First synthesis of 3,6′- and 3,7′-biquinoline derivatives

Article abstract of DOI:10.1055/s-2008-1067108

The preparation of new 3,6′- and 3,7′-biquinoline derivatives was achieved by microwave-assisted Suzuki cross-coupling between N-protected 6- or 7-bromoquinolin-2(lH)-ones and quino-lin-3-ylboronic acid. Moreover, a new synthesis of 7-bromoquino-lin-2(lH)-one leading solely to the 7-substituted isomer was carried out. Thieme Stuttgart.

Full text of DOI:10.1055/s-2008-1067108

PAPER
2039
First Synthesis of 3,6¢- and 3,7¢-Biquinoline Derivatives
Synthesis of
3
i
¢
-
and
d
3,7
¢
-Biquin
o
D
erivat
n
ives ie Broch, Fabrice Anizon, Pascale Moreau*
Laboratoire de Synthèse Et Etude de Systèmes d’Intérêt Biologique-UMR CNRS 6504, Université Blaise Pascal,
24 Avenue des Landais, 63177 Aubière Cedex, France
Fax +33(4)73407717; E-mail: Pascale.MOREAU@univ-bpclermont.fr
Received 12 February 2008; revised 4 March 2008
6-Bromoquinolin-2(1H)-one (3) was prepared in three
steps according to procedures already described in the lit-
erature. Iodination of 4-bromoaniline with benzyltrimeth-
ylammonium dichloroiodate in dichloromethane–
Abstract: The preparation of new 3,6¢- and 3,7¢-biquinoline deriv-
atives was achieved by microwave-assisted Suzuki cross-coupling
between N-protected 6- or 7-bromoquinolin-2(1H)-ones and quino-
lin-3-ylboronic acid. Moreover, a new synthesis of 7-bromoquino-
lin-2(1H)-one leading solely to the 7-substituted isomer was carried methanol in the presence of calcium carbonate produced
out.
4-bromo-2-iodoaniline (1), which was reacted with meth-
yl acrylate in the presence of palladium(II) acetate and
tributylamine under microwave irradiation to give methyl
(E)-3-(2-amino-5-bromophenyl)prop-2-enoate (2). The
quinolinone formation to give 3 was achieved by reflux-
ing compound 2 in ethylene glycol (Scheme 2).9–11
Keywords: quinoline, quinolinone, 6-bromoquinolin-2(1H)-one,
7-bromoquinolin-2(1H)-one, Suzuki cross-coupling
In the course of studies on new compounds with biologi-
cal activity, we became interested in the synthesis of 3,6¢-
and 3,7¢-biquinoline derivatives by the coupling of a quin-
oline moiety with a quinolin-2(1H)-one derivative bear-
ing a halogen atom in the 6- or 7-position. However, only
a few examples of functionalization at the 6- and 7-posi-
tions of 6- and 7-haloquinolin-2(1H)-ones have been car-
ried out. The reported methods involved either halogen/
magnesium exchange,1 halogen/lithium exchange,2,3
palladium-catalyzed amino carbonylation,4 palladium-
catalyzed carboxylation,5 copper-catalyzed aromatic nu-
cleophilic substitution,6,7 or Heck cross-coupling.8 To our
knowledge, only one example of the Suzuki cross-cou-
pling has been described with an N-unprotected 6-halo-
quinolin-2(1H)-one derivative and various substituted
phenylboronic acids in the presence of tetrakis(triphe-
nylphosphine)palladium, lithium chloride, and potassium
carbonate.9
While already described synthetic methods allowed the
preparation of the 6-bromoquinolin-2(1H)-one (3), to our
knowledge, no regioselective preparation of the corre-
sponding 7-isomer has been reported. This compound was
previously synthesized in two steps from 3-bromoaniline
as an inseparable regioisomeric mixture of 5- and 7-bro-
moquinolin-2(1H)-ones (Scheme 3).12–17
Therefore, a new synthesis of 7-bromoquinolin-2(1H)-
one was carried out that led only to the 7-substituted iso-
mer. We report here a convenient four-step synthesis of
this heterocyclic compound in 41% overall yield starting
from 4-bromo-2-nitroaniline. Diazotization of 4-bromo-
2-nitroaniline followed by iodination as described by Flatt
et al.18 afforded the corresponding aryl iodide 5. The re-
duction of the nitro group was carried out in the presence
of tin(II) chloride.19 Literature data reported a reduction
yield of 69% using four equivalents of tin(II) chloride.
Under these conditions, we observed the formation of a
deiodinated product. When the reaction was carried out in
the presence of three equivalents of tin(II) chloride, the
starting material was partially recovered. This reaction
Thus, for the preparation of 3,6¢- and 3,7¢-biquinoline de-
rivatives, we decided to follow this latter method by react-
ing 6- or 7-bromoquinolin-2(1H)-one derivatives and
quinolin-3-ylboronic acid under Suzuki cross-coupling
conditions (Scheme 1).
