Methyl trifluoropyruvate in cyclocondensation with 1,3-bis(nucleophiles)

Full text of DOI:10.1134/S0012500813010096

ISSN 0012ꢀ5008, Doklady Chemistry, 2013, Vol. 448, Part 1, pp. 31–34. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © V.B. Sokolov, A.Yu. Aksinenko, T.V. Goreva, T.A. Epishina, I.V. Martynov, 2013, published in Doklady Akademii Nauk, 2013, Vol. 448, No. 3, pp. 310–313.
CHEMISTRY
Methyl Trifluoropyruvate in Cyclocondensation
with 1,3ꢀBis(nucleophiles)
V. B. Sokolov, A. Yu. Aksinenko, T. V. Goreva, T. A. Epishina,
and Corresponding Member of the RAS I. V. Martynov
Received July 17, 2012
DOI: 10.1134/S0012500813010096
The directed synthesis of fiveꢀmembered heterocyꢀ MTFP 1 as available fluorineꢀcontaining 1,2ꢀbis(elecꢀ
clic systems by the cyclocondensation of 1,2ꢀbis(elecꢀ
trophiles) with 1,3ꢀbis(nucleophiles) is a topical task
of organic chemistry in spite of the well developed but
continuously updated by new data methodology of
these transformations. In our opinion, the present
study is a new original evolution of this synthetic pracꢀ
tice as applied to the synthesis of trifluoromethylꢀconꢀ
taining fiveꢀmembered heterocyclic compounds.
trophile) in cyclocondensation reactions with 1,3ꢀ
bis(nucleophiles) resulting in various heterocyclic
derivatives of trifluoroꢀ2ꢀhydroxypropionic acid.
The reaction of compound
1 with 1,3ꢀbis(nucleoꢀ
philes) was accomplished as a twoꢀstage cyclocondenꢀ
sation reaction: addition of bis(nucleophile) at highly
electrophilic C=O bond followed by heterocyclization
with methanol elimination. 6ꢀAminoꢀ1ꢀbenzyluracil
Methyl trifluoropyruvate (MTFP) derivatives, in
particular its Nꢀsubstituted imines, are well studied in
cyclocondensation reactions, for the synthesis of bioꢀ
logically active compounds including [1–6]. However,
(
2
), 3ꢀaminocyclohexenones (5a
nonitrile ( ), and ꢀsubstituted benzamidines (7a
were used in these transformations as 1,3ꢀbis(nucleoꢀ
philes). In the reaction of with compound , we isoꢀ
lated in a pure state and characterized a primary reacꢀ
tion product, 6ꢀaminouracil ( ), which undergoes
,
5b), 3ꢀaminocrotoꢀ
6
N
,
7b)
1
2
the question on the direct use of MTFP
1 in these
reactions—except for the reaction of with phenols
1
3
[7], anilines [8], 2ꢀaminophenols [9], and 2ꢀmercapꢀ
tophenol [10] resulting in fiveꢀ and sixꢀmembered hetꢀ
erocyclic compounds—remained open. The aim of
heterocyclization on heating at 90–100°C in DMF for
2 h in the presence of catalytic amounts of Et3N to give
this work is a declaration of synthetic possibilities of dihydroꢀ1Hꢀpyrrolo[2,3ꢀd]pyrimidinꢀ2,4,6ꢀtrione (4).
3'
O
O
4
HO
HO CF3
2'
3
HN
2
1'
CF3
HN
C(O)OCH3
O
+
6
C(O)OCH3
O
N
NH2
O
N1 NH2
CH2C6H5
CH2C6H5
1
2
3
O
4
3
CF3
5
HN
OH
Et3N
2
6
–CH3OH
O
N
N
H
O
1
CH2C6H5
4
3ꢀAminocrotononitrile 6 and Nꢀsubstituted benzaꢀ absence of catalyst to form 4,5ꢀdihydroꢀ1Hꢀpyrrole
midines 7a and 7b combine with MTFP
1 in the
(
9
) and 4,5ꢀdihydroimidazolꢀ5ꢀones (10a
nucleophilic 3ꢀaminocyclohexenones 5a
cyclocondensation with in the presence of catalytic
amounts of Et3N to yield 4,5,6,7ꢀtetrahydroꢀ1Hꢀ
indoleꢀ2,4ꢀdiones (8a 8b).
