Synthesis of 5-Aryl- and 5-Heteroaryl-7-carboxyl-8-hydroxyquinaldines through Suzuki cross-coupling reaction with potassium organotrifluoroborates

Article abstract of DOI:10.1055/s-0029-1218585

A series of 5-aryl- and 5-heteroaryl-7-carboxyl-8-hydroxyquinaldines were prepared from 5-bromo-7-methoxycarbonyl-8-benzyloxyquinaldine based on the Suzuki cross-coupling reaction using potassium organotrifluoroborates. An efficient method of deprotection of the 8-hydroxy group using a microwave-assisted hydrogen transfer reaction is reported. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0029-1218585

PAPER
619
Synthesis of 5-Aryl- and 5-Heteroaryl-7-carboxyl-8-hydroxyquinaldines
through Suzuki Cross-Coupling Reaction with Potassium
Organotrifluoroborates
5
-Aryl- and 5-
a
H
eteroaryl-
t
7-carbo
e
xyl-8-hydr
n
oxyquinaldines Sliman, Didier Desmaële*
Université Paris-Sud, Faculté de Pharmacie, UMR CNRS 8076, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France
Fax +33(1)46835752; E-mail: didier.desmaele@u-psud.fr
Received 5 August 2009; revised 28 October 2009
tivity.5 Owing to the availability of a large array of
boronic acid derivatives we chose to explore the Suzuki
cross-coupling reaction6 to access the 5-substituted
quinaldines 3, which could be further elaborated into the
Abstract: A series of 5-aryl- and 5-heteroaryl-7-carboxyl-8-hy-
droxyquinaldines were prepared from 5-bromo-7-methoxycarbon-
yl-8-benzyloxyquinaldine based on the Suzuki cross-coupling
reaction using potassium organotrifluoroborates. An efficient meth-
od of deprotection of the 8-hydroxy group using a microwave- corresponding 2-styrylquinoline 2 through Perkin-type
condensation with aromatic aldehydes (Scheme 1).4a Al-
assisted hydrogen transfer reaction is reported.
though several reports emphasized the efficiency of the
Suzuki reaction to obtain 5-aryl-8-alkoxyquinolines,7
none of these substrates displayed a carboxyl or an alk-
oxycarbonyl group. Suspecting that the need of a strong
base in the Suzuki–Miyaura coupling reaction (such as
aqueous K2CO3) precluded the presence of a hydrolytical-
ly unstable ester, we first chose to explore the regioselec-
tive Suzuki cross-coupling of 5,7-dibromoquinaldines.
Key words: quinolines, cross-coupling, boron, palladium, aryla-
tions
The 8-hydroxyquinoline framework is a well-known scaf-
fold, which has been decorated with substituents in con-
nection with a variety of applications such as fluorescent
sensors,1 metal chelates,2 or enzymatic inhibitors.3 For ex-
ample, we have reported that polyhydroxylated
styrylquinolines (SQLs), exemplified by 1, are potent
HIV-1 integrase inhibitors in in vitro experiments, block
the replication of HIV-1 in cell culture, and are devoid of
cytotoxicity. Within the framework of SQLs, structure–
activity relationship studies have clearly identified the sal-
icylic acid moiety at C-7 and C-8 of the quinoline ring, as
critical pharmacophore elements for antiviral activity.4 In
connection with a systematic modulation of the 7-carbox-
yl-8-hydroxystyrylquinoline scaffold we decided to intro-
duce an additional aromatic or heteroaromatic nucleus at
the C-5 position, since previous modulation of this posi-
tion led to substantial improvement of the biological ac-
Thus condensation of 5,7-dibromo-8-methoxyquinaldine
(5) with phenylboronic acid under standard Suzuki reac-
tion conditions afforded the 5-phenylquinaldine 6 in 80%
yield along 10% of the 5,7-diphenyl derivative 78
(Scheme 2). Although quite useful, this approach was
abandoned since we were unable to achieve efficiently the
introduction of the required carboxyl group at C-7 by lith-
ium–bromine exchange reaction. We therefore studied the
Suzuki cross-coupling reaction with the fully protected
bromo ester 11. The latter was obtained from hydroxy
acid 89 in 82% overall yield by selective methylation of
the carboxyl group using MeI/KHCO3,10 C-5 bromination
with NBS in DMF at 0 °C, and benzylation of the phenolic
R1
5
7
OH
OH
HO2C
N
8
HO2C
N
OH
OH
OH
OH
2
1
R1
Br
Suzuki cross-
coupling and
deprotection
Perkin
condensation
R2O2C
N
HO2C
N
2
OR3
OH
R1 = aryl, heteroaryl
R2, R3 = protecting groups
4
3
Scheme 1 Retrosynthetic analysis of styrylquinolines 2
SYNTHESIS 2010, No. 4, pp 0619–0630
x
x
.
x
x
.2
0
1
0
Advanced online publication: 07.12.2009
DOI: 10.1055/s-0029-1218585; Art ID: T15509SS
© Georg Thieme Verlag Stuttgart · New York

620
F. Sliman, D. Desmaële
PAPER
hydroxy group. Our initial attempts to couple 10 or 11 equally effective. Interestingly, other bidendate phos-
with phenylboronic acid using conventional Suzuki reac- phines such as dppe and dppp were totally unproductive.
tion conditions met with failure probably due to concom- The reaction was carried out in the presence of 7 mol% of
itant hydrolysis of the ester group inducing deactivation of catalyst in combination with Hünig’s base in methanol.
the palladium catalyst and/or decarboxylation.11 This dis- Attempts to reduce the amount of palladium catalyst gave
appointing results could not be improved despite many at- remaining starting material despite increasing reaction
tempts to vary the protecting groups and the reaction time. The influence of the base was also briefly examined.
conditions. After considerable experiments, we found that Although some product was obtained in the absence of
the desired aryl–aryl cross coupling could be achieved base (entry 11) the yield was dramatically reduced.
through the trifluoroborate modification of the Suzuki re-
Furthermore, a mineral base such as Cs2CO3 (entry 10)
action. The use of aryl trifluoroborates in Suzuki-type re-
appeared to be less effective than tertiary amines. As de-
actions was first reported by Genet’s group using
picted in Table 2, a large array of aryl and heteroaryl tri-
fluoroborates reacted with 11 to give the expected
coupling products in moderate to good yields when these
simple conditions were applied. Electron-rich and elec-
aryldiazonium salts.12 Subsequently, the reaction of aryl
trifluoroborates with aryl halides as coupling partners was
developed by Molander et al.13 Organotrifluoroborates
proved to be more reactive than the corresponding boronic
tron-poor aryl trifluoroborates are equally efficient. In few
acids, but most importantly their coupling can be carried
cases (entries 2, 12, and 16) a small amount of dehaloge-
out in the presence of a tertiary amine as base in a non-
nation products (13, R1 = H) was formed together with the
desired cross-coupling product. As previously reported,
aqueous solvent. Thus, condensation of 11 with potassium
phenyltrifluoroborate using palladium acetate and triphe-
no clear structural factors favoring the reduction process
nylphosphine as catalyst and N,N-diisopropylethylamine
could be defined.15 A low yield of the coupling product
13q was obtained using the electron-deficient 3-pyridyl
derivative 12q. Attempts to improve the yield led to no
success although previous reports indicated that good
as base in refluxing methanol afforded 13a with 59% iso-
lated yield (Scheme 3). To find out the optimum reaction
conditions for an efficient coupling, the reaction was stud-
ied by varying several parameters as summarized in
yields of cross-coupling products were obtained using this
Table 1. The nature of the palladium catalyst was first sur-
derivative.13a As expected, the phenethyl trifluoroborate
veyed. Although Pd(OAc)2/Ph3P, Pd(PPh3)4, Pd2(dba)3/
12t gave mainly the reduced product 13 (R1 = H) presum-
ably through a b-elimination process.
Ph3P, and PdCl2(MeCN)2 used under ligandless condi-
tions, gave the desired product, the reaction did not go to
completion even after an extended period of time. Nano-
Several methods were investigated to deprotect the quin-
oline derivatives 13. Treatment of 13a with BBr3 or
TMSCl/NaI provided a mixture of partially deprotected
products. On the other hand, treatment with 48% aqueous
HBr in refluxing AcOH cleanly converted 13a to 3a
particular palladium systems made from a palladium(II)
salt and tetrabutylammonium bromide14 were ineffective
(entry 7). Optimal conditions were found to involve the
use of Pd(dppf)Cl2, although Pd(PPh3)2Cl2 was almost
Table 1 Transformation of 11 to 13a
Entry
Palladium (mol%)
Ligand/additive
Base
Yield of 13a (%)a,b SM (%)
Reduction product
13: R1 = H
1
2
3
4
Pd(OAc)2 (12)
Pd(PPh3)4 (7)
Pd2(dba)3 (5)
Ph3P
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
Cs2CO3
none
59
75
40c
0
41
19
–
–
–
–
–
–
15
3
–
1
–
–
–
Ph3P
Pd(OAc)2 (10)
Pd(OAc)2 (10)
PdCl2(MeCN)2(7)
PdCl2 (6)
dppe
100
100
34
50
9
dppp
0
6
7
–
50
38
85
86
26
36
Bu4NBr
8
Pd(PPh3)2Cl2 (7)
Pd(dppf)Cl2 (7)
Pd(dppf)Cl2 (7)
Pd(dppf)Cl2 (7)
–
–
–
–
9
–
10
11
40
59
a Conditions: 11 (1 equiv), potassium phenyltrifluoroborate (1.35 equiv), base (3 equiv), MeOH, reflux 16 h.
b Isolated yields.
c Yield established by NMR spectroscopy.
Synthesis 2010, No. 4, 619–630 © Thieme Stuttgart · New York

PAPER
5-Aryl- and 5-Heteroaryl-7-carboxyl-8-hydroxyquinaldines
621
R1
(Scheme 3). Satisfactory yields were obtained in these
conditions (Method A) for compounds 13a,b,c,h,m,r,s
(Table 2). In search of milder conditions best suited for
sensitive substrates we explored the hydrogenolysis of the
acid 14a.
