Preparation of 6-fluoro-8-quinolinol and related 6-fluoroquinolines

Article abstract of DOI:10.1007/s00706-002-0513-8

6-Fluoro-8-quinolinol was prepared from 2-amino-5-fluorophenol by a Skraup synthesis. No synergism was observed between 5-fluoro- and 6-fluoro-8-quinolinols or between 6-fluoro- and 7-fluoro-8-quinolinols against any of the six fungi in our test system (Aspergillus niger, A. oryzae, Myrothecium verrucaria, Trichoderma viride, Mucor cirinelloides, and Trichophyton mentagrophytes) in Sabouraud dextrose broth. Unlike the fluoro-8-quinolinols, the 8-quinolinols comparably substituted with chlorine or bromine did form synergistic mixtures. This is attributed to steric factors.

Full text of DOI:10.1007/s00706-002-0513-8

Monatshefte f€ur Chemie 133, 1437–1442 (2002)
DOI 10.1007/s00706-002-0513-8
Preparation of 6-Fluoro-8-quinolinol
and Related 6-Fluoroquinolines
Herman Gershon1;2;ꢀ, Donald D. Clarke1, and Muriel Gershon2
1
Department of Chemistry, Fordham University, Bronx, NY 10458-9993, USA
2
New York Botanical Garden, Bronx, NY 10458-9993, USA
Received May 23, 2002; accepted May 29, 2002
Published online October 7, 2002 # Springer-Verlag 2002
Summary. 6-Fluoro-8-quinolinol was prepared from 2-amino-5-fluorophenol by a Skraup synthesis.
No synergism was observed between 5-fluoro- and 6-fluoro-8-quinolinols or between 6-fluoro- and 7-
fluoro-8-quinolinols against any of the six fungi in our test system (Aspergillus niger, A. oryzae,
Myrothecium verrucaria, Trichoderma viride, Mucor cirinelloides, and Trichophyton mentagrophytes)
in Sabouraud dextrose broth. Unlike the fluoro-8-quinolinols, the 8-quinolinols comparably substituted
with chlorine or bromine did form synergistic mixtures. This is attributed to steric factors.
Keywords. 6-Fluoro-8-quinolinol; Antifungal activity.
Introduction
5-Fluoro- [1] and 7-fluoro-8-quinolinols [2] had been prepared previously. These
are the only monofluoro-8-quinolinols reported to this time. All the possible mono-
chloro and monobromo compounds [3] have been prepared and tested against the
six fungi [4] in our test system. It was considered of interest to pepare additional
monofluoro-8-quinolinols.
Results and Discussion
Since the 5-fluoro- and 7-fluoro-8-quinolinols were obtained in satisfactory yields
from the corresponding amino-8-quinolinols by the Baltz-Schiemann reaction, we
attempted to prepare 6-fluoro-8-quinolinol from 6-amino-8-quinolinol in the same
manner. The product obtained was a mixture of approximately 50% 6-fluoro-8-
quinolinol and 25% each of the 5-fluoro- and 7-fluoro- analogues as determined by
19F NMR spectroscopy. The mixture proved to be difficult to separate, and there-
fore this approach was abandoned.
ꢀ
Corresponding author. E-mail: clarke@fordham.edu

1438
H. Gershon et al.
Scheme 1
In our earlier work on the peparation of 3,6-dichloro- and 3,6-dibromo-8-qui-
nolinols [5] as well as 3-bromo-6-chloro- and 6-bromo-3-chloro-8-quinolinols [6],
we have found that the 6-bromo- and 6-chloro substituents were resistant to hydro-
lysis in 70% sulfuric acid at 200ꢁC. It was decided to undertake the approach in which
8-amino-6-fluoroquinoline, as well as its 3-bromo and 3-chloro analogues were
hydrolyzed in 70% sulfuric acid. The purification of the products was by steam
distillation. This synthetic sequence is outlined in Scheme 1. The known compound
6-fluoro-8-nitroquinoline (1) [7], was reduced to 8-amino-6-fluoroquinoline (2) [7]
and subjected to hydrolysis by 70% aqueous sulfuric acid at 200ꢁC for 8 h. The
product 3 was not volatile with steam as expected and was not isolated.
Since halogen in position 3 of 8-quinolinol seemed to stabilize the halogen in
position 6 toward hydrolysis by sulfuric acid [4, 5], we halogenated 1 with the
respective N-halosuccinimide (NXS) to yield 3-chloro-6-fluoro-8-nitroquinoline
(4a) and 3-bromo-6-fluoro-8-nitroquinoline (4b). These were reduced to the
amines 5a, and 5b followed by sulfuric acid hydrolysis. 3-Chloro-6-8-dihydroxy-
quinoline (6a) was obtained in 90% yield and the bromo analogue, 6b was pro-
duced in 97% yield. None of the expected products containing fluorine were
obtained.