,
10b). Less
,
5b undergo
1
Institute of Physiologically Active Substances,
Russian Academy of Sciences, Severnyi pr. 1, Chernogolovka,
Moscow oblast, 142432 Russia
,
31

32
SOKOLOV et al.
O
CH3
NH
CH3
R
O
CF3
4
3
5
6
5a, 5b
OH
2
CH3
CH3
N1
R
O
7
8a, 8b
NCNC
CF3
OH
NC
CH3
CF3
CH3
NH2
6
O
C(O)OCH3
N
H
O
1
9
NH
NH
Ph
CF3
3
4
R
N
OH
7a, 7b
5
2
1
Ph
N
O
R
10a, 10b
5, 8: R = CH2C6H5 (a), 3,4ꢀ(CH3)2C6H3 (b);
7, 10: R = C3H7 (a), CH2CH2C6H5 (b).
Methyl 3ꢀaminocrotonate (11) undergoes cycloꢀ
(12), which is anomalous in comparison with considꢀ
condensation with MTFP to produce pyrrolidine ered above 1,3ꢀC,Nꢀbis(nucleophiles).
1
O
CF3
4
3
2
O
OH
CF3
CH3O
+
5
O
CH3O
1N
H
O
C(O)OCH3
CH3
NH2
1
11
12
The composition and structure of all obtained 188.29 MHz, respectively, using tetramethylsilane as
compounds were proved by the data of elemental analꢀ an internal reference and CF3COOH as an external
1
19
19
ysis and H and F NMR spectra. F NMR spectra reference, respectively. Melting points were deterꢀ
show typical signals of trifluoromethyl group at mined in a glass capillary. Initial 6ꢀaminoꢀ1ꢀbenzylꢀ
1.11 ppm for
–1.8 to –2.0 ppm for 10a
Thus, MTFP can be successfully used as 1,2ꢀ
bis(electrophilic) reagent in the cyclocondensation
with 1,3ꢀbis(nucleophiles) to obtain trifluoromethylꢀ
containing fiveꢀmembered heterocyclic derivatives of
trifluoroꢀ2ꢀhydroxypropionic acid.
4
, 1.1–1.3 ppm for 8a
,
8b, 2.2 ppm for
9
,
uracil
obtained by procedures [11, 12], 3ꢀaminocrotononiꢀ
trile and ꢀsubstituted benzamidines 7a 7b (Aldꢀ
rich) were used as received.
Methyl 2ꢀ(6ꢀaminoꢀ1ꢀbenzylꢀ2,4ꢀdioxoꢀ1,2,3,4ꢀ
tetrahydropyrimidinꢀ5ꢀyl)ꢀ3',3',3'ꢀtrifluoroꢀ2'ꢀhydroꢀ
2 and 3ꢀaminocyclohexenones 5a, 5b were
,
10b, and 12
.
6
N
,
1
xypropionate (3). Uracil
added to a solution of 1.56 g (0.01 mol) of methyl trifꢀ
luoropyruvate in 20 mL of DMF with stirring, the
2 (2.17 g, 0.01 mol) was
1
EXPERIMENTAL
reaction mixture was stirred for 30 min and poured
1H and 19F NMR spectra were recorded on a into 50 mL of water. The resultant precipitate was sepꢀ
Bruker DXP 200 spectrometer operating at 200.13 and arated by filtration and recrystallized from 50% EtOH
DOKLADY CHEMISTRY Vol. 448
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METHYL TRIFLUOROPYRUVATE IN CYCLOCONDENSATION
33
to give 3.4 g (91%) of the title compound, mp 133– 6.95–7.05 (m, 2H, CHAr), 7.23 (s, 1H, OH), 7.31
135°C.
1H NMR (CDCl3,
MeO), 5.17 (AB system, 2H, CH2,
2H, NH2), 7.32 (m, 5H, CHAr), 8.04 (s, 1H, OH),
10.70 (s, 1H, NH).
(s, 1H, CHAr).
19F NMR (DMSOꢀd6
, δ, ppm): 1.32 s.