Br
R1BF3
K
12
Pd(dppf)Cl2
MeO2C
N
MeO2C
N
MeOH, reflux
i-Pr2NEt
OBn
OBn
13a–s
11
Ph
HBr, AcOH
reflux, 16 h
6 N NaOH, MeOH
dioxane
Br
N
Br
OMe
+
6
R1
R1
PhB(OH)2
Pd(PPh3)4
Ph
Br
N
Na2CO3, H2O, DME
90 °C, 16 h
Pd/C, cyclohexa-1,4-diene
HO2C
N
OMe
MeOH, EtOAc
MW, 10–15 min
HO2C
N
OH
5
OBn
Ph
N
3a–s
14a–s
OMe
NH2
7
NH2
KHCO3, MeI
DMF
HO2C
N
MeO2C
N
93%
OH
OH
HO2C
N
HO2C
N
H
9
8
OH
15a
OH
NBS, DMF 96%
Br
16
OHC
1)
OH
OH
Br
K2CO3, BnBr
DMF, 90 °C
17
Ac2O, 140 °C, 72 h
MeO2C
N
MeO2C
N
92%
3a,h
2a,h
OBn
OH
10
2) Py, H2O, 100 °C, 3 h
11
Scheme 3 Suzuki cross-coupling reaction of quinoline 11, depro-
tection of the adducts 13a–s and synthesis of representative styrylqui-
nolines 2a,h
Scheme 2 Regioselective Suzuki cross-coupling reaction of 5 and
synthesis of the 5-bromoquinaldine 11
Table 2 Synthesis of 5-Substituted Quinaldines 13a–s and Deprotection to 3a–s
Entry
R1
Product
Yield (%)
Reduction product Deprotection
13: R1 = H
Method Aa
Yield (%)
Method Bb
Yield (%)
1
2
13a
13b
86
75
3
7
77
92
82
–
3
13c
75
–
59
40
4
5
13d
13e
72
85
–
–
–
–
84
64
Cl
F
HO
6
13f
65
–
–
80
Synthesis 2010, No. 4, 619–630 © Thieme Stuttgart · New York

622
F. Sliman, D. Desmaële
PAPER
Table 2 Synthesis of 5-Substituted Quinaldines 13a–s and Deprotection to 3a–s (continued)
Entry
R1
Product
Yield (%)
Reduction product Deprotection
13: R1 = H
Method Aa
Yield (%)
Method Bb
Yield (%)
7
8
13g
13h
95
78
–
–
85
HO
O2N
–
95
80c
9
13i
13j
85
84
–
–
–
–
93
61
MeO
MeS
10
11
13k
87
–
0
–
Me
O
12
13
13l
87
95
13
–
74
–
13m
90
36
HO2C
OHC
14
15
13n
13o
61
59
–
–
–
–
65
O
16
17
13p
13q
69
9
–
–
–
57
–
Me
S
<10
N
18
13r
87
–
76
–
N
76d
–
N
O
N
19
20
13s
13t
quant
<10
–
85
–
45
a Method A: 48% HBr, AcOH, reflux, 16 h.
b Method B: i. aq 6 N NaOH, MeOH–dioxane, reflux, 16 h; ii. Pd/C, cyclohexa-1,4-diene, microwave irradiation, 100 °C, 10 min.
c The 3-aminophenyl derivative was obtained.
d Compound 16 was obtained.
Unexpectedly, catalytic hydrogenolysis of 14a using Pd/ cyclohexa-1,4-diene, MeOH–EtOAc) most reactions oc-
C or Pd(OH)2 gave rise to the 1,2,3,4- tetrahydroquinoline curred smoothly in few minutes, with the exception of the
15a. On the other hand catalytic transfer hydrogenation sulfur containing quinolines 13j and 13p whose reduction
using cyclohexane-1,4-diene and Pd/C catalyst in isopro- required a longer reaction time. When, quinolines 13 were
pyl alchohol at reflux16 was more successful delivering subjected to this simple two-step protocol (Method B),
the expected quinoline 3a in 75% overall yield. The pro- moderate to good yields of the corresponding fully depro-
cess can be further improved using microwave irradia- tected quinolines 3 were obtained. As expected, concom-
tion.17 Under standard conditions (MW, 100 °C, 50 equiv itant reduction of the nitro group to the corresponding
Synthesis 2010, No. 4, 619–630 © Thieme Stuttgart · New York

PAPER
5-Aryl- and 5-Heteroaryl-7-carboxyl-8-hydroxyquinaldines
623
washed with brine (10 mL), dried (MgSO4), filtered and concentrat-
ed under reduced pressure to afford 19.9 g (93%) of 9; off-white
solid; mp 102–104 °C.
amino group was observed with quinoline 13h. Likewise,
the major product formed upon reduction of the benzo-
furazan 14s was found to be the o-phenylenediamine 16
whose synthesis is highly straightforward by using the
present method.
IR (neat): 3200–3000, 2965, 1664, 1622, 1606, 1557, 1435, 1421,
1360, 1334, 1318, 1263, 1238, 1211, 1194, 1153, 1142, 1088, 1037,
981, 849, 820, 763, 722 cm–1.
Finally, the formation of styrylquinoline derivatives 2
from the 5-arylquinaldines 3 was briefly investigated. In
the event, heating 3a with an excess of 3,4-dihydroxy-
benzaldehyde (17) in acetic anhydride for 3 days followed
by hydrolysis with aqueous pyridine afforded the expect-
ed styrylquinoline 2a in 41% yield. Similarly, styrylquin-
oline 2h was obtained in 43% yield from the 5-(3-
nitrophenyl)quinaldine 3h (Scheme 3). These results indi-
cated that the 5-aryl substituent did not interfere with the
Perkin-type condensation process. The syntheses of the
other styryquinolines and their biological evaluation are
currently under studies and will be reported in due course.
1H NMR (300 MHz, CDCl3): d = 8.72 (br s, 1 H, OH), 8.24 (d,
J = 8.5 Hz, 1 H, H-4), 7.61 (d, J = 8.7 Hz, 1 H, H-6), 7.56 (d, J = 8.5
Hz, 1 H, H-3), 7.38 (d, J = 8.7 Hz, 1 H, H-5), 3.92 (s, 3 H, CO2CH3),
2.69 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 170.7 (C), 159.1 (C), 158.6 (C),
139.0 (C), 135.7 (CH), 130.4 (C), 124.7 (CH), 124.3 (CH), 117.3
(CH), 109.1 (C), 52.3 (CH3), 25.3 (CH3).
Anal. Calcd for C12H11NO3: C, 66.35; H, 5.10; N, 6.45. Found: C,
66.50; H, 4.97; N, 6.45.
5-Bromo-8-hydroxy-2-methylquinoline-7-carboxylic Acid
Methyl Ester (10)
To an ice-cooled solution of quinaldine 9 (10.0 g, 46.3 mmol) in an-
hyd DMF (150 mL) was added NBS (9.83 g, 55.2 mmol) by portion.
The reaction mixture was stirred for 1 h at 0 °C and then 5 h at
40 °C. After concentration in vacuo, the crude product was purified
by flash chromatography on silica gel eluting with cyclohexane–
EtOAc (85:15) to afford bromoquinoline 10 (13.1 g, 96%); color-
less solid; mp 107–108 °C.
In conclusion the neutral conditions associated with the
trifluoroborate modified Suzuki–Myaura cross-coupling
reaction provided a convenient and efficient access to a
large variety of 5-aryl- and 5-heteroaryl-7-carboxyl-8-hy-
droxyquinaldines. We anticipate that such conditions will
find application with other hydrolytically sensible materi-
als. This method may be useful for obtaining otherwise
difficultly accessible highly decorated quinolines that
may afford products of interest for physicochemical and
pharmaceutical applications.
IR (neat): 3200–3000, 2958, 1672, 1619, 1603, 1440, 1422, 1404,
1363, 1333, 1310, 1229, 1215, 1204, 1152, 1094, 1042, 985, 921,
893, 836, 777, 746, 728, 670 cm–1.
1H NMR (300 MHz, CDCl3): d = 11.72 (br s, 1 H, OH), 8.32 (d,
J = 8.7 Hz, 1 H, H-4), 8.08 (s, 1 H, H-6), 7.49 (d, J = 8.7 Hz, 1 H,
H-3), 4.02 (s, 3 H, CO2CH3), 2.83 (s, 3 H, CH3).
Melting points were determined on a Büchi apparatus and are un-
corrected. IR spectra were recorded on a Fourier Transform Bruker
Vector 22 spectrometer. The 1H and 13C NMR spectra were record-
ed on a Bruker Avance 300 spectrometer. When diffuse, easily ex-
changeable protons were not listed. Recognition of methyl,
methylene, methine, and quaternary carbon nuclei in 13C NMR
spectra rests on the J-modulated spin-echo sequence. Mass spectra
were recorded on a Bruker Esquire-LC spectrometer. Elemental
analyses were performed by the Service de microanalyse, Centre
d’Etudes Pharmaceutiques, Châtenay-Malabry, France, with a
Perkin-Elmer 2400 analyzer. Analytical TLC was performed on
Merck silica gel 60 F254 glass precoated plates (0.25 mm layer).
Column chromatography was performed on Merck silica gel 60
(230–400 mesh ASTM). MeOH was dried over Mg and distilled.
DMF and CH2Cl2 were distilled from CaH2. All reactions involving
air- or water-sensitive compounds were routinely conducted in
glassware, which was flame-dried under a positive pressure of N2.
Microwave activation was carried out using a CEM Corp Discover
LabMate microwave synthesis system. Chemicals obtained from
commercial suppliers were used without further purification.
Pd(dppf)Cl2 was prepared from PdCl2 and dppf according to litera-
ture procedure.18 Most potassium organotrifluoroborates were pur-
chased from Aldrich or Alpha Aesar (France). Compounds 12o,q,r
were prepared from the commercially available corresponding bo-
ronic acids.19
13C NMR (75 MHz, CDCl3): d = 169.6 (C), 159.5 (C), 158.7 (C),
139.8 (C), 135.6 (CH), 129.5 (C), 127.6 (CH), 125.8 (CH), 110.0
(C), 109.9 (C), 52.7 (CH3), 25.2 (CH3).
MS (+APCI): m/z (%) = 298 (100), 296 (100, [M + H]+).
Anal. Calcd for C12H10BrNO3: C, 48.67; H, 3.40; N, 4.73. Found: C,
48.82; H, 3.20; N 4.74.
8-Benzyloxy-5-bromo-2-methylquinoline-7-carboxylic Acid
Methyl Ester (11)
To a mixture of bromoquinoline 10 (13.0 g, 43.9 mmol) and K2CO3
(15.2 g, 109.7 mmol) in anhyd DMF (120 mL) was added BnBr
(18.8 g, 109.7 mmol). The reaction mixture was heated for 18 h at
90 °C. After concentration in vacuo, the residue was taken into H2O
(40 mL) and extracted with CH2Cl2 (3 × 50 mL). The combined or-
ganic phases were washed by brine (10 mL), dried (MgSO4), fil-
tered, and concentrated. The crude product was purified by
chromatography on silica gel eluting with cyclohexane–EtOAc
(90:10) to give of compound 11 (15.6 g, 92%); colorless solid; mp
93–94 °C.