6-Fluoro-8-quinolinol
1439
Scheme 2
A successful preparation of 6-fluoro-8-quinolinol (8) in 57% yield was
achieved by a Skraup synthesis starting with 2-amino-5-fluorophenol (7) [8]
(Scheme 2).
The fluorination of 8-quinolinol in position 3 was attempted. Based on the ease
of halogenation of 8-nitroquinoline in the 3 position and the stability of halogen in
this position to the conditions of hydrolysis of the amino group at 200ꢁC in the
presence of 70% sulfuric acid [4, 5], we attempted fluorinating 8-nitroquinoline
and its 6-bromo and 6-chloro analogues with electrophilic fluorinating agents
(N-fluorobenzenesulfonimide [9] and 1-chloromethyl-4-fluoro-1,4-diazoniabicy-
clo[2,2,2]octanebis(tetrafluoroborate) [10]. No fluorination was observed, and 3-
fluoro-8-quinolinol has yet to be made.
5-Chloro- and 7-chloro-, 5-bromo- and 7-bromo-, and 5-iodo- and 7-iodo-8-
quinolinols have formed synergistic mixtures, whereas 5-fluoro- and 7-fluoro- 8-
quinolinols did not [11]. This has been rationalized on the basis of steric effects
introduced into the molecule by the halogen substituent. Since fluorine and hydro-
gen are nearly isosteric, it would not be expected to observe synergism between
mixtures of 5-fluoro- and 7-fluoro-8-quinolinols [11]. When minimal inhibitory
concentrations (MICs) of 5-fluoro- and 6-fluoro-8-quinolinols or 6-fluoro- and 7-
fluoro-8-quinolinol were tested against the fungi only additivity of toxicity was
observed. This is consistent with results reported earlier. Table 1 contains data
comparing the fungitoxicity of the three monofluoro-8-quinolinols.
Table 1. Comparison of the antifungal activity of 5-fluoro-, 6-fluoro-, and 7-fluoro-8-quinolinols in
Sabouraud dextrose broth at 28ꢁC in shake culture after six days
Minimal Inhibitory Concentrations=mmol dmꢂ 3 (mg cmꢂ 3 a
)
8-Quinolinol
A. niger
A. oryzae
M. verrucaria
5-fluorob
0.11 (18)
0.025 (4)
0.049 (8)
0.086 (14)
0.025 (4)
0.025 (4)
0.025 (4)
< 0.0062 (<1)
0.018 (3)
6-fluoro (8)
7-fluorob
8-Quinolinol
T. viride
M. cirinelloides
T. mentagrophytes
5-fluorob
0.11 (18)
0.025 (4)
0.037 (6)
0.016 (26)
0.025 (4)
0.037 (6)
0.025 (4)
0.012 (2)
0.012 (2)
6-fluoro (8)
7-fluorob
a
MICs from 1–10 were obtained in increments of 1 and from 11–20 in increments of 2 mg=cm3,
< indicates below 1 mg=cm3 (the lowest level tested); Taken from Ref. [11]
b

