HETEROCYCLES

Paper | Regular issue | Vol. 78, No. 2, 2009, pp. 435-447
Received, 15th August, 2008, Accepted, 29th September, 2008, Published online, 6th October, 2008.
DOI: 10.3987/COM-08-11524

■ Synthesis of Fluoroalkylated Dihydroazolo[1,5-a]pyrimidines and Their Ring-Chain Isomerism

Marina V. Goryaeva,* Yanina V. Burgart, Victor I. Saloutin, Elena V. Sadchikova, and Evgeny N. Ulomskii

I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, Ekaterinburg, 620041, Russia

Abstract

Cyclisation of ethyl 2-ethoxymethylidene-3-polyfluoroalkyl-3-oxo-propionates with 3-amino-1H-[1,2,4]triazole, 3-amino-5-methylpyrazole, ethyl 3-aminopyrazole-4-carboxylate and ethyl 5-aminoimidazole-4-carboxylate hydrochloride results in the formation of polyfluoroalkylated dihydroazolo[1,5-a]pyrimidines. The latter are subject to ring-chain isomerisation in solutions depending on the solvent and the “length” of the fluoroalkyl substituent to yield ethyl 3-polyfluoroalkyl-3-oxo-2-[(azol-3-yl)aminomethylidene]propionates via opening of the heterocycle at the C-N bond. Dehydration of dihydroazolo[1,5-a]pyrimidine were realized.

INTRODUCTION
Azolo[a]pyrimidines containing a bridging nitrogen atom are structural analogues (isosteres) of purine bases and can therefore disturb the metabolism and hinder the protein biosynthesis.1 New families of antiviral compounds have been found among these compounds.2 Syntheses of such azolopyrimidines widely employ condensations of 1,3-dielectrophiles with aminoazoles that contain an NH group at the α-position. Convenient 1,3-dielectrophiles include 1,3-dicarbonyl compounds3 and unsaturated ketones.4 It is most promising to synthese azolo[a]pyrimidines with functional groups that are capable of various conversions. Compounds suitable for this purpose include 1,3-dicarbonyl compounds functionalised at position 2. In fact, 2-arylmethylidene-5 and 2-ethoxymethylidene-3-oxoesters6 are suitable for building azolo[1,5-a]pyrimidines containing an alkoxycarbonyl fragment. A distinctive feature of polyfluoroalkylated derivatives of 3-oxoesters in these syntheses is that they can form stable tetrahydroazolo[1,5-a]pyrimidines with a gem-aminoalcohol fragment at the polyfluoroalkyl substituent.4a,5d

RESULTS AND DISCUSSION
In this work, aimed at the synthesis of potential biologically-active compounds, we have studied the reactions of ethyl 2-ethoxymethylidene-3-oxo-3-polyfluoroalkylpropionates 1a-c with aminoazoles (3-amino-1H-[1,2,4]triazole 2, 3-amino-5-methylpyrazole 3a, ethyl 3-aminopyrazole-4-carboxylate 3b and ethyl 5-aminoimidazole-4-carboxylate hydrochloride 4).
It has been found that esters 1a-c on refluxing in 1,4-dioxane with aminoazoles 2, 3a,b, 4 undergo conjugate substitution - addition at the ethoxymethylidene - fluoroacyl fragment to give dihydroazolo[1,5-a]pyrimidines 5a-c, 7a-d, 9a,b (Scheme 1). The reaction could not be repeated by heating to reflux in ethanol or by heating in DMF at ~ 80 ºC.

Condensation of 2-ethoxymethylidene-substituted acetoacetic ester with 3-amino-1H-[1,2,4]triazole and 3-aminopyrazoles is known to give 6-ethoxycarbonylazolo[1,5-a]pyrimidines.6b
X-Ray diffraction analysis of crystalline compound 5b (Figure 1) reveals that it is ethyl 7-hydroxy-7-tetrafluoroethyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate, in which XRD data show the existence of an O(1)…H(1) intramolecular hydrogen bond (IMHB). The IMHB parameters for compound 5b are as follows: the intramolecular distance O(1)…H(1) is 1.89(0) Ǻ; the O(1) – H(1)…O(3) and C(8) – O(1)…H(1) angles are 148.28° and 99.03°. The existence of an IMHB in triazolopyrimidine 5b is also supported by its IR spectrum where a low-frequency shift of the ethoxycarbonyl group's stretching vibration absorption band (1682 cm-1) is observed in comparison with the values of C=O groups in α,β-unsaturated esters (1730-1710 cm-1).7

