Synthesis of Fluorine-Containing Derivatives of 5-Arylisoxazoles and 4,5-Dichlorothiazole

Article abstract of DOI:10.1134/S1070363218020081

Alkylation of fluorophenols and phenolic aldehydes with 5-phenyl(p-tolyl)-3-chloromethylisoxazole under the Williamson reaction conditions afforded the corresponding ethers. Condensation of the resulting phenolic aldehyde derivatives and 5-phenyl(p-tolyl)

Full text of DOI:10.1134/S1070363218020081

ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 2, pp. 234–240. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © S.K. Petkevich, E.A. Dikusar, A.V. Kletskov, I.B. Rozenzveig, G.G. Levkovskaya, P.V. Kurman, R.M. Zolotar’, V.I. Potkin, 2018,
published in Zhurnal Obshchei Khimii, 2018, Vol. 88, No. 2, pp. 255–261.
Synthesis of Fluorine-Containing Derivatives
of 5-Arylisoxazoles and 4,5-Dichlorothiazole
S. K. Petkevicha*, E. A. Dikusara, A. V. Kletskova, I. B. Rozenzveigb,
G. G. Levkovskayab, P. V. Kurmanc, R. M. Zolotar’c, and V. I. Potkina
a Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus,
ul. Surganova 13, Minsk, 220072 Belarus
*e-mail: petkevich@ifoch.bas-net.by
b Favorskii Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, Irkutsk, Russia
c Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk, Belarus
Received July 13, 2017
Abstract—Alkylation of fluorophenols and phenolic aldehydes with 5-phenyl(p-tolyl)-3-chloromethyliso-
xazole under the Williamson reaction conditions afforded the corresponding ethers. Condensation of the
resulting phenolic aldehyde derivatives and 5-phenyl(p-tolyl)isoxazole-3-carbaldehydes with p-fluoroaniline
resulted in fluorine-containing azomethines. Acylation of fluorinated amines with 5-(p-tolyl)isoxazole- and 4,5-
dichloroisothiazole-3-carbonyl chlorides gave rise to fluorinated amides bearing isoxazole and isothiazole
fragments, representatives of which showed a synergistic effect in compositions with insecticides.
Keywords: 5-arylisoxazoles, isothiazoles, ethers, azomethines, amides
DOI: 10.1134/S1070363218020081
Studies in the field of synthesis of fluorine-
containing organic compounds are actively developing
alongside with the study of the features of their
chemical behavior and the physicochemical properties
of these species, as well as of various directions of
their practical use [1, 2]. The steadily growing interest
is preserved in the development of fluorine-substituted
biologically active compounds, since it has been
established that the selective introduction of fluorine
atoms into an organic molecule may significantly
increase its biological activity [3]. In recent years, a
fraction of fluorine-containing compounds among
medicinal substances, including effective antitumour
agents, has increased to 18%, and among new
pesticides, up to 30% [4, 5].
chemotherapy of tumors, which allows a significant
reduction of their dose and toxic effect on the patient
[6–8]. In addition, ethers, azomethines, and amides of
isothiazole series increase the effect of insecticides
against the Colorado potato beetle and fleas in 5–10%
dose; the observed effect is considerably dependent on
the functional environment of the heterocycle [9, 10].
Available 5-phenyl(p-tolyl)isoxazole-3-carbaldehydes
1 and 2, products of their transformations like 5-phenyl-
(p-tolyl)-3-chloromethylisoxazoles 3 and 4, as well as
5-(p-tolyl)isoxazole- and 4,5-dichloroisothiazole-3-
carbonyl chlorides 5 and 6 that we obtained via
successive transformations of trichlorethylene dimer
[11, 12] were used as the starting compounds for the
preparation of fluorinated derivatives of isoxazoles and
isothiazoles.
The purpose of our work was to obtain fluorinated
derivatives of 5-arylisoxazoles and 4,5-dichloroiso-
thiazole of ethers, azomethines and amides series,
which are promising for bioscreening as synergists for
insecticides and cytostatics. Previously it has been
found that some functionally substituted isoxazoles
and isothiazoles, along with antitumor effect, show a
synergistic effect in compositions with drugs used in
The reaction of 5-phenyl(p-tolyl)-3-chloromethyl-
isoxazoles 3 and 4 with fluorophenols and phenolic
aldehydes under Williamson reaction conditions
(boiling in ethanol in the presence of K2CO3 for 24 hs)
[13] gave mixed ethers of arylisoxazole series 7–12
(Scheme 1). Compounds 7–10 were identified by
1
elemental analysis data, IR, H, 13C, and 19F NMR
234

SYNTHESIS OF FLUORINE-CONTAINING DERIVATIVES
235
Scheme 1.