IR (neat): 2949, 1699, 1593, 1497, 1434, 1401, 1316, 1249, 1211,
1210, 1138, 1093, 975, 965, 909, 845, 829, 772, 756, 728, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.39 (d, J = 8.7 Hz, 1 H, H-4),
8.07 (s, 1 H, H-6), 7.64 (d, J = 7.0 Hz, 2 H, OCH2C6H5), 7.50–7.25
(m, 4 H, H-3, OCH2C6H5), 5.50 (s, 2 H, OCH2Ph), 3.89 (s, 3 H,
CO2CH3), 2.83 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 165.8 (C), 159.7 (C), 155.1 (C),
143.7 (C), 137.6 (C), 135.8 (CH), 129.4 (CH), 129.0 (C), 128.8 (2
CH), 128.3 (2 CH), 128.1 (CH), 124.8 (C), 124.6 (CH), 115.8 (C),
77.6 (CH2), 52.5 (CH3), 25.4 (CH3).
8-Hydroxy-2-methylquinoline-7-carboxylic Acid Methyl Ester
(9)
To a stirred solution of 8-hydroxy-2-methylquinoline-7-carboxylic
acid9 (20 g, 98.4 mmol) in anhyd DMF (150 mL) were added
KHCO3 (11.8 g, 118.1 mmol) and MeI (20.9 g, 147.6 mmol). The
reaction mixture was stirred at 40 °C for 4 h. After concentration in
vacuo, the solid residue was taken into H2O (40 mL) and extracted
with CH2Cl2 (3 × 50 mL). The combined organic phases were
MS (+APCI): m/z (%) = 386 (90), 388 (100, [M + H]+).
Synthesis 2010, No. 4, 619–630 © Thieme Stuttgart · New York

624
F. Sliman, D. Desmaële
PAPER
Anal. Calcd for C19H16BrNO3: C, 59.08; H, 4.18; N, 3.63. Found: C,
59.25; H, 4.19; N, 3.53.
13C NMR (75 MHz, CDCl3): d = 167.1 (C), 158.7 (C), 154.6 (C),
143.0 (C), 137.9 (C), 136.3 (C), 135.5 (C), 134.6 (CH), 133.4 (C),
132.7 (C), 128.9 (CH), 128.7 (2 CH), 128.3 (C), 128.2 (2 CH),
128.0 (2 CH), 127.9 (CH), 127.8 (CH), 127.7 (CH), 126.7 (CH),
126.5 (CH), 126.3 (CH), 123.8 (C), 123.4 (CH), 77.5 (CH2), 52.3
(CH3), 25.5 (CH3).
Cross-Coupling Reaction of Potassium Organotrifluoroborates
12 with 11; General Procedure
A mixture of 11 (1.16 g, 3 mmol), potassium organotrifluoroborate
12 (4.0 mmol), i-Pr2NEt (1.16 g, 9 mmol), and Pd(dppf)Cl2 (154
mg, 0.21 mmol, 7 mol%) in anhyd MeOH (25 mL) was heated at re-
flux for 18 h. After cooling to r.t., the mixture was concentrated in
vacuo. H2O (25 mL) was added and the mixture was extracted with
CH2Cl2 (3 × 30 mL). The combined organic phases were dried
(MgSO4), filtered, and concentrated. The crude product was puri-
fied by chromatography on silica gel eluting with EtOAc–cyclohex-
ane to give the title compound.
MS (+APCI): m/z (%) = 434 (100, [M + H]+).
Anal. Calcd for C29H23NO3: C, 80.35; H, 5.35; N, 3.23. Found: C,
80.11; H, 5.44; N, 3.11.
Methyl 8-(Benzyloxy)-5-(4-chlorophenyl)-2-methylquinoline-7-
carboxylate (13d)
Colorless solid; mp 181–182 °C.
IR (neat): 2946, 1720, 1607, 1509, 1436, 1373, 1253, 1210, 1127,
1083, 1013, 978, 911, 835, 787, 762, 747 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.05 (d, J = 8.7 Hz, 1 H, H-4),
7.72 (s, 1 H, H-6), 7.71 (d, J = 7.7 Hz, 2 H, OCH2C6H5), 7.49–7.30
(m, 7 H), 7.31 (d, J = 8.7 Hz, 1 H, H-3), 5.55 (s, 2 H, PhCH2O), 3.89
(s, 3 H, CO2CH3), 2.80 (s, 3 H, CH3).
Methyl 8-(Benzyloxy)-2-methyl-5-phenylquinoline-7-carbox-
ylate (13a)
Colorless solid; mp 129–130 °C.
IR (neat): 2960, 1708, 1606, 1445, 1435, 1375, 1355, 1252, 1204,
1126, 1085, 1031, 982, 915, 898, 853, 833, 786, 772, 744, 702 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.11 (d, J = 8.7 Hz, 1 H, H-4),
7.74 (s, 1 H, H-6), 7.72 (d, J = 8.7 Hz, 2 H, OCH2C6H5), 7.50–7.35
(m, 8 H), 7.31 (d, J = 8.7 Hz, 1 H, H-3), 5.56 (s, 2 H, PhCH2O), 3.89
(s, 3 H, CO2CH3), 2.81 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 167.0 (C), 158.6 (C), 154.4 (C),
142.9 (C), 138.7 (C), 137.9 (C), 135.5 (C), 134.5 (CH), 129.9 (2
CH), 128.6 (2 CH), 128.4 (2 CH), 128.2 (2 CH), 128.0 (C), 127.8
(CH), 127.6 (CH), 126.4 (CH), 123.7 (C), 123.3 (CH), 77.4 (CH2),
52.2 (CH3), 25.5 (CH3).
13C NMR (75 MHz, CDCl3): d = 167.0 (C), 158.8 (C), 154.7 (C),
143.0 (C), 137.9 (C), 137.2 (C), 134.2 (CH), 133.8 (C), 131.2 (2
CH), 128.7 (2 CH), 128.6 (2 CH), 128.2 (2 CH), 128.0 (C), 127.9
(CH), 126.5 (CH), 123.8 (C), 123.5 (CH), 77.5 (CH2), 52.3 (CH3),
25.5 (CH3).
MS (+APCI): m/z (%) = 418 (100), 420 (30, [M + H]+).
Anal. Calcd for C25H20ClNO3: C, 71.85; H, 4.82; N, 3.35. Found: C,
71.70; H, 4.90; N, 3.20.
MS (+APCI): m/z (%) = 384.2 (100, [M + H]+).
Methyl 8-(Benzyloxy)-5-(4-fluorophenyl)-2-methylquinoline-7-
carboxylate (13e)
Beige solid; mp 161–163 °C.
Anal. Calcd for C26H21O3·H2O: C, 77.40; H, 5.59; N, 3.61. Found:
C, 77.39; H, 5.73; N, 3.34.
IR (neat): 2950, 1713, 1606, 1512, 1441, 1418, 1371, 1276, 1254,
1218, 1161, 1126, 1089, 985, 910, 850, 782, 758, 738 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.05 (d, J = 8.6 Hz, 1 H, H-4),
7.75–7.65 (m, 3 H), 7.47–7.30 (m, 5 H), 7.33 (d, J = 8.6 Hz, 1 H, H-
3), 7.18 (t, J = 8.7 Hz, 2 H, HCCF), 5.54 (s, 2 H, OCH2Ph), 3.90 (s,
3 H, CO2CH3), 2.81 (s, 3 H, CH3).
Methyl 8-(Benzyloxy)-2-methyl-5-(4-methylphenyl)quinoline-
7-carboxylate (13b)
Yellowish solid; mp 151–152 °C.
IR (neat): 2960, 1711, 1606, 1516, 1496, 1436, 1373, 1355, 1254,
1209, 1172, 1125, 1086, 974, 899, 836, 821, 787, 753, 736 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.13 (d, J = 8.7 Hz, 1 H, H-4),
7.72 (s, 1 H, H-6), 7.70 (d, J = 8.7 Hz, 2 H, OCH2C6H5), 7.40–7.25
(m, 8 H), 5.55 (s, 2 H, PhCH2O), 3.89 (s, 3 H, CO2CH3), 2.80 (s, 3
H, CH3), 2.45 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 167.2 (C), 158.6 (C), 154.3 (C),
143.0 (C), 138.0 (C), 137.4 (C) 135.9 (C), 135.6 (C), 134.6 (CH),
129.8 (2 CH), 129.2 (2 CH), 128.7 (2 CH), 128.3 (2 CH), 128.2 (C),
127.9 (CH), 126.3 (CH), 123.8 (C), 123.3 (CH), 77.4 (CH2,
OCH2Ph), 52.2 (CH3), 25.5 (CH3), 21.2 (CH3).
13C NMR (75 MHz, CDCl3): d = 167.1 (C), 162.5 (d, JC,F = 247.3
Hz, CF), 158.8 (C), 154.6 (C), 143.0 (C), 137.9 (C), 134.7 (d,
JC,F = 3.3 Hz, C), 134.4 (C), 134.3 (CH), 131.6 (d, JC,F = 8.2 Hz, 2
CH), 128.7 (2 CH), 128.3 (2 CH), 128.2 (C), 127.9 (CH), 126.5
(CH), 123.8 (C), 123.5 (CH), 115.6 (d, JC,F = 21.0 Hz, 2 CH), 77.5
(CH2), 52.3 (CH3), 25.5 (CH3).
19F NMR (188 MHz CDCl3): d = –114.9 (tt, J = 7.5 Hz, 5.6 Hz).
MS (+ESI): m/z (%) = 825.8 (6, [2 M + Na]+), 424 (100, [M + Na]+),
402.3 (7, [M + H]+), 333.2 (8).
MS (+APCI): m/z (%) = 398 (100, [M + H]+).
Anal. Calcd for C25H20FNO3: C, 74.80; H, 5.02; N, 3.49. Found: C,
74.61; H, 5.07; N, 3.31.
Anal. Calcd for C26H23NO3· H2O: C, 77.69; H, 5.89; N, 3.48. Found:
C, 77.63; H, 5.87; N, 3.40.
Methyl 8-(Benzyloxy)-5-(3-hydroxyphenyl)-2-methylquinoline-
7-carboxylate (13f)
Yellow solid; mp 192–194 °C.
Methyl 8-(Benzyloxy)-2-methyl-5-(2-naphthyl)quinoline-7-car-
boxylate (13c)
Ochred solid; mp 138–140 °C.
IR (neat): 3500–2900, 1727, 1610, 1580, 1429, 1375, 1351, 1253,
1238, 1203, 1160, 1126, 1096, 988, 972, 839, 776, 744, 731, 694
cm–1.