A comparison of the IR spectra of compounds 5a,c nujol did not reveal considerable differences in their features.
The IR spectra of compounds 7a,b nujol contain one intense ethoxycarbonyl group’s absorption band at 1680-1670 cm-1. In the IR spectra of products 7c,d, 9a,b, having two ethoxycarbonyl groups, two absorption bands at 1673-1672 and 1690-1689 cm-1 are observed.
Based on the above data, it is believed that the compounds 5a-c, 7a-d, 9a,b in the solid state exist as cyclic form of dihydroazolo[1,5-a]pyrimidines.
The structure of products 5a-c, 7a-d, 9a,b in solutions was studied by NMR spectroscopy.
The 1H NMR spectra of compounds 5a-c, recorded in (CD3)2SO, contain signals of ethoxy-group protons, singlet signals of two methine protons (H(2), H(5)) and broadened low-field singlet signals of NH and OH protons. These signals should be assigned to the resonance absorption of protons in bicyclic form 5. The 19F NMR spectrum of product 5a contains a singlet signal of the fluorine atoms at the trifluoromethyl group at δ ~ 83.94 ppm, which is typical for the CF3 group at the sp3-hydridized carbon atom in form 5.5d However, the 1H and 19F NMR spectra of compound 5c, recorded in (CD3)2SO, as well as containing the set of signals belonging to cyclic form 5 (80 %), is also two additional sets of signals corresponding to the (Z)-5' (11 %) and (E)-5' (9%) isomers. Ethyl-2-(het)arylmethylidene-3-oxo-3-fluoroalkylpropionates have previously discovered to exist in a mixture of Z,E-isomeric forms.8
Furthermore the 13C NMR spectrum 5c in (CD3)2SO confirms the presence of the bicyclic form 5 and the (Z)-5' and (E)-5' open-chain isomers. In this spectrum, the signals of carbon atoms at the heptafluoropropyl substituent are significant; they have the shape of a triplet due to interactions with the nearby fluorine atoms of the α-CF2 group. The two low-field triplet signals (δ 179.43 and 180.74 ppm) are due to the resonance absorption of the C(3) carbonyl atoms of the (Z)- 5' and (E)- 5' forms, whereas a triplet signal of resonance absorption of the C(7) atom of the predominant cyclic form 5 is observed at 86.53 ppm, which is characteristic of the sp3-hybridised carbon atom.5d
Earlier8, assignment of signals of C(1) and C(3) atoms for the (Z)-5' and (E)-5' isomers was performed. Thus the signal of the C(1) atom in the ethoxycarbonyl of the (Z)- 5' form is observed in lower field (165.09 ppm) in comparison with the corresponding signal of the (E)-5' form (164.11 ppm), whereas the signals of the C(3) carbonyl atom at the polyfluoroacyl fragment of isomeric forms (Z)-5' and (E)-5' are arranged in the opposite order.8
In the 1Н and 19F NMR spectra of trifluoromethylated compounds 7a,c in (CD3)2SO are observed signals corresponding to the only cyclic form 7. However the 1Н and 19F NMR spectra of compounds 7b,d having longer fluoroalkyl substituents (RF = (CF2)2H, C3F7) contain in addition to the signals of cyclic form 7, the signals of the (Z)-7' and (E)-7' isomers of open forms.
According to the data of the 1Н and 19F NMR spectroscopy in (CD3)2SO the compounds 9a,b exist as a mixture of (Z)-9' and (E)-9' isomers of open forms ((2-[(imidazolyl)aminomethylidene]-3-oxo- 3-polyfluoroalkylpropionates)) and cyclic (1,4-dihydroimidazo[1,5-a]pyrimidine) form 9.
The discovery of the ability of heterocycles 5c, 7b, 7d, 9a,b to undergo open-chain isomerism in (CD3)SO prompted us to study the 1H and 19F NMR spectra of compounds 5, 7, 9 in various solvents. The result of this study is depicted in Table, where the existence of compounds 5, 7, 9 depends on the NMR solvent used.
It is found that the 1H NMR spectra of compounds 5b,c, 7b,d and 9a in (CD3)2CO contain, in addition to the signals corresponding to cyclic form, also signals of the Z- and E-isomers of open form 5', 7', 9'. In contrast, the 1H NMR spectra of compounds 5a, 7a,c in (CD3)2CO show that only cyclic form are present.
However, the 1H NMR spectra of compounds recorded in CD3CN show that the cyclic form and the Z- and E-isomers are presented not only for compounds 5b,c, 7b,d, 9a but for the product 5a as well (Table 1).
1H NMR spectra of compound 9b in (CD3)2CO and CD3CN contain non-cyclic form (Z)-9'b and (E)-9'b (Table 1).
The signals of the cyclic form are found in the 1H NMR spectra of compounds 5a-c, 7a-d measuring in CD3OD (Table 1). The compounds 7d and 9a,b in CD3OD exist as a mixture of the open and cyclic forms. The heterocycles 5a-c, 7a-d, 9a,b are insoluble in CDCl3.