6'
3
7'
N
R
O
B(OH)2
N
6
7
Br
+
N
O
N
R
6- or 7-bromoquinolin-2(1H)-one
quinolin-3-ylboronic acid
6'
7'
3
N
R
O
N
H
O
Scheme 1 Retrosynthetic approach to biquinoline derivatives
SYNTHESIS 2008, No. 13, pp 2039–2044
x
x.
x
x
.
2
0
0
8
Advanced online publication: 21.05.2008
DOI: 10.1055/s-2008-1067108; Art ID: P01808SS
© Georg Thieme Verlag Stuttgart · New York

2040
S. Broch et al.
PAPER
CO2Me
Br
Br
I
Br
CO2Me
(BnNMe3)+(ICl2)–
Pd(OAc)2 , Bu3N
MW, 153 °C
80%
CH2Cl2 / MeOH
81%
NH2
NH2
NH2
1
2
Br
Br
ethylene
glycol
(Boc)2O
N
H
N
O
NaH, THF
77%
74%
O
Boc
3
4
Scheme 2 Synthesis of 6-bromoquinolin-2(1H)-one derivatives
R1
R2
R1CH=CHCOCl
AlCl3 or H2SO4
R
1 = OEt or Ph
R3
N
Br
NH2
Br
N
H
O
O
H
R2 = H, R3 = Br and R2 = Br, R3 = H
Scheme 3 Preparation of 5- and 7-bromoquinolin-2(1H)-ones as a regioisomeric mixture
was optimized by using 3.5 equivalents of tin(II) chloride The coupling reaction was first unsuccessfully conducted
to obtain 6 in 90% yield. The quinolinone formation was on the unprotected 6-bromoquinolin-2(1H)-one (3) in the
achieved in two steps following the procedure described presence of tetrakis(triphenylphosphine)palladium, sodi-
before for the synthesis of the 6-bromo analogue. Com- um carbonate, and lithium chloride as previously de-
pound 6 was treated with methyl acrylate in the presence scribed for an N-unprotected 6-bromoquinolin-2(1H)-one
of palladium acetate and tributylamine under microwave derivative with phenylboronic acids.9 Despite several
irradiation to give 7 in 80% yield as well as the disubsti- trials using different catalytic conditions [Pd(OAc)2/
tuted analogue 8 in 9% yield. The cyclization to 9 was per- NaOMe or PdCl2(PPh3)2/Na2CO3] the coupling product
formed in 73% yield by refluxing 7 in ethylene glycol was not obtained using unprotected 6-bromoquinolin-
(Scheme 4).
2(1H)-one (3). Subsequently, the Suzuki coupling was
performed using 6-bromo-1-(tert-butoxycarbonyl)quino-
lin-2(1H)-one (4), which was prepared by treatment of 3
with di-tert-butyl dicarbonate in the presence of sodium
hydride in tetrahydrofuran (Scheme 2).
For the preparation of biquinoline derivatives, coupling
between quinolin-2(1H)-ones and quinolin-3-ylboronic
acid subunits was achieved by Suzuki cross-coupling
(Scheme 5). Quinolin-3-ylboronic acid was prepared as
previously described from 3-bromoquinoline.20
i) BF3·Et2O, t-BuONO
THF
NH2
NO2
I
I
SnCl2, HCl (37%)
ii) KI, I2, MeCN
78%
EtOH
90%
Br
Br
NO2
Br
NH2
5
6
CO2Me
ethylene glycol
73%
Br
NH2
Br
N
O
CO2Me
H
7 80%
9
+
Pd(OAc)2, Bu3N
CO2Me
DMF, MW, 153 °C
Boc2O, NaH
THF
84%
MeO2C
NH2
8 9%
Br
N
O
Boc
10
Scheme 4 Preparation of 7-bromoquinolin-2(1H)-one
Synthesis 2008, No. 13, 2039–2044 © Thieme Stuttgart · New York

PAPER
Synthesis of 3,6¢- and 3,7¢-Biquinoline Derivatives
2041
6
7
Br
N
O
Boc
4 R = 6-Br
10 R = 7-Br
PdCl2(PPh3)2
B(OH)2
2 M aq Na2CO3
THF, MW, 64 °C
N
6'
7'
N
N
Boc
O
MCPBA, CH2Cl2
TFA, CH2Cl2
11 6'-substituted, 47%
12 7'-substituted, 63%
6'
6'
7'
7'
N
N
O
N
N
O
Boc
O
H
15 6'-substituted, 80%
16 7'-substituted, 79%
13 6'-substituted, 94%
14 7'-substituted, 99%
TsCl
10% aq K2CO3
CH2Cl2
TFA, CH2Cl2
6'
7'
6'
7'
HN
HN
N
O
N
O
Boc
H
O
O
17 6'-substituted, 90%
18 7'-substituted, 71%
19 6'-substituted, 86%
20 7'-substituted, 83%
Scheme 5 Preparation of 3,6¢- and 3,7¢-biquinoline derivatives
Different catalytic systems were tested either in the pres- 16 with tosyl chloride in the presence of potassium car-
ence of Pd(OAc)2/Na2CO3 or PdCl2(PPh3)2/Na2CO3. The bonate led to the biquinolinone derivatives 17 and 18 in
best result was obtained with PdCl2(PPh3)2/Na2CO3 under 90% and 71% yields, respectively. The final deprotection
microwave irradiation. When the reaction was performed step using trifluoroacetic acid in dichloromethane gave
between 4 and quinolin-3-ylboronic acid in refluxing tet- 3,6¢-biquinoline-2,2¢(1H,1¢H)-dione (19) and 3,7¢-biquin-
rahydrofuran using PdCl2(PPh3)2/Na2CO3, the product 11 oline-2,2¢(1H,1¢H)-dione (20) in 86% and 83% yields,
was obtained in 34% yield after four hours, while product respectively (Scheme 5).
