Preparation and antifungal activity of 3-Iodo- and 6-Iodo-8-quinolinols

Article abstract of DOI:10.1007/s00706-002-0495-6

3-Iodo- and 6-Iodo-8-quinolinols were prepared and tested against six fungi: Aspergillus niger, A. oryzae, Myrothecium verrucaria, Trichoderma viride, Mucor cirinelloides, and Trichophyton mentagrophytes in Sabouraud dextrose broth. A comparison with the previously known 5-iodo- and 7-iodo-8-quinolinols showed that the 6-iodo isomer was the most active.

Full text of DOI:10.1007/s00706-002-0495-6

Monatshefte f€ur Chemie 133, 1325–1330 (2002)
DOI 10.1007/s00706-002-0495-6
Preparation and Antifungal Activity
of 3-Iodo- and 6-Iodo-8-quinolinols
Herman Gershon1;2;ꢀ, Donald D. Clarke1, John J. McMahon1,
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 15, 2002; accepted June 11, 2002
Published online September 2, 2002 # Springer-Verlag 2002
Summary. 3-Iodo- and 6-Iodo-8-quinolinols were prepared and tested against six fungi: Aspergillus
niger, A. oryzae, Myrothecium verrucaria, Trichoderma viride, Mucor cirinelloides, and Trichophyton
mentagrophytes in Sabouraud dextrose broth. A comparison with the previously known 5-iodo- and
7-iodo-8-quinolinols showed that the 6-iodo isomer was the most active.
Keywords. 3-Iodo-8-quinolinol; 6-Iodo-8-quinolinol; Antifungal activity.
Introduction
A monoiodo-8-quinolinol (m.p. 127–128ꢁC) had been reported in 1927 [1]. Al-
though the structure had not been established, it had been accepted as ‘‘5-iodo-8-
quinolinol’’. Because of our interest in the antifungal activities of halo-8-quinolinols,
we prepared what we believed to be ‘‘7-iodo-8-quinolinol’’ (m.p. 112–113ꢁC) [2].
This structure was assigned because the two monoiodo-8-quinolinols had different
melting points and a mixture of the two resulted in a depressed melting point.
In 1995 a monoiodo-8-quinolinol (m.p. 135ꢁC) had been prepared by a proce-
dure similar to that for ‘‘5-iodo-8-quinolinol’’ and had been reported to be 7-iodo-
1
8-quinolinol [3]. The assignment of structure had been based on the H decoupled
13C NMR spectrum, which we found to be similar to that of the spectrum of
‘‘5-iodo-8-quinolinol’’. To establish unequivocally which of these compounds was
5- or 7-iodo-8-quinolinol, a crystal of monoiodo-8-quinolinol (m.p. 127–128ꢁC)
suitable for X-ray crystal structure determination had been prepared. It was found
that this compound was in fact, 7-iodo-8-quinolinol [4]. Consequently, the
monoiodo-8-quinolinol, m.p. 112–113ꢁC was really 5-iodo-8-quinolinol.
Because of our interest in the antifungal properties of the halo-8-quinolinols,
we undertook the preparation of 3-iodo- and 6-iodo-8-quinolinols.
ꢀ
Corresponding author. E-mail: clarke@fordham.edu

1326
H. Gershon et al.
Results and Discussion
For the preparation of 3-iodo-8-quinolinol, the methods employed in the synthesis
of the 3-chloro and 3-bromo analogues [5] were used. 8-Nitroquinoline (1) was
iodinated at position 3 with N-iodosuccinimide (NIS), the nitro group reduced,
and the amino group hydrolysed to yield 3-iodo-8-quinolinol (4) (Scheme 1) in
an overall yield of 55% starting from 1.
6-Chloro and 6-bromo-8-quinolinols have been prepared in high yield from their
respective 8-aminoquinolines by hydrolysis with 70% sulfuric acid at 220ꢁC [5].
However the same route was unsuccessful for the preparation of 6-fluoro-8-quino-
linol. The product of that hydrolysis was not volatile on steam distillation and has
not been characterized [6]. Since in aromatic bimolecular substitution the order of
halogen as a leaving group is F>I>Br>Cl, it was thought that some 6-iodo-8-
quinolinol (11) might survive the sulfuric acid hydrolysis conditions of 8-amino-6-
iodoquinoline (7). 4-Iodo-2-nitroaniline (5) was prepared from 2-nitroaniline by
iodination with NIS. A Skraup synthesis starting with 5 yielded 6-iodo-8-nitroquino-
line (6), which was reduced to the 8-amino analogue 7 and hydrolyzed with 70%
sulfuric acid at 220ꢁC. No volatile product was obtained on steam distillation
(Scheme 2).
A Skraup synthesis starting with 2-amino-5-fluorophenol [7] has yielded the
desired 6-fluoro-8-quinolinol [7]. We thus decided to use a similar approach for
Scheme 1
Scheme 2

