Methyl 3,3,3-trifluoro-2-(thiazol-2-ylimino)propionate in cycloaddition and cyclocondensation reactions

Article abstract of DOI:10.1007/s11172-012-0300-6

The behavior of methyl 3,3,3-trifluoro-2-(thiazol-2-ylimino)propionate (1) in cycloaddition and cyclocondensation reactions was studied. Cycloaddition of dimethylcyanamide to imine 1 gave a thiazolo[3,2-a][1,3,5]triazine derivative. Cyclocondensations of

Full text of DOI:10.1007/s11172-012-0300-6

Russian Chemical Bulletin, International Edition, Vol. 61, No. 11, pp. 2137—2139, November, 2012
2137
Methyl 3,3,3ꢀtrifluoroꢀ2ꢀ(thiazolꢀ2ꢀylimino)propionate
in cycloaddition and cyclocondensation reactions
V. B. Sokolov, A. Yu. Aksinenko, T. A. Epishina, and T. V. Goreva
Institute of Physiologically Active Compounds, Russian Academy of Sciences,
1 Severnyi pr., 142432 Chernogolovka, Moscow Region, Russian Federation.
Fax: +7 (496) 524 9508. Eꢀmail: alaks@ipac.ac.ru
The behavior of methyl 3,3,3ꢀtrifluoroꢀ2ꢀ(thiazolꢀ2ꢀylimino)propionate (1) in cycloaddiꢀ
tion and cyclocondensation reactions was studied. Cycloaddition of dimethylcyanamide to
imine 1 gave a thiazolo[3,2ꢀa][1,3,5]triazine derivative. Cyclocondensations of imine 1 with
2ꢀaminothiazoline, Nꢀcyclohexylbenzamidine, methyl (Z)ꢀ3ꢀaminobutꢀ2ꢀenoate, and 6ꢀamiꢀ
noꢀ1ꢀbenzyluracil yielded dihydroimidazo[2,1ꢀb]thiazolꢀ5(6H)ꢀone, 4,5ꢀdihydroimidazolꢀ5ꢀ
one, 4,5ꢀdihydroꢀ1Hꢀpyrrolꢀ5ꢀone, and dihydroꢀ1Hꢀpyrrolo[2,3ꢀd]pyrimidineꢀ2,4,6ꢀtrione deꢀ
rivatives, respectively.
Key words: methyl 3,3,3ꢀtrifluoroꢀ2ꢀ(thiazolꢀ2ꢀylimino)propionate, dimethylcyanamide,
thiazolo[3,2ꢀa][1,3,5]triazine, 1,3ꢀbinucleophiles, dihydroimidazo[2,1ꢀb]thiazolꢀ5(6H)ꢀone,
4,5ꢀdihydroimidazolꢀ5ꢀone, 4,5ꢀdihydroꢀ1Hꢀpyrrolꢀ5ꢀone, dihydroꢀ1Hꢀpyrrolo[2,3ꢀd]pyrꢀ
imidineꢀ2,4,6ꢀtrione, cycloaddition, cyclocondensation.
Scheme 1
Trifluoromethylꢀcontaining heterodienes are imporꢀ
tant precursors for the synthesis of fluorinated heterocycles,
which constitute a promising class of biologically active
compounds used in medical and agrochemical practice.1—3
Such heterodienes as Nꢀacyl imines derived from hexafluꢀ
oroacetone and methyl trifluoropyruvate are best studied
in heterocyclization (cycloaddition and cyclocondensaꢀ
tion) reactions. Data on the behavior of these Nꢀacyl imiꢀ
nes in the azaꢀDiels—Alder reaction4 and cyclocondensaꢀ
tions with 1,3ꢀbinucleophilic reagents5—11 have been pubꢀ
lished.
The present work was aimed at further developing the
methodology for practical use of trifluoromethylated
heterodienes in heterocyclic synthesis. Here we examined
methyl 3,3,3ꢀtrifluoroꢀ2ꢀ(thiazolꢀ2ꢀylimino)propionate
(1) as a precursor in heterocyclization reactions of two
types: cycloaddition and cyclocondensation.
Scheme 2
We proposed a synthetic route to compound 1 via sucꢀ
cessive addition to a solution of 2ꢀaminothiazole (2) of
equimolar amounts of pyridine, methyl trifluoropyruꢀ
vate (3), and SOCl2 (Scheme 1).
Imine 1 is a crystalline solid; its composition and structure
were confirmed by elemental analysis and NMR spectroꢀ
scopy. The 19F NMR spectra of imine 1 show a characterisꢀ
tic signal for the CF3 group at the azomethine bond5 ( 8.37).
In [2+4] cycloaddition, imine 1 acts as an electronꢀ
deficient heterodiene. For instance, it reacts with dimethꢀ
ylcyanamide (4) at 90 C to give a thiazolo[3,2ꢀa]ꢀ
[1,3,5]triazine derivative (5) as an azaꢀDiels—Alder reacꢀ
tion product (Scheme 2). It should be noted that this reacꢀ
tion reaches completion under more drastic conditions
compared to similar transformations involving Nꢀacyl imiꢀ
nes derived from polyfluorinated ketones.12
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2120—2122, November, 2012.
1066ꢀ5285/12/6111ꢀ2137 © 2012 Springer Science+Business Media, Inc.

