4-Aryl-8-hydroxyquinolines from 4-chloro-8-tosyloxyquinoline using a Suzuki-Miyaura cross-coupling approach

Article abstract of DOI:10.1016/j.tet.2008.10.097

4-Chloro-8-tosyloxyquinoline was successfully cross-coupled with various arylboronic acids in anhydrous Suzuki-Miyaura conditions. The protective tosyl group was stable during the anhydrous coupling. The use of tosyl protection in association with anhydro

Full text of DOI:10.1016/j.tet.2008.10.097

Tetrahedron 65 (2009) 518–524
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4-Aryl-8-hydroxyquinolines from 4-chloro-8-tosyloxyquinoline using
a Suzuki–Miyaura cross-coupling approach
*
Juha P. Heiskanen, Osmo E.O. Hormi
Department of Chemistry, University of Oulu, P. O. Box 3000, 90014 Oulu, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 August 2008
Received in revised form 13 October 2008
Accepted 30 October 2008
Available online 5 November 2008
4-Chloro-8-tosyloxyquinoline was successfully cross-coupled with various arylboronic acids in anhy-
drous Suzuki–Miyaura conditions. The protective tosyl group was stable during the anhydrous coupling.
The use of tosyl protection in association with anhydrous Suzuki–Miyaura reaction conditions allows the
use of commercially available but relative inert 5-chloro-8-hydroxyquinoline for the synthesis of
5-phenyl-8-hydroxyquinoline. Deprotection could easily be made by using suitable nucleophiles to af-
ford the final 5-phenyl and 4-aryl-8-hydroxyquinolines in high yields. Under acidic conditions the to-
syloxy group is sufficiently stable to allow selective further modification of acid labile functional groups.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
boronic esters by using Pd(PPh3)4 as the catalyst and anhydrous
Tl2CO3 or K3PO4 as the base.6 It has also been observed that
Suzuki–Miyaura coupling is widely used in organic synthesis to
create carbon–carbon bonds. The palladium catalyzed reaction can
be conducted by using a wide variety of phosphine ligands in the
presence of suitable bases such as carbonates, hydroxides, phos-
phates, or alkoxides.1 A base is needed to accelerate the trans-
metallation step of the catalytic cycle.1a,2 Brominated and iodinated
aromatic compounds are favored over chlorinated counterparts
due to lower reactivity of the C–Cl bond in the oxidative addition
step.3 A generally accepted reactivity order is I[OTf>Br[Cl.1
Furthermore, it has also been shown that some substituted o-flu-
oronitrobenzenes can cross-couple with arylboronic acids and
fluorobenzene undergoes the coupling if supported Pd catalyst is
used.4 However, the rate of the modified Suzuki–Miyaura coupling
between fluorobenzene and phenylboronic acid is much lower than
the rate of the corresponding cross-coupling between bromo or
chlorobenzene and phenylboronic acid.4c Chlorinated aromatic
compounds have many advantages compared to other halogenated
starting materials. They are usually cheaper and they have often
better commercial availability.
Na2B4O7, CsF, and KF can be used as bases in Suzuki–Miyaura
reactions.7
b
-Oxo amides have been used as ligands for Pd but the yields of
the coupling products have been low with chlorinated aryl
reagents.3b On the other hand, some aryl and heteroaryl chlorides
have been successfully coupled under anhydrous conditions with
electron rich or electronically neutral arylboronic acids by using
specially tailored phosphine ligands.8 Recently, it has also been
shown that electron-deficient chlorinated heteroaromatic com-
pounds, such as pyridines, naphthyridones, and pyrimidines un-
dergo Suzuki–Miyaura coupling in moderate to high yields under
anhydrous conditions.9
2-Chloro10 and 4-chloro5,11 quinolines and 1-chloro isoquino-
line12 have been efficiently coupled with various arylboronic acids
in the presence of water. Nakano et al. and Anzenbacher et al. have
reported that 5-aryl-8-hydroxyquinolines can be synthesized by
using aqueous Suzuki–Miyaura coupling between 5-bromo-8-
benzyloxyquinoline and arylboronic acids.3a,13 The products were
collected in low to high (41–88%) yields. Removal of the benzyl
protection by using Pd/C catalyzed hydrogenolyses with cyclo-
hexadiene as the hydrogen source was problematic and gave the
deprotected compounds in varying yields (20–95%).3a,13
Although a tosyloxy group is most frequently used as a good
leaving group in synthetic organic chemistry, the tosyl group has
also recently become an important protective group for phenolic
hydroxyl groups.14 It is stable in some acidic conditions14a,e and
toward NaH.15a However, the stability is not obvious in a Suzuki–
Miyaura reaction because it has previously been found that Pd
catalysts may decompose tosyl groups, for example, during stan-
dard Pd/C-catalyzed hydrogenation.14e Pd-catalyzed lactonization
The reaction is usually carried out in the presence of water.1a
Addition of water to the reaction medium has been shown to ac-
celerate the coupling reaction considerably.5 However, there are
also some reports on the use of anhydrous conditions in successful
Suzuki–Miyaura reactions. For example, aromatic iodo and bromo
compounds have been coupled in benzene or in DMF with various
* Corresponding author. Tel.: þ358 8 553 1631; fax: þ358 8 553 1593.
E-mail address: osmo.hormi@oulu.fi (O.E.O. Hormi).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.097

J.P. Heiskanen, O.E.O. Hormi / Tetrahedron 65 (2009) 518–524
5 mol% Pd(PPh3)4
519
may also lead to undesirable detosylation if it is performed in DMF
1. 5a-d and 5f: NaOH (aq)
5e: NaSBu
in the presence of K2CO3.14b
Ar
N
Ar
K2CO3
arylboronic acid
DMF
Cl
5g: NaOEt
4-Arylquinolines and 8-hydroxyquinoline derivatives have in-
teresting applications, for example, as maxi-K channel openers and
as an inhibitor of mitogen-activated protein kinase.16 Furthermore,
dichloro-8-hydroxyquinolines show improved antifungal activity
compared to the parent 8-hydroxyquinoline.17 Aluminum com-
plexes of 8-hydroxyquinolines with electron poor aryl substituents
at the 5-position or an electron donating methyl substituent at the
4-position have enhanced photoluminescence (PL) quantum effi-
ciencies compared with the PL quantum efficiency of the parent
aluminum tris(8-hydroxyquinoline), Alq3. They also exhibit en-
hanced electroluminescence (EL) characteristics in OLED applica-
tions.13,18 Furthermore, the emission wavelength of Alq3 can be
tuned simply by attaching suitable substituents to the 8-hydroxy-
quinoline ligands.13
2. HCl (aq)
60-89%
91-99%
N
N
OTs
OTs
OH
5a-g
6a-g
4
Me
OMe
CN
N
Ar =
OEt
Me
O
g
a
b
c
d
e
f
Scheme 2.
