Synthesis and antimicrobial activity of 2-(4-halophenyl)-2-(oxyaryl)propanes

Full text of DOI:10.1023/A:1010495500525

Pharmaceutical Chemistry Journal
Vol. 34, No. 12, 2000
SYNTHESIS AND ANTIMICROBIAL ACTIVITY
OF 2-(4-HALOPHENYL)-2-(OXYARYL)PROPANES
D. A. Pisanenko,1 A. A. Grigorenko,2 and G. K. Palii2
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 34, No. 12, pp. 17 – 18, December, 2000.
Original article submitted April 17, 1990.
Antioxidants [1, 2] and drugs [3 – 4] have been designed
based on substituted phenols. But the antimicrobial proper-
ties of halophenols of the 2,2-diarylpropane series have not
been studied, and the multistep organomagnesium synthesis
for these compounds described in [5] is not very efficient.
When attempting to obtain phenols of this series more sim-
ply by catalytic arylalkylation of arenes with a-methyl-
styrene, dimerization of the olefin occurs [6] due to attack by
the cumyl cation on the nucleophilic multiple bond followed
by cyclization [7]. Obviously we can avoid dimerization by
introducing halogens, for which the I-effect predominates,
into the a-methylstyrene ring. This makes it possible to de-
crease the nucleophilicity of the C atoms of both the methy-
lene group and the aromatic ring, which is demonstrated for
the example of styrene and its substituted derivatives in [8].
In this paper, we describe the synthesis of
2-(4-halophenyl)-2-(oxyaryl)propanes by reaction of 4-ha -
lo-a-methylstyrenes with phenol or o-, m-, and p-cresols in
the presence of BF3×H3PO4 in CCl4 medium, and we study
their antimicrobial properties.
In GLC analysis of the reaction products, we do not ob-
serve dimers of the olefins. The products are chromatogra-
phically pure 2-(4-halophenyl)-2-(oxyaryl)propanes, whose
structure has been established with the help of elemental
analysis and IR spectroscopy. In the IR spectra of these com-
pounds, we see split bands at 805 – 832, 870 – 885 cm – 1
(1,4- and 1,2,4-substituted benzene), 1365 and 1380 cm – 1
(gem. dimethyl group). Absorption in the 545 – 710 cm – 1
region corresponds to the C–Cl, C–Br bonds, while the in-
tense absorption bands at 1225 – 1230 cm – 1 correspond to
the C–F bonds. The broad absorption bands for the OH group
appear in the 3400 – 3510 cm – 1 region, while for the reac-
tion products for reaction with m- and p-cresols, the stretch-
ing vibrations of the OH group give a narrow absorption
band at 3515 – 3525 cm – 1 which is typical for sterically hin-
dered o-substituted phenols.
CCl4
CH2
+
R1
TABLE 1. Physicochemical Constants for 2-(4-halophenyl)-2-
C
X
(oxyaryl)propanes
BF3 · H3PO4
R
CH3
m.p., °C
or b.p.,
°C (Torr)
Com-
pound
Empirical
formula
X
R
R¢
Yield, %
R1
R
C(CH3)2
X
I
F
F
H
4-OH
86
84
81
75
85
80
73
75
70
77
73
74
59
55
64
C15H15FO
C16H17FO
C16H17FO
II
3-Me 4-OH
4-Me 2-OH
5-Me 2-OH
I –XII
X = F, Cl, Br; R = Me, R1 = OH
III
IV
V
F
F
165 – 167(5) C16H17FO
Cl
Cl
Cl
Cl
Br
Br
Br
Br
H
4-OH
56[5]
86
C15H15ClO
C16H17ClO
C16H17ClO
By varying the mole ratios of the reagents and the catalyst,
the reaction temperature and the reaction time, we have es-
tablished that the maximum product yields can be obtained
for a styrene–phenol– BF3×H3PO4 mole ratio of 4 : 1 : 0.3, at a
temperature of 40°C and for a reaction time of 5 h.
VI
VII
VIII
IX
X
3-Me 4-OH
4-Me 2-OH
5-Me 2-OH
40
187 – 190(4) C16H17ClO
H
4-OH
84[5]
98
C15H15BrO
C16H17BrO
C16H17BrO
3-Me 4-OH
4-Me 2-OH
5-Me 2-OH
XI
XII
89
1
National Technical University of Ukraine, Kiev Polytechnical Institute.
2
218 – 219(8) C16H17BrO
Vinnits N. I. Pirogov State Medical University.
644
0091-150X/00/3412-0644$25.00 © 2001 Plenum Publishing Corporation

Synthesis and Antimicrobial Activity of 2-(4-Halophenyl)-2-(oxyaryl)propanes
645
ture was stirred at the same temperature for four more hours.
then water was added to decompose the catalyst and the or-
ganic layer was separated. It was treated with a 5% solution
of sodium hydroxide and water and then dried with MgSO4.
The solvent and unreacted materials were driven off and the
residue was distilled under vacuum; the solid products were
crystallized from ethanol.
TABLE 2. Antimicrobial Properties of Compounds I – XII (mini-
mum bacteriostatic concentrations, mg/ml)
S. aureus
E. coli
B. antracoides C. albicans
Compound
209
365
297
688
I
0.25
0.5
0.5
1.0
0.25
0.5
0.5
2.0
0.25
0.5
0.5
0.5
0.5
15.6
0.5
0.5
0.5
2.0
0.5
1.0
1.0
1.0
2.0
4.0
2.0
4.0
0.5
0.5
0.5
1.0
2.0
1.0
4.0
1.0
1.0
0.5
2.0
1.0
2.0
8.0
II
31.25
31.25
62.5
III
IV
V
EXPERIMENTAL BIOLOGICAL PART
15.6
VI
31.25
31.25
31.25
31.25
62.5
The antimicrobial activity of the synthesized compounds
was studied by the serial dilution method in liquid nutrient
medium; we used dimethylsulfoxide to prepare the initial so-
lutions of the compounds. We used collection and clinical
strains of Gram-positive and Gram-negative microorganisms
as the test microbes. The microbial load per mL nutrient me-
dium was up to 500,000 microbe bodies according to the tur-
bidity standard, depending on the species of microorganism
[9]. The minimum bacteriostatic concentrations for
dimethylsulfoxide ranged from 125,000 to 500,000 mg/ml.
The reference drug was decamethoxin.
VII
VIII
IX
X
XI
31.25
62.5
XII
Decamethoxin
31.25
As we see from Table 2, all the synthesized compounds
exhibit antimicrobial activity comparable with the action of
decamethoxin.
EXPERIMENTAL CHEMICAL PART
The IR spectra of compounds I – XII were recorded on a
UR-20; the liquid compounds were analyzed in a thin layer
and the solid compounds were analyzed in KBr disks. The
purity of the reaction products was established by GLC on a
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Tsvet-4 with flame-ionization detector (column 4 ´ 1000 mm
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4-Halo-a-methylstyrenes were obtained by dehydration
of alcohols synthesized by reaction of 4-haloacetophenones
with methylmagnesium iodide.
The catalyst BF3 × H3PO4 was prepared by impregnation
of anhydrous H3PO4 with boron fluoride [6]. 2-(4-Halophe-
nyl)-2-(oxyaryl)propanes (I – XII). 0.1 moles of 4-halo-a-
methylstyrene were added over a period of 1 h with stirring
to a mixture of 0.4 moles phenol or cresols and 0.03 moles of
catalyst in 20 ml CCl4, heated up to 40°C. The reaction mix-