November 2003
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triphenylmethane derivatives described here revealed a wide
range of significant anti-HSV-1 activity. In addition, there are
a great many combinations of starting phenols and aromatic
aldehydes to provide a considerable number of target com-
pounds. Considering the results described in this paper, to-
gether with the information in our previous report on 2,2Ј-di-
hydroxytriphenylmethanes,2) further study is warranted.
3,3
-Dibromo-4؆-trifluotomethyl-4,4
-dihydroxytriphenylmethane (2d)
(Method D) A mixture of PPA (66 mmol), 2,6-dibromophenol (4 mmol),
and 4-(trifluoromethyl)benzaldehyde (2 mmol) was heated at 85 °C for 1 d.
Ice-water (40 ml) was added to the resulting mixture, which was then ex-
tracted with ether (40 mlϫ3), washed with brine (5 ml), and dried over
MgSO4. After evaporation of the solvent, centrifugal chromatography (n-
hexane–AcOEt) gave 2d. Recrystallization from cyclohexane gave pale yel-
low crystals.
The reaction conditions, yields, physical data, and spectroscopic (1H- and
13C-NMR) data on 1—3 are summarized in Table 1—3.
Experimental
Antiviral Activity Assay The antiviral activities of the compounds were
measured by plaque reduction assays3) as described below. Confluent mono-
layers of Vero cells (5ϫ105 cells) in 6-well plastic plates were infected with
100 PFU of HSV-1 (KOS). After a 1 h adsorption period at 37 °C, the cul-
tures were overlaid with 2 ml of DULBECCO’s modified Eagle’s minimum
essential medium (DMEM) containing 2% heat-inactivated fetal calf serum
and various concentrations of the target compounds. The cultures infected
with HSV-1 were incubated in a CO2 incubator, fixed with formalin and
stained with crystal violet in methanol at 3 d after infection. After washes
with water and drying, the plaques were enumerated. Calculated EC50 values
for the tested compounds are summarized in Table 4. Roughly estimated cy-
totoxicity (CC50) values obtained from the dose for inhibition of Vero cell
culture are recorded in the Notes.9)
Melting points were determined using a micro melting point apparatus
(Yanagimoto MP-S3) without correction. IR spectra were measured with a
Shimadzu FTIR-8100 IR spectrophotometer. Low- and high-resolution mass
spectra (LR-MS and HR-MS) were taken with a JEOL JMS HX-110 double-
focusing model equipped with a FAB ion source interfaced with a JEOL
1
JMA-DA 7000 data system. H- and 13C-NMR spectra were obtained on a
JEOL JNM A-500. Chemical shifts were expressed in d ppm downfield
from an internal tetramethylsilane (TMS) signal for 1H-NMR and the carbon
signal of the corresponding solvent [CDCl3 (77.0 ppm) and DMSO-d6
(39.5 ppm)] for 13C-NMR. Microanalyses were performed with a Yanaco
MT-6 CHN corder. Routine monitoring of reactions was carried out using
precoated Kieselgel 60F254 plates (E. Merck). Centrifugal chromatography
was performed on silica gel (Able-Biott) with a UV detector. Commercially
available starting materials were used without further purification.
Acknowledgments We thank Mr. Jun Taniguchi for technical assistance.
4,4
-Dihydroxy-4؆-methylthiotriphenylmethane (1b) (Method A) To
a melted mixture of phenol (6 mmol) and 4-(methylthio)benzaldehyde (3
mmol) was added TFA (3 mmol). After stirring for 2 d at room temperature,
TFA was removed under reduced pressure. The residue was purified by chro-
matography (CH2Cl2–EtOH as solvent) to yield 1b as bright reddish crys-
tals. The compounds 2a and 4,4Ј,4Љ-trihydroxy-3Љ-methoxytriphenylmethane
(3) were prepared using substantially the same procedure changing only the
molar ratio of phenol : aldehyde : TFA (see Table 1).
4؆-Chloro-4,4
-dihydroxytriphenylmethane (2a) (Method B) To a so-
lution of phenol (4 mmol) and 4-chlorobenzaldehyde (2 mmol) in AcOH
(0.9 ml) was added conc. H2SO4 (4 mmol) and the mixture was stirred for
1 h. The reaction mixture was poured into ice-water (10 ml) and extracted
with ether (30 mlϫ3). The organic layer was washed with brine and dried
(Na2SO4). After evaporation, centrifugal chromatography (CH2Cl2 as sol-
vent) gave 2a as pale yellow oil. The compounds 2b and 3,3Ј-dichloro-4Љ-tri-
fluotomethyl-4,4Ј-dihydroxytriphenylmethane (2c) were also prepared using
this method (see Table 1).
References and Notes
1) Mibu N., Sumoto K., Chem. Pharm. Bull., 48, 1810—1813 (2000).
2) Sumoto K., Mibu N., Yokomizo K., Uyeda M., Chem. Pharm. Bull.,
50, 298—300 (2002).
3) Schinazi R. F., Peters J., Williams C. C., Chance D., Nahmias A. J.,
Antimicrob. Agents Chemother., 22, 499—507 (1982).
4) Lee C.-H., Lindsey J. S., Tetrahedron, 50, 11427—11440 (1994).
5) Driver J. E., Sousa J. B., J. Chem. Soc., 1954, 985—989.
6) The yields shown in Table 1 (method A) may not be crucial. Some
other reaction conditions employed in the preparation of 2a gave lower
yields. Alteration of the molar ratio of reactants including TFA [phe-
nol : aldehyde : TFAϭ4 : 1 : 89] gave a 52% yield, and we could not iso-
late the target 2a using TiCl2(OiPr)2 or Lewatit K2621, because of
complex reactions including polymerization.
7) Desideri N., Oliveri S., Stein M. L., Sgro R., Orsi N., Conti C., Antivi-
ral Chem. Chemother., 8, 545—555 (1997).
8) Shigeta S., Mori S., Kira T., Takahashi K., Kodama E., Konno K.,
Nagata T., Kato H., Wakayama T., Koike N., Saneyoshi M., Antiviral
Chem. Chemother., 10, 195—209 (1999).
9) The other CC50 values estimated are 10—20, 5—10, and 10—
20 mg/ml for 2b, 2c, and 2d, respectively.
10) Bacon T. H., Howard B. A., Spender L. C., Boyd M. R., J. Antimicrob.
Chemother., 37, 303—313 (1996).
4؆-Trifluoromethyl-4,4
-dihydroxytriphenylmethane (2b) (Method C)
A
solution of phenol (20 mmol) and 4-(trifluoromethyl)benzaldehyde
(5 mmol) in absolute ether (40 ml) was degassed for 20 min, and then
BF3·OEt2 (5 mmol) was injected. After refluxing for 1 d, the resulting solu-
tion was diluted with ether (100 ml) and immediately washed with 0.1 M
aqueous NaOH (50 ml). The organic layer was washed with water and dried
(MgSO4), then evaporated under reduced pressure. Purification by chro-
matography (n-hexane–EtOAc as solvent) afforded 2b. A yellow powder was
obtained by dissolving in benzene and keeping the preparation at room tem-
perature.
Mibu, Nobuko
