Synthesis of 5-hydroxyquinolines

Article abstract of DOI:10.1016/j.tetlet.2010.05.058

A series of 5-hydroxyquinolines has been prepared via the Skraup reaction. Several regioisomers were made either by selective displacement of a leaving group or by using a bromo substituent as a blocking group. The bromo group was found to be an excellent blocking group due to its stability during the Skraup reaction and easy removal thereafter. Halides at the 5-position of quinoline were found to be much more reactive than those at the 7- and 8-positions. Finally, we have also found a unique method to reduce the pyridyl ring on quinolines, leaving a halogen substituent untouched.

Full text of DOI:10.1016/j.tetlet.2010.05.058

Tetrahedron Letters 51 (2010) 3876–3878
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 5-hydroxyquinolines
*
Jianke Li, Daniel W. Kung, David A. Griffith
Department of Cardiovascular, Metabolic and Endocrine Diseases, Pfizer Global Research and Development, Groton, CT 06340, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 5-hydroxyquinolines has been prepared via the Skraup reaction. Several regioisomers were
made either by selective displacement of a leaving group or by using a bromo substituent as a blocking
group. The bromo group was found to be an excellent blocking group due to its stability during the
Skraup reaction and easy removal thereafter. Halides at the 5-position of quinoline were found to be
much more reactive than those at the 7- and 8-positions. Finally, we have also found a unique method
to reduce the pyridyl ring on quinolines, leaving a halogen substituent untouched.
Ó 2010 Published by Elsevier Ltd.
Received 7 April 2010
Revised 12 May 2010
Accepted 13 May 2010
Available online 21 May 2010
Quinolines are important building blocks for pharmaceutical
agents. They exist in many drugs, such as the antimalarial drugs
Chloroquine, Quinine, Mefloquine, and Primaquine, and the antiar-
rhythmic drug Quinidine.1 Quinolines have also proven useful for
targeting antiviral, antibacterial, anti-inflammatory, and antican-
cer drugs.2 Although a large number of methods to make quino-
lines have been developed, the synthesis of highly substituted
quinolines is still a formidable task. We report herein the syntheses
of some 5-hydroxyquinoline derivatives.
A series of methyl- and chloro-substituted 5-hydroxyquinolines
was needed for the systematic exploration of SAR during a recent
project (Fig. 1). Among the well-established methods for preparing
quinolines, such as the Combes,3 Conrad–Limpach,4 Friedlander,5
Gould–Jacobs,6 Meth-Cohn,7 Pfizinger,8 and Skraup quinoline syn-
theses,9 the Skraup quinoline synthesis was attractive because the
readily available aniline and crotonaldehyde starting materials
were expected to enable the synthesis of most of our desired
compounds.
complete, the mixture was cooled to room temperature and
2 equiv of solid zinc chloride was added in one portion, and the
resulting mixture was stirred at room temperature for 30 min
and then at 0 °C for 1.5 h. The precipitate was collected by filtration
and was washed sequentially with 1 N HCl, isopropanol, and water.
Finally, the zinc chloride quinoline complex was broken by treat-
ment with NH4OH and extraction with ether to afford the desired
Skraup products.
For the synthesis of the methyl-substituted isomers of 8-chloro-
5-hydroxyquinoline, the requisite anilines and crotonaldehydes
Cl
N
N
Me
Cl
OH
OH
1
2
The synthesis of methyl-substituted 8-chloro-5-hydroxyquino-
line derivatives is outlined in Scheme 1.
Figure 1. Methyl- and chloro-substituted 5-hydroxyquinoline targets.
The Skraup quinoline synthesis, ‘the worse witch’s brew’,10 is
notorious for the difficult purification that follows the reaction.
Typical reported yields are around 50%. In our hands, provided that
the mixture of compound 3 in hydrochloric acid was homogeneous
before compound 4 was added, the cyclization between anilines 3
and crotonaldehydes 4 proceeded cleanly as determined by LC–MS.
However, analysis by thin-layer chromatography showed multiple
impurities, and purification by flash column chromatography was
inefficient.
Cl
Cl
O
O
NH2
N
R1
R2
5N HCl
+
R1
R3
reflux, 1h
R4
R4
R2
toluene
O
3
R3
5
4
Cl
N
HBr/AcOH
reflux, overnight
R1
R2
Purification was greatly simplified by forming the quinoline’s
R4
zinc chloride complex.11 After the cyclization reaction was
OH R3
6
* Corresponding author. Tel.: +1 860 441 6215; fax: +1 860 715 8324.
E-mail address: david.a.griffith@pfizer.com (D.A. Griffith).
Scheme 1. Synthesis of 6 via the Skraup reaction.
0040-4039/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2010.05.058