F
O
H2N
F
R
N
N
MeOH, AcOH
O
N
R
O
13, 14
1, 2
(1) NaBH4, (CH3)2CHOH
(2) SOCl2, CH2Cl2
F
F
Cl
HO
O
R
N
O
K2CO3, EtOH
R
N
O
3, 4
7_10
CHO
HO
K2CO3, EtOH
R = H
F
N
O
O
H2N
F
R
N
N
CHO
MeOH, AcOH
O
O
R
11, 12
15, 16
R = H (1, 3, 7, 8, 11, 13, 15), 4-CH3 (2, 4, 9, 10, 12, 14, 16), 2-FC6H4O (7, 9), 4-FC6H4O (8, 10), 2-(CHO)C6H4O (11),
4-(CHO)C6H4O (12), 2-OC6H4CH=N– (15), 4-OC6H4CH=N– (16).
spectra. Physicochemical constants of compounds 11
and 12 coincided with those previously published in
[12].
Azomethines of this type correspond to aldimines, for
which the E-form is preferred [14].
Acylation of the fluorinated aliphatic amines 5-(p-
tolyl)isoxazole- and 4,5-dichloroisothiazole-3-carbonyl
chlorides 5 and 6 in diethyl ether in the presence of
triethylamine afforded a series of fluorine-substituted
amides 17–21 (Scheme 2). In the IR spectra of the
resulting amides the characteristic bands of stretching
vibrations of the amide bond were observed in the
region 1671–1697 cm–1.
Condensation of phenolic aldehyde derivatives 11
and 12, as well as 5-phenyl(p-tolyl)isothiazole-3-carb-
aldehydes 1 and 2 with p-fluoroaniline in anhydrous
methanol in the presence of catalytic amounts of
glacial acetic acid afforded fluorine-substituted azo-
methines 13–16 (Scheme 1).
In the IR spectra of the obtained compounds 13–16
there were no absorption bands of the C=O bond of the
initial aldehydes; and the bands of stretching vibrations
of the azomethine C=N fragment were observed in the
1615–1635 cm–1 region. In the NMR spectra of 1H-
azomethines 13–16, singlets of the azomethine frag-
ment appeared in the range of 8.37–8.95 ppm.
19
In the F NMR spectra of all synthesized fluorine
derivatives 7–10 and 13–21 the signals of the
corresponding fluorine-containing fragments were
observed. In 13C NMR spectra the intensity of the
signals of polyfluoro-substituted carbon atoms was
extremely low due to the large spin-lattice relaxation
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 2 2018

236
PETKEVICH et al.
Scheme 2.
O
Cl
O
N
O
R
N
H
5
N
O
O
Cl
Cl
17, 18
H2NR
Et2O, NEt3
N
S
O
R
Cl
Cl
NH
N
Cl
S
19_21
R = CH2C3F7 (17, 19), CH2CH2C8F17 (18, 20), CH2C6F13 (21).
time of these atoms, as well as the complex multi-
plicity of the signals, which hampers their correct
assignment. The signals of other atoms and fragments
were clearly identified and were consistent with the
molecular structure of the synthesized compounds.
1H, 13C, and 19F NMR spectra were registered on an
Avance-500 Bruker spectrometer; chemical shifts were
measured with respect to residual signals of the
solvents. For 19F NMR spectra, chemical shifts were
measured relative to C6F6 or CF3COOD as references.
In laboratory conditions, the possibility of using
synthesized fluorine-containing amides 17–19, 21 as
synergists of insecticides KerberR (neonicotinoids
group) and VitanR (pyrethroids group) was studied.
KerberR was used at a concentration of 0.0005% of the
active substance, VitanR was used at a concentration of
0.002% according to the previous studies data. The test
compounds were added in a 5% dose.
