Diethoxyphosphorylimine of methyl trifluoropyruvate in cyclocondensation with 1,3-C,N-and-N,N-binucleophiles

Article abstract of DOI:10.1007/s11172-007-0353-0

Reaction of diethoxyphosphorylimine of methyl trifluoropyruvate with 1,3-C,N-and-N,N-binucleophiles led to a variety of N-phosphorylated fluorine-containing heterocycles, including the fused ones.

Full text of DOI:10.1007/s11172-007-0353-0

Russian Chemical Bulletin, International Edition, Vol. 56, No. 11, pp. 2252—2254, November, 2007
2252
Diethoxyphosphorylimine of methyl trifluoropyruvate in cyclocondensation
with 1,3ꢀC,Nꢀ and ꢀN,Nꢀbinucleophiles
V. B. Sokolovꢀ and A. Yu. Aksinenko
Institute of Physiologically Active Compounds, Russian Academy of Sciences,
142432 Chernogolovka, Moscow Region, Russian Federation.
Fax: +7 (496) 524 9508. Eꢀmail: alaks@ipac.ac.ru
Reaction of diethoxyphosphorylimine of methyl trifluoropyruvate with 1,3ꢀC,Nꢀ and
ꢀN,Nꢀbinucleophiles led to a variety of Nꢀphosphorylated fluorineꢀcontaining heterocycles,
including the fused ones.
Key words: diethoxyphosphorylimine, 1,3ꢀC,Nꢀ and ꢀN,Nꢀbinucleophiles, Nꢀphosphoryꢀ
lated heterocycles, hexahydroꢀ1Нꢀpyrrolo[2,4ꢀd]pyrimidines, 4,5ꢀdihydroꢀ1Нꢀpyrroles, 2,5ꢀdiꢀ
oxoimidazolidine, 4,5ꢀdihydroꢀ1Нꢀimidazole, tetrahydroimidazo[2,1ꢀb]thiazole, cycloꢀ
condensation.
Scheme 1
In the preparation of heterocycles containing phosꢀ
phorus and fluorine, diethoxyphosphorylimine of methyl
trifluoropyruvate is a prospective synthon, for example,
when it is used in the Mannich reaction with indole,1 in
the azaꢀDiels—Alder reaction with cyclopentadiene2
and in the synthesis of Nꢀphosphorylated αꢀ(trifluoroꢀ
methyl)azahistidine.3 The present communication deals
with the application of this compound as the 1,2ꢀbiꢀ
electrophile in the cyclocondensation reactions with
1,3ꢀC,Nꢀ and ꢀN,Nꢀbinucleophiles for the synthesis of
fiveꢀmembered heterocycles containing phosphorus and
fluorine. The data obtained by us earlier on the reaction
of Nꢀacylimines of methyl trifluoropyruvate with various
1,3ꢀC,Nꢀ and ꢀN,Nꢀbinucleophiles, which led to differꢀ
ent fiveꢀ and sixꢀmembered fluorineꢀcontaining heteroꢀ
cycles,4—8 served as the prerequisite for this research.
Diethoxyphosphorylimine of methyl trifluoropyruvate
(1) was used in the reaction with a number of biꢀ
nucleophiles, which proceed according to the twoꢀstep
scheme: the addition of 1,3ꢀbinucleophile at the C=N
bond of imine 1 and the subsequent cyclization with elimiꢀ
nation of МеОН.
In the case of the reaction of imine 1 with Nꢀbenzylꢀ
urea (2) (Scheme 1), we isolated and identified the addiꢀ
tion product, the corresponding phosphamide 3, which
upon heating in DMF in the presence of catalytic amount
of Et3N for 1 h at 90—100 °C was converted to imidꢀ
azolidine 4.
The cyclocondensation of phosphorylimine 1 with
other binucleophiles (Scheme 2), viz., methyl 2ꢀaminoꢀ
crotonate (5), Nꢀbenzylbenzamidine (7), 2ꢀaminothiazoꢀ
line 9, 6ꢀaminouracils 11a,b, and 6ꢀaminothiouracils
13a,b, was carried out upon heating of a mixture of the
reagents in DMF for 1 h at 90—100 °C and in the case of
the reaction of imine 1 with compounds 11a,b and 13a,b,
in the presence of catalytic amount of Et3N.