J. Li et al. / Tetrahedron Letters 51 (2010) 3876–3878
3877
Table 1
The isolated yields of 5 and 6
X
NIS
X = I:
NH
NH2
N
2 100%
acrolein
R1
R2
R3
R4
Yield of 5a (%)
Yield of 6 (%)
or
5N HCl
Cl
Cl
Cl
NBS
58%
22%
Me
H
H
H
Me
H
H
H
Me
H
H
H
H
Me
23
27
35
30
22
77
88
79
OMe
OMe
OMe
19
17
20
X = I
22 X = Br
H
H
acrolein
a
X = Br:
No attempt was made to recover additional desired product from the filtrate
5N HCl, 52%
after isolation of the zinc complex.
HBr/AcOH;
X
X
N
PhNH2
76%
N
were readily available. 5-Methoxyquinolines 5 were selected as the
penultimate intermediates based on the expectation that the
methyl ether would be a suitable protecting group for the harsh
Skraup conditions. The isolated yields of intermediates 5 from
unoptimized reaction conditions are shown in Table 1.
Cl
Cl
OMe
18 X = H
OH
24 X = Br
21
16
X = H
X = I
23 X = Br
Initial attempts to cleave the methyl ether by treating the
5-methoxyquinolines with BCl3 (0 °C) or diethylaminoethane-
thiol/NaOEt (160 °C) afforded no detectable conversion. However,
heating the methyl ether 5 in a refluxing mixture of 1:1 acetic acid
and 49% hydrobromic acid afforded the desired 5-hydroxyquino-
line 6 after purification by column chromatography. In general
the demethylation was very sluggish, especially for R3 = methyl,
likely due to steric hindrance, although the yields were generally
reasonable (Table 1).
Scheme 3. Synthesis of 16 using blocking group.
hydroxyl group prior to NaOMe displacement. Treatment of com-
pound 10 with TFA/Et3SiH at room temperature afforded no
detectable reaction. However, when the reaction was heated at
60 °C overnight, compound 12 was isolated in 60% yield. The selec-
tive reduction of the pyridine ring in the presence of the halogens
and the benzylic alcohol is an uncommon transformation that may
be of significant synthetic utility. Further studies will be conducted
to explore its scope.
Activating the benzylic alcohol for reduction by conversion to
the corresponding bromide was accomplished by treatment of 10
with HBr/AcOH. Attempts to remove the bromide from 13 with
Zn/HBr/AcOH and Zn/NaOH were not successful,13 however, lith-
ium aluminum hydride readily cleaved the bromide to afford com-
pound 14 in high yield. Selective displacement of one chloro group
was achieved by heating compound 14 with NaOMe in methanol at
reflux for 18 h to afford compound 15. The assigned 8-chloro-5-
methoxy structure was verified by observation of NOE enhance-
ments between the methoxy and adjacent aromatic protons. The
methyl ether protecting group was removed with HBr/AcOH to af-
ford compound 7.
The synthesis of 8-chloro-7-methyl-5-hydroxyquinoline (7)
using the procedure outlined in Scheme 1 was not pursued because
the required aniline was not readily available. An alternate ap-
proach to 7 is outlined in Scheme 2. Complete reduction of the acid
was envisioned to provide the desired 7-methyl group. Based on a
few literature examples suggesting that 5-halo-quinolines are more
reactive to nucleophilic substitution than 7- or 8-halo-quinolines12
,
the selective reaction at one of the chlorine-bearing carbons was
expected to allow the introduction of the 5-hydroxy group.
The reduction of compound 8 with lithium aluminum hydride
gave compound 9, which underwent Skraup cyclization to afford
compound 10. Attempted displacement of the 5-chloro group from
10 with sodium methoxide afforded a complex product mixture.
We reasoned that the benzylic alcohol was interfering with the
desired transformation and therefore attempted to remove the
Thesynthesis of the 6- and 7-chloro-5-hydroxyquinolineisomers
via the Skraup reaction afforded challenges in achieving the desired
regiochemistry. The synthesis of 6-chloro derivative 16 is outlined in
Scheme 3. To avoid the probability that compound 17 used directly
in the Skraup reaction would form both the desired isomer 18 and
its isomer 19, an iodo substituent was placed para to the methoxy
group to act as a removable blocking group. Treatment of compound
17 with N-iodosuccinimide gave a quantitative yield of compound
20. The subsequent Skraup reaction, however, did not give desired
compound 21, but exclusively compound 19, whose structure was
confirmed by COSY NMR. Assessment of the stability of compound
20 under the Skraup reaction conditions demonstrated that 60% of
compound 20 decomposed to compound 17 within 10 min at
100 °C, likely by the mechanism outlined in Scheme 4.
OH Cl
OH Cl
NaOMe
Cl
N
N
R
NH2
acrolein
X
5N HCl
toluene
48%
Cl
10
OMe
11
Cl
8
R = CO2H
9 R = CH2OH
HBr/AcOH
5 min
TFA, Et3SiH
60 °C
87%
OH Cl
Br Cl
Cl
Cl
H
N
LAH,THF
N
N
10 min.
89%
Cl
12
Cl
14
A bromo, rather than iodo, substituent was expected to be less
labile to reductive cleavage during the Skraup reaction (Scheme 3).
13
NaOMe/MeOH
reflux, overnight
Cl
I
Cl
Cl
I
HBr/
H
H
NH2
N
N
NH2
NH2
AcOH
89%
Cl
Cl
Cl
(2 steps)
OH
7
OMe
15
OMe
20
OMe
OMe
17
Scheme 2. Synthesis of compound 7.
Scheme 4. Mechanism for conversion of 20 to give 17.