3-Iodo- and 6-Iodo-8-quinolinols
1327
Scheme 3
Table 1. Comparison of the antifungal activity of 3-iodo-, 5-iodo-, 6-iodo-, and 7-iodo-8-quinolinols
in Sabouraud dextrose broth at 28ꢁC in shake culture after six days
8-Quinolinol
Minimal inhibitory concentrations=[mmol ꢂ dmꢃ 3 (ꢀgcmꢃ 3)]
A. niger
A. oryzae
M. verrucaria
3-iodo (4)
5-iodoa
0.033 (9)
0.015 (4)
0.026 (7)
0.0074 (2)
0.011 (3)
0.0074 (2)
0.0074 (2)
<0.0037 (<1)b
<0.0037 (<1)b
0.018 (5)
<0.0037 (<1)b
0.0074 (2)
6-iodo (11)
7-iodoa
8-Quinolinol
T. viride
M. cirinelloides
T. mentagrophytes
3-iodo (4)
5-iodoa
0.030 (8)
0.030 (8)
0.0074 (2)
0.015 (4)
0.15 (40)
0.15 (40)
0.037 (10)
0.037 (10)
0.018 (5)
0.0074 (2)
<0.0037 (<1)b
<0.0037 (<1)b
6-iodo (11)
7-iodoa
Taken from Refs. [8, 9]; b < indicates below 1 mg=cm3 (the lowest level tested); MICs from 1–10
were obtained in increments of 1 and from 11–20 in increments of 2 mg=cm3
a
the preparation of 6-iodo-8-quinolinol (11). Iodination of benzoxazolinone-2 (9)
with NIS yielded 6-iodo-benzoxazolinone-2 (10) which was hydrolyzed to 2-
amino-5-iodophenol in situ under the conditions of the Skraup synthesis, and was
then converted to 11 (Scheme 3). The over-all yield from 9 was 2.7%, and the
amount obtained was 0.3 g, which was sufficient for characterization, antifungal
evaluation, and preparation of the copper(II) biscomplex, which will be part of
the subject for further study.
Table 1 contains the antifungal data of the four monoiodo-8-quinolinols against
the six fungi in our test system: Aspergillus niger, A. oryzae, Myrothecium verru-
caria, Trichoderma viride, Mucor cirinelloides, and Trichophyton mentagrophytes.
Compound 11, with the iodine in the 6 position, was the most fungitoxic of the four
iodo analogues. This is consistent with the results for the 6-fluoro- [6] and for 6-
chloro- and 6-bromo-8-quinolinols [10].
Experimental
Antifungal testing
Antifungal testing was performed in Sabouraud dextrose broth (Difco) according to published methods
[8, 11–13]. The six fungi employed included Aspergillus niger (ATCC 1004), A. oryzae (ATCC 1011),
Myrothecium verrucaria (ATCC 9095), Trichoderma viride (ATCC 8678), Mucor cirinelloides (ATCC
7941), Trichophyton mentagrophytes (ATCC 9129).