In this paper, we describe a synthetic method to produce 4-aryl-
8-hydroxyquinolines and 4-hydroxypyridinoanthrene19 from the
readily available 4-chloro-8-tosyloxyquinoline.15b We demonstrate
that the tosyl group is stable during anhydrous Suzuki–Miyaura
coupling and that the electron-deficient chlorinated starting ma-
terial couples efficiently with various arylboronic acids under an-
hydrous conditions. We also show that the commercially available
5-chloro-8-hydroxyquinoline20 can, after tosyl protection, act as
a starting material for synthesis of 5-phenyl-8-hydroxyquinoline.
Removal of the tosyl group can be executed efficiently by using
suitable nucleophiles in the final deprotection step.
because the reaction gave 5a only in a moderate yield (47%) (Table
1, entry 4). A plausible explanation for the result is that some of the
chlorine atoms were substituted by fluorine atoms and the result-
ing C–F bonds were considerably less reactive or even unreactive
compared with the original C–Cl bonds in Suzuki–Miyaura
couplings.4c,22
We also studied Suzuki–Miyaura coupling in aqueous condi-
tions. Interestingly, the results show clearly that the Suzuki–Miyaura
coupling in aqueous conditions between 4 and the especially elec-
tron poor 4-pyridylboronic acid had a deleterious effect on yield
(Table 1, entry 11). The conversion of the starting material was very
low and a simultaneous formation of the deprotected 5f could be
observed. The yield of 5f was only 24%. On the other hand, 4-pyr-
idylboronic acid and 4 undergoes Suzuki–Miyaura coupling readily
if anhydrous coupling conditions are employed. 4-(4-Pyridyl)-8-
tosyloxyquinoline 5f could be isolated in 60% yield (Table 1, entry
10). The Suzuki–Miyaura coupling between 4 and phenylboronic
acid was also considerably more successful in anhydrous conditions
than in aqueous conditions (Table 1, entries 3 and 5, respectively).
Table 1 shows clearly that anhydrous Suzuki–Miyaura couplings
between 4 and electron rich 4-methoxyphenylboronic, 4-methyl-
phenylboronic, and 2-methylphenylboronic acids as well as the
electron poor 4-cyanophenylboronic and 2-(ethoxycarbon-
yl)phenylboronic acids proceed efficiently. Compounds 5b–e and
5g were collected in medium 64% to high 89% yields (Table 1,
entries 6–9 and 12).
2. Results and discussion
The starting material in our synthetic route, 4-chloro-8-tosyl-
oxyquinoline 4,15b can be prepared on a large scale and in high yield
from the readily available 4-hydroxy-8-tosyloxyquinoline15a
3
(Scheme 1). Compound 3 can be produced from commercially
available xanthurenic acid 1 by decarboxylation and selective
tosylation during the consequent step. Suzuki–Miyaura coupling
between 4 and various arylboronic acids was made in dry DMF by
using anhydrous potassium carbonate as the base (Scheme 2). The
yields of the arylated 8-tosyloxyquinolines 5a–g are presented in
Table 1.
We studied the effect of catalyst loadings in the anhydrous
Suzuki–Miyaura coupling. Compound 4 was treated with phenyl-
boronic acid by using 1 mol % of Pd(PPh3)4. The low catalyst loading
led to a diminished conversion of the starting material and after 2 h
product 5a was produced only in a moderate yield (45%) (Table 1,
entry 1). Elevation of the catalyst loading to 5 mol % enhanced the
yield of the coupling product 5a to 75% (entry 2). Furthermore, we
also observed that a doubling of the reaction time slightly improved
the yield of 5a (78%, entry 3). We were also interested to see how
fluoride ion works as the base in the Suzuki–Miyaura coupling
between 4 and phenylboronic acid.21 The result was disappointing
The C–OTs bond was stable during Suzuki–Miyaura couplings. A
feasible reason for the stability is that nitrogen of the quinoline ring
Table 1
Reaction times and the yields in Suzuki–Miyaura couplings of 4
Entry
Product
Time
Yield %
1
2
3
4
5
6
7
8
5aa
5a
2 h
2 h
4 h
4 h
4 h
4 h
4 h
4 h
7 h
81⁄2
81⁄2
2 h
45b
75
78
47b
62
79
89
76
65
60
24b
64
5a
5ac
5ad
5b
5c
OH
OH
N
DPE
245 °C
5d
5e
OH
96%
N
9
OH
1
O
OH
OH
10
11
12
5f
h
h
5fd
5g
2
Cl
1. NaOH (aq)
2. TsCl
POCl3
94%
General reaction conditions: 5 mol % of Pd(PPh3)4, anhydrous K2CO3 (2.1 equiv), and
ArB(OH)2 (1.05 equiv).
a
N
N
The amount of Pd(PPh3)4 was 1 mol %.
96%
b
The amount of the product was estimated from 1H NMR spectrum of the crude
OTs
OTs
mixture.
4
3
c
KF (2.1 equiv) was used instead of K2CO3.
2 M K2CO3 (aq) (2.1 equiv).
d
Scheme 1.

520
J.P. Heiskanen, O.E.O. Hormi / Tetrahedron 65 (2009) 518–524
Table 2
5 mol% Pd(PPh3)4
K2CO3
Phenylboronic acid
DMF
Yields of 4-aryl-8-hydroxyquinolines
Cl
Cl
1. NaOH (aq)
2. TsC
>99%
Entry
Product
Yield %
l
1a
2a
3a
4a
5b
6a
7c
8a
6a
6b
6c
6d
6e
6f
92
97
99
98
96
91
92
92
N
N
61%
OH
OTs
9
8
6g
6h
1. NaOH (aq)
2. HCl (aq)
98%
a
Deprotection reagent: NaOH (aq).
Deprotection reagent: NaSBu in t-amylalcohol.
Deprotection reagent: NaOEt in ethanol.
b
c
N
N
OH
OTs
10
11
Scheme 4.
suppresses the ability of Pd(0) to oxidatively add to the C–OTs bond
combined with that the C–Cl bond in the 4-position is especially
weak and prone to Suzuki–Miyaura coupling due to the
quinoline ring.
p-deficient
In the case of compound 6h, we were also interested to in-
vestigate the possibility to produce a new tetracyclic 8-hydroxy-
quinoline derivative 6i from 6h (Scheme 3). We found that 6h
underwent an intramolecular Friedel–Crafts acylation cleanly in
concentrated sulfuric acid and that 4-hydroxypyridinoanthrene 6i
could be collected in a high yield (88%).
Alkaline deprotection of 5a–d and 5f was carried out efficiently
by using aqueous sodium hydroxide (Scheme 2). The final products
6a–d and 6f were collected by filtration from neutralized water
solutions in high yields (91–98%) (Table 2, entries 1–4 and 6).