A specific feature of signals of the open-chain isomers 5', 7', 9' in the 1H NMR spectrum is the character of resonance absorption of the =CH and NH protons of their aminomethylidene fragment that are observed as low-field doublets with a coupling constant of ~ 14 Hz, which is evidence of their trans-configuration.9 The signals of fluorine atoms of the CF3 and α-CF2 groups of open form 5'c, 7'b,d and 9'a,b in the 19F NMR spectra in (CD3)2SO are characterised by a downfield shift (δCF3 90.83-91.82, δα-CF2((CF2)2H) 42.98-43.11, δα-CF2(C3F7) 49.61-50.23 ppm) with respect to the corresponding signals of fluorine atoms in cyclic form 9a, 5b (δCF3 81.38, δα-CF2((CF2)2H) 32.29-41.79, δα-CF2(C3F7) 46.13-46.26 ppm). Assignment of the Z- and E-isomers of open form in the 1H NMR spectra was made using the regularities that we reveled previously for 2-alkyl(aryl)aminomethylidene-3-fluoroalkyl-3-oxopropionates, according to which the protons of the =CН and NH groups of the E-isomer are observed in weaker field than the corresponding protons of the Z-isomer.8
Dehydration of 4,7-dihydrotriazolo[1,5-a]pyrimidines 5a-c is hindered. In fact, prolonged refluxing (~60 h) in acetic acid is necessary to obtain ethyl 7-polyfluoroalkyl-[1,2,4]triazolo[1,5-a]pyrimidine- 6-carboxylates 6a-c.
Dehydration of 4,7-dihydropyrazolo[1,5-a]pyrimidine 7a,b,d in boiling acetic acid proceeds easily to give ethyl-7-(fluoroalkyl)pyrazolo[1,5-a]pyrimidine-6-carboxylates 8a-c.
An attempts to dehydrate dihydroimidazo[1,5-a]pyrimidine 9a,b under similar conditions were unsuccessful because of their resinification.
To summarize the obtained data, it can be concluded that fluoroalkyl-containing dihydroazolo[1,5-a]pyrimidines 5, 7, 9 can undergo ring-chain isomerism. Thus, they have cyclic structures in the solid state, whereas in solution, depending on the solvent and the “length” of the fluoroalkyl substituent, they may also exist in open-chain form 5', 7', 9'. It should be noted that this kind of isomerism is not typical for their non-fluorinated analogues, viz, 2-azolylaminomethylidene-3-oxoalkanoates. The latter compounds are only capable of irreversible intramolecular condensation to give azolopyrimidines.6b Ring-chain isomerism becomes possible owing to the presence of an electron-withdrawing polyfluoroalkyl substituent that prevents easy elimination of a water molecule and the formation of azolopyrimidines 6, 8, on the one hand, and facilitates the addition of an amine to give dihydroazolopyrimidines 5, 7, 9 that are stabilized due to formation of the strong IMHBs, on the other hand.