δ
, ppm,
J
, Hz): 3.71 (s, 3H,
J
= 17.6), 6.97 (s,
For C19H20F3NO3 anal. calcd. (%): C, 62.12;
H, 5.49; N, 3.81.
Found (%): C, 62.30; H, 5.31; N, 3.66.
19F NMR (DMSOꢀd6
, δ, ppm): –0.64 s.
4ꢀHydroxyꢀ2ꢀmethylꢀ5ꢀoxoꢀ4ꢀtrifluoromethylꢀ3ꢀcyꢀ
anoꢀ4,5ꢀ dihydroꢀ1Hꢀpyrrol (9). 3ꢀAminocrotononiꢀ
For C15H14F3N3O5 anal. calcd. (%): C, 48.26;
H, 3.78; N, 11.26.
trile
6
(0.82 g, 0.01 mol) was added to a solution of
in
1.56 g (0.01 mol) of methyl trifluoropyruvate
1
Found (%): C, 48.45; H, 3.95; N, 11.42.
20 mL of DMF with stirring, the reaction mixture was
heated for 2 h at 90–100°C and poured into 50 mL of
water. The resultant precipitate was separated by filtraꢀ
tion and recrystallized from 50% EtOH to give 1.6 g
(78%) of the title compound, mp 88–90°C.
1ꢀBenzylꢀ5ꢀhydroxyꢀ5ꢀtrifluoromethylꢀ5,6ꢀdihyꢀ
droꢀ1Hꢀpyrrolo[2,3ꢀ
solution of 3.73 g (0.01 mol) of compound
d
]pyrimidinꢀ2,4,6ꢀtrione (4).
A
3
and 0.1 g
of Et3N in 20 mL of DMF was heated for 2 h at 90–
100°C and poured into 50 mL of water. The resultant
precipitate was separated by filtration and recrystalꢀ
lized from 50% EtOH to give 3.0 g (88%) of the title
compound, mp 158–159°C.
1H NMR (CDCl3,
(s, 1H, OH), 11.09 (s, 1H, NH).
19F NMR (DMSOꢀd6
, ppm): –0.63 s.
For C7H5F3N2O2 anal. calcd. (%): C, 40.79; H, 2.45;
N, 13.59.
δ
, ppm): 2.20 (s, 3H, Me), 7.79
,
δ
1H NMR (DMSOꢀd6
, δ, ppm): 5.03 (s, 2H, CH2),
7.05 (s, 1H, OH), 7.18–7.42 (m, 5H, CHAr), 10.96 (s,
1H, NH), 11.62 (s, 1H, NH).
Found (%): C, 40.96; H, 2.31; N, 13.40.
19F NMR (CDCl3,
, ppm): 1.11 s.
δ
4ꢀHydroxyꢀ1ꢀpropylꢀ2ꢀphenylꢀ4ꢀtrifluoromethylꢀ
4,5ꢀdihydroimidazolꢀ5ꢀone (10a) was obtained simiꢀ
For C14H10F3N3O4 anal. calcd. (%): C, 49.28;
H, 2.95; N, 12.31.
larly to compound
125°C.
9. Yield 2.4 g (84%), mp 123–
Found (%): C, 49.47; H, 3.13; N, 12.23.
1H NMR (CDCl3,
= 7.4), 1.43 (q, 2H, CH2,
= 7.4), 7.60 (m, 3H, CHAr), 7.72 (m, 2H, CHAr),
δ
, ppm,
J, Hz): 0.8 (t, 3H, Me,
1ꢀBenzylꢀ3ꢀhydroxyꢀ6,6ꢀdimethylꢀ3ꢀtrifluoromethylꢀ
4,5,6,7ꢀtetrahydroꢀ1Hꢀindoleꢀ2,4ꢀdione (8a). 3ꢀAmiꢀ
nocyclohexenone 5a (2.29 g, 0.01 mol) was added to a
solution of 1.56 g (0.01 mol) of methyl trifluoropyruꢀ
J
J
J
= 7.4), 3.55 (t, 2H, CH2,
7.88 (s, 1H, OH).
vate
1 in 20 mL of DMF with stirring, the reaction
19F NMR (DMSOꢀd6
, δ, ppm): –1.95 s.
mixture was stirred for 30 min, 0.1 g of Et3N was
added, the mixture was heated for 2 h at 90–100°C
and poured into 50 mL of water. The resultant precipꢀ
itate was separated by filtration and recrystallized from
50% EtOH to give 2.9 g (82%) of the title compound,
mp 93–95°C.