3878
J. Li et al. / Tetrahedron Letters 51 (2010) 3876–3878
chlorine gas and subsequent distillation.15 To avoid safety hazards
Cl
NH2
Cl
N
acrolein
with this route, an alternative to the Skraup synthesis was em-
ployed (Scheme 6). Regioselective nitration of compound 31 with
fuming nitric acid gave compound 32, which was then reduced with
tin dichloride to afford compound 33 in nearly quantitative yield.
The conversion of aniline 33 into phenol 30 proved to be prob-
lematic. The stepwise conversion, treating compound 33 first with
sodium nitrite in sulfuric acid and then with aqueous NaOH gave
only trace amounts of the desired product. The Bucherer reaction
with sodium hydrogensulfite,16 a direct conversion from aniline
to phenol, failed to give the desired result. We reasoned that so-
dium hydrogensulfite might not be sufficiently acidic for the quin-
oline substrate and therefore heated compound 33 at 210 °C for 2 h
in a microwave reactor in the presence of phosphoric acid resulting
in complete transformation of compound 33 to 5-hydroxyquino-
line 30.
5N HCl
38%
Cl
26
Cl
27
1) NaOMe, µwave,
140 °C;
HBr, AcOH, 41%
2) Pd/C, H2,
82%
X
N
R
28 X = Cl, R = OMe
25 X = Cl, R = OH
29
X = H, R = OH
Scheme 5. Synthesis of compound 25.
In summary, a series of 5-hydroxyquinolines has been prepared.
Several regioisomers were made either by selective displacement
of a leaving group or by using a bromo substituent as a blocking
group in the Skraup reaction. The bromo group was found to be
an excellent blocking group due to its stability during the Skraup
conditions and easy removal thereafter. Halides at the 5-position
of quinoline were found to be much more reactive than those at
the 7- and 8-positions. Finally, we have also found a unique meth-
od to reduce the pyridyl ring on quinolines, leaving a halogen sub-
stituent untouched.
Compound 22 underwent Skraup cyclization to provide the desired
compound 23, without evidence of debromination. Heating meth-
oxyquinoline 23 in HBr/AcOH afforded the expected compound 24,
with trace amounts of compound 16 also observed.
Although it has been reported that bromo groups para or ortho
to an amino group are readily removed with HBr/AcOH,14 extended
heating time did not further promote debromination of 24. We
hypothesized that the addition of a reagent to scavenge any Br2
produced might further promote the debromination reaction. In
the presence of aniline (3 equiv) as bromine-scavenger, compound
23 was completely transformed to the desired compound 16 after
heating at 120 °C with HBr/AcOH overnight. Upon cooling to room
temperature, the solid was removed by filtration and the filtrate
was then treated with saturated aqueous Na2CO3 solution to give
a brown precipitate. Rinsing the isolated precipitate with ether fol-
lowed by drying gave compound 16, as determined by 1H NMR.
The planned synthesis of 7-chloro derivative 25 was based on
the belief that regioselective chloride displacement from 27 could
be achieved (Scheme 5).12 Compound 27 was readily prepared by
the Skraup reaction. Treatment of compound 27 with NaOMe at
140 °C in a microwave reactor for 4 h afforded an inseparable mix-
ture of compounds 28 and 25. Pure compound 25 was isolated
after demethylation with HBr/AcOH. Unfortunately 1H NMR analy-
sis could not exclude the possibility that 5-chloro-7-hydroxyquin-
oline had been formed rather than the desired compound 25.
Confirmation of the desired and expected regioselectivity was
achieved by hydrogenolysis to produce the known compound 29.
Synthesis of 3-chloro derivative 30 using the Skraup reaction
would require the starting material 2-chloroacrolein. The literature
preparation of 2-chloroacrolein reports the reaction of acrolein with
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Scheme 6. Synthesis of compound 30 via the Bucherer reaction.