11 was obtained in 47% yield when the reaction was con-
ducted for ten minutes under microwave irradiation. The
same procedure applied to 7-bromo analogue 10, which
was obtained in 84% yield by treating 9 with di-tert-butyl
dicarbonate in the presence of sodium hydride in tetrahy-
drofuran (Scheme 4), afforded compound 12 in 63%
yield. In this case, the use of microwave irradiation result-
ed in considerably shortened reaction times (Scheme 5).
In conclusion, the first synthesis of pure 7-bromoquinolin-
2(1H)-one (9) has been described. The preparation of new
3,6¢- and 3,7¢-biquinoline derivatives was achieved by
microwave-assisted Suzuki cross-coupling between N-
protected 6- or 7- bromoquinolin-2(1H)-ones and quino-
lin-3-ylboronic acid. Moreover, this is, to our knowledge,
the first time that a substitution of 7-haloquinolin-2(1H)-
one derivative using a Suzuki cross-coupling reaction has
Deprotection of compounds 11 and 12 with trifluoroacetic been reported.
acid in dichloromethane gave the corresponding depro-
tected products 13 and 14 in 94% and 99% yields, respec-
tively.
IR Spectra were recorded on a Perkin-Elmer Paragon 500 spectro-
photometer. NMR spectra were performed on a Bruker AVANCE
400 (1H: 400 MHz, 13C: 100 MHz). Mass spectra (ESI+) were de-
termined on a high resolution Waters Micro Q-Toff apparatus.
Chromatographic purifications were performed on flash silica gel
Geduran SI 60 (Merck) 0.040–0.063 mm column chromatography.
TLC were performed on fluorescent silica gel plates (60 F254 from
Merck). Experiments under microwave irradiation were performed
The biquinolinone derivatives 17 and 18 were obtained
using a classical two-step oxidation procedure to convert
the quinoline moiety into the corresponding quinolinone
ring. Compounds 11 and 12 were firstly reacted with 3-
chloroperoxybenzoic acid in dichloromethane to give the
corresponding N-oxide derivatives 15 and 16 in 80% and using a CEM Discover Benchmate microwave apparatus.
79% yields, respectively. Treatment of compounds 15 and
Synthesis 2008, No. 13, 2039–2044 © Thieme Stuttgart · New York

2042
S. Broch et al.
PAPER
6-Bromo-1-(tert-butoxycarbonyl)quinolin-2(1H)-one (4);
Typical Procedure
7-Bromoquinolin-2(1H)-one (9)
A soln of 7 (4.58 g, 17.9 mmol) in ethylene glycol (60 mL) was re-
fluxed for 15 h. After cooling, the mixture was poured into H2O
(200 mL) and the solid was filtered and washed with Et2O and
CH2Cl2 to give 9 (2.94 g, 73%) as a brown solid; mp 270–272 °C.
Compound 3 (1.50 g, 6.69 mmol) was added to a suspension of NaH
(60% in a mineral oil, 1.07 g, 26.8 mmol) in anhyd THF (20 mL).
The mixture was stirred at 50 °C for 1 h. After cooling, a soln of
(Boc)2O (5.84 g, 26.8 mmol) in anhyd THF (10 mL) was added and
the mixture was stirred at 50 °C for 2 h. After cooling, the mixture
was poured into sat. aq NH4Cl (150 mL) and extracted with EtOAc.
The organic fractions were dried (MgSO4) and evaporated. The res-
idue was purified by flash chromatography (cyclohexane–EtOAc,
9:1) to give 4 (1.67 g, 77%) as a white solid; mp 98–99 °C.
