Methyl Trifluoropyruvate in Cyclocondensation Reactions with N-Substituted Ureas

Article abstract of DOI:10.1134/S1070363219010286

The transformations of methyl trifluoropyruvate in cyclocondensation reactions with N-substituted ureas, leading to 3-substituted 5-hydroxy- or 5-methoxy-5-trifluoromethylimidazolidine-2,4-diones, were studied. The possibility of using 5-hydroxy-3-(prop-2

Full text of DOI:10.1134/S1070363219010286

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 1, pp. 153–156. © Pleiades Publishing, Ltd., 2019.
Russian Text © V.B. Sokolov, A.Yu. Aksinenko, 2019, published in Zhurnal Obshchei Khimii, 2019, Vol. 89, No. 1, pp. 143–147.
LETTERS
TO THE EDITOR
Methyl Trifluoropyruvate in Cyclocondensation Reactions
with N-Substituted Ureas
V. B. Sokolova and A. Yu. Aksinenkoa*
a Institute of Physiologically Active Compounds of the Russian Academy of Sciences,
Severnyi proezd 1, Chernogolovka, 142432 Russia
*e-mail: alaks@ipac.ac.ru
Received May 31, 2018; revised May 31, 2018; accepted June 7, 2018
Abstract—The transformations of methyl trifluoropyruvate in cyclocondensation reactions with N-substituted
ureas, leading to 3-substituted 5-hydroxy- or 5-methoxy-5-trifluoromethylimidazolidine-2,4-diones, were
studied. The possibility of using 5-hydroxy-3-(prop-2-in-1-yl)-5-trifluoromethylimidazolidine-2,4-dione for
modifying phenothiazine with a copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition was shown.
Keywords: methyl trifluoropyruvate, N-substituted ureas, 5-trifluoromethylimidazolidine-2,4-diones, phenothiazine,
1,3-dipolar cycloaddition
DOI: 10.1134/S1070363219010286
The study of the transformations of methyl tri-
fluoropyruvate N-substituted imines in cyclocondensa-
tion reactions with 1,3-binucleophiles [1–3] allowed us
the synthetic possibilities of cyclocondensation of
methyl trifluoropyruvate with N-substituted ureas for
the preparation of 3-substituted 5-trifluoromethyl-
imidazolidine-2,4-diones.
to propose
a
synthetic approach to various
trifluoromethyl containing five- and six-membered
heterocycles. This method allows modification of
drugs, for example, piracetam [4] and acetazolamide
[5], which are subunits of methyl trifluoropyruvate
imines molecules. The purpose of this study is to study
Methyl trifluoropyruvate 1 reacted readily with N-
substituted ureas 2a–2c to give the corresponding 3,3,3-
trifluoro-2-hydroxypropionates 3a–3c with a yield of
80–85%. The obtained 3,3,3-trifluoro-2-hydroxy-
Scheme 1.
O
O
C(O)OCH3
NH OH
R
O
N
F3C
H
CF3
O
3а−3c
1
−CH3OH
+
Et3N
O
O
CF3
R
N
NH2
−CH3OH
R
N
OH
NH
H
2а−2f
O
4а−4f
R = C6H5CH2 (а), C6H5CH2СH2 (b), prop-2-yn-1-yl (c), (pyridin-2-yl)methyl (d), (pyridin-3-yl)methyl (e), (pyridin-4-yl)-
methyl (f).
153