Removal of the protecting tosyl group from 5e by alkaline hy-
drolysis was unsuccessful due to a simultaneous hydrolysis of the
cyano group.23a Various nucleophilic reagents were tested and it
was finally found that sodium 1-butylthiolate in 2-methyl-2-bu-
tanol cleanly removed the protective tosyl group to afford 6e in 96%
yield (Table 2, entry 5). We also observed that the reaction between
5e and sodium 1-butylhiolate with 1-butanol as the solvent, in-
stead of tert-amylalcohol, led to the formation of sodium butoxide,
which then added to the cyano group.23b
4-o-Ethoxycarbonylphenyl-8-hydroxyquinoline 6g can be pre-
pared from 5g by using sodium ethoxide in ethanol as the depro-
tecting agent instead of aqueous sodium hydroxide (Scheme 2).
Compound 6g was collected in a high 92% yield (Table 2, entry 7). It
is also worthy of mention that during the deprotections of 5e with
sodium butylthiolate and 5g with sodium ethoxide, no potential
SNAr reaction products, 4-p-cyanophenyl-8-butylthioquinoline and
4-o-ethoxycarbonylphenyl-8-ethoxyquinoline, could be detected.
Deprotection of 5g with aqueous sodium hydroxide (Scheme 3)
led to a simultaneous hydrolysis of the ethyl ester group and gave
4-o-carboxyphenyl-8-hydroxyquinoline 6h in 92% yield (Table 2,
entry 8). We also observed that when 5g was treated with aqueous
hydrochloric acid, the ethyl ester group was hydrolyzed selectively
to give 4-o-carboxyphenyl-8-tosyloxyquinoline 7 in a good yield
(73%) (Scheme 3).
Finally, we were also keen to demonstrate the usefulness of
the protective tosyl group in a Suzuki–Miyaura coupling between
a relatively inert but commercially available 5-chloro-8-hydroxy-
quinoline 8 and phenylboronic acid. Compound 8 was tosylated
by using 1 equiv of sodium hydroxide and p-toluenesulfonyl
chloride (Scheme 4) to give 5-chloro-8-tosyloxyquinoline 9 in
a quantitative yield (>99%). Compound 9 and phenylboronic acid
underwent Suzuki–Miyaura coupling readily under anhydrous
conditions to give 5-phenyl-8-tosyloxyquinoline 10 in 61% yield.
This is an interesting result because it has been reported pre-
viously that 5-chloro-8-benzyloxyquinoline is completely inactive
in an attempted Suzuki–Miyaura reaction.3a
p-Deficient hetero-
aryl chlorides are known to be much more reactive in Suzuki–
Miyaura couplings than the electronically neutral or electron rich
aryl chlorides.1 Compared with an electron donating benzyloxy
group (Hammett sp¼ꢀ0.33),24a a tosyloxy group is much more
electron withdrawing (Hammett sp¼þ0.28)24b and 5-chloro-8-
tosyloxyquinoline 9 is, therefore, more
p-deficient than 5-chloro-
8-benzyloxyquinoline. Apparently, a benzyloxy group deactivated
5-chloroquinoline in the attempted Suzuki–Miyaura reaction.
The deprotection of 10 with aqueous sodium hydroxide occurred
readily to give 5-phenyl-8-hydroxyquinoline 11 in high yield
(98%).25
3. Conclusions
OEt
OH
Nine 8-hydroxyquinoline derivatives have been synthesized.
Readily available 4-chloro-8-tosyloxyquinoline and various aryl-
boronic acids were efficiently coupled by using anhydrous Suzuki–
Miyaura conditions and commercially available Pd(PPh3)4 as the
catalyst. The protective tosyl group was stable during the coupling
reactions. The use of tosyl protection in association with anhydrous
Suzuki–Miyaura reaction conditions also enables the use of 5-
chloro-8-hydroxyquinoline in the synthesis of 5-phenyl-8-hydroxy-
quinoline. Detosylation could be successfully accomplished by using
various nucleophilic deprotection agents. The final 5-phenyl-8-
hydroxyquinoline and 4-aryl-8-hydroxyquinolines were produced
in high yields. The formation of undesired by-products during the
deprotection step could be avoided by choosing the conditions and
nucleophileswith care. Underacidic conditions the tosyloxygroup is
stable enough to allow further modification of acid labile
1. NaOH (aq)
2. HCl (aq)
92%
O
O
N
OTs
5g
N
OH
6h
H2SO4
rt, 3h
OH
O
HCl (aq)
73%
O
88%
N
N
OTs
7
OH
6i
Scheme 3.

J.P. Heiskanen, O.E.O. Hormi / Tetrahedron 65 (2009) 518–524
521
functionalities. Similarly, to our previous observations15 our present
work demonstrates that the tosyl group is an extremely useful
protective group in the synthetic chemistry of 8-hydroxyquinolines.
DMSO-d6):
d
¼1.93 (3H, s), 2.39 (3H, s), 7.22 (1H, d, J¼7.2 Hz), 7.31–
7.58 (9H, m), 7.83 (2H, d, J¼8.3 Hz), 8.88 (1H, d, J¼4.3 Hz). 13C NMR
(50 MHz, DMSO-d6):
d¼19.7, 21.3, 122.2, 122.8, 125.0, 126.2, 126.7,
128.2, 128.6, 128.9, 129.5, 130.0, 130.4, 132.6, 135.5, 136.7, 141.3,
145.4, 145.7, 147.6, 150.8. HRMS: calcd for C23H19NO3NaS ([MþNa]þ)
412.0983, found 412.0981.
4. Experimental section
4.1. General remarks
4.2.4. 4-p-Methoxyphenyl-8-tosyloxyquinoline (5d)
Commercially available reagents were used as received. DMF
and n-hexane were dried with molecular sieves (4 Å). Silica gel
with 0.040–0.063 mm particle size was used as a support in every
flash chromatography purification procedure.
The specific amounts of chemicals used were: 4-chloro-8-tosyl-
oxyquinoline 4 (1.00 g, 3.00 mmol), Pd(PPh3)4 (173 mg, 0.15 mmol),
anhydrous K2CO3 (872 mg, 6.31 mmol), 4-methoxyphenylboronic
acid (479 mg, 3.15 mmol), and DMF (20 mL). The reaction time was
4 h. Purification by flash chromatography (1:1 ethyl acetate/n-
hexane) afforded the title compound (924 mg, 76%) as off-white
4.2. General procedure for synthesis of 5-phenyl-8-
tosyloxyquinoline and 4-aryl-8-tosyloxyquinolines
crystals. Mp: 135–138 ꢁC. IR (KBr):
n
¼3039 (w), 2991 (w), 2923 (m),
2837 (w), 1657 (s), 1601 (m). 1H NMR (200 MHz, DMSO-d6):
d
¼2.41
Chloro-8-tosyloxyquinoline and 5 mol % Pd(PPh3)4 were dis-
solved in DMF (14 mL). Anhydrous K2CO3 (2.1 equiv) and arylboro-
nic acid (1.05 equiv) were mixed together in DMF (6 mL). After
10 min, the two mixtures were combined. The resulting mixture
was refluxed under nitrogen atmosphere. The reaction was moni-
tored by TLC. The solvent was removed in vacuum. Chloroform
(30 mL) was added and the solution was extracted with three 10 mL
portions of distilled water. The organic layer was dried with Na2SO4
and filtered. The filtrate was concentrated in vacuum. Purification
of the residue by flash chromatography afforded the coupled
products.