1H NMR (300 MHz, CDCl3): d = 8.12 (d, J = 8.7 Hz, 1 H, H-4),
7.71 (s, 1 H, H-6), 7.69 (d, J = 7.8 Hz, 2 H, OCH2C6H5), 7.45–7.32
(m, 4 H), 7.29 (d, J = 8.7 Hz, 1 H, H-3), 6.98 (d, J = 7.8 Hz, 1 H, H-
6¢), 6.93 (dd, J = 8.1, 2.1 Hz, 1 H, H-4¢), 6.87 (br s, 1 H, H-2¢), 5.54
(s, 2 H, OCH2Ph), 5.35 (s, 1 H, OH), 3.88 (s, 3 H, CO2CH3), 2.79 (s,
3 H, CH3).
IR (neat): 3030, 2947, 1730, 1706, 1607, 1510, 1436, 1401, 1371,
1334, 1257, 1210, 1168, 1136, 1119, 1087, 1040, 983, 909, 861,
835, 816, 784, 752, 730 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.15 (d, J = 8.7 Hz, 1 H, H-4),
7.96 (d, J = 8.3 Hz, 1 H), 7.95–7.87 (m, 3 H), 7.85 (s, 1 H), 7.73 (d,
J = 7.2 Hz, 2 H), 7.60–7.50 (m, 3 H), 7.44 (t, J = 7.2 Hz, 2 H), 7.43
(d, J = 7.2 Hz, 1 H), 7.37 (d, J = 7.2 Hz, 1 H), 7.31 (d, J = 8.7 Hz, 1
H), 5.60 (s, 2 H, PhCH2O), 3.91 (s, 3 H, CO2CH3), 2.82 (s, 3 H,
CH3).
Synthesis 2010, No. 4, 619–630 © Thieme Stuttgart · New York

PAPER
5-Aryl- and 5-Heteroaryl-7-carboxyl-8-hydroxyquinaldines
MS (+APCI): m/z (%) = 414 (100, [M + H]+).
625
13C NMR (75 MHz, DMSO-d6): d = 166.2 (C), 158.6 (C), 157.4
(C), 153.1 (C), 142.0 (C), 139.2 (C), 137.6 (C), 135.2 (C), 134.3
(CH), 129.6 (CH), 128.3 (2 CH), 128.1 (2 CH), 127.8 (CH), 127.2
(C), 125.2 (CH), 123.8 (CH), 123.6 (C), 120.3 (CH), 116.5 (CH),
114.8 (CH), 76.5 (CH2), 52.4 (CH3), 25.0 (CH3).
Anal. Calcd for C26H23NO4: C, 75.53; H, 5.61; N, 3.39. Found: C,
75.43; H, 5.65; N, 3.20.
Methyl 8-(Benzyloxy)-2-methyl-5-[4-(methylthio)phenyl]quin-
oline-7-carboxylate (13j)
MS (+APCI): m/z (%) = 400 (100, [M + H]+).
Colorless solid; mp 142–144 °C.
Anal. Calcd for C25H21NO4·H2O: C, 74.33; H, 5.36; N, 3.47. Found:
C, 74.01; H, 4.96; N, 3.33.
IR (neat): 2914, 1728, 1606, 1556, 1495, 1433, 1369, 1242, 1207,
1169, 1134, 1081, 1036, 1007, 991, 934, 831, 777, 741 cm–1.
Methyl 8-(Benzyloxy)-5-(4-hydroxymethylphenyl)-2-methyl-
quinoline-7-carboxylate (13g)
Yellow solid; 114–116 °C.
1H NMR (300 MHz, CDCl3): d = 8.11 (d, J = 8.7 Hz, 1 H, H-4),
7.72 (s, 1 H, H-6), 7.70 (d, J = 7.0 Hz, 2 H, OCH2C6H5), 7.45–7.35
(m, 7 H), 7.31 (d, J = 8.7 Hz, 1 H, H-3), 5.55 (s, 2 H, OCH2Ph), 3.89
(s, 3 H, CO2CH3), 2.80 (s, 3 H, CH3), 2.56 (s, 3 H, SCH3).
13C NMR (75 MHz, CDCl3): d = 167.1 (C), 158.7 (C), 154.4 (C),
143.0 (C), 138.2 (C), 137.9 (C), 135.4 (C), 135.0 (C), 134.5 (CH),
130.4 (2 CH), 128.7 (2 CH), 128.3 (2 CH), 128.1 (C), 127.9 (CH),
126.4 (3 CH), 123.8 (C), 123.4 (CH), 77.5 (CH2), 52.3 (CH3), 25.5
(CH3), 15.7 (CH3).
IR (neat): 3330–2900, 1731, 1708, 1608, 1438, 1372, 1255, 1215,
1130, 1089, 1038, 835, 783, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.10 (d, J = 8.7 Hz, 1 H, H-4),
7.72 (s, 1 H, H-6), 7.71 (d, J = 7.7 Hz, 2 H), 7.55–7.30 (m, 5 H),
7.31 (d, J = 8.7 Hz, 1 H, H-3), 5.55 (s, 2 H, PhCH2O), 4.80 (s, 2 H,
CH2OH), 3.89 (s, 3 H, CO2CH3), 2.80 (s, 3 H, CH3).
13C NMR (75 MHz, DMSO-d6): d = 168.7 (C), 160.9 (C), 155.3
(C), 144.2 (C), 143.0 (C), 139.2 (C), 139.1 (C), 137.5 (C), 136.3
(CH), 131.3 (2 CH), 130.2 (2 CH), 129.7 (C), 129.5 (2 CH), 129.4
(CH), 128.5 (2 CH), 127.5 (CH), 125.6 (C), 125.2 (CH), 79.0 (CH2),
65.2 (CH2), 53.2 (CH3), 25.5 (CH3).
MS (+APCI): m/z (%) = 430 (100, [M + H]+).
Anal. Calcd for C26H23NO3S: C, 72.70; H, 5.40; N, 3.26. Found: C,
72.41; H, 5.59; N, 3.19.
Methyl 8-(Benzyloxy)-2-methyl-5-[(E)-2-(4-methylphenyl)vi-
nyl]quinoline-7-carboxylate (13k)
MS (+APCI): m/z (%) = 414 (100, [M + H]+).
Yellow solid; mp 97–99 °C.
Anal. Calcd for C26H23NO4·H2O: C, 74.71; H, 5.67; N, 3.35. Found:
C, 74.90; H, 5.68; N, 3.35.
IR (neat): 3031, 2943, 1728, 1703, 1630, 1606, 1555, 1502, 1437,
1364, 1248, 1213, 1196, 1156, 1098, 1025, 988, 963, 915, 857, 807,
795, 776, 748, 723, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.42 (d, J = 8.7 Hz, 1 H, H-4),
8.01 (s, 1 H, H-6), 7.68 (d, J = 6.8 Hz, 2 H, OCH2C6H5), 7.63 (d,
J = 16.1 Hz, HC=), 7.48 (d, J = 8.0 Hz, 2 H, H-2¢, H-6¢), 7.47–7.30
(m, 4 H), 7.21 (d, J = 8.0 Hz, 2 H, H-3¢, H-5¢), 7.15 (d, J = 16.1 Hz,
HC=), 5.52 (s, 2 H, OCH2Ph), 3.92 (s, 3 H, CO2CH3), 2.81 (s, 3 H,
CH3), 2.39 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 167.3 (C), 158.6 (C), 154.4 (C),
143.0 (C), 138.1 (C), 138.0 (C), 134.4 (C), 132.4 (CH), 132.5 (CH),
130.7 (C), 129.5 (2 CH), 128.7 (2 CH), 128.2 (2 CH), 127.9 (CH),
127.7 (C), 126.6 (2 CH), 124.3 (C), 123.2 (CH), 123.1 (CH), 122.4
(CH), 77.4 (CH2), 52.3 (CH3), 25.5 (CH3), 21.8 (CH3).
Methyl 8-(Benzyloxy)-5-(3-nitrophenyl)-2-methylquinoline-7-
carboxylate (13h)
Yellow solid; mp 131–133 °C.
IR (neat): 2949, 1722, 1607, 1528, 1438, 1347, 1250, 1211, 1137,
1092, 1042, 960, 900, 833, 780, 743, 725, 694 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.33 (s, 1 H, H-2¢), 8.32 (d, J = 7.8
Hz, 1 H, H-4¢), 7.99 (d, J = 8.7 Hz, 1 H, H-4), 7.80 (d, J = 7.8 Hz, 1
H, H-6¢), 7.77 (s, 1 H, H-6), 7.72–7.65 (m, 3 H), 7.50–7.30 (m, 4 H)
5.58 (s, 2 H, OCH2Ph), 3.91 (s, 3 H, CO2CH3), 2.83 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 166.7 (C), 159.2 (C), 155.5 (C),
148.4 (C), 143.1 (C), 140.5 (C), 137.7 (C), 136.0 (CH), 133.6 (CH),
132.6 (C), 129.6 (CH), 128.7 (2 CH), 128.3 (2 CH), 128.0 (CH),
127.7 (C), 127.1 (CH), 124.9 (CH), 124.0 (CH), 123.8 (C), 122.7
(CH), 77.6 (CH2), 52.4 (CH3), 25.6 (CH3).
MS (+APCI): m/z (%) = 424 (100, [M + H]+).
Anal. Calcd for C28H25NO3: C, 79.41; H, 5.95; N, 3.31. Found: C,
79.13; H, 5.55; N, 3.11.
MS (+APCI): m/z (%) = 429.3 (100, [M + H]+).
Anal. Calcd for C25H20N2O5: C, 70.03; H, 4.71; N, 6.54. Found: C,
70.14; H, 4.63; N, 6.42.
Methyl 5-(4-Acetylphenyl)-8-(benzyloxy)-2-methylquinoline-7-
carboxylate (13l)
Yellowish solid; 167–169 °C.
Methyl 8-(Benzyloxy)-5-(4-methoxyphenyl)-2-methylquinoline-
7-carboxylate (13i)
Colorless solid; mp 180–182 °C.
IR (neat): 1729, 1680, 1601, 1556, 1498, 1434, 1417, 1372, 1354,
1264, 1246, 1208, 1186, 1169, 1135, 1089, 1036, 988, 935, 867,
842, 780, 746 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.09 (d, J = 8.2 Hz, 2 H, H-3¢, H-
5¢), 8.06 (d, J = 8.7 Hz, 1 H, H-4), 7.75 (s, 1 H, H-6), 7.70 (d, J = 7.0
Hz, 2 H, OCH2C6H5), 7.56 (d, J = 8.2 Hz, 2 H, H-2¢, H-6¢), 7.45–
7.30 (m, 4 H), 5.57 (s, 2 H, OCH2Ph), 3.89 (s, 3 H, CO2CH3), 2.81
(s, 3 H, CH3), 2.69 (s, 3 H, COCH3).
13C NMR (75 MHz, CDCl3): d = 197.7 (C), 167.0 (C) 158.9 (C),
155.1 (C), 143.7 (C), 143.1 (C), 137.8 (C), 136.3 (C), 134.2 (C),
134.1 (CH), 130.3 (2 CH), 128.7 (2 CH), 128.6 (2 CH), 128.3 (2
CH), 128.0 (CH), 127.8 (C), 126.6 (CH), 123.8 (C), 123.7 (CH),
77.6 (CH2), 52.4 (CH3), 26.7 (CH3), 25.5 (CH3).