The starting 5-phenyl(p-tolyl)isoxazole-3-carbal-
dehydes 1 and 2, 5-phenyl(p-tolyl)-3-chloromethyl-
isoxazoles 3 and 4, 5-(p-tolyl)isoxazole- and 4,5-di-
chloroisothiazole-3-carbonyl chlorides 5 and 6 were
prepared according to the procedures reported in [11, 12].
General procedure for the synthesis of ethers 7–10.
A mixture of 1 mmol of chloromethylisoxazole 5 or 6,
1.3 mmol of the corresponding fluorophenol, and
0.18 g (1.3 mmol) of anhydrous K2CO3 in 30 mL of
96% ethanol was boiled under argon for 24 h, after
which the reaction mixture was cooled to 20–23°C and
poured into 100 mL of a 10% aqueous NaCl solution.
The precipitate formed was washed with 500 mL of
distilled water and dried in air at 30–35°C. Final
purification was carried out by column chromato-
graphy on silica gel (60–100 μm, eluent benzene) and
subsequent recrystallization from a mixture of benzene–
hexane (1 : 1).
As a result of bioscreening, amides 17, 18 and 21
enhance the action of both insecticidal preparations.
Amide 21 showed the maximum effect, which in the
combination with KerberR increased the death of larvae
3.7 times in comparison with the individual prepara-
tion. This amide showed the maximum potentiating
effect in a mixture with VitanR, but its synergistic
effect did not exceed 1.7 times, which is apparently
explained by the resistance of the Colorado beetle to
pyrethroids. Potentiating action of amide 19 was
insignificant. The obtained bioscreening data are a
stimulus for further study of synthesized substances in
binary mixtures with pesticides and other biologically
active compounds.
3-[(2-Fluorophenoxy)methyl]-5-phenylisoxazole
(7). Yield 66%, mp 73–74°C. IR spectrum, ν, cm–1:
3160, 3124, 3070, 3060, 3045, 3020, 2980, 2960,
2940, 2890, 2870, 1614, 1591, 1574, 1509, 1452,
1371, 1312, 1285, 1260, 1238, 1204, 1158, 1111,
1070, 1060, 1040, 1014, 980, 940, 915, 870, 853, 815,
EXPERIMENTAL
IR spectra were recorded on an IR Fourier
spectrometer Protégé-460 Nicolet from KBr pellets.
1
804, 766, 745, 692, 685, 670, 640, 580. H NMR
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SYNTHESIS OF FLUORINE-CONTAINING DERIVATIVES
237
spectrum (500 MHz, CF3COOD), δ, ppm: 5.30 s (2H,
CH2), 6.77 s (1H, isoxazole), 6.87–7.02 m (4HAr), 7.34–
7.43 m (3HAr), 7.02 d (2HAr, J = 7.4 Hz). 13C NMR
spectrum (125 MHz, CF3COOD), δC, ppm: 65.38
(CH2), 100.98 (CH, isoxazole), 118.56 d (2CHAr, J =
18.6 Hz), 119.11 d and 126.19 d (2CHAr, J = 7.2 Hz),
126.64 d (2CHAr, J = 3.8 Hz), 128.10 (2CHAr), 131.09
(2CHAr), 134.04 (1CHAr); 127.17, 146.74 d (J =
11.2 Hz), 155.43 d (J = 244.0 Hz), 163.15 and 174.96
(5Ctert). 19F NMR spectrum (470 MHz, CF3COOD), δF,
ppm: –136.27 (=CF). Found, %: C 71.19; H 4.74; N
5.02. C16H12FNO2. Calculated, %: C 71.37; H 4.49; N
5.20. М 269.28.
19F NMR spectrum (470 MHz, CDCl3 + CF3COOD),
δF, ppm: from –136.62 to –136.57 m (=CF). Found, %:
C 72.28; H 5.04; N 4.77. C17H14FNO2. Calculated, %:
C 72.07; H 4.98; N 4.94. М 283.30.