154
SOKOLOV, AKSINENKO
Scheme 2.
O
O
C(O)OCH3
NH OH
C(O)OCH3
CF3
SOCl2
Py
N
N
N
H
H
CF3
3а
5
O
O
N
CF3
CF3
N
OCH3
NH
+
CH3OH
−CH3OH
N
O
O
7
6
propionates were converted to 5-hydroxy-5-trifluoro-
methylimidazolidine-2,4-diones 4a–4c in 76–81%
yield when heated (40°C) in the presence of catalytic
amounts of triethylamine (Scheme 1).
5-Hydroxy-3-(prop-2-yn-1-yl)-5-trifluoromethylimida-
zolidin-2,4-dione 4c was found to be a promising
fluorine-containing precursor in the reaction of the
copper-catalyzed alkyne azide 1,3-dipolar cyclo-
addition [6]. Thus, in the presence of catalytic amounts
of Cu(I), imidazolidine-2,4-dione 4c reacted with azide-
containing phenothiazine to produce 1,4-substituted
1,2,3-triazole 9 with high yield (Scheme 3).
N-Pyridyl ureas 2d–2f underwent cyclocon-
densation with methyl trifluoropyruvate 1 in the
absence of triethyl amine to form 3-pyridyl-5-hydroxy-
5-trifluoromethylimidazolidine-2,4-diones 4d–4f in 76–
81% yield. The intermediate reaction products could
not be isolated; apparently, in this case, the sufficiently
basic ureas 3d–3f themselves act as catalysts.
Composition and structure of the obtained com-
pounds were confirmed by elemental analysis and
NMR spectroscopy data. In the 19F NMR spectra, the
singlet signals of the CF3 group in the range of 3–
1
An attempt to obtain imine 5 by dehydrating the
adduct of N-benzylurea and methyltrifluoropyruvate
3a unexpectedly led to the formation of 3-benzyl-5-
6 ppm are characteristic. The H NMR spectrum of
conjugate 9 represents the superposition of the spectra
of the phenothiazine and imidazolidin-2,4-dione
fragments and contains the characteristic singlet signal
of the CH-proton of the triazole ring at 7.93 ppm.
methoxy-5-trifluoromethylimidazolidine-2,4-dione
7
in 73% yield (Scheme 2). Probably, the reaction occurs
through heterocyclization of the resulting imine 5 to
imidazole-2,5-dione 6 followed by the addition of
methanol released during the cyclocondensation
process.
In conclusion, depending on the reaction condi-
tions, cyclocondensation of methyl trifluoropyruvate
with N-substituted ureas afforded 3-substituted 5-hyd-
Scheme 3.
O
O
CF3
OH
CF3
S
N3
Cu(I)
S
N
N
+
N
N
OH
NH
N
NH
O
N
N
O
O
O
9
8
4c
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METHYL TRIFLUOROPYRUVATE IN CYCLOCONDENSATION REACTIONS
155
roxy- or 5-methoxy-5-trifluoromethylimidazolidine-
2,4-diones. The use of functionally substituted ureas in
these transformations allows one to obtain precursors
for the subsequent modification of biologically active
substances, for example, phenothiazine.
48.34; Н 3.07; N 9.96. C11H9F3N2O3. Calculated, %: C
48.18; H 3.31; N 10.22.
5-Hydroxy-5-trifluoromethyl-3-(2-phenethyl)imi-
dazolidine-2,4-dione (4b) was prepared similarly.
1
Yield 0.22 g (76%), mp 161–163°C. Н NMR spec-
N-Substituted ureas 2a–2f [3] and azide 8 [4] were
obtained by the known methods.
trum (CDCl3), δ, ppm (J, Hz): 2.80 t (2H, CHAr, 3JHH
=
3
7.1), 3.61 t (2H, CHAr, JHH = 7.1), 7.01–7.32 m (5H,
CHAr), 8.39 s (1H, NH), 9.60 s (1H, OH). 19F NMR
spectrum (CDCl3): δF –4.62 ppm. Found, %: С 50.19;
Н 3.68; N 9.96. C12H11F3N2O3. Calculated, %: C
50.01; H 3.85; N 9.72.
Methyl 2-(benzylureido)-3,3,3-trifluoro-2-hydroxy-
propionate (3a). To a solution of 2 mmol of urea 2a in
20 mL of acetonitrile was added 2 mmol of methyl
trifluoropyruvate 1. The reaction mixture was stirred
for 2 h at 20°C, then 50 mL of water was added. The
precipitate was filtered and recrystallized from 50%
5-Hydroxy-3-(prop-2-yn-1-yl)-5-trifluoromethyl-
imidazolidine-2,4-dione (4c) was prepared similarly.
Yield 0.18 g (81%), mp 108–110°С. 1Н NMR
spectrum (CDCl3), δ, ppm (J, Hz): 2.30 t (1H, CH,
1
ethanol. Yield 0.5 g (82%), mp 153–155°C. Н NMR
spectrum (СDCl3), δ, ppm: 3.88 s (3H, MeO), 4.20–
4.46 m (2H, CH2), 5.74 s (1H, OH), 6.59 s (1H, NH),
7.19–7.40 m (5H, CHAr), 7.49 s (1H, NH). 19F NMR
spectrum (CDCl3): δF –4.47 ppm. Found, %: С 47.34;
Н 4.07; N 8.96. C12H13F3N2O4. Calculated, %: C
47.06; H 4.28; N 9.15.
3
3JHH = 2.1), 4.31 d (2Н, CH2, JHH = 2.2), 5.68 br. s
(2Н, OH + NH). 19F NMR spectrum (CDCl3): δF
–6.22 ppm. Found, %: С 37.63; Н 2.48; N 12.80.
C7H5F3N2O3. Calculated, %: C 37.85; H 2.27; N 12.61.
5-Hydroxy-3-(pyridin-2-yl)methyl-5-trifluoro-
methylimidazolidine-2,4-dione (4d). To a solution of
1 mmol of urea 2a in 20 mL of acetonitrile was added
1 mmol of methyl trifluoropyruvate 1. The reaction
mixture was stirred for 3 h at 40°C, then 50 mL of
water was added. The precipitate was filtered off and
recrystallized from 50% ethanol. Yield 0.22 g (80%),
Methyl 2-hydroxy-2-(2-phenetylureido)-3,3,3-tri-
fluoropropionate (3b) was prepared similarly. Yield
1
0.51 g (80%), mp 135–137°C. Н NMR spectrum
3
(CDCl3), δ, ppm (J, Hz): 2.66 t (2H, CH2, JHH = 4.4),
3.18–3.33 m (2H, CH2), 3.72 s (3H, MeO), 5.74 s (1H,
OH), 5.92 s (1H, NH), 6.85–7.10 m (5H, CHAr), 7.18 s
(1H, NH). 19F NMR spectrum (CDCl3): δF –4.44 ppm.
Found, %: С 48.54; Н 4.57; N 8.97. C13H15F3N2O4.
Calculated, %: C 48.75; H 4.72; N 8.75.
1
mp 197–198°C. Н NMR spectrum (CDCl3), δ, ppm
(J, Hz): 4.67 s (2H, CH2), 7.10–7.39 m (5H, CHAr),
8.56 s (1H, NH), 9.79 s (1H, OH). 19F NMR spectrum
(CDCl3): δF -–4.68 ppm. Found, %: С 43.44; Н 3.18; N
15.44. C10H8F3N3O3. Calculated, %: C 43.65; H 2.93;
N 15.27.
Methyl 2-hydroxy-2-[3-(prop-2-yn-1-yl)ureido]-
3,3,3-trifluoropropionate (3c) was obtained similarly.
1
Yield 0.43 g (85%), mp 113–155°C. Н NMR spec-
3
trum (CDCl3), δ, ppm (J, Hz): 2.12 t (1H, CH, JHH
=
5-Hydroxy-3-(pyridin-3-yl)methyl-5-trifluoro-
methylimidazolidine-2,4-dione (4e) was prepared
similarly. Yield 0.2 g (73%), mp 239–241°C. 1Н NMR
spectrum (CDCl3), δ, ppm (J, Hz): 4.63 s (2H, CH2),
7.28–7.43 m (1H, CHAr), 7.60 s (1H, CHAr, 3JHH = 8.1),
8.39–8.52 m (2H, CHAr), 8.57 s (1H, NH), 9.65 s (1H,
OH). 19F NMR spectrum (CDCl3): δF –4.79 ppm.
Found, %: С 43.44; Н 2.78; N 15.42. C10H8F3N3O3.
Calculated, %: C 43.65; H 2.93; N 15.27.
2.1), 3.51 s (3H, MeO), 3.56–3.62 m (3Н, CH2 + OH),
5.90 s (1H, NH), 7.23 s (1H, NH). 19F NMR spectrum
(CDCl3): δF –4.89 ppm. Found, %: С 37.64; Н 3.38; N
8.96. C8H9F3N2O4. Calculated, %: C 37.80 H, 3.57; N
9.12.
3-Benzyl-5-hydroxy-5-trifluoromethylimidazol-
idine-2,4-dione (4a). To a solution of 1 mmol of urea
3a in 20 mL of acetonitrile was added 0.1 g of tri-
ethylamine. The reaction mixture was stirred for 3 h at
40°C, then 50 mL of water was added. The precipitate
was filtered off and recrystallized from 50% ethanol.
5-Hydroxy-3-(pyridin-4-yl)methyl-5-trifluoro-
methylimidazolidine-2,4-dione (4f) was prepared
1
similarly. Yield 0.21 g (76%), mp 237–239°C. Н
1
Yield 0.22 g (80%), mp 154–156°C. Н NMR spec-
NMR spectrum (CDCl3), δ, ppm (J, Hz): 4.64 s (2H,
CH2), 6.85 d (2H, CHAr, 3JHH = 7.9), 7.19 d (2H, CHAr,
3JHH = 4.8), 8.64 s (1H, NH), 9.92 s (1H, OH). 19F NMR
spectrum (CDCl3): δF –4.71 ppm. Found, %: С 43.48;
trum (CDCl3), δ, ppm: 4.57 s (2H, CH2), 7.10–7.39 m
(5H, CHAr), 8.56 s (1H, NH), 9.79 s (1H, OH). 19F
NMR spectrum (CDCl3): δF –2.98 ppm. Found, %: С
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 1 2019

