Preparation and fungitoxicity of some trichloro-, tribromo-, tetrachloro-, and tetrabromo-8-quinolinols

Article abstract of DOI:10.1007/s007060170048

3,5,6-, 3,5,7-, 4,5,7-, and 5,6,7-trichloro- and -tribromo-8-quinolinols as well as 3,5,6,7-tetrachloro- and -tetrabromo-8-quinolinols were prepared and tested against six fungi (Aspergillus niger, Aspergillus oryzae, Myrothecium verrucaria, Trichoderma viride, Mucor cirinelloides, and Trichophyton mentagrophytes) in Sabouraud dextrose broth. The compounds strongly inhibit five fungi but not M. cirinelloides. They are less active than the related dichloro-8-quinolinols which is attributed to steric hindrance.

Full text of DOI:10.1007/s007060170048

Monatshefte fuÈr Chemie 132, 1075±1080 (2001)
Preparation and Fungitoxicity of Some
Trichloro-, Tribromo-, Tetrachloro-,
and Tetrabromo-8-Quinolinols
Herman Gershon1;2;Ã, 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
Summary. 3,5,6-, 3,5,7-, 4,5,7-, and 5,6,7-trichloro- and -tribromo-8-quinolinols as well as 3,5,6,7-
tetrachloro- and -tetrabromo-8-quinolinols were prepared and tested against six fungi (Aspergillus
niger, Aspergillus oryzae, Myrothecium verrucaria, Trichoderma viride, Mucor cirinelloides, and
Trichophyton mentagrophytes) in Sabouraud dextrose broth. The compounds strongly inhibit ®ve
fungi but not M. cirinelloides. They are less active than the related dichloro-8-quinolinols which is
attributed to steric hindrance.
Keywords. Trichloro-8-quinolinols; Tribromo-8-quinolinols; Tetrachloro-8-quinolinols; Tetrabromo-
8-quinolinols; Antifungal activity.
Introduction
It has been shown previously that the antifungal activity of monochloro- and
monobromo-8-quinolinols, with the exception of the 2-substituted analogues,
exceeds that of 8-quinolinol [1]. This has been attributed to intramolecular
synergism [2]. The enhanced activity of the dihalo-8-quinolinols over the monohalo
analogues has been explained similarly by intramolecular synergism [2±4]. It
seemed of interest to determine if further enhancement of toxicity would result from
tri- and tetrasubstitution.
Results and Discussion
The 3,5,6-Trichloro- and 3,5,6-tribromo-8-quinolinols 2a,b were prepared from the
respective 3,6-dihalo-8-quinolinols 1a,b [5] by reaction with one equivalent of N-
chloro-succinimide (NCS) or N-bromosuccinimide (NBS) in 93% sulfuric acid at
ambient temperature. The 3,5,6,7-tetrahalo-8-quinolinols 3a,b were obtained by
halogenation with two equivalents of N-halosuccinimide (NXS) in acetic acid. For
the preparation of 3,5,7- (4a,b) and 5,6,7-trihalo-8-quinolinols (4c,d), the respective
monohalo-8-quinolinol [6] was reacted with two equivalents of NXS in glacial
Ã
Corresponding author. E-mail: clarke@fordham.edu

1076
H. Gershon et al.
Scheme 1
Scheme 2
acetic acid at ambient temperature (Scheme 1). The preparation of the 4,5,7-trihalo-
8-quinolinols 6a,b from the respective monohalo-8-quinolinols 5a,b [6] was
achieved in a manner similar to that employed for 4a±d (Scheme 2). Compounds 4a
and 4c were obtained previously as by-products from the chlorination of the
respective monochloro-5-sulfonic acids [3]. 1H and 13C NMR data characterize the
new compounds and are reported in the experimental section. Whereas all com-
pounds reported here are stable inde®nitely in the solid state, 6a,b and 7a,b were
unstable in DMSO solution; thus, spectra and antifungal activity had to be measured
using freshly prepared solutions in these cases.
Antifungal data for the ten tri- and tetrahalo-8-quinolinols are shown in Table 1.
In general, the compounds were highly fungitoxic. Except for M. cirinelloides,
almost all of them were more active than 8-quinolinol (1) against the other ®ve
fungi. Where comparisons are possible, all chloro derivatives were more inhibitory
than the corresponding bromo analogues, which is consistent with what has been
reported for the dichloro- and dibromo-8-quinolinols [4]. Comparisons can be made
of the activity of the compounds against A. niger and T. viride, since the minimal