1440
H. Gershon et al.
Experimental
Antifungal Testing
Antifungal testing was performed in Sabouraud dextrose broth (Difco) according to Refs. [12–15]. The
fungi employed included Aspergillus niger (ATCC 1004), A. oryzae (ATCC 1011), Myrothecium
verrucaria (ATCC 9095), Trichoderma viride (ATCC 8678), Mucor cirinelloides (ATCC 7941), and
Trichophyton mentagrophytes (ATCC 9129).
Compounds
Melting points were taken on a Thomas-Hoover apparatus and are uncorrected. 5-Fluoro-2-nitrophenol
and 4-fluoro-2-nitroaniline were purchased from Aldrich. Reactions were monitored by gas chromatog-
raphy using a Varian Aerograph Model 1400 gas chromatograph with a flame ionization detector to
which a Varian Model 20 recorder was attached. The column employed was 5 feetꢃ 1=8 inch o.d.,
packed with 10% SE-30 on Chromosorb W. Purity of products was established by 1H and 13C NMR
spectroscopy at 300 MHz and 75MHz with a Bruker DPX-300 spectrometer using DMSO-d6 as
solvent and TMS as internal standard. Elemental analyses matched the calculated values satisfactorily
for 4a, 5a (C, H, Cl, F, N), 4b, 5b (C, H, Br, F, N),and 8 (C, H, F, N).
6-Fluoro-8-nitroquinoline (1)
A mixture was prepared to which 117.8 g of H2SO4, 50.4cm3 of H2O, 58.4g (0.213mol) of sodium
3-nitrobenzene sulfonate, and 52.8cm3 of glycerol were added in that order. It was warmed gently
with stirring to form a solution, and 31.2g 4-fluoro-2-nitroaniline (0.20 mol) was added in portions.
The mixture was heated to reflux slowly with vigorous stirring and continued for 4 h. After cooling, the
mixture was diluted with 2000cm3 H2O and adjusted to pH 6–7 with NH4OH. The product was
recovered by filtration, washed with H2O, and dried at 50ꢁC. Yield 26g (68%); mp 122–123ꢁC (aq alc)
1
(Ref. [7]: mp 119.2–120ꢁC (benzene), yield (46%); H NMR (300 MHz, ꢀ, DMSO-d6): 9.07 (dd,
J23 ¼ 4.2 Hz, J24 ¼ 1.6 Hz, H-2), 8.57 (dd, J34 ¼ 8.3Hz, H-4), 8.50 (dd, J57 ¼ 2.8 Hz, J6F7H ¼ 8.0 Hz,
H-7), 8.17 (dd, J5H6F ¼ 9.0 Hz, H-5), 7.80 (dd, J34 ¼ 8.3 Hz, H-3) ppm; 13C NMR (75 MHz, ꢀ, DMSO-
d6): 157.5 (JCF ¼ 248.3Hz, C-6), 152.2 (JCF ¼ 2.3 Hz, C-2), 148.6 (JCF ¼ 10.3 Hz, C-8), 136.1
(JCF ¼ 5.2 Hz, C-4), 135.7 (JCF ¼ 1.4 Hz, C-8a), 129.2 (JCF ¼ 10.4Hz, C-4a), 124.0 (JCF ¼ <1 Hz,
C-3), 115.2 (JCF ¼ 21.7Hz, C-5), 114.1 (JCF ¼ 31.5Hz, C-7) ppm.
8-Amino-6-fluoroquinoline (2)
A mixture containing 19.2g 1 (0.1mol) and 3 g 10% Pd=C in 250cm3 CH3OH was subjected to 3 atm
of H2 in a Parr hydrogenator. After the theoretical quantity of H2 was taken up, the mixture was freed
of catalyst by filtration, and the solvent was evaporated under a stream of air. Yield 15.6g (96%): mp
49–50ꢁC (aq alc) (Ref. [7]: mp 50–50.6ꢁC (aq alc), yield (79%); 1H NMR (300 MHz, ꢀ, DMSO-d6):
8.75 (dd, J23 ¼ 4.1 Hz, J24 ¼ <1.0 Hz, H-2), 8.20 (dd, J34 ¼ 8.3 Hz, H-4), 7.54 (dd, H-3), 6.87 (dd,
J7H6F 9.6 Hz, H-7), 6.83 (dd, J57 ¼ 2.8 Hz, J6F5H ¼ 11.3 Hz, H-5) 6.40 (s, NH2) ppm; 13C NMR (75
MHz, ꢀ, DMSO-d6): 161.4 (JCF ¼ 241.2 Hz, C-6), 147.7 (JCF ¼ 13.9Hz, C-8), 146.4 (JCF ¼ 2.3 Hz,
C-2), 135.7 (JCF ¼ 5.74 Hz, C-4), 135.0 (JCF ¼ <1 Hz, C-8a), 129.3 (JCF ¼ 13.1Hz, C-4a), 122.6
(JCF ¼ <1 Hz, C-3), 97.6 (JCF ¼ 29.1Hz, C-7), 96.6 (JCF ¼ 22.4 Hz, C-5) ppm.
3-Chloro-6-fluoro-8-nitroquinoline (4a, C9H4ClFN2O2)
To 200 cm3 of acetic acid were added 12.5g 1 (0.065mol) and 8.7 g NCS (0.065 mol). The mixture was
heated to 50ꢁC with stirring for 5 h. Unreacted 1 was still present as shown by gas chromatography.