IR (KBr): 3100–2800, 1698 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 6.52 (d, J = 9.5 Hz, 1 H), 7.33
(dd, J1 = 8.5 Hz, J2 = 2.0 Hz, 1 H), 7.47 (d, J = 1.5 Hz, 1 H), 7.61
(d, J = 8.5 Hz, 1 H), 7.89 (d, J = 9.5 Hz, 1 H), 11.74–11.86 (br s, 1
H, NH).
13C NMR (100 MHz, DMSO-d6): d = 117.3, 122.4, 124.6, 129.8,
139.7 (CH), 118.1, 123.4, 139.9 (Carom), 161.6 (C=O).
IR (KBr): 1747, 1592, 1488, 1374, 1280, 1254, 1213, 1145 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.52 (s, 9 H, CH3), 7.48 (d,
J = 8.5 Hz, 1 H), 7.87 (d, J = 9.0 Hz, 1 H), 7.92 (dd, J1 = 9.0 Hz,
J2 = 2.0 Hz, 1 H), 8.36 (d, J = 2.0 Hz, 1 H), 8.52 (d, J = 8.5 Hz, 1 H).
HRMS (ES+): m/z [M + H]+ for C9H779BrNO: 223.9711; found:
223.9711.
13C NMR (100 MHz, DMSO-d6): d = 27.2 (3 CH3), 116.6, 130.0 (2
C), 133.5, 140.1 (CH), 84.2, 119.5, 128.1, 144.4 (C), 150.2, 156.2
(C=O).
HRMS (ES+): m/z [M + H – CO2 – C4H8]+ calcd for C9H779BrNO:
223.9711; found: 223.9601.
7-Bromo-1-(tert-butoxycarbonyl)quinolin-2(1H)-one (10)
Following the typical procedure for 4 and using 9 (2.10 g, 9.4
mmol), NaH (60% in a mineral oil, 750 mg, 18.8 mmol) in anhyd
THF (30 mL) and (Boc)2O (4.10 g, 18.8 mmol) in anhyd THF (20
mL) with purification by flash chromatography (cyclohexane–
EtOAc, 8:2) gave 10 (2.56 g, 84%) as a white solid; mp 95–96 °C.
Methyl (2E)-3-(2-Amino-4-bromophenyl)prop-2-enoate (7) and
Dimethyl (2E,2¢E)-3,3¢-(2-Aminobenzene-1,4-diyl)bisprop-2-
enoate (8)
IR (KBr): 1766, 1610, 1489, 1261, 1215, 1144, 1118 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.52 (s, 9 H, CH3), 7.47 (d,
J = 8.5 Hz, 1 H), 7.80 (dd, J1 = 8.5 Hz, J2 = 2.0 Hz, 1 H), 8.03 (d,
J = 8.5 Hz, 1 H), 8.16 (d, J = 2.0 Hz, 1 H), 8.57 (d, J = 8.5 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 27.2 (3 CH3), 116.1, 129.8,
129.9 (2 C), 141.1 (CH), 84.3, 123.9, 125.7, 146.4 (C), 150.2, 156.7
(C=O).
To a soln of compound 6 (4.44 g, 14.9 mmol) in anhyd DMF (30
mL) were added methyl acrylate (1.41 mL, 1.35 g, 15.6 mmol),
Bu3N (3.55 mL, 2.76 g, 14.9 mmol) and Pd(OAc)2 (33.5 mg, 0.149
mmol). The mixture was stirred under microwave irradiation (153
°C, 50 W, Patm) for 5 min then poured into H2O (300 mL) and ex-
tracted with EtOAc. The organic fractions were dried (MgSO4) and
evaporated. The residue was purified by flash chromatography (cy-
clohexane–EtOAc, 8:2) to give 7 (3.07 g, 80%) and 8 (364 mg, 9%)
as yellow solids.
HRMS (ES+): m/z [M + Na]+ for C14H1479BrNNaO3: 346.0055;
found: 346.0058.
1¢-(tert-Butoxycarbonyl)-3,6¢-biquinolin-2¢(1¢H)-one (11);
Typical Procedure
Methyl (2E)-3-(2-Amino-4-bromophenyl)prop-2-enoate (7)
Mp 112–114 °C.
IR (KBr): 3700–3000, 1713, 1649, 1621 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.70 (s, 3 H, CH3), 5.87–5.96
(br s, 2 H, NH2), 6.40 (d, J = 15.5 Hz 1 H), 6.66 (dd, J1 = 8.5 Hz,
J2 = 2.0 Hz, 1 H), 6.90 (d, J = 2.0 Hz, 1 H), 7.40 (d, J = 8.5 Hz, 1
H), 7.80 (d, J = 15.5 Hz, 1 H).