(3H, s), 3.85 (3H, s), 7.14 (2H, d, J¼8.7 Hz), 7.44–7.52 (6H, m), 7.57
(1H, t, J¼8.3 Hz), 7.84–7.89 (3H, m), 8.86 (1H, d, J¼4.4 Hz). 13C NMR
(50 MHz, DMSO-d6):
d
¼21.4, 55.5, 114.5, 122.0, 122.5, 125.2, 126.5,
127.9, 128.5, 129.2, 130.1, 131.1, 132.8, 141.7, 145.4, 145.7, 147.5, 150.8,
159.9. HRMS: calcd for C23H19NO4NaS ([MþNa]þ) 428.0932, found
428.0917.
4.2.5. 4-p-Cyanophenyl-8-tosyloxyquinoline (5e)
The specific amounts of chemicals used were: 4-chloro-8-tosyl-
oxyquinoline 4 (1.00 g, 3.00 mmol), Pd(PPh3)4 (173 mg, 0.15 mmol),
anhydrous K2CO3 (871 mg, 6.30 mmol), 4-cyanophenylboronic acid
(463 mg, 3.15 mmol), and DMF (20 mL). The reaction time was 7 h.
Purification by flash chromatography (1:1 ethyl acetate/n-hexane)
and recrystallization from ethanol afforded the title compound
(784 mg, 65%) as off-white crystals. Mp: 164–167 ꢁC. IR (KBr):
4.2.1. 4-Phenyl-8-tosyloxyquinoline (5a)
The specific amounts of chemicals used were: 4-chloro-8-tosyl-
oxyquinoline 4 (1.00 g, 3.00 mmol), Pd(PPh3)4 (173 mg, 0.15 mmol),
anhydrous K2CO3 (870 mg, 6.29 mmol), phenylboronic acid
(384 mg, 3.15 mmol), and DMF (20 mL). The reaction time was 4 h.
Purification by flash chromatography (1:1 ethyl acetate/n-hexane)
afforded the title compound (872 mg, 78%) as off-white crystals.
n
¼3067 (w), 2920 (w), 2227 (m), 1592 (m). 1H NMR (200 MHz,
DMSO-d6):
d
¼2.42 (3H, s), 7.44–7.64 (5H, m), 7.70–7.78 (3H, m),
7.86 (2H, d, J¼8.3 Hz), 8.06 (2H, d, J¼8.2 Hz), 8.93 (1H, d, J¼4.3 Hz).
13C NMR (50 MHz, DMSO-d6):
d
¼21.4,111.8,111.8,118.8,122.4,122.7,
Mp: 168–171 ꢁC. IR (KBr):
n
¼3042 (w), 2996 (w), 2913 (w), 1590 (s).
124.7, 127.1, 128.6, 130.2, 130.8, 132.7, 132.9, 141.6, 141.8, 145.4, 145.8,
146.0, 150.8. HRMS: calcd for C23H17N2O3S ([MþH]þ) 401.0960,
found 401.0957.
1H NMR (200 MHz, DMSO-d6):
d
¼2.42 (3H, s), 7.44–7.62 (10H, m),
7.79–7.89 (3H, m), 8.89 (1H, d, J¼4.3 Hz). 13C NMR (50 MHz, DMSO-
d6):
d
¼21.7,122.0,122.2,125.1,125.7,128.2,128.6,128.7,129.4,129.5,
133.3, 137.5, 142.1, 145.0, 145.8, 148.2, 150.3. HRMS: calcd for
4.2.6. 4-(4-Pyridine)-8-tosyloxyquinoline (5f)
C22H18NO3S ([MþH]þ) 376.1007, found 376.1011.
The specific amounts of chemicals used were: 4-chloro-8-tosyl-
oxyquinoline 4 (1.00 g, 3.00 mmol), Pd(PPh3)4 (173 mg, 0.15 mmol),
anhydrous K2CO3 (870 mg, 6.29 mmol), 4-pyridineboronic acid
(387 mg, 3.15 mmol), and DMF (20 mL). The reaction time was 81⁄2
h. Purification by flash chromatography (1:9 methanol/ethyl ace-
tate) and recrystallization from ethanol afforded the title com-
pound (677 mg, 60%) as off-white crystals. Mp: 181–184 ꢁC. IR
4.2.2. 4-p-Methylphenyl-8-tosyloxyquinoline (5b)
The specific amounts of chemicals used were: 4-chloro-8-tosyl-
oxyquinoline 4 (1.00 g, 3.00 mmol), Pd(PPh3)4 (173 mg, 0.15 mmol),
anhydrous K2CO3 (871 mg, 6.30 mmol), 4-methylphenylboronic
acid (428 mg, 3.15 mmol), and DMF (20 mL). The reaction time was
4 h. Purification by flash chromatography (1:1 ethyl acetate/n-
hexane) afforded the title compound (920 mg, 79%) as off-white
(KBr):
DMSO-d6):
n
¼3041 (m), 2914 (w), 1588 (s), 1540 (m). 1H NMR (200 MHz,
d
¼2.42 (3H, s), 7.44–7.65 (7H, m), 7.77 (1H, dd, J¼1.5,
crystals. Mp: 144–147 ꢁC. IR (KBr):
n
¼3030 (w), 2919 (m), 1589 (s).
8.3 Hz), 7.86 (2H, dd, J¼1.6, 6.7 Hz), 8.78 (2H, dd, J¼1.6, 4.4 Hz), 8.94
1H NMR (200 MHz, DMSO-d6):
d
¼2.41 (6H, m), 7.36–7.49 (8H, m),
(1H, d, J¼4.4 Hz). 13C NMR (50 MHz, DMSO-d6):
¼21.4,122.5,122.5,
d
7.57 (1H, t, J¼8.2 Hz), 7.81–7.88 (3H, m), 8.87 (1H, d, J¼4.4 Hz). 13C
124.5, 124.6, 126.9, 127.2, 128.6, 130.2, 132.7, 141.5, 144.7, 145.1,
145.4, 145.8, 150.2, 150.9. HRMS: calcd for C21H17N2O3S ([MþH]þ)
377.0960, found 377.0971.