Amidophosphates 4, 6, 8, 10, 12a,b, and 14a,b, obꢀ
tained in 69—83% yield, are solid crystalline substances,
their composition and structures were confirmed by elꢀ
emental analysis and NMR spectroscopy data. A signal of
the amide NH proton in form of a doublet with J =
6—7 Hz in the region δ 6—7 is characteristic of the
1H NMR spectra, signals of trifluoromethyl group at
δ –1.5—4, of the 19F NMR spectra, and singlets in the
region δ 4—6, of the 31Р NMR spectra.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2176—2178, November, 2007.
1066ꢀ5285/07/5611ꢀ2252 © 2007 Springer Science+Business Media, Inc.

Methyl trifluoropyruvate diethoxyphosphorylimine
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007 2253
Scheme 2
Scheme 3
(depending on the nature of 1,3ꢀbinucleophile used) fluoꢀ
rineꢀcontaining heterocycles, including the biologically
active ones.
Experimental
1
H, 19F, and 31P NMR spectra were recorded on a Bruker
DXP 200 spectrometer (200.13, 188.29, and 81.01 MHz, respecꢀ
tively) relatively to Me4Si (the internal standard), CF3COOH
and H3PO4 (the external standards). Melting points were deterꢀ
mined in a glass capillary tube. The starting 6ꢀaminouracils
11a,b and 6ꢀaminothiouracils 13a,b were synthesized by
the known procedure;9 Nꢀbenzylurea (2), methyl 2ꢀaminoꢀ
crotonate (5), 2ꢀaminothiazoline 9, diethoxyphosphamide 15,
and methyl trifluoropyruvate (16) (Aldrich) were used without
additional purification.
Methyl 2ꢀ(diethoxyphosphoryl)iminoꢀ3,3,3ꢀtrifluoroproꢀ
pionate (1). Methyl trifluoropyruvate 16 (15.6 g, 0.1 mol), pyriꢀ
dine (15.6 g, 0.2 mol), and SOCl2 (11.9 g, 0.1 mol) were sequenꢀ
tially added to a suspension of diethoxyphosphamide 15 (15.3 g,
0.1 mol) in benzene (100 mL). The reaction mixture was stirred
for 2 h, the precipitate formed was filtered off, the filtrate was
concentrated, the residue fractionally distilled in vacuo. Imine 1
(21.3 g, 73%) was obtained, b.p. 95—97 °C (1 Torr). Physicoꢀ
chemical and spectral characteristics are in agreement with those
reported in Refs 1, 2.
Methyl 2ꢀ(3ꢀbenzylureido)ꢀ2ꢀ(diethoxyphosphoryl)aminoꢀ
3,3,3ꢀtrifluoropropionate (3). Imine 1 (2.91 g, 0.01 mol) was
added to a stirred suspension of Nꢀbenzylurea (2) (1.5 g,
0.01 mol) in benzene (20 mL). The reaction mixture was stirred
for 1 h, benzene was evaporated, the residue was recrystallized
from heptane. Amidophosphate 3 (3.9 g, 88%) was obtained,
m.p. 126—128 °C. Found (%): C, 43.38; H, 5.11; N, 9.63.
C16H23F3N3O6Р. Calculated (%): C, 43.64; H, 5.25; N, 9.52.
1H NMR (DMSOꢀd6), δ: 1.21, 1.33 (both t, 3 H each, 4 Me, J =
6.5 Hz); 3.82 (s, 3 H, OMe); 3.85—4.10 (m, 4 H, OCH2); 4.26
(m, 2 H, NCH2); 5.19 (d, 1 H, NH, J = 7.0 Hz); 6.94 (t, 1 H,
NHCH2, J = 6.0 Hz); 7.13—7.34 (m, 5 H, СHAr); 7.37 (s,
1 H, NHCO). 19F NMR (DMSOꢀd6), δ: 0.49 (s). 31P NMR
(DMSOꢀd6), δ: 2.31 (s).
Diethyl [1ꢀbenzylꢀ2,5ꢀdioxoꢀ4ꢀ(trifluoromethyl)imidazolidinꢀ
4ꢀyl]amidophosphate (4). A solution of compound 3 (2.2 g,
0.005 mol) and Et3N (0.1 g) in DMF (10 mL) was heated for 1 h
at 90—100 °C, diluted with water (50 mL), the precipitate formed
was filtered off and recrystallized from 50% aq. EtOH. Amidoꢀ
phosphate 4 (1.6 g, 78%) was obtained, m.p. 124—126 °C.