Fungitoxicity of Polyhalo-8-quinolinols
1077
Table 1. Antifungal activity of trichloro-, tribromo-, tetrachloro-, and tetrabromo-8-quinolinols in
Sabouraud dextrose broth at 28ꢀC in shake culture after six days
3
3
Minimal Inhibitory Concentrations/mmol Á dm (mg Á cm
)
A. niger
A. oryzae
M. verrucaria
2a
4ab
6ac
4c
0.012 (3)
< 0.0040 (< 1)
0.025 (5)
< 0.0040 (< 1)a
< 0.0040 (< 1)
< 0.0040 (< 1)
< 0.0040 (< 1)
< 0.0035 (< 1)
< 0.0026 (< 1)
< 0.0026 (< 1)
0.0052 (2)
< 0.0040 (< 1)
< 0.0040 (< 1)
< 0.0040 (< 1)
< 0.0040 (< 1)
< 0.0035 (< 1)
< 0.0026 (< 1)
< 0.0026 (< 1)
< 0.0026 (< 1)
< 0.0026 (< 1)
< 0.0022 (< 1)
0.034 (5)
0.0080 (2)
< 0.0035 (< 1)
> 0.26 (> 100)
0.0052 (2)
0.026 (10)
0.018 (7)
3a
2b
4b
6bc
4d
3b
1d
< 0.0026 (< 1)
< 0.0022 (< 1)
0.12 (18)
> 0.22 (> 100)
0.14 (20)
T. viride
M. cirinelloides
T. mentagrophytes
2a
0.025 (5)
< 0.0040 (< 1)
0.025 (5)
> 0.40 (> 100)
> 0.40 (> 100)
> 0.40 (> 100)
> 0.40 (> 100)
> 0.35 (> 100)
> 0.26 (> 100)
> 0.26 (> 100)
> 0.26 (> 100)
> 0.26 (> 100)
> 0.22 (> 100)
0.17 (24)
< 0.0040 (< 1)
< 0.0040 (< 1)
< 0.0040 (< 1)
< 0.0040 (< 1)
< 0.0035 (< 1)
< 0.0026 (< 1)
< 0.0026 (< 1)
< 0.0026 (< 1)
< 0.0026 (< 1)
< 0.0026 (< 1)
0.041 (6)
4ab
6ac
4c
0.028 (7)
3a
0.018 (5)
2b
4b
6bc
4d
3b
1d
> 0.26 (> 100)
< 0.0026 (< 1)
0.026 (10)
0.079 (30)
> 0.22 (> 100)
0.14 (20)
a
The symbol < indicates below 1 mg/cm3 (the lowest level tested), > indicates above 100 mg/cm3 (the
highest level tested); MICs from 1±10 were obtained in increments of 1 and from 10±100 in increments
b
c
of 10; Ref. [3]; for reproducible results, fresh solutions had to be prepared for each test (cf. text);
ddata taken from Ref. [6].
inhibitory concentrations were above 1 mg=cm3, and relationships might be deter-
mined. When the fungitoxicity of the dichloro-8-quinolinols [3] is compared with
that of the trichloro compounds containing substituents in positions corresponding
to those in the dichloro-8-quinolinols, the dichloro compounds were almost always
more active than the trichloro analogues. The good activity of 3,5,6-trichloro-8-
quinolinol (2a) and its 3,5,6,7-tetrachloro analogue 3a should be noted as compared
with the corresponding tri- (2b) and tetrabromo (3b) analogues which do not inhibit
the fungi below 100 mg=cm3, the highest level tested. 3,6- and 5,7-dichloro-8-
quinolinols and their dibromo analogues form synergistic mixtures [2]. In view
of prior results concerning intramolecular synergism in mono- and dihalo-8-
quinolinols it might have been expected that the tri- and tetrahalo-8-quinolinols
would owe their activities to intramolecular synergism. Since this was not observed,
steric hindrance might be an explanation for the diminished fungitoxicity of the
latter groups of 8-quinolinols. If this is the case, it would suggest that position, size,