6-Fluoro-8-quinolinol
1441
Additional NCS was added equal to unreacted 1. Heating and stirring were continued for 1 h and then
brought to boiling. This may have to be repeated until the gas chromatogram indicates the absence of
1. The solution was poured into 1200 cm3 H2O with stirring, and the product was removed by filtration
and air dried. Yield 12 g (82%); mp 158ꢁC (aq alc, Darco G-60); 1H NMR (300MHz, ꢀ, DMSO-d6):
8.97 (d, J24 ¼ 2.3 Hz, H-2), 8.86 (d, H-4), 8.40 (dd, J57 ¼ 2.8 Hz, J6F7H ¼ 8.8 Hz, H-7), 8.07 (dd,
J5H6F ¼ 7.9 Hz, H-5), ppm; 13C NMR (75 MHz, ꢀ, DMSO-d6): 158.3 (JCF ¼ 250.5 Hz, C-6), 150.9
(JCF ¼ 2.7 Hz, C-2), 148.2 (JCF ¼ 10.4Hz, C-8), 134.2 (JCF ¼ 5.3 Hz, C-4), 133.7 (JCF ¼ 15.9 Hz, C-
8a), 130.5 (JCF ¼ <1 Hz, C-3), 129.5 (JCF ¼ 10.7Hz, C-4a), 114.9 (JCF ¼ 14.9 Hz, C-5), 114.6
(JCF ¼ 24.1Hz, C-7) ppm.
3-Bromo-6-fluoro-8-nitroquinoline (4b, C9H4BrFN2O2)
Compound 4b was prepared from 1 in the same manner as 4a was from 1. NBS was the haloge-
nating agent in place of NCS, and the reaction was based on a 0.1mol run. Yield: 26 g (96%);
1
mp 165–166ꢁC (95% alc, Darco G-60); H NMR (300 MHz, ꢀ, DMSO-d6): 9.08 (d, J24 ¼ 1.8 Hz,
H-2), 8.87 (d, H-4), 8.53 (dd, J57 ¼ 2.6 Hz, J7H6F ¼ 8.0 Hz, H-7), 8.10 (dd, J5H6F ¼ 8.8 Hz,
H-5), ppm; 13C NMR (75 MHz, ꢀ, DMSO-d6): 158.1 (JCF ¼ 250.1Hz, C-6), 152.7 (JCF ¼ 2.6 Hz,
C-2), 148.4 (JCF ¼ 10.5Hz, C-8), 137.4 (JCF ¼ 5.4 Hz, C-4), 133.9 (JCF ¼ <1 Hz, C-8a),
130.0 (JCF ¼ 10.8Hz, C-4a), 119.7 (JCF ¼ <1 Hz, C-3), 114.72 (JCF ¼ 32.0Hz, C-7), 114.65
(JCF ¼ 22.1Hz, C-5) ppm.
8-Amino-3-chloro-6-fluoroquinoline (5a, C9H6ClFN2)
To a solution of 9.1 g 4a (0.04 mol) in 250cm3 ethanol was added 8.4 g Fe powder (0.14 mol) and
0.8 cm3 HCl. The suspension was stirred under reflux for 3 h. The solids were filtered off, and the
solvent evaporated under a stream of air to yield 5a. Yield 7.9 g (100%); mp 127–128ꢁC (sublimation);
1H NMR (300 MHz, ꢀ, DMSO-d6): 8.63 (d, J24 ¼ 2.3 Hz, H-2), 8.32 (d, H-4), 6.78 (dd, J7H6F ¼ 9.7 Hz,
H-7), 6.70 (dd, J57 ¼ 2.7 Hz, J6F5H ¼ 11.5Hz, H-5) ppm; 13C NMR (75 MHz, ꢀ, DMSO-d6): 162.1
(JCF ¼ 242.6 Hz, C-6), 148.0 (JCF ¼ 14.4Hz, C-8), 144.6 (JCF ¼ 2.6 Hz, C-2), 133.5 (JCF ¼ 5.8 Hz, C-
4), 132.9 (JCF ¼ <1 Hz, C-8a), 129.8 (JCF ¼ 13.8Hz, C-4a), 128.9 (JCF ¼ <1 Hz, C-3), 97.5
(JCF ¼ 29.1Hz, C-7), 95.7 (JCF ¼ 23.7Hz, C-5) ppm.
8-Amino-3-bromo-6-fluoroquinoline (5b, C9H6BrFN2)
Compound 5a was reduced to 5b in the same manner as 4a was converted to 5a. The reaction was
carried out on 0.08 mol of 4b. Yield 17 g (88%); mp 145ꢁC (aq alc); 1H NMR (300MHz, ꢀ, DMSO-d6):
8.71 (s, H-2), 8.49 (s, H-4) 6.68–6.78 (m, H-5 and H-7), 6.45 (s, NH2) ppm; 13C NMR (75 MHz, ꢀ,
DMSO-d6): 161.9 (JCF ¼ 242.5 Hz, C-6), 148.1 (JCF ¼ 14.34 Hz, C-8), 146.3 (JCF ¼ <1 Hz, C-2),
136.7 (JCF ¼ 5.5 Hz, C-4), 133.0 (JCF ¼ <1 Hz, C-8a), 130.5 (JCF ¼ 13.9Hz, C-4a), 118.1
(JCF ¼ <1 Hz, C-3), 97.5 (JCF ¼ 29.0Hz, C-5), 95.6 (JCF ¼ 23.6 Hz, C-7) ppm.
3-Chloro-6,8-dihydroxyquinoline (6a)
Compound 5a (3.9g, 0.02mol) was hydrolyzed in the presence of 70% aq H2SO4 (w=w) in the same
way as 3 was formed from 2. Upon steam distillation of the mixture, no solid material volatilized. The
residual aqueous solution was cooled to room temperature, and 6a crystals formed which were
recovered by filtration. Yield 3.5 g (90%); mp 182–183ꢁC (aq alc, Darco G-60) (Ref. [6]: mp
182–184ꢁC); NMR data in Ref. [6].