NMR (50 MHz, DMSO-d6):
d
¼21.0, 21.4, 122.1, 122.5, 125.1, 126.5,
127.8, 128.5, 129.6, 129.7, 130.1, 132.8, 134.1, 138.6, 141.7, 145.4, 145.7,
147.7,150.8. HRMS: calcd for C23H20NO3S ([MþH]þ) 390.1164, found
390.1173.
4.2.7. 4-o-Ethoxycarbonylphenyl-8-tosyloxyquinoline (5g)
The specific amounts of chemicals used were: 4-chloro-8-tosyloxy-
quinoline 4 (502 mg, 1.50 mmol), Pd(PPh3)4 (87.5 mg, 0.076 mmol),
anhydrous K2CO3 (436 mg, 3.15 mmol), 2-(ethoxycarbonyl)-
phenylboronic acid (306 mg, 1.05 mmol), and DMF (10 mL). The
reaction time was 2 h. Purification by flash chromatography (2:5
acetone/n-hexane, 10 mL methanol in 1.5 L) and recrystallization
from ethanol afforded the title compound (433 mg, 64%) as off-
4.2.3. 4-o-Methylphenyl-8-tosyloxyquinoline (5c)
The specific amounts of chemicals used were: 4-chloro-8-
tosyloxyquinoline
4 (502 mg, 1.50 mmol), Pd(PPh3)4 (87.4 mg,
0.076 mmol), anhydrous K2CO3 (436 mg, 3.15 mmol), 2-methyl-
phenylboronic acid (215 mg, 1.05 mmol), and DMF (10 mL). The
reaction time was 4 h. Purification by flash chromatography (2:5
acetone/n-hexane, 10 mL methanol in 1.5 L) afforded the title
compound (522 mg, 89%) as off-white crystals. Mp: 146–149 ꢁC. IR
white crystals. Mp: 121–123 ꢁC. IR (KBr):
2959 (w), 1723 (s), 1593 (m), 1510 (m). 1H NMR (200 MHz,
DMSO-d6):
¼0.49 (3H, t, J¼7.1 Hz), 2.41 (3H, s), 3.72 (2H, q,
n
¼3075 (w), 2989 (m),
(KBr):
n
¼3059 (w), 2961 (w), 2923 (w),1592 (m).1H NMR (200 MHz,
d

522
J.P. Heiskanen, O.E.O. Hormi / Tetrahedron 65 (2009) 518–524
J¼7.1 Hz), 7.31 (1H, dd, J¼2.5, 7.3 Hz), 7.37–7.54 (6H, m), 7.64–
7.82 (2H, m), 7.86 (2H, d, J¼8.3 Hz), 8.04 (1H, dd, J¼1.4, 7.5 Hz),
product was collected (480 mg, 99%) as yellow powder. A small
amount of the product was recrystallized from ethanol for analyt-
8.87 (1H, d, J¼4.4 Hz). 13C NMR (50 MHz, DMSO-d6):
d¼13.7,
ical purposes. Mp: 106–109 ꢁC. IR (KBr):
n
¼3317 (s), 3049 (m), 2967
(w), 1628 (w), 1597 (w), 1565 (m), 1514 (s). 1H NMR (200 MHz,
DMSO-d6):
¼1.97 (3H, s), 6.79 (1H, d, J¼8.2 Hz), 7.09 (1H, d,
22.0, 61.3, 122.5, 122.6, 125.3, 127.1, 129.2, 129.3, 129.9, 130.8,
131.0, 131.3, 131.8, 133.4, 138.2, 141.5, 145.9, 146.3, 148.9, 151.3,
166.8. HRMS: calcd for C25H22NO5S ([MþH]þ) 448.1219, found
448.1221.
d
J¼7.2 Hz), 7.21 (1H, d, J¼7.1 Hz), 7.30–7.46 (5H, m), 8.90 (1H, d,
J¼4.3 Hz), 9.91 (1H, br s). 13C NMR (50 MHz, DMSO-d6):
¼19.7,
d
111.4,115.4,122.3, 126.1,127.6,128.0, 128.6, 129.4,130.3, 135.5,137.5,
138.9, 147.8, 147.9, 153.9. HRMS: calcd for C16H14NO ([MþH]þ)
236.1075, found 236.1081.
4.2.8. 5-Phenyl-8-tosyloxyquinoline (10)
The specific amounts of chemicals used were: 5-chloro-8-tosyl-
oxyquinoline
9
(502 mg, 1.50 mmol), Pd(PPh3)4 (88.0 mg,
0.076 mmol), anhydrous K2CO3 (436 mg, 3.15 mmol), phenyl-
boronic acid (1.93 mg, 1.58 mmol), and DMF (10 mL). The reaction
time was 4 h. Purification by flash chromatography (2:5 acetone/n-
hexane, 10 mL methanol in 1.5 L) afforded the title compound
(343 mg, 61%) as off-white crystals. Mp: 159–161 ꢁC. IR (KBr):
4.3.4. 4-p-Methoxyphenyl-8-hydroxyquinoline (6d)
The specific amounts of chemicals used were: 4-p-methoxy-
phenyl-8-tosyloxyquinoline 5d (800 mg, 1.97 mmol) and NaOH (aq)
(1 M, 5.91 mL, 5.91 mmol). The reaction time was 2 h. The product
was collected (487 mg, 98%) as yellow powder. A small amount of
the product was recrystallized from ethanol for analytical purposes.
n
¼3035 (w), 1591 (m). 1H NMR (200 MHz, DMSO-d6):
¼2.41 (3H,
d
s), 7.44–7.60 (10H, m), 7.88 (2H, d, J¼8.3 Hz), 8.18 (1H, dd, J¼1.4,
Mp: 149–151 ꢁC. IR (KBr):
n
¼3310 (s), 3042 (m), 3007 (m), 2954
8.6 Hz), 8.87 (1H, dd, J¼1.4, 4.1 Hz). 13C NMR (50 MHz, DMSO-d6):
(m), 2928 (m), 2832 (m), 1607 (s), 1561 (m), 1502 (s). 1H NMR
d
¼21.4, 121.7, 122.8, 126.9, 127.4, 128.3, 128.5, 128.9, 130.0, 130.2,
(200 MHz, DMSO-d6):
d
¼3.85 (3H, s), 7.09–7.15 (3H, m), 7.31–7.52
132.8, 134.1, 138.0, 139.5, 141.2, 144.4, 145.7, 151.1. HRMS: calcd for
(5H, m), 8.86 (1H, d, J¼4.3 Hz), 9.82 (1H, br s). 13C NMR (50 MHz,
C22H18NO3S ([MþH]þ) 376.1007, found 376.1002.
DMSO-d6):
d
¼55.5, 111.2, 114.4, 115.5, 122.1, 127.2, 127.8, 130.0,
130.9, 139.2, 147.6, 147.9, 153.9, 159.8. HRMS: calcd for C16H14NO2
4.3. General procedure for synthesis of 4- and 5-aryl-8-
hydroxyquinolines (6a)–(6d), (6f), and (11)
([MþH]þ) 252.1025, found 252.1032.