1328
H. Gershon et al.
General
Melting points were taken on a Thomas-Hoover apparatus and are uncorrected. 8-Nitroquinoline and
benzoxazolinone-2 were purchased from Aldrich. Reactions were monitored by gas chromatography
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 feetꢄ 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 75 MHz with a Bruker DPX-300 spectrometer using DMSO-d6 as solvent and TMS as
internal standard. Elemental analyses matched the calculated values satisfactorily for 2–4 (C, H, I, N).
3-Iodo-8-nitroquinoline (2; C9H5IN2O2)
Compound 1 (34.8g, 0.2 mol) was dissolved in 450cm3 acetic acid and 34.6g NIS (0.2mol) was added
in portions over 1 h at near boiling. Heating under reflux was continued for 5 min, and let stir for 2 h at
ambient temperatures. The solution was poured into 5000 cm3 H2O with stirring, and adjusted to pH 6
with NH4OH. Product 2 was removed by filtration, washed with deionized H2O, and air dried. Yield:
50.8g (93%); m.p. 119–120ꢁC (aq alc); 1H NMR (300MHz, ꢁ, DMSO-d6): 9.15 (d, J24 ¼ 1.91Hz, H-
2), 8.96 (d, H-4), 8.31 (d, J57 ¼ 2.74Hz, H-7), 8.17 (d, H-5), 7.81 (t, J56 ¼ 8.29Hz, J67 ¼ 7.42Hz, H-6)
ppm; 13C NMR (75 MHz, ꢁ, DMSO-d6): 157.40 (C-2), 147.39 (C-8), 143.96 (C-4), 136.39 (C-8a),
131.33 (C-5), 129.64 (C-4a), 126.78 (C-6), 124.00 (C-7), 92.96 (C-3) ppm.
8-Amino-3-iodoquinoline (3; C9H7IN2)
To a solution of 15g (0.05 mol) of 2 in 670 cm3 ethanol was added 10.5 g Fe powder (0.19 g atom) and
1 cm3 HCl. The mixture was stirred vigorously under reflux for 3 h. The solids were removed by
filtration, and the filtrate was poured into 5000cm3 H2O with stirring. After 15min, the precipitate was
1
recovered by filtration, washed with H2O and air dried. Yield: 12.5g (93%); m.p. 129ꢁC (aq alc); H
NMR (300 MHz, ꢁ, DMSO-d6): 8.87 (d, J24 ¼ 2.02 Hz, H-2), 8.64 (d, H-4), 7.37 (t, J56 ¼ 7.85 Hz,
J67 ¼ 7.86Hz, H-6), 7.03 (d, H-5), 6.99 (d, H-7), 3.93 (s, NH2) ppm; 13C NMR (75 MHz, ꢁ, DMSO-d6):
151.56 (C-2), 145.15 (C-8), 143.26 (C-4), 135.25 (C-8a), 130.29 (C-4a), 128.69 (C-6), 112.93 (C-5),
109.61 (C-7), 90.83 (C-3) ppm.
3-Iodo-8-quinolinol (4; C9H6INO)
A mixture of 8.1g (0.03 mol) of 3, 14.3cm3 H2O, and 9.5cm3 H2SO4 in a glass tube was sealed in
a stainless steel pressure vessel containing a small amount of H2O. The pressure vessel was heated
at 220ꢁC for 8 h. After cooling to room temperature, the contents of the glass tube were poured into
800 cm3 deionized H2O, brought to pH 6–7 with NH4OH, and steam distilled. The solid product 4 was
obtained by filtration and air dried. The distillate was reduced to half its volume under a stream of air
and steam distilled a second time. An additional yield of 4 was obtained and air dried. Yield: 5.2 g
1
(64%); m.p. 139–141ꢁC (CH3CN); H NMR (300 MHz, ꢁ, DMSO-d6): 8.99 (d, J24 ¼ 1.97 Hz, H-2),
8.82 (d, H-4), 7.51 (dd, J56 ¼ 7.90Hz, H-6), 7.37 (d, H-5), 7.17 (d, J67 ¼ 7.45 Hz, H-7) ppm; 13C NMR
(75 MHz, ꢁ, DMSO-d6): 153.78 (C-8), 153.18 (C-2), 143.94 (C-4), 136.89 (C-8a), 130.90 (C-4a),
128.98 (C-6), 117.33 (C-5), 112.75 (C-7), 91.64 (C-3) ppm.
4-Iodo-2-nitroaniline (5; C6H5IN2O2)
A mixture of 330 cm3 acetic acid, 27.6g (0.2mol) 2-nitroaniline, and 47g (0.21 mol) NIS was heated to
95ꢁC over 1 h until the starch-iodide test was negative. The reaction mixture was poured into 3000cm3
H2O, stirred 15 min, and the solids removed by filtration, washed with H2O and air dried. Yield: 52.6g
1
(quant); m.p. 123–124ꢁC (95% alc) (Ref. [14] m.p. 122ꢁC, yield not given); H NMR (300 MHz, ꢁ,