1078
H. Gershon et al.
and number of substituents will have to be considered in developing compounds
showing intramolecular synergism.
Experimental
Antifungal testing
Antifungal testing was performed in Sabouraud dextrose broth (Difco) according to Refs. [7±10]. The
fungi employed included Aspergillus niger (ATCC 1004), Aspergillus 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. Purity and identity of
samples were established by 1H and 13C NMR spectroscopy at 300 and 75 MHz with a Bruker DPX-
300 spectrometer using DMSO-d6 as solvent and TMS as internal standard. Elemental analysis
matched the calculated values satisfactorily for 2a, 3a, 6a (C, H, Cl, N), 2b, 3b, 6b (C, H, Br, N), 7a
(C, H, Cl, N, S), and 7b (C, H, Br, N, S).
3,5,6-Trichloro-8-quinolinol (2a; C9H4Cl3NO)
1a [5] (1.22 g, 0.006 mol) dissolved in 25 cm3 of 93% H2SO4 was reacted with NCS (0.88 g,
0.0066 mol) under stirring at ambient temperature overnight. The solution was poured into 300 cm3 of
deionized H2O and stirred for 10 min. 2a was obtained by ®ltration, washing with deionized H2O, and
drying at 50ꢀC.
1
Yield 1.4 g (93%); m.p.: 207±208ꢀC (CH3CN); H NMR: ꢀ ˆ 8.91 (d, J24 ˆ 1:94 Hz, H-2), 8.50
(d, H-4), 7.27 (s, H-7), 11.01 (s, OH) ppm; 13C NMR: ꢀ ˆ 153.70 (C-8), 147.69 (C-2), 136.13 (C-8a),
131.81 (C-6), 130.73 (C-4), 130.48 (C-3), 127.11 (C-4a), 115.53 (C-5), 113.19 (C-7) ppm.
3,5,6-Tribromo-8-quinolinol (2b; C9H4CBr3NO)
2b was prepared from 1b [5] by reaction with NBS in the same manner as 2a was obtained from 1a.
Yield: 90% (0.002 mol run); m.p.: 235±236ꢀC (EtOH, 2x); 1H NMR: ꢀ ˆ 8.94 (d, J24 ˆ 1:53 Hz,
H-2), 8.59 (d, H-4), 7.44 (s, H-7), 3.63 (bs, OH and H2O) ppm; 13C NMR: ꢀ ˆ 154.10 (C-8), 149.47
(C-2), 136.76 (C-4), 136.55 (C-8a), 125.40 (C-3), 120.02 (C-6), 125.16 (C-4a), 116.40 (C-5), 109.67
(C-7) ppm.
3,5,7-Trichloro-8-quinolinol (4a; C9H4Cl3NO)
Preparation and NMR spectra of 4a have been described previously [3].
3,5,7-Tribromo-8-quinolinol (4b; C9H4Br3NO)
To a solution of 3-bromo-8-quinolinol [6] (1.5 g, 0.0067 mol) in 150 cm3 of acetic acid at 60ꢀC, NBS
(2.6 g, 0.015 mol) was added, and the mixture was stirred for 5 days. The solution was poured into
500 cm3 of deionized H2O with stirring. The product was obtained by ®ltration, washing with
deionized H2O, and air drying.