4.3.5. 4-(4-Pyridyl)-8-hydroxyquinoline (6f)
Aryl-8-tosyloxyquinoline was dissolved in a mixture of acetone
(15 mL) and ethanol (15 mL). NaOH (1 M, 3 equiv) was added. The
solution was refluxed and the reaction was monitored by TLC. The
solvents were removed by evaporation. Distilled water (10 mL) was
added and pH was adjusted to 6.5 with 1 M HCl (aq). The product
was collected by filtration and washed with distilled water to give
the product.
The specific amounts of chemicals used were: 4-(4-pyridyl)-8-
tosyloxyquinoline 5f (800 mg, 2.13 mmol) and NaOH (aq) (1 M,
6.39 mL, 6.39 mmol). The reaction time was 1 h. The product was
collected (430 mg, 91%) as off-white powder. A small amount of the
product was recrystallized from ethanol for analytical purposes.
Mp: 184–187 ꢁC. IR (KBr):
1513 (s). 1H NMR (200 MHz, DMSO-d6):
7.59 (4H, m), 8.77 (2H, d, J¼5.6 Hz), 8.93 (1H, d, J¼4.3 Hz), 10.00
(1H, s). 13C NMR (50 MHz, DMSO-d6):
n
¼3325 (s), 3035 (m), 1625 (m), 1594 (m),
¼7.13–7.23 (2H, m), 7.42–
d
4.3.1. 4-Phenyl-8-hydroxyquinoline (6a)
d
¼111.7, 114.8, 122.0, 124.4,
The specific amounts of chemicals used were: 4-phenyl-8-
tosyloxyquinoline 5a (800 mg, 2.13 mmol) and NaOH (1 M,
6.39 mL, 6.39 mmol). The reaction time was 2 h. The product was
collected (432 mg, 92%) as a yellow powder. A small amount of the
product was recrystallized from ethanol for analytical purposes.
126.2, 128.5, 139.0, 145.1, 145.5, 147.9, 150.2, 154.0. HRMS: calcd for
C14H11N2O ([MþH]þ) 223.0871, found 223.0884.
4.3.6. 5-Phenyl-8-hydroxyquinoline (11)
The specific amounts of chemicals used were: 5-phenyl-8-
tosyloxyquinoline 10 (450 mg, 1.20 mmol) and NaOH (aq) (1 M,
3.60 mL, 3.60 mmol). The reaction time was 21⁄2 h. The product
was collected (260 mg, 98%) as yellow powder. A small amount of
the product was recrystallized from ethanol for analytical purposes.
Mp: 110–112 ꢁC. IR (KBr):
n
¼3332 (s), 3056 (m), 3034 (m), 1585 (m),
1560 (s), 1512 (s). 1H NMR (200 MHz, DMSO-d6):
d
¼7.11 (1H, d,
J¼7.4 Hz), 7.25 (1H, d, J¼8.5 Hz), 7.40 (1H, d, J¼7.7 Hz), 7.46 (1H, d,
J¼4.2 Hz), 7.55 (5H, m), 8.88 (1H, d, J¼4.2 Hz), 9.81 (1H, s). 13C NMR
(50 MHz, DMSO-d6):
d
¼111.3, 115.3, 122.2, 127.0, 128.0, 128.8, 128.9
Mp: 96–98 ꢁC.26 1H NMR (200 MHz, DMSO-d6):
J¼7.9 Hz), 7.39–7.58 (7H, m), 8.20 (1H, dd, J¼1.5, 8.6 Hz), 8.89 (1H,
dd, J¼1.5, 4.1 Hz).
d
¼7.16 (1H, d,
129.5, 137.8, 139.1, 147.8, 147.9, 153.9. HRMS: calcd for C15H12NO
([MþH]þ) 222.0919, found 222.0910.
4.3.2. 4-p-Methylphenyl-8-hydroxyquinoline (6b)
4.4. 4-p-Cyanophenyl-8-hydroxyquinoline (6e)
The specific amounts of chemicals used were: 4-p-methyl-
phenyl-8-tosyloxyquinoline 5b (800 mg, 2.05 mmol) and NaOH
(aq) (1 M, 6.15 mL, 6.15 mmol). The reaction time was 2 h. The
product was collected (468 mg, 97%) as yellow powder. A small
amount of the product was recrystallized from ethanol for ana-
NaH (108 mg, 4.50 mmol) in 60% oil dispersion was washed with
n-hexane (5 mL). 1-Butanethiol (0.50 mL, 4.52 mmol) was added
and the mixture was stirred vigorously. 4-p-Cyanophenyl-8-tosyl-
oxyquinoline 5e (600 mg, 1.50 mmol) in 2-methyl-2-butanol
(20 mL) was added and the mixture was refluxed for 10 min. For-
mation of an extensive precipitate could be observed. tert-Amyl-
alcohol was removed in vacuum and distilled water (10 mL) was
added. pH was adjusted to 6.5 with hydrochloric acid (1 M) and the
resulting mixture was concentrated in vacuum. The crude product
was washed with distilled water to give the product (354 mg, 96%)
as an off-white powder. A small amount of the product was
recrystallized for analytical purposes from ethanol. Mp: 202–
lytical purposes. Mp: 148–150 ꢁC. IR (KBr):
n
¼3304 (s), 3024 (m),
2917 (w), 1615 (w), 1560 (m). 1H NMR (200 MHz, DMSO-d6):
d
¼2.41 (3H, s), 7.11 (1H, d, J¼7.2 Hz), 7.27–7.45 (7H, m), 8.87 (1H,
d, J¼4.3 Hz), 9.85 (1H, br s). 13C NMR (50 MHz, DMSO-d6):
¼21.0,
d
111.2, 115.4, 122.1, 127.1, 127.9, 129.5, 134.9, 138.2, 139.1, 147.8,
147.9, 153.9. HRMS: calcd for C16H14NO ([MþH]þ) 236.1075, found
236.1090.
4.3.3. 4-o-Methylphenyl-8-hydroxyquinoline (6c)
205 ꢁC. IR (KBr):
n
¼3316 (s), 3043 (m), 2224 (s), 1607 (m), 1563 (m),
The specific amounts of chemicals used were: 4-o-methyl-
phenyl-8-tosyloxyquinoline 5c (800 mg, 2.05 mmol) and NaOH
(aq) (1 M, 6.15 mL, 6.15 mmol). The reaction time was 2 h. The
1500 (s). 1H NMR (200 MHz, DMSO-d6):
d
¼7.12–7.19 (2H, m), 7.43
(1H, d, J¼8.1 Hz), 7.52 (1H, d, J¼4.2 Hz), 7.75 (2H, d, J¼7.9 Hz), 8.05
(2H, d, J¼7.9 Hz), 8.92 (1H, d, J¼4.2 Hz), 9.98 (1H, s). 13C NMR

J.P. Heiskanen, O.E.O. Hormi / Tetrahedron 65 (2009) 518–524
523
(50 MHz, DMSO-d6):
d
¼111.6, 111.7, 114.9, 118.8, 122.2, 126.4, 128.5,
4.8. 4-o-Carboxyphenyl-8-tosyloxyquinoline (7)
130.6, 132.8, 139.0, 142.6, 146.0, 147.9, 154.0. HRMS: calcd for
C16H11N2O ([MþH]þ) 247.0871, found 247.0863.