13C NMR (400 MHz, DMSO-d6): d = 51.3 (CH3), 115.8, 118.1,
118.8, 129.1, 139.6 (CH), 116.6, 124.5, 149.6 (Carom), 166.9 (C=O).
To a soln of 4 (200 mg, 0.62 mmol) in THF (7 mL) were added
PdCl2(PPh3)2 (21.7 mg, 0.031 mmol), aq 2 M Na2CO3 (1.54 mL,
3.08 mmol) and quinolin-3-ylboronic acid (160 mg, 0.92 mmol).
The mixture was stirred under microwave irradiation (64 °C, 50 W,
Patm) for 10 min then poured into H2O (20 mL) and extracted with
EtOAc. The organic fractions were dried (MgSO4) and evaporated.
The residue was purified by flash chromatography (cyclohexane–
EtOAc, 8:2 then 6:4) to give 11 (109 mg, 47%) as a white solid; mp
143–144 °C.
IR (KBr): 1758, 1213, 1145 cm–1.
HRMS (ES+): m/z [M + H]+ for C10H1179BrNO2; 255.9973; found:
255.9981.
1H NMR (400 MHz, DMSO-d6): d = 1.54 (s, 9 H, CH3), 7.49 (d,
J = 8.5 Hz, 1 H), 7.68 (ddd, J1 = 8.0 Hz, J2 = 7.0 Hz, J3 = 1.0 Hz, 1
H), 7.81 (ddd, J1 = 8.0 Hz, J2 = 7.0 Hz, J3 = 1.0 Hz, 1 H), 8.07–8.12
(m, 3 H), 8.35 (dd, J1 = 9.0 Hz, J2 = 2.0 Hz, 1 H), 8.60–8.65 (m, 2
H), 8.83 (d, J = 2.0 Hz, 1 H), 9.42 (d, J = 2.0 Hz, 1 H).
Dimethyl (2E,2¢E)-3,3¢-(2-Aminobenzene-1,4-diyl)bisprop-2-
enoate (8)
Mp 148–149 °C.
13C NMR (100 MHz, DMSO-d6): d = 27.2 (3 CH3), 116.2, 126.1,
127.2, 128.5, 128.7, 128.8, 129.6, 129.9, 133.5, 141.2, 149.5 (CH),
84.1, 127.2, 127.6, 131.8, 135.1, 145.4, 147.0 (C), 150.4, 156.2
(C=O).
HRMS (ES+): m/z [M + H]+ for C23H21N2O3: 373.1552; found:
373.1561.
IR (KBr): 3750–3000, 1700, 1635 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 3.71 (s, 3 H, CH3), 3.72 (s, 3
H, CH3), 5.72–5.78 (br s, 2 H, NH2), 6.45 (d, J = 16.0 Hz, 1 H), 6.48
(d, J = 16.0 Hz, 1 H), 6.91 (dd, J1 = 8.0 Hz, J2 = 1.5 Hz, 1 H), 6.94
(d, J = 1.5 Hz, 1 H), 7.47 (d, J = 16.0 Hz, 1 H), 7.52 (d, J = 8.0 Hz,
1 H), 7.87 (d, J = 16.0 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 51.2, 51.5 (CH3), 116.0,
116.1, 116.2, 118.0, 127.9, 139.8, 144.3 (CH), 119.5, 136.4, 148.4
(Carom), 166.5, 166.9 (C=O).
HRMS (ES+): m/z [M + H]+ for C14H16NO4: 262.1079; found:
262.1092.
1¢-(tert-Butoxycarbonyl)-3,7¢-biquinolin-2¢(1¢H)-one (12)
Following the typical procedure for 11 using 10 (100 mg, 0.308
mmol) in THF (5 mL), PdCl2(PPh3)2 (10.8 mg, 0.015 mmol), aq 2
M Na2CO3 (0.77 mL, 1.54 mmol), and quinolin-3-ylboronic acid
(80.0 mg, 0.46 mmol) with microwave irradiation (64 °C, 50 W,
Patm) for 5 min. Work up used H2O (10 mL) and purification was by
flash chromatography (cyclohexane–EtOAc, 8:2 then 7:3) to give
12 (72.6 mg, 63%) as a white solid; mp 145–146 °C.
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Synthesis of 3,6¢- and 3,7¢-Biquinoline Derivatives
2043
IR (KBr): 1763, 1652, 1219, 1143 cm–1.
H), 8.60 (d, J = 8.5 Hz, 1 H), 8.62 (d, J = 2.0 Hz, 1 H), 9.18 (d,
J = 1.5 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 27.2 (3 CH3), 116.3, 118.8,
122.9, 126.5, 128.7, 129.1, 129.3 (2 C), 130.5, 134.0, 141.3 (CH),
84.2, 127.1, 130.1, 133.1, 133.3, 139.9, 145.7 (C), 150.3, 156.4
(C=O).