3-[(4-Fluorophenoxy)methyl]-5-(p-tolyl)isoxazole
(10). Yield 69%, mp 110–111°C. IR spectrum, ν, cm–1:
3150, 3115, 1068, 3034, 2960, 2923, 2880, 2854,
1616, 1599, 1580, 1565, 1510, 1505, 1475, 1462,
1451, 1418, 1374, 1300, 1290, 1245, 1237, 1202,
1183, 1161, 1015, 1101, 1052, 1022, 949, 921, 827,
1
807, 797, 789, 733, 710, 680, 640. H NMR spectrum
(500 MHz, CDCl3 + CF3COOD), δ, ppm: 2.40 s (3H,
Ме), 5.15 s (2H, CH2), 6.59 s (1H, isoxazole), 6.92–
6.97 m (2HAr), 7.00 t (2HAr, J = 8.6 Hz), 7.26 d (2HAr,
J = 8.0 Hz), 7.67 d (2HAr, J = 8.0 Hz). 13C NMR
spectrum (125 MHz, CDCl3 + CF3COOD), δC, ppm:
21.62 (Ме), 62.51 (CH2), 99.32 (CH, isoxazole),
116.04 d (2CHAr, J = 8.0 Hz), 116.17 d (2CHAr, J =
23.1 Hz), 125.97 (2CHAr), 129.84 (2CHAr); 124.48,
140.98, 154.24 d (J = 2.1 Hz), 157.85 d (J = 239.4 Hz),
161.38 and 170.99 (6Ctert). 19F NMR spectrum
(470 MHz, CDCl3 + CF3COOD), δF, ppm: from
–125.41 to –125.36 m (=CF). Found, %: C 71.94; H
5.15; N 5.03. C17H14FNO2. Calculated, %: C 72.07; H
4.98; N 4.94. М 283.30.
3-[(4-Fluorophenoxy)methyl]-5-phenylisoxazole
(8). Yield 65%, mp 66–67°C. IR spectrum, ν, cm–1:
3160, 3145, 3085, 3070, 3040, 3015, 2950, 2923,
2900, 2875, 2850, 1620, 1590, 1575, 1505, 1465,
1454, 1381, 1290, 1248, 1236, 1222, 1210, 1179,
1097, 1053, 1041, 1016, 860, 823, 810, 791, 763, 735,
1
687, 670. H NMR spectrum (500 MHz, CDCl3 +
CF3COOD), δ, ppm: 5.24 s (2H, CH2), 6.74 s (1H, iso-
xazole), 6.93–6.98 m (2HAr), 7.02 t (2HAr, J = 8.5 Hz),
7.47–7.54 m (3HAr), 7.76–7.84 m (2HAr). 13C NMR
spectrum (125 MHz, CDCl3 + CF3COOD), δC, ppm:
62.31 (CH2), 99.38 (CH, isoxazole), 116.29 d (2CHAr,
J = 8.2 Hz), 116.38 d (2CHAr, J = 23.3 Hz), 126.37
(2CHAr), 129.40 (2CHAr), 131.47 (1CHAr); 125.04,
153.89 d (J = 2.1 Hz), 158.24 d (J = 240.0 Hz), 161.87
and 171.55 (5Ctert). 19F NMR spectrum (470 MHz,
CDCl3 + CF3COOD), δF, ppm: –124.78÷–124.73 m
(=CF). Found, %: C 71.49; H 4.27; N 5.33.
C16H12FNO2. Calculated, %: C 71.37; H 4.49; N 5.20.
М 269.28.
General procedure for the synthesis of azo-
methines 13–16. Two drops of glacial acetic acid were
added to a solution of 1 mmol of aldehyde 1, 2, 11, or
12 and 0.12 g (1 mmol) of 4-fluoroaniline in 30 mL of
anhydrous methanol and refluxed for 2 h. The hot
solution was filtered through a pleated paper filter,
cooled to 0–5°C, and kept for 10–15 h. The precipitate
was separated by filtration on a glass frit filter, washed
with a small amount (5–10 mL) of cold methanol, and
dried in air.