11, 12: R = R´ = Me (a); R = H, R´ = 4ꢀFC6H4 (b)
13, 14: R = СH2=CH(Me)CH2 (a), 2ꢀFC6H4 (b)
It should be noted that diethoxyphosphorylimine of
methyl trifluoropyruvate (1), in contrast to the proceꢀ
dures proposed earlier,1,2 was synthesized in 73% yield by
the oneꢀpot method, including the sequential treatment
of a suspension of diethoxyphosphamide 15 in benzene
with methyl trifluoropyruvate (16), pyridine, and SOCl2
(Scheme 3).
In conclusion, the reaction of diethoxyphosphorylꢀ
imine of methyl trifluoropyruvate with the mentioned
1,3ꢀС,Nꢀ and ꢀN,Nꢀbinucleophiles leads to the Nꢀphosꢀ
phorylated fluorineꢀcontaining heterocycles of three strucꢀ
tural types: imidazolidines, pyrroles, and imidazoles. The
experimental date obtained allow one to introduce into
the molecules of the phosphorus acid amides various

2254
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007
Sokolov and Aksinenko
Found (%): C, 44.19; H, 4.82; N, 10.11. C15H19F3N3O5Р. Calꢀ
culated (%): C, 44.02; H, 4.59; N, 10.27. 1H NMR (DMSOꢀd6),
δ: 1.19 (t, 6 H, 2 Me, J = 5.1 Hz); 3.91 (m, 4 H, OCH2); 4.52
(АВꢀsystem, 2 H, CH2, J = 17.2 Hz); 6.71 (d, 1 H, NH, J =
6.2 Hz); 6.22 (m, 5 H, CHAr); 9.34 (s, 1 H, NH). 19F NMR
(DMSOꢀd6), δ: –1.05 (s). 31P NMR (DMSOꢀd6), δ: 4.07 (s).
Methyl 4ꢀ(diethoxyphosphoryl)aminoꢀ2ꢀmethylꢀ5ꢀoxoꢀ
4ꢀtrifluoromethylꢀ4,5ꢀdihydroꢀ1Нꢀpyrroleꢀ3ꢀcarboxylate (6).
Imine 1 (2.91 g, 0.01 mol) was added to a solution of methyl
2ꢀaminocrotonate (5) (1.15 g, 0.01 mol) in DMF (10 mL). The
reaction mixture was heated for 1 h at 90—100 °C, diluted with
water (50 mL), the precipitate formed was filtered off and reꢀ
crystallized from 50% aq. EtOH. Pyrrole 6 (3.1 g, 83%) was
obtained, m.p. 127—129 °C. Found (%): C, 38.35; H, 4.68;
N, 7.37. C12H18F3N2O6Р. Calculated (%): C, 38.51; H, 4.85;
N, 7.49. 1H NMR (DMSOꢀd6), δ: 1.27, 1.32 (both t, 3 H each,
2 Me, J = 6.7 Hz); 2.38, 3.72 (both s, 3 H each, 2 OMe); 3.93,
4.04 (both m, 2 H each, 2 OCH2); 5.53 (d, 1 H, NH, J =
6.4 Hz); 10.73 (s, 1 H, NH). 19F NMR (DMSOꢀd6), δ: 2.84 (s).
31P NMR (DMSOꢀd6), δ: 5.50 (s).
Diethyl (1ꢀbenzylꢀ5ꢀoxoꢀ2ꢀphenylꢀ4ꢀtrifluoromethylꢀ4,5ꢀ
dihydroꢀ1Нꢀimidazolꢀ4ꢀyl)amidophosphate (8). The product was
obtained similarly to compound 6 from benzamidine 7 (2.1 g,
0.01 mol) and imine 1 (2.91 g, 0.01 mol). The yield was 3.8 g
(81%), m.p. 116—118 °C. Found (%): C, 53.87; H, 4.78; N, 8.81.
C21H23F3N3O4Р. Calculated (%): C, 53.73; H, 4.94; N, 8.95.
1H NMR (DMSOꢀd6), δ: 1.27, 1.32 (both t, 3 H each, 2 Me, J =
6.5 Hz); 4.06 (m, 4 H, OCH2); 4.56, 4.77 (both d, 1 H each,
CH2, J = 16.1 Hz); 6.90 (d, 1 H, NH, J = 6.6 Hz); 7.15 (m, 2 H,
CHAr); 7.24 (m, 3 H, CHAr); 7.44 (m, 5 H, CHAr). 19F NMR
(DMSOꢀd6), δ: 0.30 (s). 31P NMR (DMSOꢀd6), δ: 6.2 (s).