EXPERIMENTAL
Melting points were measured in open capillaries by apparatus “Stuart SMP3”. The infrared spectra were recorded on Perkin Elmer Spectrum One FT-IR and Thermo Nicolet 6700 FT-IR spectrometers at 4000-400 cm-1 in Nujol mulls. The 1H and 13C NMR spectra were measured on a Bruker DRX-400 spectrometer (1H, 400; 13C, 100.6 MHz) relative to SiMe4. The 19F NMR spectra were obtained on a Bruker DRX-400 spectrometer (19F, 376 MHz) using C6F6 as an internal standard. The microanalyses were carried out on a Perkin Elmer PE 2400 series II elemental analyzer.
Ethyl 2-ethoxymethylidene-3-polyfluoroalkyl-3-oxopropionates 1a-c were prepared according to a reported procedure,8 ethyl 5-aminoimidazole-4-carboxylate hydrochloride 4 – procedure.11 3-Amino-1H-[1,2,4]tria- zole 2, 3-amino-5-methylpyrazole 3a, ethyl 3-aminopyrazole-4-carboxylate 3b are commercial compounds.
Crystallographic data for 5b: at 295 К, C10H10F4N4O3 (M = 310.22) are monoclinic, space group P21/c, a = 16.737(2) Å, b= 8.7692(10) Å, c = 8.8892(10) Å, β = 100.022(10) º, V = 1284.7(3) Å3, Z = 4, dcalc = 1.604 g/cm-1, μ (Mo-Kα) = 0.157 cm -1, F(000) = 632. The intensities of 14817 were measured with a Xcalibur 3 at 295 К (ω/2θ-scans, Mo-Kα, graphite monochromator, CCD-detector) and 3963 independent reflection (Rint = 0.0211) were used in further refinement. The structure was solved by the direct methods with the set programs SHELXL-9710 and refined by full-matrix least-squares method. The refinement converged to wR2 = 0.1885 and GOF = 1.000 for all independent reflections (R1 = 0.0633 for 2225 reflection with Fo>4σ(Fo)). CCDC 646963 contains the supplementary crystallographic data for this compound.1
General procedure A: A mixture of ester 1 (3 mmol) and aminoazole 2, 3a,b (3 mmol) in 1,4-dioxane (20 mL) was refluxed for 16-18 h. The reaction mixture was poured into water. The resulting precipitate was filtered off and recrystallized from EtOH.
General procedure B: The solution of pyrimidine 5, 7 (1 mmol) in glacial acetic acid was refluxed for 6-60 h. The reaction mixture was poured into water and was reduced to pH 7. The resulting precipitate was filtered off and recrystallized from hexane.
General procedure C: A mixture of ester 1a,b (3 mmol), ethyl 5-aminoimidazole-4-carboxylate hydrochloride (0.575 g, 3 mmol) and NaOAc*3H2O (0.408 g, 3 mmol) in 1,4-dioxane (20 mL) was refluxed for 12-14 h. The reaction mixture was poured into water. The resulting precipitate was filtered off and recrystallized from EtOH.
Ethyl 7-hydroxy-7-(trifluoromethyl)-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (5a).