3-[(2-Fluorophenoxy)methyl]-5-(p-tolyl)isoxazole
(9). Yield 68%, mp 122–123°C. IR spectrum, ν, cm–1:
3122, 3070, 3030, 3020, 2960, 2940, 2921, 2870,
2845, 1615, 1598, 1588, 1515, 1504, 1476, 1459,
1437, 1371, 1310, 1280, 1260, 1238, 1197, 1159,
1114, 1053, 1034, 1019, 995, 949, 919, 844, 822, 808,
750, 720, 685, 640, 570. 1H NMR spectrum (500 MHz,
CDCl3 + CF3COOD), δ, ppm: 2.40 s (3H, Ме), 5.28 s
(2H, CH2), 6.67 s (1H, isoxazole), 6.94–7.00 m (1HAr),
7.04–7.16 m (3HAr), 7.27 d (2HAr, J = 8.0 Hz), 7.67 d
(2HAr, J = 8.0 Hz). 13C NMR spectrum (125 MHz,
CDCl3 + CF3COOD), δC, ppm: 21.58 (Ме), 63.12
(CH2), 98.48 (CH, isoxazole), 115.94, 116.64 d
(2CHAr, J = 18.1 Hz), 122.54 d (2CHAr, J = 6.8 Hz),
124.61 d (2CHAr, J = 3.6 Hz), 126.03 (2CHAr), 129.86
(2CHAr); 124.25, 141.19, 146.08 d (J = 10.6 Hz),
153.01 d (J = 246.2 Hz), 161.28 and 171.14 (6Ctert).
(E)-N-(4-Fluorophenyl)-1-(5-phenylisoxazol-3-
yl)methaneimine (13). Yield 64%, mp 93–94°C. IR
spectrum, ν, cm–1: 3155, 3040, 3105, 3090, 3070,
3042, 2923, 2890, 2853; 1623 (C=N); 1610, 1592,
1571, 1504, 1450, 1330, 1295, 1228, 1199, 1185,
1153, 1094, 1080, 1040, 1030, 1009, 965, 945, 930,
920, 874, 843, 807, 767, 720, 689, 675, 655, 540, 525.
1H NMR spectrum (500 MHz, CDCl3 + C6F6), δ, ppm:
7.07 s (1H, isoxazole), 7.11 t (2HAr, J = 8.6 Hz), 7.26–
7.31 m (2HAr), 7.43–7.51 m (3HAr), 7.80–7.85 m
(2HAr), 8.62 s (1H, CH=N). 13C NMR spectrum
(125 MHz, CDCl3 + C6F6), δC, ppm: 97.27 (CH,
isoxazole), 116.28 d (2CHAr, J = 22.7 Hz), 122.85 d
(2CHAr, J = 8.4 Hz), 126.01 (2CHAr), 129.20 (2CHAr),
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PETKEVICH et al.
130.65 (1CHAr), 150.09 (CH=N); 127.11, 146.61 d
(J = 2.2 Hz), 162.18 d (J = 247.0 Hz), 162.91 and
170.81 (5Ctert). 19F NMR spectrum (470 MHz, CDCl3 +
C6F6), δF, ppm: from –118.07 to –118.02 m (=CF).
Found, %: C 72.29; H 4.04; N 10.42. C16H11FN2O.
Calculated, %: C 72.17; H 4.16; N 10.52. М 266.28.
(E)-N-(4-Fluorophenyl)-1-{4-[(5-phenylisoxazol-
3-yl)methoxy]phenyl}methaneimine (16). Yield
62%, mp 153–154°C. IR spectrum, ν, cm–1: 3121,
3070, 3040, 3030, 2925, 2890, 2845, 1629 (C=N),
1606, 1585, 1514, 1501, 1464, 1454, 1422, 1377,
1310, 1297, 1257, 1235, 1223, 1190, 1162, 1151,
1110, 1090, 1039, 1019, 980, 945, 920, 910, 890, 865,
(E)-N-(4-Fluorophenyl)-1-[5-(p-tolyl)isoxazol-3-
yl]methaneimine (14). Yield 66%, mp 137–138°C. IR
spectrum, ν, cm–1: 3115, 3080, 3060, 3040, 2977,
2919, 2889, 2865; 1635 (C=N); 1616, 1592, 1566,
1501, 1446, 1410, 1377, 1321, 1226, 1198, 1184,
1149, 1115, 1092, 1041, 1006, 955, 946, 936, 872,
1
837, 828, 777, 766, 692, 540. H NMR spectrum
(500 MHz, CDCl3 + C6F6), δ, ppm: 5.27 s (2H, CH2),
6.66 s (1H, isoxazole), 7.06 t (2HAr, J = 8.6 Hz), 7.10 d
(2HAr, J = 8.7 Hz), 7.14–7.20 m (2HAr), 7.43–7.50 m
(3HAr), 7.74–7.81 m (2HAr), 7.86 d (2HAr, J = 8.7 Hz),
8.37 s (1H, CH=N). 13C NMR spectrum (125 MHz,
CDCl3 + C6F6), δC, ppm: 62.07 (CH2), 98.90 (CH,
isoxazole), 115.18 (2CHAr), 115.98 d (2CHAr, J =
22.5 Hz), 122.40 d (2CHAr, J = 8.3 Hz), 126.04
(2CHAr), 129.20 (2CHAr), 130.60 (CHAr), 130.73
(2CHAr), 159.38 (CH=N); 127.29, 130.13, 148.37 d
(J = 2.8 Hz), 160.28, 161.15, 161.25 d (J = 244.2 Hz)
and 170.90 (7Ctert). 19F NMR spectrum (470 MHz,
CDCl3 + C6F6), δF, ppm: from –121.00 to –120.55 m
(=CF). Found, %: C 74.02; H 4.75; N 7.54.