For C13H13F3N2O2 anal. calcd. (%): C, 54.55; H,
4.58; N, 9.79.
Found (%): C, 54.66; H, 4.75; N, 9.91.
4ꢀHydroxyꢀ2ꢀphenylꢀ1ꢀphenylethylꢀ4ꢀtrifluoromꢀ
ethylꢀ4,5ꢀdihydroimidazolꢀ5ꢀone (10b) was obtained
similarly to compound 10a. Yield 2.8 g (80%), mp
112–114°C.
1H NMR (DMSOꢀd6
, δ, ppm): 1.04 (s, 3H, Me),
1.08 (s, 3H, Me), 2.21 (s, 2H, CH2), 2.45–2.53 (m,
2H, CH2), 4.73–4.92 (m, 2H, CH2), 7.22 (m, 2H,
CHAr), 7.25 (s, 1H, OH), 7.28–7.40 (m, 3H, CHAr).
1H NMR (DMSOꢀd6
CH2 Jt = 7.1, Jd = 2.8), 3.78 (t, 2H, CH2,
,
δ
, ppm,
J
, Hz): 2.77 (td, 2H,
,
J
= 7.1),
19F NMR (CDCl3,
, ppm): 1.39 s.
δ
6.98 (m, 2H, CHAr), 7.18 (m, 3H, CHAr), 7.52 (m,
5H, CHAr), 7.90 (s, 1H, OH).
For C18H18F3NO3 anal. calcd. (%): C, 61.19;
H, 5.13; N, 3.96.
19F NMR (CDCl3,
, ppm): –1.86 s.
δ
Found (%): C, 61.35; H, 5.26; N, 4.15.
For C18H15F3N2O2 anal. calcd. (%): C, 62.07;
H, 4.34; N, 8.04.
3ꢀHydroxyꢀ1ꢀ(3,4ꢀdimethylphenyl)ꢀ6,6ꢀdimethylꢀ
3ꢀtrifluoromethylꢀ4,5,6,7ꢀtetrahydroꢀ1Hꢀindoleꢀ2,4ꢀ
Found (%): C, 62.22; H, 4.53; N, 8.18.
dione (8b). The compound was obtained similarly to 8a
Yield 3.0 g (82%), mp 138–140°C.
1H NMR (DMSOꢀd6
, ppm): 1.09 (s, 3H, Me),
1.12 (s, 3H, Me), 2.18–2.43 (m, 10H, 2Me + 2CH2),
.
Methyl 4ꢀhydroxyꢀ5ꢀoxoꢀ4ꢀtrifluoromethylpyrroliꢀ
dinꢀ(2
nate 11 (1.15 g, 0.01 mol) was added to a solution of
1.56 g (0.01 mol) of methyl trifluoropyruvate in
E)ꢀylideneacetate (12). Methyl 3ꢀaminocrotoꢀ
,
δ
1
DOKLADY CHEMISTRY Vol. 448
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34
SOKOLOV et al.
20 mL of DMF with stirring, the reaction mixture was
heated for 2 h at 90–100°C and poured into 50 mL of
water. The resultant precipitate was separated by filtraꢀ
tion and recrystallized from 50% EtOH to give 1.9 g
(71%) of the title compound, mp 95–97°C.
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1H NMR (DMSOꢀd6
, δ, ppm): 3.04 (s, 2H, CH2),
3.70 (s, 3H, MeO), 5.08 (s, 1H, C=CH), 7.38 (s, 1H,
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N, 5.86.
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ACKNOWLEDGMENTS
This work was supported by the Division of Chemꢀ
istry and Materials Science of the Russian Academy of
Sciences (Program “Medicinal Chemistry: Molecular
Design of Physiologically Active Compounds and
Pharmaceuticals”) and the Russian Foundation for
Basic Research (project nos. 11–03–00480ꢀa, 11–
03–00496ꢀa, 11–03–12076ꢀofiꢀmꢀ2011, and 12–
03–00828ꢀa).
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DOKLADY CHEMISTRY Vol. 448
Part 1
2013