Synthesis and antimicrobial properties of 4-(2-thiocyanato-3-arylpropionyloxy)butyl acrylates

Full text of DOI:10.1023/A:1012703203772

Pharmaceutical Chemistry Journal
Vol. 35, No. 7, 2001
SYNTHESIS AND ANTIMICROBIAL PROPERTIES
OF 4-(2-THIOCYANATO-3-ARYLPROPIONYLOXY)BUTYL ACRYLATES
B. D. Grishchuk,1 S. I. Klimnyuk,1 V. S. Baranovskii,2 O. V. Boichak,2 and P. M. Gorbovoi2
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 35, No. 7, pp. 26 – 27, July, 2001.
Original article submitted November 12, 2000.
Previously [1] we developed the synthesis of 1-thiocya-
nato-1-alkoxycarbonyl-2-arylethanes and showed that some
of these compounds possess antibacterial properties [2, 3].
Of certain interest in the search for new antibacterial
agents are 4-(2-thiocyanato-3-arylpropionyloxy)butyl acryla-
tes which can be obtained using reactions of aryldiazonium
tetrafluoroborates with 4-acryloyloxybutyl acrylate in the
presence of rhodanides. The process of thiocyanatoarylation,
involving a single multiple bond, leads to the formation of
4-(2-thiocyanato-3-arylpropionyloxy)butyl acrylates (I – III).
on of the 4-acryloyloxybutyl acrylate thiocyanatoarylation
reaction nor changes the target product yield. Thus, 4-acrylo-
yloxybutyl acrylate offers an example of the unsaturated
compound with molecules containing two like multiple
bonds in which the anionarylation process can proceed only
at one of these bonds.
The yields, physicochemical constants, data of elemental
1
analyses, and the parameters of the IR and H NMR spectra
of the synthesized 4-(2-thiocyanato-3-arylpropionyloxy)bu-
tyl acrylates are presented in Table 1.
O
The IR spectra display the characteristic absorption
bands due to carbonyl and thiocyanate groups in the region
of 1716 and 2152 – 2156 cm – 1, respectively. The multiple
bond of the terminal vinyl group is manifested by the absorp-
tion band at 1636 – 1640 cm – 1. The out-of-plane CH vibrati-
ons in this group can be assigned to narrow absorption bands
C
CH2
H2C
CH
O
CH2
+ MSCN
C
R
C6H4N2BF4
+
CH2 CH2
O
CH CH2
O
O
S
C N
C
CH2
CH2
CH2
C
H
O
C
O
CH2 CH2
O
CH CH2
in the region of 812 and 984 cm – 1
.
+ MBF4 + N2
The 1H NMR spectra of compounds I – III show the sig-
nals from protons of the aromatic nuclei in the form of a mul-
tiplet at 7.44 – 7.26 ppm. The signals from methylene pro-
tons of the terminal vinyl group are manifested as a doublet
of doublets in the region of 6.36 – 6.33 ppm (cis-H) and
5.98 – 5.93 ppm (trans-H) with spin – spin coupling cons-
tants J = 11 and 14 Hz, respectively. The signals from methi-
ne protons of the terminal vinyl group are manifested as a
doublet of doublet with a chemical shift of 6.18 – 6.16 ppm
and a spin – spin coupling constant of J = 10 Hz.
I – III
R
R = H (I), CH3 (II), NO2 (III); M = Na, K, NH4
The interaction of aryldiazonium tetrafluoroborates with
4-acryloyloxybutyl acrylate proceeds in a water – acetone
(1 : 2) mixture in the temperature interval from –10 to –5°C
in the presence of a catalytic amount of copper tetrafluorobo-
rate and alkali metal or ammonium rhodanide additives. The
catalyst is necessary for this reaction to proceed. The opti-
mum ratio of reagents is as follows: aromatic diazonium
salt – 4-acryloyloxybutyl acrylate – sodium (potassium, ammo-
nium) rhodanide – copper tetrafluoroborate, 1 : 1.2 : 1.3 : 0.1.
The side products in this reaction are arylisothiocyanates, the
yield of which amounts to 10 – 12 %.
EXPERIMENTAL CHEMICAL PART
The IR spectra of compounds I – III were recorded on a
Specord M80 spectrophotometer (Germany) using thin opti-
cal cells. The 1H NMR spectra were measured with a Varian
Gemini spectrometer (working frequency 300 MHz, internal
standard HMDS). The purity of the synthesized compounds
was checked by TLC on Silufol UV-254 plates and by co-
lumn chromatography using a Milikhrom-4 liquid chroma-
tograph equipped with an UV detector and a Separon
A twofold increase in the amount of diazonium salt, so-
dium (potassium, ammonium) rhodanide, or copper tetraflu-
oroborate against the optimum level neither alters the directi-
1
State Pedagogical University, Ternopol, Ukraine.
State Medical Academy, Ternopol, Ukraine.
2
373
0091-150X/01/3507-0373$25.00 © 2001 Plenum Publishing Corporation