3-Iodo- and 6-Iodo-8-quinolinols
1329
DMSO-d6): 8.22 (d, J35 ¼ 1.96 Hz, H-3), 7.61 (dd, H-5), 7.59 (s, NH2), 6.89 (d, J56 ¼ 8.96 Hz, H-6)
ppm; 13C NMR (75 MHz, ꢁ, DMSO-d6): 145.54 (C-1), 143.06 (C-5), 132.87 (C-3), 131.30 (C-2),
121.46 (C-6), 74.75 (C-4) ppm.
6-Iodo-8-nitroquinoline (6; C9H5IN2O2)
A mixture was prepared of 10 g H2SO4 (0.1mol), 10g glycerol (0.11 mol), and 5 g As2O5 (0.022mol)
and warmed with stirring until a solution was formed. 5 g of compound 5 (0.02 mol) was added in
portions with stirring and continued heating. The mixture was refluxed for 3 h, cooled and poured into
450 cm3 H2O with stirring. The solids were removed by filtration, and the filtrate adjusted to pH 7 with
NH4OH. The precipitate was filtered off, washed with H2O and air dried. Yield: 12g (50%); m.p. 175–
1
177ꢁC (95% alc) (Ref. [15] m.p. 180ꢁC (alc), yield 53%); H NMR (300MHz, ꢁ, DMSO-d6): 9.06
(q, J23 ¼ 4.20 Hz, J24 ¼ 1.47Hz, H-2), 8.75 (d, H-7), 8.50 (d, J57 ¼ 1.70 Hz, H-5), 8.45 (q, H-4), 7.78
(d, J34 ¼ 7.00Hz, H-3) ppm; 13C NMR (75 MHz, ꢁ, DMSO-d6): 153.05 (C-2), 147.83 (C-8), 140.18
(C-5), 137.26 (C-8a), 135.47 (C-4), 130.66 (C-7), 130.04 (C-4a), 123.91 (C-3), 89.87 (C-6) ppm.
8-Amino-6-iodoquinoline (7; C9H7IN2)
A mixture of 3 g 6 (0.01 mol), 2.1 g Fe powder (0.038mol), 135 cm3 95% alc, and 0.2 cm3 HCl was
heated under reflux for 3 h with vigorous stirring. The suspension was filtered while hot, and the filtrate
poured into 1000 cm3 H2O with stirring for 15 min. Product 7 was removed by filtration, washed with
H2O, air dried, and steam distilled. Yield: 2.3 g (85%); m.p. 108ꢁC (alc) (Ref. [15] m.p. 108ꢁC (alc),
yield 58%); 1H NMR (300 MHz, ꢁ, DMSO-d6): 8.74 (q, J24 ¼ 1.65Hz, H-2), 8.12 (q, J34 ¼ 8.31 Hz, H-
4), 7.47 (d, J57 ¼ 2.74 Hz, H-5), 7.17 (q, H-3) 6.20 (d, H-7) ppm; 13C NMR (75 MHz, ꢁ, DMSO-d6):
147.31 (C-2), 146.62 (C-8), 136.35 (C-8a), 134.62 (C-4), 130.02 (C-4a), 122.21 (C-5), 121.48 (C-3),
116.14 (C-7), 94.25 (C-6) ppm. 1H NMR (300 MHz, ꢁ, CDCl3): 8.72 (q, J23 ¼ 4.16, J24 ¼ 1.52 Hz, H-
2), 7.90 (q, J34 ¼ 8.31 Hz, H-4), 7.49 (d, J57 ¼ 1.51Hz, H-5), 7.34 (q, H-3), 7.15 (d, H-7), 5.06 (s, NH2)
ppm; 13C NMR (75 MHz, ꢁ, DMSO-d6): 147.58 (C-2), 144.89 (C-8), 1337.26 (C-8a), 134.76 (C-4),
130.12 (C-4a), 124.41 (C-5), 1222.07 (C-3), 118.13 (C-7), 93.36 (C-6) ppm.
Unidentified (8)
Compound 7 (5.4g, 0.02mol) and 50 cm3 70% H2SO4 (w=w) in a glass container were sealed in a
stainless steel pressure vessel containing a small amount of H2O. The vessel was kept at 220ꢁC for 8 h
and cooled. The mixture was diluted with 500 cm3 H2O, adjusted to pH 6–7 with NH4OH, and steam
distilled. No volatile product was obtained, and the residue was not characterized.
6-Iodobenzoxazolinone-2 (10; C7H4INO2)
A mixture of 1.4 g (0.01 mol) benzoxazolinone-2, (9), 2.3g NIS (0.01 mol), and 200cm3 acetic acid
was stirred at ambient temperatures for 5 days and monitored by g.c. Additional NIS was added if
needed until all of 9 was iodinated. The solution was transferred to 1200 cm3 H2O, stirred for 15min,
and 10 was removed by filtration, washed with H2O and air dried. Yield: 2.4 g (96%); m.p. 217–218ꢁC
1
(95% alc) (Ref. [16] m.p. 211–212ꢁC, yield 12%); H NMR (300MHz, ꢁ, DMSO-d6): 8.88 (dd,
J23 ¼ 4.18Hz, J24 ¼ 1.01Hz, H-2), 8.29 (dd, J34 ¼ 8.37 Hz, H-4), 7.88 (d, J57 ¼ 1.39 Hz, H-5), 7.59
(dd, H-3), 7.38 (d, H-7) ppm; 13C NMR (75 MHz, ꢁ, DMSO-d6): 154.06 (C-2), 143.99 (C-1a), 132.36
(C-5), 130.15 (C-3a), 117.81 (C-7), 111.88 (C-4), 83.62 (C-6) ppm.
6-Iodo-8-quinolinol (11; C9H6INO)
A mixture of 20 g H2SO4 (0.2mol), 20.2g glycerol (0.22 mol), 10.1g As2O5 (0.044mol), and 10.4g 10
(0.04 mol) was prepared in that order with stirring. It was heated slowly until boiling, and kept under