4-o-Ethoxycarbonylphenyl-8-tosyloxyquinoline 5g (601 mg,
1.34 mmol) was refluxed with a mixture of acetone (5 mL), 37%
hydrochloric acid (2.5 mL), and distilled water (5 mL) for 48 h. The
reaction mixture was allowed to cool to the room temperature. pH
was adjusted to 3.5 with 1 M NaOH (aq). The precipitate was col-
lected by filtration and washed with distilled water. The procedure
gave the product (413 mg, 73%) as an off-white powder. A small
amount of the product was recrystallized from ethanol for analyt-
4.5. 4-o-Ethoxycarbonylphenyl-8-hydroxyquinoline (6g)
NaH (114 mg, 4.75 mmol) in 60% oil dispersion was washed with
n-hexane (5 mL) and ethanol (10 mL) was added. 4-o-Ethoxy-
carbonylphenyl-8-tosyloxyquinoline 5g (701 mg, 1.57 mmol) was
added and the reaction mixture was refluxed for 30 min. The re-
action mixture was evaporated to dryness. Distilled water (5 mL)
was added and pH was adjusted to 4.0 with 1 M HCl (aq). The
resulting precipitate was collected by vacuum filtration and washed
with distilled water. The procedure gave the product (423 mg, 92%)
as a light-yellow powder. A small amount of the product was
recrystallized for analytical purposes from ethanol. Mp: 100–
ical purposes. Mp: 243–246 ꢁC. IR (KBr):
2757 (w), 2481 (w), 1699 (s), 1621 (w), 1592 (s), 1509 (s). 1H NMR
(200 MHz, DMSO-d6):
¼2.42 (3H, s), 7.33–7.53 (7H, m), 7.62–7.77
n
¼3054 (w), 2871 (w),
d
(2H, m), 7.85 (2H, d, J¼8.3 Hz), 8.04 (1H, dd, J¼1.2, 7.4 Hz), 8.84 (1H,
d, J¼4.3 Hz), 12.75 (1H, br s). 13C NMR (50 MHz, DMSO-d6):
¼21.4,
d
121.8, 122.0, 124.9, 126.4, 128.5, 128.7, 129.2, 130.2, 130.4, 131.2,
131.7, 132.3, 132.8, 137.7, 141.0, 145.3, 145.7, 148.8, 150.6, 167.7.
HRMS: calcd for C23H18NO5S ([MþH]þ) 420.0906, found 420.0932.
102 ꢁC. IR (KBr):
n
¼3304 (s), 3061 (w), 2980 (m), 2900 (w), 1712 (s),
1595 (m), 1566 (m), 1512 (s). 1H NMR (200 MHz, DMSO-d6):
d¼0.57
(3H, t, J¼7.1 Hz), 3.77 (2H, q, J¼7.1 Hz), 6.78 (1H, d, J¼8.1 Hz), 7.06
(1H, d, J¼7.1 Hz), 7.29–7.47 (3H, m), 7.63–7.80 (2H, m), 8.01 (1H, dd,
J¼1.0, 7.5 Hz), 8.87 (1H, d, J¼4.3 Hz), 9.87 (1H, br s). 13C NMR
4.9. 5-Chloro-8-tosyloxyquinoline (9)
A mixture of 5-chloro-8-hydroxyquinoline 8 (3.02 g, 16.8 mmol)
and 1 M NaOH (aq) (16.8 mL) was refluxed for 30 min. The mixture
was cooled to room temperature and p-toluenesulfonyl chloride
(3.19 g, 16.7 mmol) in acetone (11 mL) was added. The resulting
mixture was stirred for 2 h. The product was collected by filtration
and washed with distilled water to give the product (5.56 g, >99%)
as an off-white powder. A small amount of the product was
recrystallized from ethanol for analytical purposes. Mp: 130–
(50 MHz, DMSO-d6):
d
¼13.2, 60.6, 111.1, 115.0, 121.5, 127.8, 127.9,
129.0,130.1,130.8, 131.1, 132.6, 138.3, 138.5, 147.7,148.2,153.8, 166.4.
HRMS: calcd for C18H16NO3 ([MþH]þ) 294.1130, found 294.1159.
4.6. 4-o-Carboxyphenyl-8-hydroxyquinoline (6h)
Sodium hydroxide (2.19 g, 54.8 mmol) was dissolved in distilled
water (5 mL). 4-o-Ethoxycarbonylphenyl-8-tosyloxyquinoline 5g
(500 mg, 1.12 mmol) and acetone (2 mL) were added. The reaction
mixture was refluxed 5 h. The reaction mixture was allowed to cool
to room temperature and pH was adjusted to 3.5 with HCl (aq). The
water solution was extracted with four 20 mL portions of ethyl
acetate. The separated organic layers were combined and evapo-
rated to dryness. The precipitate was boiled with water (5 mL) and
cooled with ice bath. The product was collected by filtration and
washed with distilled water to give the product (272 mg, 92%) as
a yellow powder. A small amount of the product was recrystallized
from ethanol for analytical purposes. Mp: 104–105 ꢁC. IR (KBr):
132 ꢁC. IR (KBr):
DMSO-d6):
n
¼3088 (w), 2920 (w), 1589 (s). 1H NMR (200 MHz,
d
¼2.37 (3H, s), 7.40 (2H, d, J¼8.2 Hz), 7.49 (1H, d,
J¼8.4 Hz), 7.69–7.82 (4H, m), 8.54 (1H, dd, J¼1.1, 8.6 Hz), 8.91 (1H,
dd, J¼1.1, 4.1 Hz). 13C NMR (50 MHz, DMSO-d6):
d
¼22.0, 123.3,
124.5, 127.3, 127.5, 129.3, 129.8, 130.8, 132.9, 133.4, 142.2, 144.9,
146.5, 152.7. HRMS: calcd for C16H13NO3SCl ([MþH]þ) 334.0305,
found 334.0307.