1442
H. Gershon et al.: 6-Fluoro-8-quinolinol
3-Bromo-6,8-dihydroxyquinoline (6b)
The method of preparation of 6b and 5b was the same as for 6a from 5a. The results are based on a
0.015 mol run. Yield 3.5 g (97%); mp 179–180ꢁC (aq alc, Darco G-60) (Ref. [6]: mp 179–180ꢁC);
NMR data in Ref. [6].
6-Fluoro-8-quinolinol (8, C9H6FNO)
A mixture of 47g H2SO4, 20.2cm3 H2O, 23.4g sodium 3-nitrobenzensulfonate (0.1 mol), and 21.1 cm3
glycerol was assembled in that order and heated until all went into solution. 2-Amino-5-fluorophenol
[8] (10.2 g, 0.08 mol) was added to the warm solution with stirring and heating slowly until boiling.
This was continued for 3.5h under reflux. The mixture was cooled to about 80ꢁC and poured into
1500 cm3 deionized H2O with stirring. It was brought to pH 6–7 with NH4OH and steam distilled. The
major yield of 8 was obtained by filtration. An additional yield of product was recovered by concen-
1
tration of the filtrate under a stream of air. Yield 7.5 g (57%); mp 139–140ꢁC (95% alc); H NMR
(300 MHz, ꢀ, DMSO-d6): 8.87 (dd, J24 ¼ 1.4 Hz, J23 ¼ 4.1 Hz, H-2), 8.35 (dd, J34 ¼ 8.4 Hz, H-4), 7.63
(dd, H-3), 7.22 (dd, J57 ¼ 2.7 Hz, J5H6F ¼ 9.5 Hz, H-5), 7.05 (dd, J57 ¼ 2.7 Hz, J7H6F ¼ 10.7Hz, H-7)
ppm; 13C NMR (75 MHz, ꢀ, DMSO-d6): 160.5 (JCF ¼ 243.5Hz, C-6), 155.4 (JCF ¼ 14.2Hz, C-8),
147.7 (JCF ¼ 2.4 Hz, C-2), 136.2 (JCF ¼ 21.8 Hz, C-8a), 135.9 (JCF ¼ 5.9 Hz, C-4), 129.0
(JCF ¼ 12.8Hz, C-4a), 122.9 (JCF ¼ <1 Hz, C-3), 101.6 (JCF ¼ 28.6Hz, C-7), 100.9 (JCF ¼ 22.2Hz,
C-5) ppm.
Acknowledgments
Partial support for this work was provided by the National Science Foundation’s Division of Under-
graduate education through grant DUE #9650684.
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