IR (neat): 2946, 2836, 1721, 1608, 1514, 1456, 1423, 1372, 1346,
1239, 1201, 1171, 1133, 1087, 1032, 988, 971, 936, 914, 839, 794,
780, 756, 734, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.12 (d, J = 8.7 Hz, 1 H, H-4),
7.71 (d, J = 7.5 Hz, 2 H, OCH2C6H5), 7.70 (s, 1 H, H-6), 7.50–7.28
(m, 5 H), 7.30 (d, J = 8.7 Hz, 1 H, H-3), 7.03 (d, J = 8.5 Hz, 2 H, H-
3¢, H-5¢), 5.55 (s, 2 H, OCH2Ph), 3.89 (s, 6 H, CO2CH3,OCH3), 2.80
(s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 167.2 (C), 159.3 (C), 158.6 (C),
154.2 (C), 143.0 (C), 138.0 (C), 135.3 (C), 134.6 (CH), 131.2 (C),
131.1 (2 CH), 128.7 (2 CH), 128.3 (C), 128.2 (2 CH), 127.9 (2 CH),
126.3 (CH), 123.8 (C), 123.2 (CH), 113.9 (2 CH), 77.4 (CH2), 55.4
(CH3), 52.3 (CH3), 25.5 (CH3).
MS (+APCI): m/z (%) = 426 (100, [M + H]+).
Synthesis 2010, No. 4, 619–630 © Thieme Stuttgart · New York

626
F. Sliman, D. Desmaële
PAPER
Methyl 8-(Benzyloxy)-2-methyl-5-(5-methyl-2-thienyl)quino-
Anal. Calcd for C27H23NO4: C, 76.22; H, 5.45; N, 3.29. Found: C,
76.11; H, 5.12; N, 302.
line-7-carboxylate (13p)
Colorless solid; mp 126–128 °C.
Methyl 5-(4-Carboxyphenyl)-8-(benzyloxy)-2-methylquinoline-
7-carboxylate (13m)
Colorless solid; mp 195–196 °C.
IR (neat): 2946, 1731, 1708, 1606, 1435, 1370, 1321, 1251, 1203,
1120, 1084, 1032, 982, 782, 732 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.46 (d, J = 8.7 Hz, 1 H, H-4),
7.83 (s, 1 H, H-6), 7.69 (d, J = 7.1 Hz, 2 H, OCH2C6H5), 7.45–7.30
(m, 4 H), 6.97 (d, J = 3.0 Hz, 1 H), 6.83 (d, J = 3.0 Hz, 1 H), 5.54
(s, 2 H, OCH2Ph), 3.89 (s, 3 H, CO2CH3), 2.80 (s, 3 H, CH3), 2.57
(s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 166.9 (C), 158.7 (C), 154.7 (C),
143.1 (C), 140.8 (C), 137.9 (C), 137.4 (C), 134.5 (CH), 133.6 (C),
128.7 (2 CH), 128.4 (C), 128.3 (2 CH), 127.9 (CH), 127.6 (CH),
127.3 (CH), 125.6 (CH), 123.8 (C), 123.5 (CH), 77.4 (CH2), 52.3
(CH3), 25.5 (CH3), 15.3 (CH3).
IR (neat): 3300–2600, 1723, 1701, 1687, 1609, 1433, 1352, 1254,
1210, 1178, 1093, 914, 780, 727 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.24 (d, J = 7.8 Hz, 2 H, H-3¢),
8.08 (d, J = 8.7 Hz, 1 H, H-4), 7.77 (s, 1 H, H-6), 7.70 (d, J = 7.8
Hz, 2 H, OCH2C6H5), 7.57 (d, J = 8.7 Hz, 2 H, H-2¢), 7.43 (t, J = 7.8
Hz, 2 H, OCH2C6H5), 7.39–7.32 (m, 2 H), 5.58 (s, 2 H, OCH2Ph),
3.90 (s, 3 H, CO2CH3), 2.82 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 170.9 (C), 167.0 (C), 159.0 (C),
155.0 (C), 144.3 (C), 143.1 (C), 137.8 (C), 134.3 (C), 134.2 (CH),
130.4 (2 CH), 130.2 (2 CH), 128.7 (2 CH), 128.3 (2 CH), 128.0
(CH), 127.8 (C), 126.7 (CH), 123.8 (C), 123.7 (CH), 77.6 (CH2),
52.3 (CH3), 25.5 (CH3), 1 C undetected.
MS (+APCI): m/z (%) = 404 (100, [M + H]+).
Anal. Calcd for C24H21NO3S·H2O: C, 70.65; H, 5.25; N, 3.47.
Found: C, 70.72; H, 5.28; N, 3.25.
MS (–ESI): m/z (%) = 425.9 (100, [M – H]–).
Anal. Calcd for C26H21NO5· H2O: C, 71.55; H, 5.08; N, 3.21. Found:
C, 71.36; H, 5.09; N, 3.24.
Methyl 8¢-(Benzyloxy)-2¢-methyl-3,5¢-biquinoline-7¢-carbox-
ylate (13r)
Light brown solid; 156–157 °C.
Methyl 5-(3-Formylphenyl)-8-(benzyloxy)-2-methylquinoline-
7-carboxylate (13n)
Light brown solid; 167–169 °C.
IR (neat): 3059, 1715, 1608, 1555, 1489, 1428, 1373, 1316, 1249,
1220, 1206, 1167, 1123, 1084, 1043, 969, 898, 837, 781, 751, 729,
696 cm–1.
IR (neat): 2948, 1731, 1700, 1608, 1579, 1556, 1510, 1437, 1401,
1372, 1352, 1312, 1261, 1214, 1158, 1127, 1092, 1040, 983, 914,
838, 803, 781, 740, 698, 648 cm–1.
1H NMR (300 MHz, CDCl3): d = 10.11 (s, 1 H, CHO), 8.03 (d,
J = 8.7 Hz, 1 H, H-4), 7.97 (m, 2 H), 7.76 (s, 1 H, H-6), 7.65–7.72
(m, 4 H), 7.44 (t, J = 7.0 Hz, 2 H), 7.38 (t, J = 7.0 Hz, 1 H), 7.34 (d,
J = 8.7 Hz, 1 H, H-3), 5.56 (s, 2 H, OCH2Ph), 3.90 (s, 3 H,
CO2CH3), 2.81 (s, 3 H, CH3).
1H NMR (300 MHz, CDCl3): d = 9.02 (d, J = 2.0 Hz, 1 H, H-2¢),
8.24 (d, J = 1.6 Hz, 1 H, H-4¢), 8.21 (d. J = 8.5 Hz, 1 H, H-8¢), 8.07
(d, J = 8.7 Hz, 1 H, H-4), 7.89 (d, J = 8.2 Hz, 1 H, H-5¢), 7.86 (s, 1
H, H-6), 7.79 (t, J = 7.0 Hz, 1 H, H-7¢), 7.72 (d, J = 7.0 Hz, 2 H,
OCH2C6H5), 7.63 (t, J = 7.0 Hz, 1 H, H-6¢), 7.43 (t, J = 7.0 Hz, 2 H,
OCH2C6H5), 7.36 (t, J = 7.0 Hz, 1 H, OCH2C6H5), 7.35 (d, J = 8.7
Hz, 1 H, H-3), 5.60 (s, 2 H, OCH2Ph), 3.91 (s, 3 H, CO2CH3), 2.82
(s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 192.9 (C), 166.9 (C), 162.9 (C),
158.9 (C), 155.0 (C), 139.8 (C), 137.8 (C), 136.7 (C), 135.9 (CH),
134.0 (CH), 133.9 (C), 131.0 (CH), 129.3 (CH), 129.0 (CH), 128.7
(2 CH), 128.3 (2 CH), 128.0 (CH), 127.9 (C), 126.8 (CH), 123.8
(C), 123.7 (CH), 77.6 (CH2), 52.4 (CH3), 25.6 (CH3).
13C NMR (75 MHz, CDCl3): d = 166.9 (C), 159.0 (C), 155.3 (C),
151.9 (CH), 147.4 (C), 143.2 (C), 137.8 (C), 136.4 (CH), 133.9
(CH), 131.8 (C), 131.7 (C), 129.9 (CH), 129.4 (CH), 128.7 (2 CH),
128.3 (2 CH), 128.2 (C), 128.0 (CH), 127.9 (CH), 127.7 (C), 127.4
(CH), 127.3 (CH), 124.0 (C), 123.9 (CH), 77.4 (CH2), 52.4 (CH3),
25.6 (CH3).
MS (+ESI): m/z (%) = 412 (100, [M + H]+).
MS (+APCI): m/z (%) = 435 (100, [M + H]+).
Anal. Calcd for C26H21NO4: C, 75.90; H, 5.14; N, 3.40. Found: C,
75.58; H, 4.81; N, 3.27.
Anal. Calcd for C28H22N2O3·H2O: C, 76.61; H, 5.17; N, 6.38.
Found: C, 76.62; H, 5.06; N, 6.20.
Methyl 8-(Benzyloxy)-5-(3-furyl)-2-methylquinoline-7-carbox-
ylate (13o)
Colorless solid; mp 158–159 °C.
Methyl 5-(2,1,3-Benzoxadiazol-5-yl)-8-(benzyloxy)-2-methyl-
quinoline-7-carboxylate (13s)
Beige solid; mp 172–174 °C.
IR (neat): 2914, 1707, 1611, 1497, 1439, 1424, 1369, 1347, 1273,
1213, 1157, 1136, 1089, 1023, 966, 914, 872, 843, 827, 788, 759,
734, 696 cm–1.
IR (neat): 1732, 1497, 1439, 1373, 1315, 1257, 1242, 1209, 1171,
1119, 1079, 1008, 961, 874, 829, 756, 739 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.31 (d, J = 8.7 Hz, 1 H, H-4),
7.76 (s, 1 H, H-6), 7.69 (d, J = 7.0 Hz, 2 H, OCH2C6H5), 7.64 (s, 1
H, H-2¢), 7.58 (s, 1 H, H-5¢), 7.45–7.34 (m, 4 H), 6.65 (s, 1 H, H-4¢),
5.53 (s, 2 H, OCH2Ph), 3.89 (s, 3 H, CO2CH3), 2.81 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 167.0 (C), 158.7 (C), 154.5 (C),
143.2 (CH), 143.1 (C), 140.5 (CH), 137.9 (C), 134.2 (CH), 128.7 (2
CH), 128.3 (2 CH), 127.9 (CH), 126.3 (CH), 126.2 (C), 123.9 (C),
123.5 (CH), 123.1 (C), 112.1 (CH), 77.5 (CH2), 52.3 (CH3), 25.5
(CH3), 1 C undetected.