2138
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 11, November, 2012
Sokolov et al.
Scheme 3
Imine 1 reacts exothermically with such highly reacꢀ
tive 1,3ꢀN,Nꢀ and C,Nꢀbinucleophiles as 2ꢀaminothiazolꢀ
ine (6), Nꢀcyclohexylbenzamidine (7), and methyl (Z)ꢀ3ꢀ
aminobutꢀ2ꢀenoate (8). The reactions follow the cycloꢀ
condensation pattern: first a 1,3ꢀbinucleophile adds to the
C=N bond of compound 1 and then the adduct undergoes
cyclization with elimination of MeOH. Shortꢀtime heatꢀ
ing at 50 C is required for the reaction to be completed.
The above cyclocondensations yield 6ꢀtrifluoromethylꢀ
imidazo[2,1ꢀb]thiazolꢀ5ꢀone (10), 2ꢀphenylꢀ4ꢀtrifluoroꢀ
methylꢀ4,5ꢀdihydroꢀ1Hꢀimidazolꢀ5ꢀone (11), and 2ꢀmethꢀ
ylꢀ4ꢀtrifluoromethylꢀ4,5ꢀdihydroꢀ1Hꢀpyrrolꢀ5ꢀone (12),
respectively. Heating of less reactive 6ꢀaminouracil (9)
with imine 1 at 100 C for 2 h in the presence of a catalytic
amount of Et3N gives 5ꢀtrifluoromethylꢀ5,7ꢀdihydroꢀ1Hꢀ
pyrrolo[2,3ꢀd]pyrimidineꢀ2,4,6ꢀtrione (13) (Scheme 3).
Compounds 10—13 are crystalline solids; their comꢀ
positions and structures were proved by elemental analysis
and 1H and 19F NMR spectroscopy. The 19F NMR spectra
show characteristic signals at  0.59 (for 10), –1.17 (11),
3.36 (12), and 3.99 (13).
To sum up, our study of the behavior of methyl 3,3,3ꢀtriꢀ
fluoroꢀ2ꢀ(thiazolꢀ2ꢀylimino)propionate in cycloaddition
and cyclocondensation reactions demonstrated that this
compound can serve as a promising precursor in the synꢀ
thesis of fluorineꢀcontaining heterocycles.
2ꢀaminothiazole (2) (10.0 g, 0.1 mol) and pyridine (15.6 g,
0.2 mol) in benzene (100 mL). The reaction mixture was stirred
for 2 h, filtered, and concentrated. The residue was fractionated.
Yield 17.2 g (72%), b.p. 98—99 C (1 Torr), m.p. 48—50 C.
Found (%): C, 35.48; H, 2.33; N, 11.59. C7H5F3N2O2S. Calcuꢀ
1
lated (%): C, 35.30; H, 2.12; N, 11.76. H NMR (DMSOꢀd6),
: 3.94 (s, 3 H, MeO); 7.54 (d, 1 H, CHAr, J = 3.4 Hz); 7.75
(d, 1 H, CHAr, J = 3.4 Hz). 19F NMR (DMSOꢀd6), : 8.37 (s).
Methyl 4ꢀdimethylaminoꢀ2ꢀtrifluoromethylꢀ2Hꢀthiazolo[3,2ꢀa]ꢀ
[1,3,5]triazineꢀ2ꢀcarboxylate (5). A solution of imine 1 (2.4 g,
0.01 mol) and dimethylcyanamide (4) (0.7 g, 0.01 mol) in toluꢀ
ene (10 mL) was heated at 100 C for 4 h. The solvent was
removed and the residue was recrystallized from hexane. Yield
2.1 g (68%), m.p. 74—76 C. Found (%): C, 38.75; H, 3.79;
N, 18.35. C10H11F3N4O2S. Calculated (%): C, 38.96; H, 3.60;
N, 18.17. 1H NMR (DMSOꢀd6), : 2.70 (s, 6 H, Me2N); 3.66
Experimental
1
H and 19F NMR spectra were recorded on a Bruker DPX 200
spectrometer (200.13 and 188.29 MHz) with Me4Si as the interꢀ
nal standard and with CF3COOH as the external standard. Meltꢀ
ing points were determined in glass capillaries. The starting comꢀ
pound 6ꢀaminoꢀ1ꢀbenzyluracil (9) was prepared as described
earlier.13 2ꢀAminothiazole (2), methyl trifluoropyruvate (3),
2ꢀaminothiazoline (6), Nꢀcyclohexylbenzamidine (7), and meꢀ
thyl (Z)ꢀ3ꢀaminobutꢀ2ꢀenoate (8) (Aldrich) were used as purꢀ
chased.
(s, 3 H, MeO); 6.45 (d, 1 H, CHAr, J = 5.4 Hz); 7.21 (d, 1 H, CHAr
J = 5.4 Hz). 19F NMR (DMSOꢀd6), : –0.26 (s).
,
6ꢀ(Thiazolꢀ2ꢀylamino)ꢀ6ꢀtrifluoromethylꢀ2,3ꢀdihydroimidꢀ
azo[2,1ꢀb]thiazolꢀ5(6H)ꢀone (10). A solution of imine 1 (2.4 g,
0.01 mol) and 2ꢀaminothiazoline (6) (1.0 g, 0.01 mol) in DMF
(10 mL) was heated at 50 C for 30 min and poured into 10%
aqueous NaCl (50 mL). The precipitate that formed was filtered
off and recrystallized from 50% EtOH. Yield 2.2 g (71%),
Methyl 3,3,3ꢀtrifluoroꢀ2ꢀ(thiazolꢀ2ꢀylimino)propionate (1).
Methyl trifluoropyruvate (3) (15.5 g, 0.1 mol) and SOCl2 (11.9 g,
0.1 mol) were successively added at 20 C to a stirred solution of