Fungitoxicity of Polyhalo-8-quinolinols
1079
1
Yield: 2.7 g (98%); m.p.: 170ꢀC (CH3CN; Ref. [11]: m.p.: 170ꢀC, yield not given); H NMR:
ꢀ ˆ 8.80 (d, J24 ˆ 2:20 Hz, H-2), 8.50 (d, H-4), 8.05 (s, H-6), 11.80 (s, OH) ppm; 13C NMR:
ꢀ ˆ 154.61 (C-8), 149.98 (C-2), 137.32 (C-4), 137.07 (C-8a), 129.76 (C-6), 125.88 (C-4a), 120.50
(C-3), 116.91 (C-5), 110.09 (C-7) ppm.
4,5,7-Trichloro-8-quinolinol (6a; C9H4Cl3NO)
6a was prepared from 4-chloro-8-quinolinol [6] (2.0 g, 0.011 mol) in 200 cm3 of acetic acid by stirring
for 6 days at room temperature with NCS (3.2 g, 0.024 mol). The solution was diluted with 1000 cm3
of deionized H2O, and the product was recovered by ®ltration, washing with deionized H2O, and
drying at 50ꢀC.
1
Yield: 3.1 g (98%); m.p.: 154ꢀC (CH3CN); H NMR: ꢀ ˆ 8.82 (d, J23 ˆ 4:68 Hz, H-2), 7.84 (d,
H-3), 7.82 (s, H-6), 11.02 (s, OH) ppm; 13C NMR: ꢀ ˆ 149.48 (C-8), 148.92 (C-2), 140.32 (C-4),
140.64 (C-8a), 131.51 (C-6), 125.84 (C-3), 121.72 (C-4a), 116.94 (C-5), 116.11 (C-7) ppm.
4,5,7-Tribromo-8-quinolinol (6b; C9H4Br3NO)
6b was prepared from 4-bromo-8-quinolinol [6] in the same manner as 6a was obtained from
4-chloro-8-quinolinol.
Yield: 1.2 g (70%); m.p.: 150±151ꢀC (CH3CN); 1H NMR: ꢀ ˆ 8.67 (d, J23 ˆ 4:43 Hz, H-2), 8.12
(d, H-3), 8.15 (s, H-6), 11.06 (s, OH) ppm; 13C NMR: 151.46 (C-8), 148.43 (C-2), 140.10 (C-8a),
137.70 (C-6), 130.91 (C-4), 130.29 (C-3), 123.79 (C-4a), 105.59 (C-5), 105.39 (C-7) ppm.
5,6,7-Trichloro-8-quinolinol (4c; C9H4Cl3NO)
4c was prepared from 6-chloro-8-quinolinol [6] as 6a was obtained from 4-chloro-8-quinolinol.
Yield: 99% (0.011 mol run); m.p.: 213±214ꢀC (CH3CN; Ref. [12]: m.p.: 213±214ꢀC, Ref. [13]:
m.p.: 220±225ꢀC, yields not given); NMR data: see Ref. [3].
5,6,7-Tribromo-8-quinolinol (4d; C9H4Br3NO)
4d was prepared from 6-bromo-8-quinolinol [6] as 6a was obtained from 6-chloro-8-quinolinol.
Yield: 97% (0.009 mol run); m.p.: 196ꢀC (CH3CN; Ref. [11]: m.p.: 192ꢀC, yield not given); H
1
NMR: ꢀ ˆ 8.98 (dd, J23 ˆ 4:11 Hz, J24 < 1 Hz, H-2), 8.63 (dd, H-4), 11.48 (s, OH) ppm; 13C NMR:
ꢀ ˆ 152.16 (C-8), 149.85 (C-2), 137.67 (C-8a), 136.67 (C-4), 127.14 (C-4a), 127.01 (C-6), 124.57
(C-3), 112.00 (C-5), 108.63 (C-7) ppm.
3,5,6,7-Tetrachloro-8-quinolinol (3a; C9H3Cl4NO)
1a [5] (1.1 g, 0.005 mol) was dissolved in acetic acid (100 cm3) to which NCS was added (1.4 g,
0.0105 mol); the mixture was stirred overnight at 40ꢀC. The solution was diluted with 500 cm3 of
deionized H2O. 3a was removed by ®ltration, washed with deionized H2O, and dried at 50ꢀC.
Yield: 1.39 g (98%); m.p.: 159±160ꢀC (CH3CN); 1H NMR: ꢀ ˆ 8.91 (d, J24 ˆ 2:22 Hz, H-2), 8.39
(d, H-4), 11.68 (s, OH) ppm; 13C NMR: ꢀ ˆ 150.83 (C-8), 148.78 (C-2), 135.41 (C-8a), 131.38 (C-6),
131.19 (C-4), 130.87 (C-3), 125.18 (C-4a), 117.19 (C-5), 116.55 (C-7) ppm.
3,5,6,7-Tetrabromo-8-quinolinol (3b; C9H3Br4NO)
3b was prepared from 1b [5] by bromination with NBS in the same manner as 3a was obtained
from 1a.