1H NMR (300 MHz, CDCl3): d = 8.04 (d, J = 8.7 Hz, 1 H, H-4),
7.95 (d, J = 9.3 Hz, 1 H, H-7¢), 7.91 (s, 1 H, H-4¢), 7.84 (s, 1 H, H-
6), 7.69 (d, J = 7.0 Hz, 2 H, OCH2C6H5), 7.53 (dd, J = 9.3 Hz, 1.1
Hz, 1 H, H-6¢), 7.38–7.45 (m, 5 H), 5.60 (s, 2 H, OCH2Ph), 3.91 (s,
3 H, CO2CH3), 2.83 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 166.6 (C), 159.2 (C), 155.8 (C),
149.3 (C), 148.4 (C), 143.2 (C), 142.3 (C), 137.6 (C), 134.7 (CH),
133.5 (CH), 132.6 (C), 128.7 (2 CH), 128.3 (2 CH), 128.1 (CH),
127.5 (C), 126.9 (CH), 124.0 (CH), 123.8 (C), 116.5 (CH), 116.4
(CH), 77.7 (CH2), 52.4 (CH3), 25.5 (CH3).
MS (+APCI): m/z (%) = 374 (100, [M + H]+).
MS (+APCI): m/z (%) = 426.2 (100, [M + H]+).
Anal. Calcd for C23H19NO4: C, 73.98; H, 5.13; N, 3.75. Found: C,
73.46; H, 5.12; N, 3.91.
Anal. Calcd for C25H19N3O4: C, 70.58; H, 4.50; N, 9.88. Found: C,
70.50; H, 4.51; N, 9.77.
Synthesis 2010, No. 4, 619–630 © Thieme Stuttgart · New York

PAPER
5-Aryl- and 5-Heteroaryl-7-carboxyl-8-hydroxyquinaldines
627
Compounds 3; General Procedure
1H NMR (300 MHz, DMSO-d6): d = 8.24 (d, J = 8.5 Hz, 1 H, H-4),
8.08–7.92 (m, 4 H), 7.87 (s, 1 H, H-6), 7.64–7.45 (m, 4 H), 2.74 (s,
3 H, CH3).
13C NMR (75 MHz, DMSO-d6): d = 171.0 (C), 161.3 (C), 156.0
(C), 138.0 (C), 136.6 (C), 136.2 (CH), 133.2 (C), 131.9 (C), 128.2
(CH), 128.1 (CH), 127.9 (3 CH), 127.7 (C), 127.5 (CH), 126.3
(CH), 126.0 (CH), 124.4 (C), 124.2 (CH), 113.4 (C), 23.2 (CH3).
Method A: To a suspension of 13 (0.5 mmol) in AcOH (4 mL) was
added a 48% aq solution of HBr (6 mL) and the resulting mixture
was heated under reflux for 18 h. After cooling to r.t., the mixture
was concentrated under reduced pressure and the residue was sus-
pended in H2O (4 mL). Aq 3 N NaOH was added until pH 10 was
reached and the mixture was then reacidified to pH 3–4 with aq 1 N
HCl. The precipitate was filtered, washed thoroughly with hot H2O,
i-PrOH, and Et2O, and dried in vacuo to give the title compound 3.
MS (–ESI): m/z (%) = 328 (100, [M – H]–, 284 (8, [M – CO2]–).
Anal. Calcd for C21H15NO3·4/3 H2O: C, 71.38; H, 5.04; N, 3.96.
Found: C, 71.36; H, 4.83; N, 3.67.
Method B: To a stirred solution of 13 (0.5 mmol) in dioxane (2 mL)
and MeOH (6 mL) was added 6 N aq NaOH (8 mL). The mixture
was heated at reflux under N2 for 16h. After cooling, the solvents
were removed under reduced pressure and the mixture was acidified
to pH 3 with aq 3 N HCl. The mixture was extracted with CH2Cl2
(3 × 15 mL). The combined organic layers were washed with brine
(5 mL) and dried (MgSO4). After removal of the solvent, the crude
acid 14 obtained was taken into a 3:1 mixture of MeOH and EtOAc
(3 mL) and placed in a 10 mL pressure tube with a stir bar. Cyclo-
hexa-1,4-diene (500 mg, 25 mmol) and 10% Pd/C (10 mg) were
added, the tube was capped and heated under microwave conditions
(100 °C, 20 bar) for 10 min. MeOH (20 mL) was added and the cat-
alyst was filtered through Celite. The filtrate was concentrated un-
der reduced pressure and the resulting solid was triturated with i-
PrOH (5 mL), filtered, and dried in vacuo to give the title compound
3.
8-Hydroxy-5-(4-chlorophenyl)-2-methylquinoline-7-carboxylic
Acid (3d)
Yellowish solid; mp 235 °C (dec.).
IR (neat): 3900–2900, 1683, 1587, 1513, 1449, 1398, 1366, 1309,
1130, 1088, 1014, 833, 785, 758 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.35 (d, J = 7.3 Hz, 1 H, H-4),
7.79 (s, 1 H, H-6), 7.70 (d, J = 7.3 Hz, 1 H, H-3), 7.58 (d, J = 7.2
Hz, 2 H), 7.48 (d, J = 7.2 Hz, 2 H), 2.83 (s, 3 H, CH3).
13C NMR (75 MHz, DMSO-d6): d = 170.5 (C), 160.7 (C), 156.1
(C), 137.3 (C), 136.4 (C), 132.0 (C), 131.5 (2 CH), 129.7 (CH),
128.6 (2 CH), 127.8 (C), 127.7 (CH), 124.9 (CH), 123.4 (C), 112.5
(C), 22.5 (CH3).
MS (–ESI): m/z (%) = 314 (30), 312 (100, [M – H]–).
8-Hydroxy-2-methyl-5-phenylquinoline-7-carboxylic Acid (3a)
Brown solid; mp 207–209 °C.
Anal. Calcd for C17H12ClNO3·3/5 H2O: C, 62.91; H, 4.10; N, 4.32.
Found: C, 63.16; H, 4.41; N, 3.92.
IR (neat): 3650–2300, 1693, 1656, 1596, 1567, 1514, 1449, 1423,
1395, 1365, 1302, 1263, 1096, 1030, 828, 788, 763, 746, 697 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.20 (d, J = 8.5 Hz, 1 H, H-4),
7.76 (s, 1 H, H-6), 7.60–7.38 (m, 6 H), 2.74 (s, 3 H, CH3).
5-(4-Fluorophenyl)-8-hydroxy-2-methylquinoline-7-carboxylic
Acid (3e)
Burgundy red solid; mp 156–161 °C.
13C NMR (75 MHz, DMSO-d6): d = 170.9 (C), 161.2 (C), 155.8
(C), 139.1 (C), 138.1 (C), 135.8 (CH), 129.7 (2 CH), 128.5 (2 CH),
127.5 (C), 127.4 (CH), 126.9 (CH), 124.5 (C), 123.9 (CH), 113.2
(C), 23.7 (CH3).
IR (neat): 3600–2600, 1699, 1662, 1604, 1522, 1511, 1464, 1419,
1372, 1285, 1234, 1160, 1106, 849, 839, 818, 781, 754 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.32 (d, J = 7.3 Hz, 1 H, H-4),
7.76 (s, 1 H, H-6), 7.69 (d, J = 7.3 Hz, 1 H, H-3), 7.48 (t J = 6.0 Hz,
2 H, H-2¢, H-6¢), 7.40–7.30 (m, 2 H, H-3¢, H-5¢), 2.82 (s, 3 H, CH3).
MS (–APCI): m/z (%) = 278 (100, [M – H]–).
13C NMR (75 MHz, DMSO-d6): d = 170.4 (C), 161.5 (d,
JC,F = 244.0 Hz, CF, C-4¢), 156.2 (C), 138.3 (CH), 135.5 (C), 134.5
(d, JC,F = 2.7 Hz, C, C-1¢), 131.7 (d, JC,F = 8.2 Hz, 2 CH, C-2¢, C-6¢),
128.2 (C), 127.7 (CH), 125.2 (CH), 123.9 (C), 115.5 (d, JC,F = 21.4
Hz, 2 CH, C-3¢, C-5¢), 111.9 (C), 22.1 (CH3).
Anal. Calcd for C17H13NO3·H2O: C, 68.68; H, 5.09; N, 4.71. Found:
C, 68.40; H, 4.96; N, 4.67.
8-Hydroxy-2-methyl-5-p-tolylquinoline-7-carboxylic Acid (3b)
Orange solid; mp 220–222 °C.
19F NMR (188 MHz, DMSO-d6): d = –113.31.
MS (–ESI): m/z (%) = 296 (100, [M – H]–).
IR (neat): 3700–3000, 2922, 1698, 1635, 1590, 1572, 1517, 1447,
1392, 1364, 1312, 1302, 1262, 1092, 1021, 856, 826, 816, 788, 737
cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.36 (d, J = 8.5 Hz, 1 H, H-4),
7.76 (s, 1 H, H-6), 7.68 (d, J = 8.5 Hz, 1 H, H-3), 7.32 (s, 4 H), 2.82
(s, 3 H, CH3), 2.39 (s, 3 H, PhCH3).
13C NMR (75 MHz, DMSO-d6): d = 170.4 (C), 159.9 (C), 156.1
(C), 138.5 (CH), 136.6 (C), 135.5 (C), 135.3 (C), 129.6 (2 CH),
129.3 (2 CH), 128.3 (C), 127.4 (CH), 125.1 (CH), 125.0 (C), 112.0
(C), 22.1 (CH3), 20.7 (CH3).
Anal. Calcd for C17H12FNO3·H2O: C, 67.66; H, 4.17; N, 4.64.
Found: C, 67.67; H, 4.65; N, 4.30.
8-Hydroxy-5-(3-hydroxyphenyl)-2-methylquinoline-7-carbox-
ylic Acid (3f)
Orange solid; mp 200 °C (dec.).
IR (neat): 3400–2400, 1636, 1595, 1572, 1458, 1405, 1379, 1358,
1318, 1259, 1223, 1096, 890, 867, 829, 788, 768, 737, 698 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 9.70 (br s, 1 H, OH), 8.22 (d,
J = 8.2 Hz, 1 H, H-4), 7.74 (s, 1 H, H-6), 7.51 (d, J = 8.2 Hz, 1 H,
H-3), 7.27 (t, J = 7.3 Hz, 1 H, H-5¢), 6.82 (br s, 3 H, H-2¢, H-4¢, H-
6¢), 2.73 (s, 3 H, CH3).
MS (–APCI): m/z (%) = 292 (100, [M – H]–).
Anal. Calcd for C18H15NO3·1/5H2O: C, 72.81; H, 5.23; N, 4.72.
Found: C, 73.08; H, 5.41; N, 4.54.
8-Hydroxy-2-methyl-5-naphthalen-2-ylquinoline-7-carboxylic
Acid (3c)
Brown solid; mp 219–222 °C.