374
B. D. Grishchuk et al.
TABLE 1. Yields and Physicochemical Characteristics of 4-(2-Thiocyanato-3-arylpropionyloxy)butyl Acrylates (I – III)
20
D
20
4
Com-
pound
Empirical
formula
1H NMR spectrum: d, ppm (J, Hz)
n
d
R
Yield, %
61
I
H
1.4928 1.1067
1.4980 1.0854
1.5112 1.1688
C17H19NO4S 7.34 – 7.26 (m, 5H, Ph), 6.33 (dd, JHH 11 Hz, H-cis, =CH2), 6.16 (dd, JHH 10 Hz,
1H, =CH–), 5.93 (dd, JHH 14 Hz, H-trans, =CH2), 4.50 (dd, JHH 7 Hz, 1H, CH),
4.11 (t, 4H, 2(–OCH2)), 3.35 (dd, JHH 8 Hz), 3.13 (dd, JHH 8 Hz, 2H, CH2Ph),
1.48 – 1.70 (m, 4H, –CH2–CH2–)
II
CH3
NO2
56
41
C18H21NO4S 7.36 – 7.26 (m, 4H, C6H4), 6.35 (dd, JHH 11 Hz, H-cis, =CH2), 6.18 (dd, JHH 10 Hz,
1H, =CH–), 5.97 (dd, JHH 14 Hz, H-trans, =CH2), 4.51 (dd, JHH 7 Hz, 1H, CH),
4.12 (t, 4H, 2(–OCH2)), 3.35 (dd, JHH 8 Hz), 3.12 (dd, JHH 8 Hz, 2H, CH2–C6H4),
2.45 (s, 3H, p-CH3–C6H4), 1.46 – 1.72 (m, 4H, –CH2–CH2–)
III
C17H18N2O6S 7.44 – 7.36 (m, 4H, C6H4), 6.36 (dd, JHH 11 Hz, H-cis, =CH2), 6.18 (dd, JHH 10 Hz,
1H, =CH–), 5.98 (dd, JHH 14 Hz, H-trans, =CH2), 4.53 (dd, JHH 7 Hz, 1H, CH),
4.14 (t, 4H, 2(–OCH2)), 3.37 (dd, JHH 8 Hz), 3.14 (dd, JHH 8 Hz, 2H, –CH2–C6H4),
1.47 – 1.69 (m, 4H, –CH2–CH2–)
Gram-negative (Escherichia coli ATCC 25922), and spo-
re-forming (Bacillus cereus ATCC 10702) bacteria.
SC ´ PR – Super C18 (5 mm) column eluted with an isopro-
panol – water – acetonitrile (6 : 11 : 33) mixture. The data of
elemental analyses coincided with the results of analytical
calculations using the empirical formulas. The yields, physi-
cochemical constants, and parameters of the 1H NMR spectra
are presented in Table 1.
Double serial dilutions of the stock solutions in 2 ml of
the nutrient medium were prepared immediately before test,
0.2 ml of a bacterial suspension (with a load of 105 bacterial
cells per ml) of the test microbe species were introduced into
tubes, and the samples were incubated at 37°C for 18 – 24 h,
after which the microbial growth was visually assessed. The
activity was characterized by the minimum inhibiting con-
4-(2-Thiocyanato-3-phenylpropionyloxy)butyl acry-
late (I). To a mixture of 0.12 mole 4-acryloyloxybutyl acry-
late, 0.01 mole copper(II) tetrafluoroborate, and 0.13 mole of
ammonium rodanide in 200 ml of a water – acetone mixture
(1 : 2) was gradually (over one hour) added 0.15 mole of
phenyldiazonium tetrafluoroborate. The reaction mixture
was kept at –5 to –10°C until the evolution of nitrogen ceases
(~2 h) and diluted with 250 ml of diethyl ether. The ether
layer was washed with water and dried over anhydrous mag-
nesium sulfate. Then the solvent was evaporated and the resi-
due was chromatographed on an Al2O3 column eluted with a
hexane – chloroform – methanol – diethyl ether (5 : 3 : 3 : 1)
mixture. Finally, the eluent was distilled off and traces of sol-
vents were removed by purging with gaseous argon to obtain
24.2g (61%) of the target compound I and 3.8 g (9.6%) of
isothiocyanatobenzene.
centration (MIC, mg/ml) corresponding to a dilution comple-
tely suppressing the test microbe growth. Each experiment
was triply repeated.
It was established that the synthesized compounds I – III
are most active with respect to St. aureus
(MIC = 62.5 – 250 mg/ml). Somewhat less sensitive were
the species of B. cereus (MIC = 312.3 mg/ml), and a mini-
mum effect was observed for E. coli (MIC = 625 – 1250
mg/ml). A comparison of the antimicrobial properties of
1-thiocyanato-1-alkoxycarbonyl-2-arylethanes with those of
4-(2-thiocyanato-3-arylpropionyloxy)butyl acrylates shows
that the introduction of acrylic acid fragments leads to a dec-
rease in this activity.
Compounds II and III were obtained using analogous
procedures with the corresponding aryldiazonium tetrafluo-
roborates.
REFERENCES
1. B. D. Grishchuk, N. G. Prodanchuk, P. M. Gorbovoi, et al.,
Khim.-Farm. Zh., 24(2), 139 – 140 (1990).
EXPERIMENTAL BIOLOGICAL PART
2. B. D. Grishchuk and P. M. Gorbovoi, Nauk. Zap., Ser. Khim.,
Ternopil’ Ped. Univ., No. 1, 3 – 16 (1997).
3. B. D. Grishchuk, L. I. Vlasik, and A. V. Blinder, in: Abstracs of
Papers. The 18th Ukrainian Conf. on Organic Chemistry [in
Ukrainian], Dnepropetrovsk (1998).
4. B. D. Grishchuk and P. M. Gorbovoi, in: Abstracs of Papers. The
18th Ukrainian Conf. on Organic Chemistry [in Ukrainian],
Dnepropetrovsk (1998).
The antimicrobial activity of the synthesized compounds
was determined by the conventional method of double serial
dilutions in a meat-infusion broth (pH 7.2 – 7.4). The initial
dilution was prepared by dissolving 10 mg of the test subs-
tance in 1 ml of ethanol, followed by adding 9 ml of distilled
water. The test objects were represented by standard strains
of Gram-positive (Staphylococcus aureus ATCC 2022),