1H NMR (400 MHz, DMSO-d6): d = 1.54 (s, 9 H, CH3), 7.45 (d,
J = 8.5 Hz, 1 H), 7.68 (ddd, J1 = 8.0 Hz, J2 = 7.0 Hz, J3 = 1.0 Hz, 1
H), 7.82 (ddd, J1 = 8.5 Hz, J2 = 7.0 Hz, J3 = 1.5 Hz, 1 H), 8.07–8.13
(m, 2 H), 8.20 (dd, J1 = 8.5 Hz, J2 = 1.5 Hz, 1 H), 8.24 (d, J = 8.5
Hz, 1 H), 8.45–8.46 (m, 1 H), 8.61 (d, J = 8.5 Hz, 1 H), 8.89 (d,
J = 2.0 Hz, 1 H), 9.45 (d, J = 2.5 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 27.2 (3 CH3), 115.8, 125.8 (2
C), 127.1, 128.6 (2 C), 128.9, 129.9, 133.9, 140.7, 149.5 (CH), 84.0,
126.4, 127.6, 131.7, 139.0, 146.1, 147.1 (C), 150.4, 156.4 (C=O).
HRMS (ES+): m/z [M + H]+ for C23H21N2O4: 389.1501; found:
389.1503.
1¢-(tert-Butoxycarbonyl)-1-oxido-3,7¢-biquinolin-2¢(1¢H)-one
(16)
HRMS (ES+): m/z [M + H]+ for C23H21N2O3: 373.1552; found:
373.1571.
Following the typical procedure for 15 using 12 (200 mg, 0.537
mmol) in CH2Cl2 (3 mL) and MCPBA (70–75%, 185 mg) in CH2Cl2
(5 mL); the mixture was stirred at r.t. for 24 h. Purification of the
residue obtained after evaporation was carried out by washing with
Et2O, without chromatography, to give 16 (164 mg, 79%) as a beige
solid; mp 180–182 °C.
3,6¢-Biquinolin-2¢(1¢H)-one (13); Typical Procedure
To a soln of 11 (191 mg, 0.51 mmol) in anhyd CH2Cl2 (5 mL) was
added TFA (0.38 mL, 583 mg, 5.12 mmol). The mixture was stirred
at r.t. for 2 h then basified with sat. aq NaHCO3. The solid was fil-
tered and thoroughly washed with H2O then with Et2O to give 13
(131 mg, 94%) as a white solid; mp 225 °C.
IR (KBr): 1761, 1585, 1370, 1255, 1212, 1141 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.54 (s, 9 H, CH3), 7.47 (d,
J = 8.5 Hz, 1 H), 7.80 (ddd, J1 = 8.0 Hz, J2 = 7.0 Hz, J3 = 1.0 Hz, 1
H), 7.86 (ddd, J1 = 8.5 Hz, J2 = 7.0 Hz, J3 = 1.5 Hz, 1 H), 8.17 (dd,
J1 = 8.5 Hz, J2 = 1.5 Hz, 1 H), 8.19 (d, J = 8.0 Hz, 1 H), 8.22 (d,
J = 8.5 Hz, 1 H), 8.45 (s, 1 H), 8.54 (s, 1 H), 8.57 (d, J = 8.5 Hz, 1
H), 8.61 (d, J = 8.5 Hz, 1 H), 9.20 (d, J = 1.5 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 27.2 (3 CH3), 116.2, 118.8,
123.4, 125.6, 126.1, 128.9, 129.2, 129.3, 130.7, 134.1, 140.7 (CH),
84.1, 126.8, 130.0, 133.1, 137.3, 140.0, 146.0 (C), 150.4, 156.5
(C=O).
IR (KBr): 3625–3000, 1675, 1565, 1430 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 6.58 (d, J = 9.5 Hz, 1 H), 7.47
(d, J = 8.5 Hz, 1 H), 7.65 (t, J = 7.5 Hz, 1 H), 7.77 (t, J = 7.5 Hz, 1
H), 8.01 (d, J = 9.5 Hz, 1 H), 8.03–8.08 (m, 3 H), 8.24 (s, 1 H), 8.67
(s, 1 H), 9.30 (d, J = 2.0 Hz, 1 H), 11.69–12.21 (br s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 116.1, 122.6, 126.3, 127.1,
128.3, 128.7, 129.2, 129.4, 132.3, 140.3, 149.3 (CH), 119.7, 127.7,
130.4, 132.0, 138.8, 146.7 (Carom), 161.9 (C=O).
HRMS (ES+): m/z [M + H]+ for C18H13N2O: 273.1028; found:
273.1029.
HRMS (ES+): m/z [M + H]+ for C23H21N2O4: 389.1501; found:
389.1508.