13C NMR (75 MHz, DMSO-d6): d = 171.2 (C), 161.0 (C), 157.5
(C), 156.0 (C), 140.3 (C), 138.0 (C), 136.1 (CH), 129.5 (CH), 127.6
(C), 127.1 (CH), 124.9 (C), 124.0 (CH), 120.4 (CH), 116.6 (CH),
114.1 (CH), 113.2 (C), 23.3 (CH3).
IR (neat): 3600–3100, 1652, 1595, 1568, 1517, 1477, 1433, 1400,
1358, 1216, 1142, 1090, 863, 829, 789, 748, 722 cm–1.
MS (–ESI): m/z (%) = 294 (100, [M – H]–), 250 (8, [M – H – CO2]–).
Synthesis 2010, No. 4, 619–630 © Thieme Stuttgart · New York

628
F. Sliman, D. Desmaële
PAPER
Anal. Calcd for C17H13NO4·HCl·H2O: C, 59.92; H, 4.44; N, 4.11.
Found: C, 59.22; H, 4.38; N, 3.71.
IR (neat): 3700–3050, 2927, 2097, 1702, 1630, 1587, 1510, 1429,
1390, 1373, 1308, 1294, 1257, 1212, 1085, 1029, 1011, 969, 829,
790, 777 cm–1.
8-Hydroxy-5-(4-hydroxymethylphenyl)-2-methylquinoline-7-
carboxylic Acid (3g)
Red solid; mp 211–214 °C.
1H NMR (300 MHz, DMSO-d6): d = 8.35 (d, J = 8.1 Hz, 1 H, H-4),
7.76 (s, 1 H, H-6), 7.67 (d, J = 8.1 Hz, 1 H, H-3), 7.38 (s, 4 H, H-2¢,
H-3¢, H-5¢, H-6¢), 2.77 (s, 3 H, CH3), 2.15 (s, 3 H, SCH3).
IR (neat): 3600–2800, 1682, 1648, 1592, 1572, 1506, 1442, 1393,
1363, 1310, 1273, 1203, 1142, 1097, 1049, 1038, 1017, 825, 804,
743, 717 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.22 (d, J = 7.0 Hz, 1 H, H-4),
7.76 (s, 1 H, H-6), 7.55 (d, J = 7.0 Hz, 1 H, H-3), 7.44 (d, J = 7.2
Hz, 2 H, H-3¢, H-5¢), 7.37 (d, J = 7.2 Hz, 2 H, H-2¢, H-6¢), 5.30 (br
s, 1 H, OH), 4.58 (s, 2 H, CH2OH), 2.75 (s, 3 H, CH3).
13C NMR (75 MHz, DMSO-d6): d = 171.0 (C), 160.7 (C), 156.0
(C), 141.4 (C), 137.4 (C), 137.2 (C), 136.6 (CH), 129.5 (2 CH),
127.8 (C), 127.4 (CH), 126.7 (2 CH), 124.9 (C), 124.3 (CH), 113.0
(C), 62.6 (CH2), 23.0 (CH3).
13C NMR (75 MHz, DMSO-d6): d = 170.3 (C), 160.1 (C), 156.1
(C), 138.3 (C), 137.3 (C), 135.6 (C), 134.6 (C), 130.1 (2 CH), 128.1
(C), 127.4 (CH), 126.0 (2 CH), 125.1 (C), 124.3 (CH), 112.0 (C),
22.1 (CH3), 14.6 (CH3).
MS (–ESI): m/z (%) = 671 (3, [2 M + Na – 2 H]–), 324 (100, [M –
H]–), 280 (3, [M – CO2H]–).
Anal. Calcd for C18H15NO3S·HCl·4/3H2O: C, 56.03; H, 4.88; N,
3.63. Found: C, 56.01; H, 4.50; N, 3.42.
5-(4-Acetylphenyl)-8-hydroxy-2-methylquinoline-7-carboxylic
Acid (3l)
Ochre solid; mp 255 °C (dec.).
MS (–APCI): m/z (%) = 308 (100, [M – H]–).
Anal. Calcd for C18H15NO4·2/3H2O: C, 67.28; H, 5.12; N, 4.36.
Found: C, 67.35; H, 5.32; N, 3.80.
IR (neat): 3800–3300, 2922, 1673, 1600, 1574, 1454, 1434, 1380,
1361, 1307, 1270, 1094, 956, 835, 786, 729 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.41 (d, J = 7.6 Hz, 1 H, H-4),
8.10 (d, J = 6.7 Hz, 2 H, H-3¢, H-5¢), 7.85 (s, 1 H, H-6), 7.72 (d,
J = 7.6 Hz, 1 H, H-3), 7.62 (d, J = 6.7 Hz, 2 H, H-2¢, H-6¢), 2.84 (s,
3 H, CH3), 2.65 (s, 3 H, COCH3).
8-Hydroxy-2-methyl-5-(3-nitrophenyl)quinoline-7-carboxylic
Acid (3h)
Yellowish solid; mp 185–188 °C.
IR (neat): 3800–2500, 1688, 1647, 1630, 1596, 1526, 1441, 1345,
1307, 1263, 1093, 839, 808, 740 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.37 (d, J = 8.7 Hz, 1 H, H-4),
8.29 (d, J = 7.8 Hz, 1 H, H-4¢), 8.22 (s, 1 H, H-2¢), 7.94 (d, J = 7.8
Hz, 1 H, H-6¢), 7.87 (s, 1 H, H-6), 7.81 (t, J = 7.8 Hz, 1 H, H-5¢),
7.69 (d, J = 8.7 Hz, 1 H, H-3), 2.83 (s, 3 H, CH3).
13C NMR (75 MHz, DMSO-d6): d = 170.2 (C), 161.3 (C), 156.2
(C), 148.0 (C), 142.0 (C), 140.0 (C), 137.7 (CH), 136.3 (CH), 136.1
(C), 130.2 (CH), 128.4 (CH), 127.8 (C), 125.3 (CH), 124.1 (CH),
122.0 (CH), 112.5 (C), 22.2 (CH3).
13C NMR (75 MHz, DMSO-d6): d = 197.5 (C), 170.4 (C), 161.6
(C), 156.2 (C), 143.4 (C), 137.5 (CH), 136.4 (C), 135.3 (C), 129.9
(2 CH), 128.6 (2 CH), 128.1 (CH), 127.7 (C), 125.0 (CH), 123.4
(C), 112.7 (C), 26.7 (CH3), 22.2 (CH3).
MS (–ESI): m/z (%) = 663 (20, [2 M – 2 H + Na]–), 320 (100, [M –
H]–).
5-(4-Carboxyphenyl)-8-hydroxy-2-methylquinoline-7-carboxy-
lic Acid (3m)
Dark brown solid; mp 280 °C (dec.).
MS (–ESI): m/z (%) = 669 (59, [2 M + Na – 2H]–), 323 (100, [M –
IR (neat): 3400–2300, 1722, 1679, 1604, 1535, 1507, 1462, 1415,
1375, 1302, 1231, 1186, 1107, 859, 781, 764 cm–1.
H]–).
Anal. Calcd for C17H12N2O5·H2O: C, 61.26; H, 3.93; N, 8.41.
Found: C, 61.08; H, 3.86; N, 8.08.
1H NMR (300 MHz, DMSO-d6): d = 13.00 (br s, 1 H, CO2H), 8.42
(d, J = 7.4 Hz, 1 H, H-4), 8.08 (d, J = 7.4 Hz, 2 H, H-3¢, H-5¢), 7.85
(s, 1 H, H-6), 7.72 (d, J = 7.4 Hz, 1 H, H-2¢, H-6¢), 7.59 (d, J = 7.4
Hz, 1 H, H-3), 2.84 (s, 3 H, CH3).
13C NMR (75 MHz, DMSO-d6): d = 170.2 (C), 167.1 (C), 160.8
(C), 156.2 (C), 142.7 (C), 138.6 (CH), 135.5 (C), 129.9 (2 CH),
129.7 (2 CH), 129.5 (C), 128.2 (CH), 128.0 (C), 125.4 (CH), 123.6
(C), 112.2 (C), 22.0 (CH3).
8-Hydroxy-2-methyl-5-(4-methoxyphenyl)quinoline-7-carbox-
ylic Acid (3i)
Orange solid; mp 236–237 °C.
IR (neat): 3400–2500, 1712, 1626, 1610, 1538, 1515, 1484, 1462,
1423, 1371, 1307, 1293, 1250, 1184, 1037, 965, 858, 831 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.28 (d, J = 8.5 Hz, 1 H, H-4),
7.74 (s, 1 H, H-6), 7.61 (d, J = 8.5 Hz, 1 H, H-3), 7.34 (d, J = 7.5
Hz, 2 H, H-2¢, H-6¢), 7.06 (d, J = 7.5 Hz, 2 H, H-3¢, H-5¢), 3.17 (s, 3
H, OCH3), 2.79 (s, 3 H, CH3).
13C NMR (75 MHz, DMSO-d6): d = 170.6 (C), 160.0 (C), 158.5
(C), 156.0 (C), 137.7 (CH), 136.2 (C), 130.8 (2 CH), 130.7 (C),
128.2 (C), 127.2 (CH), 124.8 (C), 124.7 (CH), 114.0 (2 CH), 112.3
(C), 55.1 (CH3), 22.5 (CH3).
MS (–ESI): m/z (%) = 667 (35, [2 M – 2 H + Na]–), 344 (5, [M + Na
– 2 H]–), 322 (100, [M – H]–).
Anal. Calcd for C18H13NO5·HCl·H2O: C, 58.63; H, 4.10; N, 3.80.
Found: 58.47; H, 3.81; N, 3.71.
5-(4-Formylphenyl)-8-hydroxy-2-methylquinoline-7-carbox-
ylic Acid (3n)
Red solid; mp 164–169 °C.
MS (–ESI): m/z (%) = 308 (100, [M – H]–).
IR (neat): 3800–2900, 1701, 1659, 1642, 1596, 1571, 1510, 1455,
1367, 1309, 1270, 1098, 967, 836, 786 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 10.10 (s, CHO), 8.39 (d,
J = 8.3 Hz, 1 H, H-4), 797 (br s, 2 H), 7.85 (s, 1 H, H-6), 7.80–7.60
(m, 3 H), 2.84 (s, 3 H, CH3).
13C NMR (75 MHz, DMSO-d6): d = 193.2 (CH), 170.2 (C), 160.6
(C), 156.3 (C), 139.0 (C), 138.4 (CH), 136.6 (C), 135.6 (CH), 135.5
(C), 131.0 (CH), 129.6 (CH), 128.1 (CH), 128.0 (C), 127.8 (CH),
125.4 (CH), 123.4 (C), 112.1 (C), 22.0 (CH3).
Anal. Calcd for C18H15NO4·2/3H2O: C, 67.28; H, 5.12; N, 4.36.