1330
H. Gershon et al.: 3-Iodo- and 6-Iodo-8-quinolinols
reflux for 2 h. After cooling below 100ꢁC the liquid was poured into 250 cm3 deionized H2O, adjusted
to pH 6–7 with NH4OH, and steam distilled. The product 11 was obtained by filtration and air dried.
Yield: 0.3g (2.8%); m.p. 139–141ꢁC (CH3CN); HR-MS: calcd. for C9H6INO: 270.94942, found:
1
270.94856; H NMR (300MHz, ꢁ, DMSO-d6): 8.88 (dd, J23 ¼ 4.18 Hz, J24 ¼ 1.01Hz, H-2), 8.29
(dd, J34 ¼ 8.37 Hz, H-4), 7.88 (d, J57 ¼ 1.39Hz, H-5), 7.59 (dd, H-3), 7.38 (d, H-7) ppm; 13C NMR
(75 MHz, ꢁ, DMSO-d6): 153.86 (C-8), 148.59 (C-2), 137.40 (C-8a), 135.21 (C-4), 130.28 (C-4a),
126.28 (C-5), 122.63 (C-3), 119.84 (C-7), 93.03 (C-6) ppm.
Acknowledgments
Partial support for this work was provided by the National Science Foundation’s Division of Under-
graduate education through grant DUE #9650684.
References
[1] Matsumura (1927) J Am Chem Soc 49: 810
[2] Gershon H, McNeil MW (1971) J Heterocycl Chem 8: 129
[3] Ramelo CT, Faez R, Ribeiro CA, Crespi MS (1995) Ecl Quim Sao Paulo 20: 49
[4] Shoja M, Gershon H, Clarke DD (1997) Zeit Kristall NCS 212: 387
[5] Gershon H, Clarke DD (1991) Monatsh Chem 122: 935
[6] Gershon H, Clarke DD, Gershon M (2002) Monatsh Chem, in press
[7] Levy LA, Murphy E, Raju B, London RE (1988) Biochemistry 27: 4041
[8] Gershon H, Clarke DD, Gershon M (1989) J Pharm Sci 78: 975
[9] Gershon H, Clarke DD, Gershon M (1991) J Pharm Sci 80: 542
[10] Gershon H, Clarke DD, Gershon M (1994) Monatsh Chem 125: 51
[11] Gershon H, Shanks L (1981) Can J Microbiol 27: 612
[12] Gershon H, Grefig AT, Cady DJ (1985) Can J Microbiol 31: 707
[13] Gershon H, Clarke DD, Gershon M (1993) Monatsh Chem 124: 367
[14] Brennan P (1914) Compt Rend 158: 717
[15] Hamada Y, Sugihara H, Ito K, Tomamatsu S (1966) Yakugaki Zasshi 86: 224
[16] Eckstein Z, Zukowski E (1958) Przmsl Chem 37: 418