C23H17FN2O2. Calculated, %: C 74.18; H 4.60; N 7.52.
М 372.40.
1
837, 821, 803, 745, 716, 690, 661, 630, 605, 526. H
NMR spectrum (500 MHz, CDCl3 + C6F6), δ, ppm:
2.41 s (3H, Ме), 7.01 s (1H, isoxazole), 7.11 t (2HAr,
J = 8.6 Hz), 7.25–7.31 m (4HAr), 7.72 d (2HAr, J =
8.2 Hz), 8.61 s (1H, CH=N). 13C NMR spectrum
(125 MHz, CDCl3 + C6F6), δC, ppm: 21.62 (Ме), 96.64
(CH, isoxazole), 116.27 d (2CHAr, J = 22.7 Hz),
122.84 d (2CHAr, J = 8.4 Hz), 125.95 (2CHAr), 129.88
(2CHAr), 150.21 (CH=N); 124.42, 141.01, 146.66 d
(J = 2.1 Hz), 162.16 d (J = 246.8 Hz), 162.86 and
171.02 (6Ctert). 19F NMR spectrum (470 MHz, CDCl3 +
C6F6), δF, ppm: from –118.16 to –118.11 m (=CF).
Found, %: C 72.74; H 4.51; N 10.21. C17H13FN2O.
Calculated, %: C 72.85; H 4.67; N 9.99. М 280.30.
General procedure for the synthesis of amides 17–
21. To a solution of 2 mmol of the corresponding
fluoro-substituted amine in 25 mL of anhydrous
diethyl ether were added 0.21 g (2.1 mmol) of tri-
ethylamine and 0.45 g (2 mmol) of 5-(p-tolyl)isoxazole-
or 4,5-dichloroisothiazole-3-carbonyl chloride 5 or 6.
The mixture was stirred at reflux for 2 h, then cooled
to 0°C, and kept for 12 h. The precipitate was filtered
off, washed with diethyl ether, with water, and dried in
a vacuum over P2O5.
(E)-N-(4-Fluorophenyl)-1-{2-[(5-phenylisoxazol-
3-yl)methoxy]phenyl}methaneimine (15). Yield 60%,
mp 109–110°C. IR spectrum, ν, cm–1: 3160, 3140,
3110, 3095, 3071, 3040, 3010, 2996, 2918, 2860, 1615
(C=N), 1602, 1595, 1575, 1502, 1490, 1470, 1460,
1447, 1426, 1363, 1305, 1289, 1256, 1229, 1220,
1187, 1157, 1149, 1108, 1093, 1052, 1005, 1000, 977,
948, 920, 908, 890, 855, 834, 825, 798, 780, 765, 754,
1
715, 692, 681, 674, 620, 585, 555. H NMR spectrum
N-(2,2,3,3,4,4,4-Heptafluorobutyl)-5-(p-polyl)iso-
xazole-3-carboxamide (17). Yield 80%, mp 192–193°C.