Diethyl (5ꢀoxoꢀ6ꢀtrifluoromethylꢀ2,3,5,6ꢀtetrahydroimidꢀ
azo[2,1ꢀb][1,3]thiazolꢀ6ꢀyl)amidophosphate (10). The product
was obtained similarly to compound 6 from 2ꢀaminothiazoline 9
(1.02 g, 0.01 mol) and imine 1 (2.91 g, 0.01 mol). The yield was
2.9 g (80%), m.p. 122—123 °C. Found (%): C, 33.12; H, 4.05;
N, 11.49. C10H15F3N3O4PS. Calculated (%): C, 33.25; H, 4.18;
N, 11.63. 1H NMR (DMSOꢀd6), δ: 1.31, 1.33 (both t, 3 H each,
2 Me, J = 4.8 Hz); 3.75 (m, 4 H, NCH2, SCH2); 4.01 (m, 4 H,
OCH2); 6.61 (d, 1 H, NH, J = 5.6 Hz). 19F NMR (DMSOꢀd6),
δ: –0.09 (s). 31P NMR (DMSOꢀd6), δ: 6.27 (s).
Found (%): C, 42.36; H, 3.42; N, 11.81. C17H17F4N4O6P. Calꢀ
culated (%): C, 42.51; H, 3.57; N, 11.66. 1H NMR (DMSOꢀd6),
δ: 1.21, 1.25 (both t, 3 H each, 2 Me, J = 6.5 Hz); 4.01 (m, 4 H,
OCH2); 6.64 (d, 1 H, NH, J = 6.7 Hz); 7.41, 7.55 (both m,
2 H each, CHAr); 11.33, 11.41 (both s, 1 H each, 2 NH).
19F NMR (DMSOꢀd6), δ: 4.14 (s, 3 F, CF3); –34.04 (m, 1 F,
CFAr). 31P NMR (DMSOꢀd6), δ: 5.79 (s).
Diethyl [4,6ꢀdioxoꢀ1ꢀ(2ꢀmethylallyl)ꢀ2ꢀthioxoꢀ5ꢀtrifluoroꢀ
methylꢀ2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀpyrrolo[2,3ꢀd]pyrimidinꢀ5ꢀ
yl]amidophosphate (14a). The product was obtained similarly to
compound 12а from thiouracil 13а (1.97 g, 0.01 mol) and imine 1
(2.91 g, 0.01 mol). The yield was 3.1 g (68%), m.p. 212—214 °C.
Found (%): C, 39.31; H, 4.29; N, 12.12. C15H20F3N4O5PS.
Calculated (%): C, 39.48; H, 4.42; N, 12.28. 1H NMR
(DMSOꢀd6), δ: 1.17, 1.23 (both t, 3 H each, 2 Me, J = 6.7 Hz);
2.51 (s, 3 H, Me); 3.95 (m, 4 H, OCH2); 4.47 (s, 1 H, NCH2);
4.85 (m, 3 H, =CH2 + NCH2); 6.76 (d, 1 H, NH, J = 7.2 Hz);
12.11, 12.71 (both s, 1 H each, NH). 19F NMR (DMSOꢀd6), δ:
3.47 (s). 31P NMR (DMSOꢀd6), δ: 5.32 (s).
Diethyl [1ꢀ(2ꢀfluorophenyl)ꢀ4,6ꢀdioxoꢀ2ꢀthioxoꢀ5ꢀtrifluoroꢀ
methylꢀ2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀpyrrolo[2,3ꢀd]pyrimidinꢀ5ꢀ
yl]amidophosphate (14b). The product was obtained similarly to
compound 12а from thiouracil 13b (2.37 g, 0.01 mol) and imine 1
(2.91 g, 0.01 mol). The yield was 3.1 g (71%), m.p. 204—206 °C.
Found (%): C, 41.27; H, 3.59; N, 11.13. C17H17F4N4O5PS.
Calculated (%): C, 41.14; H, 3.45; N, 11.29. 1H NMR
(DMSOꢀd6), δ: 1.27 (m, 6 H, 2 Me); 3.93 (m, 4 H, OCH2); 6.72
(d, 1 H, NH, J = 6.9 Hz); 7.38 (m, 3 H, CHAr); 7.57 (m, 1 H,
CHAr); 11.55, 12.66 (both s, 1 H each, 2 NH). 19F NMR
(DMSOꢀd6), δ: 3.23 (s). 31P NMR (DMSOꢀd6), δ: 5.21 (s).