3,7¢-Biquinolin-2¢(1¢H)-one (14)
1¢-(tert-Butoxycarbonyl)-3,6¢-biquinoline-2,2¢(1H,1¢H)-dione
(17)
Following the typical procedure for 13 using 12 (600 mg, 1.61
mmol) in anhyd CH2Cl2 (20 mL) and TFA (0.60 mL, 921 mg, 8.1
mmol) gave 14 (437 mg, 99%) as a pale yellow solid; mp 241 °C.
To a soln of 15 (300 mg, 0.77 mmol) in CH2Cl2 (8 mL) were added
10% w/v aq K2CO3 (6 mL) and TsCl (177 mg, 0.93 mmol). The
mixture was stirred at r.t. for 4 h. After decantation, the aqueous lay-
er was extracted with EtOAc. The organic fractions were dried
(MgSO4) and evaporated. The residue was washed with CH2Cl2 to
give 17 (270 mg, 90%) as a white solid; mp 284 °C.
IR (KBr): 3388, 1678 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 6.56 (d, J = 9.5 Hz, 1 H), 7.68–
7.73 (m, 3 H), 7.83 (ddd, J1 = 8.5 Hz, J2 = 7.0 Hz, J3 = 1.5 Hz, 1 H),
7.85 (d, J = 8.0 Hz, 1 H), 7.99 (d, J = 9.5 Hz, 1 H), 8.10 (d, J = 8.5
Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 8.72 (d, J = 2.0 Hz, 1 H), 9.25
(d, J = 2.5 Hz, 1 H), 11.87 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 113.4, 121.0, 122.4, 127.4,
128.3, 128.6, 128.8, 130.2, 133.9, 139.9, 149.0 (CH), 118.9, 127.6,
132.2, 138.8, 139.5, 146.5 (Carom), 162.0 (C=O).
IR (KBr): 3650–3175, 1752, 1144 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.54 (s, 9 H, CH3), 7.23 (ddd,
J1 = 8.0 Hz, J2 = 7.0 Hz, J3 = 1.0 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 1 H),
7.43 (d, J = 8.5 Hz, 1 H), 7.54 (ddd, J1 = 8.5 Hz, J2 = 7.0 Hz,
J3 = 1.5 Hz, 1 H), 7.78 (dd, J1 = 8.0 Hz, J2 = 1.0 Hz, 1 H), 7.97 (d,
J = 9.0 Hz, 1 H), 8.21 (dd, J1 = 9.0 Hz, J2 = 2.0 Hz, 1 H), 8.32 (s, 1
H), 8.50 (d, J = 2.0 Hz, 1 H), 8.59 (d, J = 8.5 Hz, 1 H), 11.99–12.17
(br s, 1 H, NH).
HRMS (ES+): m/z [M + H]+ for C18H13N2O: 273.1028; found:
273.1039.
13C NMR (100 MHz, DMSO-d6): d = 27.2 (3 CH3), 114.8, 115.7,
122.1, 127.2, 127.6, 128.3, 130.5, 131.4, 138.6, 141.1 (CH), 84.0,
119.5, 126.6, 130.4, 134.6, 138.6, 145.2 (C), 150.4, 156.1, 161.0
(C=O).
HRMS (ES+): m/z [M + H – CO2 – C4H8]+ for C18H13N2O2:
289.0977; found: 289.0984.
1¢-(tert-Butoxycarbonyl)-1-oxido-3,6¢-biquinolin-2¢(1¢H)-one
(15); Typical Procedure
A soln of 11 (600 mg, 1.61 mmol) in CH2Cl2 (5 mL) was added
dropwise to a soln of MCPBA (70–75%, 411 mg) in CH2Cl2 (10
mL) cooled to 0 °C. The mixture was stirred at r.t. for 62 h then bas-
ified with sat. aq K2CO3. The aqueous layer was extracted with
CH2Cl2. The organic fractions were dried (MgSO4) and evaporated.
The residue was purified by flash chromatography (EtOAc–MeOH,
98:2) to give 15 (500 mg, 80%) as a yellow solid; mp 168–170 °C.
1¢-(tert-Butoxycarbonyl)-3,7¢-biquinoline-2,2¢(1H,1¢H)-dione
(18)
To a soln of 16 (200 mg, 0.515 mmol) in CH2Cl2 (5 mL) were added
10% w/v aq K2CO3 (4 mL) and TsCl (118 mg, 0.62 mmol). The
mixture was stirred at r.t. for 3 h. The solid was washed with Et2O
to give 18 (142 mg, 71%) as a white solid; mp 280 °C.