156
SOKOLOV, AKSINENKO
Н 3.18; N 15.24. C10H8F3N3O3. Calculated, %: C
FUNDING
43.65; H 2.93; N 15.27.
This work was financially supported by the Russian
Foundation for Basic Research (grant no. 16-03-00696-a)
in the frame of the basic part of the governmental task
for 2018 (no. 0090-2017-0023).
3-Benzyl-5-methoxy-5-trifluoromethylimidazol-
idine-2,4-dione (7). To a solution of 1 mmol of urea
3a in 20 mL of acetonitrile were added 2 mmol of
pyridine and 1 mmol of SOCl2. The reaction mixture
was stirred for 3 h at 40°C, then 50 mL of water was
added. The precipitate was filtered off and recrystal-
lized from 50% ethanol. Yield 0.21 g (73%), mp 126–
CONFLICT OF INTEREST
No conflict of interests was declared by the authors.
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128°C. Н NMR spectrum (CDCl3), δ, ppm: 3.25 s
(3H, MeO), 4.71 s (2H, CH2), 6.72 s (1H, NH), 7.32 s
(5H, CHAr). 19F NMR spectrum (CDCl3): δF –3.72 ppm.
Found, %: С 49.88; Н 3.78; N 9.54. C12H11F3N2O3.
Calculated, %: C 50.01; H 3.85; N 9.72.
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