1080
H. Gershon et al.: Fungitoxicity of Polyhalo-8-quinolinols
1
Yield: 93% (0.0033 mol run); m.p.: 199±201ꢀC (CH3CN); H NMR: ꢀ ˆ 8.96 (d, J24 ˆ 2:04 Hz,
H-2), 8.58 (d, H-4), 11.69 (s, OH) ppm; 13C NMR: ꢀ ˆ 152.19 (C-8), 150.16 (C-2), 137.46 (C-4),
136.35 (C-8a), 128.65 (C-4a), 127.57 (C-6), 120.11 (C-3), 110.62 (C-5), 109.64 (C-7) ppm.
3,6-Dichloro-8-quinolinol-5-sulfonic acid (7a; C9H5Cl2NO4S)
1a [5] (2.0 g, 0.009 mol) was added to 14 cm3 of 20% oleum, and the mixture was heated with stirring
to 100ꢀC for 15 min. It was refrigerated overnight and poured into an ice-H2O slurry with stirring. The
crystallized material was separated by ®ltration, washed with H2O, boiled twice with acetone, and
®ltered again.
Yield: 2.0 g (73%); m.p.: 258±259ꢀC (DMSO aq.); H NMR: ꢀ ˆ 9.83 (d, H-4), 8.88 (d, J24
ˆ
1
2:22 Hz, H-2), 7.98 (s, OH), 7.10 (s, H-7) ppm; 13C NMR: ꢀ ˆ 153.50 (C-8), 145.83 (C-2), 135.70
(C-4), 134.76 (C-8a), 132.06 (C-5), 130.90 (C-6), 128.61 (C-3), 127.70 (C-4a), 114.50 (C-7) ppm.
3,6-Bromo-8-quinolinol-5-sulfonic acid (7b; C9H5Br2NO4S)
7b was prepared from 1b [6] in the same manner as the above dichloro analogue.
Yield: 68% (0.006 mol run); m.p.: 257±258ꢀC (aqueous DMSO); 1H NMR: ꢀ ˆ 8.96 (d,
J24 ˆ 1:90 Hz, H-2), 10.01 (d, H-4), 8.16 (s, OH), 7.20 (s, H-7) ppm; 13C NMR: ꢀ ˆ 155.50 (C-8),
148.83 (C-2), 137.10 (C-4), 137.9 (C-8a), 136.0 (C-5), 128.61 (C-3), 126.0 (C-4a), 118.6 (C-6), 116.6
(C-7) ppm.
Acknowledgements
Partial support for this work was provided by the National Science Foundation's Division of
Undergraduate Education through grant DUE #9650684.
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Received April 3, 2001. Accepted April 10, 2001