References
1. P. P. Onys´ko, Yu. V. Rassukanaya, and A. D. Sinitsa,
Zh. Obshch. Khim., 2002, 72, 1802 [Russ. J. Gen. Chem., 2002,
72 (Engl. Transl.)].
2. N. M. Kobel´kova, S. N. Osipov, and A. F. Kolomiets, Izv.
Akad. Nauk, Ser. Khim., 2002, 1199 [Russ. Chem. Bull., Int.
Ed., 2002, 51, 1298].
3. G. T. Shchetnikov, A. S. Peregudov, and S. N. Osipov, Synlett,
2007, 136.
4. V. B. Sokolov, A. Yu. Aksinenko, and I. V. Martynov, Izv.
Akad. Nauk, Ser. Khim., 2001, 1064 [Russ. Chem. Bull., Int.
Ed., 2001, 50, 1113].
5. V. B. Sokolov, A. Yu. Aksinenko, T. A. Epishina, T. V. Goreva,
and I. V. Martynov, Izv. Akad. Nauk, Ser. Khim., 2005, 462
[Russ. Chem. Bull., Int. Ed., 2005, 54, 472].
6. V. B. Sokolov, A. Yu. Aksinenko, T. A. Epishina, T. V. Goreva,
and I. V. Martynov, Izv. Akad. Nauk, Ser. Khim., 2005, 2755
[Russ. Chem. Bull., Int. Ed., 2005, 54, 2851].
7. A. Yu. Aksinenko, T. V. Goreva, T. A. Epishina, A. N. Pushin,
and V. B. Sokolov, Izv. Akad. Nauk, Ser. Khim., 2006, 1014
[Russ. Chem. Bull., Int. Ed., 2005, 54, 1052].
8. V. B. Sokolov, A. Yu. Aksinenko, T. A. Epishina, T. V. Goreva,
A. N. Pushin, and I. V. Martynov, Izv. Akad. Nauk, Ser.
Khim., 2005, 1619 [Russ. Chem. Bull., Int. Ed., 2005, 54, 1667].
9. W. Hatzenlaub and W. Pfleiderer, Liebigs Ann. Chem.,
1979, 1847.
Diethyl
(1,3ꢀdimethylꢀ5ꢀtrifluoromethylꢀ2,4,6ꢀtrioxoꢀ
2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀpyrrolo[2,3ꢀd]pyrimidinꢀ5ꢀyl)amidoꢀ
phosphate (12а). Imine 1 (2.91 g, 0.01 mol) and Et3N (0.1 mL)
were added to a suspension of uracil 11а (1.55 g, 0.01 mol) in
DMF (10 mL). The reaction mixture was heated for 1 h at
90—100 °C, diluted with water (50 mL), the precipitate formed
was filtered off and recrystallized from 50% aq. EtOH. Amidoꢀ
phosphate 12a (3.2 g, 77%) was obtained, m.p. 242—244 °C.
Found (%): C, 37.52; H, 4.22; N, 13.37. C13H18F3N4O6P. Calꢀ
culated (%): C, 37.69; H, 4.38; N, 13.52. 1H NMR (DMSOꢀd6),
δ: 1.23, 1.32 (both t, 3 H each, 2 Me, J = 6.5 Hz); 3.26, 3.44
(both s, 3 H each, 2 NMe); 3.92, 4.06 (both m, 2 H each,
2 OCH2); 6.32 (d, 1 H, NH, J = 7.4 Hz); 11.96 (s, 1 H, NH).
19F NMR (DMSOꢀd6), δ: 3.52 (s). 31P NMR (DMSOꢀd6),
δ: 4.73 (s).
Diethyl [1ꢀ(4ꢀfluorophenyl)ꢀ5ꢀtrifluoromethylꢀ2,4,6ꢀtrioxoꢀ
2,3,4,5,6,7ꢀhexahydroꢀ1Нꢀpyrrolo[2,3ꢀd]pyrimidinꢀ5ꢀyl]amidoꢀ
phosphate (12b). The product was obtained similarly to comꢀ
pound 12а from uracil 11b (2.21 g, 0.01 mol) and imine 1 (2.91 g,
0.01 mol). The yield was 3.2 g (69%), m.p. 181—183 °C.
Received May 24, 2007;
in revised form July 19, 2007