IR spectrum, ν, cm–1: 3315 (NH), 3133, 3085, 3054,
2965, 2921, 2848; 1697 (C=O); 1618, 1596, 1555,
1511, 1452, 1423, 1378, 1355, 1301, 1254, 1230,
1214, 1182, 1150, 1119, 1061, 1001, 955, 941, 910,
(500 MHz, CDCl3 + C6F6), δ, ppm: 5.28 s (2H, CH2),
6.22 s (1H, isoxazole), 7.03–7.12 m (4HAr), 7.18–7.24
m (2HAr), 7.42–7.47 m (4HAr), 7.73–7.78 m (2HAr),
8.20 d.d (1HAr, J = 7.7, 1.6 Hz), 8.95 s (1H, CH=N).
13C NMR spectrum (125 MHz, CDCl3 + C6F6), δC,
ppm: 62.39 (CH2), 98.77 (CH, isoxazole), 112.60
(CHAr), 115.88 d (2CHAr, J = 22.5 Hz), 121.98 (CHAr),
122.54 d (2CHAr, J = 8.3 Hz), 125.91 (2CHAr), 127.91
(CHAr), 129.09 (2CHAr), 130.53 (CHAr), 132.90
(CHAr), 155.68 (CH=N); 125.18, 127.10, 148.64 d (J =
2.8 Hz), 158.01, 160.97, 161.23 d (J = 244.4 Hz) and
170.83 (7Ctert). 19F NMR spectrum (470 MHz, CDCl3 +
C6F6), δF, ppm: –120.71÷–120.65 m (=CF). Found, %:
C 74.33; H 4.45; N 7.67. C23H17FN2O2. Calculated, %:
C 74.18; H 4.60; N 7.52. М 372.40.
1
818, 792, 740, 658, 608, 496. H NMR spectrum
(500 MHz, CF3COOD), δ, ppm: 2.20 s (3H, Ме), 4.10
t (2H, CH2, J = 13.0 Hz), 6.86 s (1H, isoxazole), 7.10
br.s (2HAr, J = 7.9 Hz), 7.49 br.s (2HAr, J = 7.9 Hz),
8.25 br.s (1H, NH). 13C NMR spectrum (125 MHz,
CF3COOD), δC, ppm: 21.82 (Ме), 41.33 t (CH2, J =
24.0 Hz), 100.56 (CH, isoxazole), 127.86 (2CHAr),
131.74 (2CHAr); 124.56, 145.29, 159.39, 163.51 and
176.29 (5Ctert). 19F NMR spectrum (470 MHz,
CF3COOD), δF, ppm: –129.78 br.s (CF2), –120.68 br.s
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SYNTHESIS OF FLUORINE-CONTAINING DERIVATIVES
239
(CF2), –83.26 br.s (CF3). Found, %: C 46.68; H 2.77;
N 7.43. C15H11F7N2O2. Calculated, %: C 46.89; H 2.89;
N 7.29. М 384.25.
13C NMR spectrum (125 MHz, CF3COOD), δC, ppm:
32.15 t (NCH2CH2, J = 6.8 Hz), 34.66 s (NCH2CH2);
126.57, 154.97, 157.23 and 163.76 (4Ctert). 19F NMR
spectrum (470 MHz, CF3COOD), δF, ppm: –128.12
br.s (CF2), –125.40 br.s (CF2), –124.44 br.s (CF2),
–123.55 br.s (2CF2), –123.26 br.s (CF2), –116.00
quintet (CH2CF2, J = 15.9 Hz), –83.42 t (CF3, J = 10.2 Hz).
Found, %: C 25.96; H 0.82; Cl 10.91; N 4.44; S 4.81.
C14H5Cl2F17N2OS. Calculated, %: C 26.15; H 0.78; Cl
11.02; N 4.36; S 4.98. М 643.14.
N-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptade-
cafluorodecyl)-5-(p-tolyl)isoxazole-3-carboxamide (18).
Yield 96%, mp 190–191°C. IR spectrum, ν, cm–1:
3308 (NH), 3133, 3085, 3054, 2965, 2929, 2855; 1678
(C=O); 1618, 1595, 1556, 1513, 1451, 1335, 1267,
1247, 1216, 1201, 1146, 1116, 1021, 977, 816, 659, 611.