Methyl trifluoroꢀ2ꢀ(thiazolylimino)propionate
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 11, November, 2012 2139
m.p. 166—168 C. Found (%): C, 35.25; H, 3.50; N, 18.34.
C9H7F3N4OS2. Calculated (%): C, 35.06; H, 2.29; N, 18.17.
1H NMR (DMSOꢀd6), : 3.54—3.86 (m, 3 H, CH2); 3.99 (m, 1 H,
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1
lated (%): C, 55.88; H, 4.69; N, 13.72. H NMR (DMSOꢀd6),
: 1.15—1.38 (m, 4 H, CH2); 1.77—2.01 (m, 4 H, CH2); 2.07—2.27
(m, 2 H, CH2); 3.37 (m, 1 H, CH2); 6.17 (d, 1 H, CHAr, J = 3.4 Hz);
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Methyl 2ꢀmethylꢀ5ꢀoxoꢀ4ꢀ(thiazolꢀ2ꢀylamino)ꢀ4ꢀtrifluoroꢀ
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from imine 1 (2.4 g, 0.01 mol) and methyl (Z)ꢀ3ꢀaminobutꢀ2ꢀ
enoate (8) (1.15 g, 0.01 mol) as described for compound 10.
Yield 2.3 g (72%), m.p. 233—235 C. Found (%): C, 41.30;
H, 3.25; N, 12.91. C11H10F3N3O3S. Calculated (%): C, 41.12;
1
H, 3.14; N, 13.08. H NMR (DMSOꢀd6), : 2.33 (s, 3 H, Me);
3.57 (s, 3 H, MeO); 6.71 (d, 1 H, CHAr, J = 3.7 Hz); 6.93 (d, 1 H,
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19F NMR (DMSOꢀd6), : 3.36 (s).
1ꢀBenzylꢀ5ꢀ(thiazolꢀ2ꢀylamino)ꢀ5ꢀtrifluoromethylꢀ7Hꢀpyrroꢀ
lo[2,3ꢀd]pyrimidineꢀ2(1H),4(3H),6(5H)ꢀtrione (13). A solution
of imine 1 (2.4 g, 0.01 mol), 6ꢀaminouracil (9) (2.2 g, 0.01 mol),
and Et3N (0.1 g) in DMF (10 mL) was heated at 100 C for 2 h
and then poured into 10% aqueous NaCl (50 mL). The precipiꢀ
tate that formed was filtered off and recrystallized from 50%
EtOH. Yield 2.3 g (72%), m.p. 178—180 C. Found (%): C, 48.06;
H, 3.03; N, 16.38. C17H12F3N5O3S. Calculated (%): C, 48.23;
H, 2.86; N, 16.54. 1H NMR (DMSOꢀd6), : 5.03 (AB system,
2 H, CH2, J = 18.8 Hz); 6.75 (d, 1 H, CHAr, J = 4.4 Hz); 6.94
(d, 1 H, CHAr, J = 4.4 Hz); 7.24 (m, 3 H, CHAr, J = 8.6 Hz);
7.33 (s, 1 H, NH); 7.42 (d, 2 H, CHAr, J = 8.6 Hz); 9.08 (s, 1 H,
NH); 11.09 (s, 1 H, NH). 19F NMR (DMSOꢀd6), : 3.99 (s).
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This work was financially supported by the Russian
Foundation for Basic Research (Project Nos 11ꢀ03ꢀ00480ꢀa,
11ꢀ03ꢀ00496ꢀa, 11ꢀ03ꢀ12076ꢀofiꢀmꢀ2011, and 12ꢀ03ꢀ
00828ꢀa).
Received July 26, 2012;
in revised form November 15, 2012