Acknowledgements
The authors thank Mrs. Pa¨ivi Joensuu for high-resolution mass
spectrometric data. This work was funded by Infotech Oulu Grad-
uate School, Kainuu regional fund of Finnish Cultural Foundation,
Tauno To¨nning Foundation, and Emil Aaltonen Foundation.
n
¼3251 (s), 3059 (w), 1702 (s), 1589 (s), 1530 (s). 1H NMR (200 MHz,
DMSO-d6):
d
¼6.81 (1H, dd, J¼0.9, 8.3 Hz), 7.05 (1H, dd, J¼0.9,
7.5 Hz), 7.29–7.40 (3H, m), 7.59–7.76 (2H, m), 8.02 (1H, dd, J¼1.4,
7.5 Hz), 8.85 (1H, d, J¼4.4 Hz), 9.83 (1H, br s), 12.7 (1H, br s). 13C
NMR (50 MHz, DMSO-d6):
d
¼111.0, 115.3, 121.6, 127.7, 128.0, 128.9,
Supplementary data
130.2, 131.1, 131.8, 132.1, 138.5, 138.5, 147.7, 148.8, 153.8, 167.8.
HRMS: calcd for C16H12NO3 ([MþH]þ) 266.0817, found 266.0825.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.10.097.
4.7. 4-Hydroxypyridinoanthrene (6i)
References and notes
4-o-Carboxyphenyl-8-hydroxyquinoline 6h(200 mg, 0.75 mmol)
was mixed vigorously with 96% sulfuric acid (4 mL) for 3 h at room
temperature. The reaction vessel was cooled in an ice bath and dis-
tilled water (5 mL) was added slowly. pH was adjusted to 4.0 with
NaOH (aq) and the resulting precipitate was collected by vacuum
filtration. The precipitate was washed with distilled water to give the
product (165 mg, 88%) as a red powder. A small amount of the
product was recrystallized for analytical purposes from a mixture of
ethyl acetate and dimethylsulfoxide (7:3). Mp: 286–289 ꢁC. IR (KBr):
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Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359–1469.
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1917–1925.
n
¼3237 (s), 3060 (w), 1713 (m), 1650 (s), 1592 (m), 1566 (s), 1517 (s).
1H NMR (200 MHz, DMSO-d6):
d
¼7.29 (1H, d, J¼8.3 Hz), 7.76 (1H, dd,
J¼7.2 Hz), 7.89 (1H, dd, J¼7.2 Hz), 8.37 (1H, d, J¼7.9 Hz), 8.51 (1H, d,
J¼8.3 Hz), 8.64–8.72 (2H, m), 9.06 (1H, d, J¼4.6 Hz). 13C NMR
(50 MHz, DMSO-d6):
d¼113.9, 118.6, 119.2, 124.4, 125.0, 127.5, 131.0,
132.3,132.7,133.5,133.6,134.3,137.5,149.0,161.6,180.2. HRMS: calcd
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L.; Cai, C.; McWilliams, J. C.; Reamer, R. A.; Dormer, P. G.; Cvetovich, R. J. J. Org.
for C16H8NO2 ([MꢀH]ꢀ) 246.0555, found 246.0551.

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19. 4-Hydroxypyridinoneanthrene is
a new compound. Tetracyclic 8-hydroxy-
11. (a) Friesen, R. W.; Trimble, L. A. Can. J. Chem. 2004, 82, 206–214; (b) Hostyn, S.;
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`
´
´
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756.
20. Previously, 5-chloro-8-hydroxyquinoline has been reported to be inactive in
Suzuki–Miyaura reaction. See Ref. 3a.
13. Montes, V. A.; Pohl, R.; Shinar, J.; Anzenbacher, P., Jr. Chem.dEur. J. 2006, 12,
4523–4535.
21. It was interesting to see how KF works with chlorinated compound. In Ref. 7a
KF gave good results with aromatic bromo compounds.
14. (a) Wolfrom, M. L.; Koos, E. W.; Bhat, H. B. J. Org. Chem. 1967, 32, 1058–1060; (b)
Yao, T.; Yue, D.; Larock, R. C. J. Org. Chem. 2005, 70, 9985–9989; (c) Kolokythas,
G.; Kostakis, I. K.; Pouli, N.; Marakos, P.; Kousidou, O. Ch.; Tzanakakis, G. N.;
Karamanos, N. K. Eur. J. Med. Chem. 2007, 42, 307–319; (d) Kamiya, M.;
Kobayashi, H.; Hama, Y.; Koyama, Y.; Bernardo, M.; Nagano, T.; Choyke, P. L.;
Urano, Y. J. Am. Chem. Soc. 2007, 129, 3918–3929; (e) Urgaonkar, S.; Shaw, J.
T. J. Org. Chem. 2007, 72, 4582–4585.
15. (a) Heiskanen, J. P.; Omar, W. A. E.; Ylikunnari, M. K.; Haavisto, K. M.; Juan, M. J.;
Hormi, O. E. O. J. Org. Chem. 2007, 72, 920–922; (b) Omar, W. A. E.; Heiskanen, J.
P.; Hormi, O. E. O. J. Heterocycl. Chem. 2008, 45, 593–595.
22. Outt, P. E.; Ares, J. J.; Roberts, G. E.; Wang, X.; Cupps, T. L.; Wireko, F. C. J. Org.
Chem. 1998, 63, 5762–5768.
23. (a) MS data showed the formation of by-product. HRMS: calculated for
C16H13N2O2 ([MþH]þ) 265.0977, found 265.0989; (b) HRMS: calculated for
C20H21N2O2 ([MþH]þ) 321.1603, found 321.1594. Also clear signals from the
butoxy group could be observed in the 1H NMR spectrum.
24. (a) Ferreira, P. C.; Kiyan, N. Z.; Miyata, Y.; Miller, J. J. Chem. Soc., Perkin Trans. 2
1976, 1648–1651; (b) Stang, P. J.; Anderson, A. G. J. Org. Chem. 1976, 41, 781–785.
25. As a point of comparison: debenzylation has been reported to give 5-phenyl-8-
hydroxyquinoline in 79% yield. See Ref. 3a.
16. (a) Hewawasam, P.; Fan, W.; Ding, M.; Flint, K.; Cook, D.; Goggins, G. D.; Myers,
R. A.; Gribkoff, V. K.; Boissard, C. G.; Dworetzky, S. I.; Starrett, J. E., Jr.; Lodge, N. J.
J. Med. Chem. 2003, 46, 2819–2822; (b) Peifer, C.; Kinkel, K.; Abadleh, M.;
Schollmeyer, D.; Laufer, S. J. Med. Chem. 2007, 50, 1213–1221.
26. Previously reported melting points of 5-phenyl-8-hydroxyquinolines: (88–
90 ꢁC) see reference 13; (91–92 ꢁC) see Vorozhtsov, N. N., Jr. J. Heterocycl. Chem.
1938, 8, 431–437 (95–96 ꢁC) see; Babudri, F.; Cardone, A.; Cioffi, C. T.; Farinola,
G. M.; Naso, F.; Ragni, R. Synthesis 2006, 1325–1332.