1H NMR spectrum (500 MHz, CF3COOD), δ, ppm:
2.27 s (3H, Ме), 2.37–2.54 m (2H, NCH2CH2), 3.81 t
(2H, NCH2CH2, J = 6.8 Hz), 6.92 s (1H, isoxazole),
7.19 d (2HAr, J = 7.9 Hz), 7.58 d (2HAr, J = 7.9 Hz),
8.33 br.s (1H, NH). 13C NMR spectrum (125 MHz,
CF3COOD), δC, ppm: 21.82 (Ме), 31.86 t (NCH2CH2,
J = 6.8 Hz), 34.88 s (NCH2CH2), 100.49 (CH, iso-
xazole), 127.92 (2CHAr), 131.78 (2CHAr); 124.62,
145.38, 159.77, 163.05 and 176.34 (5Ctert). 19F NMR
spectrum (470 MHz, CF3COOD), δF, ppm: –128.12
br.s (CF2), –125.40 br.s (CF2), –124.44 br.s (CF2),
–123.55 br.s (2CF2), –123.26 br.s (CF2), –116.15 quintet
(CH2CF2, J = 15.7 Hz), –83.42 t (CF3, J = 10.2 Hz).
Found, %: C 38.74; H 2.30; N 4.19. C21H13F17N2O2.
Calculated, %: C 38.91; H 2.02; N 4.32. М 648.32.
4,5-Dichloro-N-(2,2,3,3,4,4,5,5,6,6,7,7,7-trideca-
fluoroheptyl)isothiazole-3-carboxamide (21). Yield
85%, mp 103°C. IR spectrum, ν, cm–1: 3333 (NH),
2975, 2933, 2854; 1682 (C=O); 1540, 1483, 1428,
1373, 1357, 1296, 1267, 1241, 1233, 1206, 1188,
1149, 1120, 1071, 1050, 992, 940, 846, 800, 780, 735,
699, 650, 560. 1H NMR spectrum [500 MHz,
(CD3)2CO + C6F6], δ, ppm: 4.25–4.37 m (2H, CH2),
8.58 br.s (1H, NH). 13C NMR spectrum [125 MHz,
(CD3)2CO + C6F6], δC, ppm: 39.95 t (CH2, J = 23.3 Hz);
125.55, 151.78, 157.86 and 160.80 (4Ctert). 19F NMR
spectrum [470 MHz, (CD3)2CO + C6F6], δF, ppm: from
–128.49 to –128.41 m (CF2), –125.73 br.s (CF2),
–125.09 br.s (CF2), –124.18 br.s (CF2), –119.80 quintet
(CH2CF2, J = 14.1 Hz), –83.39 t (CF3, J = 10.0 Hz).
Found, %: C 25.14; H 0.77; Cl 13.25; N 5.31; S 5.98.
C11H3Cl2F13N2OS. Calculated, %: C 24.97; H 0.57; Cl
13.40; N 5.29; S 6.06. М 529.10.
4,5-Dichloro-N-(2,2,3,3,4,4,4-heptafluorobutyl)-
isothiazole-3-carboxamide (19). Yield 90%, mp 104°C.
IR spectrum, ν, cm–1: 3313 (NH), 2962, 2932, 2854;
1674 (C=O); 1542, 1484, 1422, 1388, 1358, 1302,
1259, 1227, 1216, 1191, 1169, 1151, 1125, 1057, 993,
ACKNOWLEDGMENTS
1
939, 912, 846, 796, 745, 647, 513. H NMR spectrum
(500 MHz, CDCl3 + CF3COOD), δ, ppm: 4.10–4.24 m
(2H, CH2), 7.39 br.s (1H, NH). 13C NMR spectrum
(125 MHz, CDCl3 + CF3COOD), δC, ppm: 39.10 t
(CH2, J = 24.0 Hz); 125.62, 151.42, 155.65 and 159.09
(4Ctert). 19F NMR spectrum (470 MHz, CDCl3 +
CF3COOD), δF, ppm: –130.14 br.s (CF2), –121.25 br.s
(CF2), –83.33 t (CF3, J = 9.2 Hz). Found, %: C 25.09;
H 0.87; Cl 18.55; N 7.50; S 8.32. C8H3Cl2F7N2OS.
Calculated, %: C 25.35; H 0.80; Cl 18.70; N 7.39; S
8.46. М 379.07.
This work was financially supported by the
Belarusian Republican Foundation for Basic Research
(project no. X15SO-006) and the Siberian Branch of
the Russian Academy of Sciences (grant no. 4).
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