Found: C, 67.02; H, 5.01; N, 4.32.
8-Hydroxy-2-methyl-5-(4-methylsulfanylphenyl)quinoline-7-
carboxylic Acid (3j)
Orange solid; mp 220 °C (dec.).
Synthesis 2010, No. 4, 619–630 © Thieme Stuttgart · New York

PAPER
5-Aryl- and 5-Heteroaryl-7-carboxyl-8-hydroxyquinaldines
629
MS (–APCI): m/z (%) = 306 (100, [M – H]–).
1H NMR (300 MHz, DMSO-d6): d = 8.46 (d, J = 8.5 Hz, 1 H, H-4),
8.15 (d, J = 9.2 Hz, 2 H, H-7¢), 8.10 (s, 1 H, H-4¢), 7.95 (s, 1 H, H-
6), 7.72 (d, J = 8.5 Hz, 2 H, H-3, H-6¢), 2.83 (s, 3 H, CH3).
13C NMR (75 MHz, DMSO-d6): d = 170.4 (C), 156.2 (C), 149.4
(C), 148.2 (C), 143.6 (C), 142.9 (C), 136.9 (CH), 136.1 (CH), 128.5
(CH), 127.6 (C), 124.8 (CH), 121.8 (C), 116.9 (C), 116.1 (CH),
114.9 (CH), 113.0 (C), 22.7 (CH3).
Anal. Calcd for C18H13NO4·H2O: C, 65.25; H, 4.77; N, 4.23. Found:
C, 65.21; H, 4.48; N, 4.11.
5-Furan-3-yl-8-hydroxy-2-methylquinoline-7-carboxylic Acid
(3o)
Orange solid; mp 230–233 °C.
IR (neat): 3600–2700, 1693, 1647, 1592, 1575, 1428, 1362, 1305,
1244, 1227, 1158, 1102, 1025, 873, 830, 805, 785 cm–1.
MS (–ESI): m/z (%) = 663 (13, [2 M – 2 H + Na]–), 320 (100, [M –
H]–).
1H NMR (300 MHz, DMSO-d6): d = 8.55 (d, J = 8.5 Hz, 1 H, H-4),
7.98 (s, 1 H, H-2¢), 7.84 (s, 2 H, H-6, H-5¢), 7.69 (d, J = 8.5 Hz, 1
H, H-3), 6.80 (s, 1 H, H-4¢), 2.81 (s, 3 H, CH3).
13C NMR (75 MHz, DMSO-d6): d = 170.4 (C), 160.2 (C), 156.0
(C), 143.7 (CH), 140.4 (CH), 137.9 (C), 136.2 (C), 128.1 (C), 127.3
(CH), 124.9 (CH), 122.6 (C), 115.5 (C), 112.4 (C), 111.9 (CH), 22.3
(CH3).
Styrylquinolines; 2-[2-(3,4-Dihydroxyphenyl)vinyl]-8-hydroxy-
5-phenylquinoline-7-carboxylic Acid (2a); Typical Procedure
To a solution of quinaldine 3a (100 mg, 0.36 mmol) in Ac2O (10
mL) was added 3,4-dihydroxybenzaldehyde (222 mg, 1.60 mmol).
The mixture was heated under reflux for 72 h and concentrated in
vacuo. The residue was taken up in pyridine–H2O (4:1, 10 mL) and
the resulting solution was heated under reflux for 3 h. After cooling,
the solvents were removed under reduced pressure. The residue was
triturated with MeOH (10 mL) and filtered through a sintered glass
funnel. The solid was washed with EtOAc (5 mL) and Et2O (5 mL)
and dried under reduced pressure to afford styrylquinoline 2a (59
mg, 41%); burgundy solid; mp >190 °C (dec.).
MS (–ESI): m/z (%) = 268 (100, [M – H]–).
Anal. Calcd for C15H11NO4·H2O: C, 62.72; H, 4.56; N, 4.88. Found:
C, 62.91; H, 4.61; N, 4.91.
8-Hydroxy-2-methyl-5-(5-methylthiophen-2-yl)quinoline-7-
carboxylic Acid (3p)
Orange solid; mp 220 °C (dec.).
IR (neat): 3600–2930, 1635, 1583, 1497, 1448, 1387, 1289, 1125,
955, 868, 794, 738, 699 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.61 (s, 1 H, OH), 9.29 (s, 1 H,
OH), 8.29 (d, J = 8.5 Hz, 1 H, H-4), 8.13 (d, J = 8.5 Hz, 1 H, H-3),
7.84 (d, J = 16.0 Hz, 1 H, HC=CH), 7.75 (s, 1 H, H-5), 7.60–7.40
(m, 6 H), 7.15 (s, 1 H, H-2¢), 7.04 (d, J = 7.8 Hz, 1 H, H-6¢), 6.84 (d,
J = 7.8 Hz, 1 H, H-5¢).
13C NMR (100 MHz, DMSO-d6): d = 170.4 (C), 160.0 (C), 152.9
(C), 148.0 (C), 145.8 (C), 139.1 (CH), 138.4 (C), 137.4 (CH), 135.9
(C), 129.8 (2 CH), 128.8 (2 CH), 128.1 (C), 127.7 (CH), 127.4
(CH), 127.3 (C), 125.5 (C), 121.0 (CH), 120.9 (CH), 120.5 (CH),
116.0 (CH), 114.3 (CH), 112.4 (C).
IR (neat): 3900–2900, 1648, 1592 1481, 1444, 1401, 1364, 1086,
867, 829, 787 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.31 (d, J = 8.6 Hz, 1 H, H-4),
7.83 (s, 1 H, H-6), 7.41 (d, J = 8.6 Hz, 1 H, H-3), 6.93 (d, J = 2.9
Hz, 1 H, H-3¢), 6.87 (d, J = 2.9 Hz, 1 H, H-4¢), 2.64 (s, 3 H, CH3),
2.50 (s, 3 H, CH3).
13C NMR (75 MHz, DMSO-d6): d = 171.5 (C), 162.5 (C), 156.1
(C), 140.5 (C), 138.8 (C), 138.5 (C), 133.6 (CH), 128.0 (CH), 127.3
(C), 126.3 (CH), 125.9 (CH), 123.5 (CH), 117.0 (C), 114.0 (C), 24.4
(CH3), 14.9 (CH3).
MS (–ESI): m/z (%) = 398 (100, [M – H]–), 354.2 (3, [M – H –
MS (+ESI): m/z (%) = 298 (100, [M – H]–).
CO2]–).
Anal. Calcd for C16H13NO3S·3/2H2O: C, 58.88; H, 4.94; N, 4.29.
Found: C, 58.34; H, 4.44; N, 4.19.
2-[2-(3,4-Dihydroxyphenyl)vinyl]-8-hydroxy-5-(3-nitrophe-
nyl)quinoline-7-carboxylic Acid (2h)
8¢-Hydroxy-2¢-methyl[3,5¢]biquinolinyl-7¢-carboxylic Acid (3r)
According to the typical procedure described above the styrylquin-
oline 2h was obtained in 43% from quinaldine 3h; orange solid; mp
>230 °C (dec.).
Olive brown solid; 270–273 °C.
IR (neat): 3800–2800, 1621, 1592, 1572, 1511, 1432, 1364, 1326,
1292, 1092, 1072, 831, 786, 729 cm–1.
1H NMR (300 MHz, TFA-d1–acetone-d6, 9:1): d = 9.11 (s, 1 H, H-
8¢), 9.07 (s, 1 H, H-6¢), 8.65 (d, J = 8.9 Hz, 1 H, H-4), 8.25 (s, 1 H,
H-6), 8.16 (t, J = 8.7 Hz, 2 H), 8.09 (t, J = 8.2 Hz, 1 H), 7.90–7.83
(m, 2 H), 2.95 (s, 3 H, CH3).
13C NMR (75 MHz, TFA-d1–acetone-d6, 9:1): d = 171.2 (C), 160.9
(C), 154.3 (C), 149.5 (CH), 145.2 (CH), 144.3 (CH), 137.9 (C),
137.7 (CH), 132.3 (CH), 132.2 (CH), 131.0 (C), 130.2 (CH), 129.9
(C), 129.7 (C), 128.5 (CH), 124.2 (C), 121.0 (CH), 20.4 (CH3), 2 C
undetected.
IR (neat): 3700–2800, 1630, 1582, 1525, 1512, 1476, 1451, 1387,
1347, 1292, 1256, 1199, 1167, 1102, 1005, 804 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.57 (s, 1 H, OH), 9.24 (s, 1 H,
OH), 8.45–8.20 (m, 2 H), 8.26 (s, 1 H, H-2¢), 8.14 (m, 1 H, H-3),
7.97 (d, J = 6.0, H-6¢), 7.89 (d, J = 16.0 Hz, 1 H, HC=CH), 7.84 (s,
1 H, H-6), 7.81), 7.52 (d, J = 16.0 Hz, 1 H, HC=CH), 7.14 (s, 1 H,
H-2¢), 7.05 (d, J = 6.7 Hz, 1 H, H-6¢), 6.83 (d, J = 6.7 Hz, 1 H, H-5¢).
13C NMR (100 MHz, DMSO-d6): d = 170.0 (C), 160.9 (C), 152.9
(C), 148.1 (C), 148.0 (C), 145.7 (C), 139.9 (C), 139.5 (CH), 137.1
(CH), 136.3 (CH), 135.9 (C), 130.3 (CH), 128.5 (CH), 127.8 (C),
127.2 (C), 124.2 (CH), 122.6 (C), 122.1 (CH), 121.3 (CH), 120.9
(CH), 120.1 (CH), 116.0 (CH), 114.2 (CH), 112.5 (C).
MS (–APCI): m/z (%) = 329 (100, [M – H]–), 285 (12, [(M –
CO2H]–).
MS (–ESI): m/z (%) = 443 (100, [M – H]–),399 (2, [M – H – CO2]–).
Anal. Calcd for C20H14N2O3·HCl: C, 65.49; H, 4.12; N, 7.64. Found:
C, 66.16; H, 4.05; N, 7.32.
Acknowledgment
5-Benzo[1,2,5]oxadiazol-5-yl-8-hydroxy-2-methylquinoline-7-
carboxylic Acid (3s)
Orange solid; mp 245 °C (dec.).
Fellowship from Tishreen University, Lattakia, Syria (F. Sliman) is
gratefully acknowledged.
IR (neat): 3800–3000, 1657, 1612, 1539, 1462, 1371, 1302, 1261,
1082, 1096, 969, 878, 843, 810 cm–1.
Synthesis 2010, No. 4, 619–630 © Thieme Stuttgart · New York

630
F. Sliman, D. Desmaële
PAPER
(5) Zouhiri, F.; Danet, M.; Bénard, C.; Normand-Bayle, M.;
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Synthesis 2010, No. 4, 619–630 © Thieme Stuttgart · New York