IR (KBr): 3650–3000, 1763, 1660, 1567, 1430, 1213, 1152 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.53 (s, 9 H, CH3), 7.23 (t,
J = 7.5 Hz, 1 H), 7.37–7.44 (m, 2 H), 7.54 (t, J = 7.5 Hz, 1 H), 7.79
IR (KBr): 1750, 1574, 1372, 1288, 1218, 1150 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.54 (s, 9 H, CH3), 7.49 (d,
J = 8.5 Hz, 1 H), 7.79 (ddd, J1 = 8.0 Hz, J2 = 7.0 Hz, J3 = 1.0 Hz, 1
H), 7.85 (ddd, J1 = 8.5 Hz, J2 = 7.0 Hz, J3 = 1.5 Hz, 1 H), 8.06 (d,
J = 9.0 Hz, 1 H), 8.17 (dd, J1 = 8.0 Hz, J2 = 1.0 Hz, 1 H), 8.32 (dd,
J1 = 9.0 Hz, J2 = 2.0 Hz, 1 H), 8.46 (s, 1 H), 8.56 (d, J = 8.5 Hz, 1
Synthesis 2008, No. 13, 2039–2044 © Thieme Stuttgart · New York

2044
S. Broch et al.
PAPER
Rosenberg, S. H.; Sham, H. L. Bioorg. Med. Chem. Lett.
(d, J = 7.5 Hz, 1 H), 8.05 (d, J = 8.5 Hz, 1 H), 8.09 (d, J = 8.5 Hz, 1
H), 8.38 (s, 1 H), 8.39 (s, 1 H), 8.55 (d, J = 8.5 Hz, 1 H), 12.00–
12.40 (br s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 27.3 (3 CH3), 114.8, 115.5,
122.0, 127.2, 127.4 (2 C), 128.4, 130.7, 139.0, 140.5 (CH), 84.0,
119.5, 126.3, 130.3, 138.4, 138.7, 145.6, 150.5 (C), 156.1, 161.0
(C=O).
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HRMS (ES+): m/z [M + H – CO2 – C4H8]+ for C18H13N2O2:
289.0977; found: 289.0992.
3,6¢-Biquinoline-2,2¢(1H,1¢H)-dione (19)
Following the typical procedure for 13 using 17 (253 mg, 0.65
mmol) in anhyd CH2Cl2 (10 mL) and TFA (0.10 mL, 154 mg, 1.35
mmol) with stirring at r.t. for 2 h gave 19 (161 mg, 86%) as a beige
solid; mp 291 °C.
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2215.
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1H NMR (400 MHz, DMSO-d6): d = 6.52 (d, J = 9.5 Hz, 1 H), 7.20
(ddd, J1 = 8.0 Hz, J2 = 7.0 Hz, J3 = 1.0 Hz, 1 H), 7.33–7.37 (m, 2 H),
7.50 (ddd, J1 = 8.5 Hz, J2 = 7.0 Hz, J3 = 1.0 Hz, 1 H), 7.73 (dd,
J1 = 8.0 Hz, J2 = 1.0 Hz, 1 H), 7.92 (dd, J1 = 8.5 Hz, J2 = 2.0 Hz, 1
H), 7.96 (d, J = 9.5 Hz, 1 H), 8.12 (d, J = 2.0 Hz, 1 H), 8.15 (s, 1 H),
11.50–12.30 (br s, 2 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 114.7 (2 C), 121.9, 122.0,
127.9, 128.0, 130.1, 130.9, 137.2, 140.4 (CH), 118.7, 119.6, 129.7,
130.6, 138.3, 138.5 (C), 161.1, 162.0 (C=O).
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HRMS (ES+): m/z [M + H]+ for C18H13N2O2: 289.0977; found:
289.0993.
3,7¢-Biquinoline-2,2¢(1H,1¢H)-dione (20)
Following the typical procedure for 13 using 18 (90 mg, 0.232
mmol) in anhyd CH2Cl2 (4 mL) and TFA (86 mL, 132 mg, 1.16
mmol) with stirring at r.t. for 3 h gave 20 (55.3 mg, 83%) as a pale
yellow solid; mp 289 °C.
IR (KBr): 3650–3200, 1662 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 6.51 (d, J = 9.5 Hz, 1 H), 7.22
(t, J = 7.5 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 1 H), 7.48–7.57 (m, 2 H),
7.71 (d, J = 8.0 Hz, 1 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.80 (s, 1 H),
7.93 (d, J = 9.5 Hz, 1 H), 8.18 (s, 1 H), 11.76 (s, 1 H, NH), 12.03 (s,
1 H, NH).
Due to the insolubility of compound 20, 13C NMR spectra could not
be recorded.
HRMS (ES+): m/z [M + H]+ for C18H13N2O2: 289.0977; found:
289.0995.
Acknowledgment
The French Ministère de l’Enseignement Supérieur et de la
Recherche is greatly acknowledged for financial support (SB). The
authors are grateful to Bertrand Légeret for mass spectra analysis.
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References
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Synthesis 2008, No. 13, 2039–2044 © Thieme Stuttgart · New York