2009, 16,
360.
12. Bernardo, P. H.; Wan, K.-F.; Sivaraman, T.; Xu, J.; Moore, F. K.; Hung, A. W.;
Mok, H. Y. K.; Yu, V. C.; Chai, C. L. L. J. Med. Chem. 2008, 51, 6699.
13. Prakesch, M.; Denisov, A. Y.; Naim, M.; Gehring, K.; Arya, P. Bioorg. Med. Chem.
2008, 16, 7443.
Step B. To a solution of 33 (20 mg, 71
added PdCl2(PPh3)2 (2.5 mg, 3.6 mol), a 2 M aqueous Na2CO3
lmol) in THF (2 mL) were
l
solution (0.18 mL, 0.36 mmol) and boronic acid 36 from step A
(89 mg). The mixture was stirred under microwave irradiation
(65 °C, 50 W, Patm) for 20 min, poured into water and extracted
with EtOAc. The assembled organic fractions were dried over
MgSO4, evaporated and the residue was purified by flash chroma-
tography (cyclohexane/EtOAc 99:1) to give 37 (31 mg, 54
lmol,
14. Janssen, C. O.; Lim, S.; Lo, E. P.; Wan, K. F.; Yu, V. C.; Lee, M. A.; Ng, S. B.; Everett,
M. J.; Buss, A. D.; Lane, D. P.; Boyce, R. S. Bioorg. Med. Chem. Lett. 2008, 18, 5771.
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Lett. 2008, 18, 236.
16. Rodriguez, J. M.; Nevola, L.; Ross, N. T.; Lee, G.-I.; Hamilton, A. D. ChemBioChem
2009, 10, 829.
75%) as a white solid.
Mp = 109 °C; IR (ATR): 1609, 1568, 1254 cmꢁ1
;
1H NMR
(400 MHz, CDCl3): 1.46 (6H, d, J = 7.0 Hz), 1.47 (6H, d, J = 7.0 Hz),
1.48 (3H, t, J = 7.0 Hz), 3.70 (1H, hept, J = 7.0 Hz), 3.78 (1H, hept,
J = 7.0 Hz), 4.13 (3H, s), 4.16 (3H, s), 4.66 (2H, q, J = 7.0 Hz), 6.97
(1H, d, J = 9.0 Hz), 7.42 (1H, ddd, J1 = 8.0 Hz, J2 = 7.0 Hz,
J3 = 1.0 Hz), 7.62ꢁ7.68 (2H, m), 7.76 (1H, d, J = 1.5 Hz), 7.81 (1H,
dd, J1 = 8.0 Hz, J2 = 1.0 Hz), 7.90 (1H, d, J = 8.5 Hz), 8.00 (1H, d,
J = 1.5 Hz), 8.03 (1H, d, J = 1.5 Hz), 8.21 (1H, s), 8.34 (1H, d,
J = 9.0 Hz), 8.44 (1H, s); 13C NMR (100 MHz, CDCl3): 14.7, 23.8
(2C), 23.9 (2C), 28.7, 28.8, 53.5, 53.8 (CH3, CH), 62.2 (CH2), 112.7,
122.1, 122.3, 124.3, 125.4, 125.8, 126.9, 127.6, 129.5, 134.2,
134.5, 138.3 (CHarom), 122.5, 122.9, 125.6, 126.1, 126.6, 138.2,
138.6, 144.6, 144.7, 146.1, 146.8, 147.3, 159.6 (2C), 162.3 (Carom);
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The French Ministère de l’Enseignement Supérieur et de la
Recherche is greatly acknowledged for financial support (S.B.). This
work was also supported by grants INSERM and UCB Lyon 1 and
additional supports from the Ligue contre le Cancer (07 and 26)
to N.B.B. The authors are grateful to Bertrand Légeret for mass
spectra analysis.