The ester 1a (0.720 g, 3 mmol) gave by procedure A 0.601 g (72 %) of product 5a, mp 184-186 ºС. Anal. Calcd for C9H9F3N4O3: C, 38.86; H, 3.26; F, 20.49; N, 20.14. Found: C, 38.86; H, 3.11; F, 20.47; N, 20.27 %. IR: ν 3200, 3114, (NH, OH), 2923 (C-H), 1678 (СO2Et), 1599, 1521 (C=C, C=N), 1267-1158 (C-F) cm-1. 1Н NMR (DMSO-d6): δ 1.23 (t, J 7.0 Hz, 3Н, ОСН2СН3), 4.15 (m, AB-system, ΔAB 0.05 ppm, JAB 10.8, J 7.0 Hz, 2Н, ОСН2СН3), 7.88, 7.91 (both s, 1H each, H(2), Н(5)), 8.48 (s, 1H, NH), 11.77 (br.s, 1H, OH) ppm. 19F NMR (DMSO-d6): δ 83.94 (s, СF3) ppm.
Ethyl 7-hydroxy-7-(1,1,2,2-tetrafluoroethyl)-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxy- late (5b).
The ester 1b (0.817 g, 3 mmol) gave by procedure A 0.633 g (68 %) of product 5b, mp 155-157 ºС. Anal. Calcd for C10H10F4N4O3: C, 38.72; H, 3.25; F, 24.50; N, 18.06. Found: C, 38.96; H, 3.20; F, 24.52; N, 18.03 %. IR: ν 3220, 3108, (NH, OH), 2930 (C-H), 1682 (СO2Et), 1614, 1529 (C=C, C=N), 1206-1078 (C-F) cm-1. 1Н NMR (DMSO-d6): δ 1.24 (t, J 7.0 Hz, 3Н, ОСН2СН3), 4.16 (m, AB-system, ΔAB 0.03 ppm, JAB 10.7, J 7.0 Hz, 2Н, ОСН2СН3), 6.70 (d.d.d.d, JH,F 53.2, 51.3, 10.5, 2.4 Hz, 1H, (CF2)2H), 7.86, 7.91 (both s, 1H each, H(2), H(5)), 8.36 (s, 1H, NH), 11.68 (br.s, 1H, OH) ppm. 1Н NMR ((CD3)2СO): δ 5b (59 %)1.24 (t, J 7.1 Hz, 3Н, ОСН2СН3,), 4.29 (q, J 7.1 Hz, 2Н, ОСН2СН3), 6.73 (d.d.d.d, JH,F 52.1, 53.0, 10.4, 2.3 Hz, 1H, (CF2)2H), 7.34 (br.s, 1Н, NH), 7.85, 8.09 (both s, 1H each, H(2), H(5)), 10.69 (s, 1H, OH); (Z)-5b' (15 %) 1.35 (t, J 7.0 Hz, 3Н, ОСН2СН3), 4.29 (q, J 7.0 Hz, 2H, ОСН2СН3), 6.66 (t.t, JH,F 52.7, 5.9 Hz, 1H, (CF2)2H), 8.48 (br.s, 1H, H(5')), 8.79 (d, J 13.5 Hz, 1H, СH), 11.08 (br.d, J 13.5 Hz, 1H, NH,), 13.20 (br.s, 1H, NH(1')); (E)-5b' (26 %) 1.34 (t, J 7.0 Hz, 3Н, ОСН2СН3), 4.36 (q, J 7.0 Hz, 2H, ОСН2СН3), 6.95 (t.t, JH,F 53.4, 5.8 Hz, 1H, (CF2)2H), 8.52 (br.s, 1H, H(5')), 8.98 (d, J 13.5 Hz, 1H, СH), 10.69 (br.d, J 13.5 Hz, 1H, NH), 13.27 (br.s, 1H, NH(1')) ppm. 19F NMR (DMSO-d6) δ: 26.04 (t.d.d, JF,F 293.71, 9.6, JF,H 53.2 Hz, 1F, CF2H), 31.02 (d.d.d.d, JF,F 293.7, 10.6, 1.4, JF,H 51.3 Hz, 1F, CF2H), 32.97 (d.d.d, JF,F 261.2, 19.6, JF,H 10.5 Hz, 1F, CF2), 41.66 (d.d.d, JF,F 261.2, 10.6, JF,H 2.4 Hz, 1F, CF2) ppm.
Ethyl 7-(1,1,2,2,3,3,3-heptafluoropropyl)-7-hydroxy-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6- carboxylate (5c).
The ester 1c (1.021 g, 3 mmol) gave by procedure A 0.681 g (60 %) of product 5c, mp 136-138 ºС. Anal. Calcd for C11H9F7N4O3: C, 34.93; H, 2.40; F, 35.16; N, 14.81. Found: C, 34.94; H, 2.11; F, 35.25; N, 14.81 %. IR: ν 3200, 3115 (NH, OH), 3015, 2924 (C-H), 1693 (СO2Et), 1602, 1599 (C=C, C=N), 1220-1119 (C-F) cm-1. 1Н NMR (DMSO-d6): δ 5c (80 %) 1.25 (t, J 7.2 Hz, 3Н, ОСН2СН3), 4.18 (m, AB-system, ΔAB 0.04 ppm, JAB 10.8, J 7.2 Hz, 2Н, ОСН2СН3), 7.89, 7.92 (both s, 1H each, H(2), Н(5)), 8.56 (s, 1H, NH), 11.81 (br.s, 1H, OH); (Z)-5c' (11 %) 1.25 (t, J 7.1 Hz, 3Н, ОСН2СН3), 4.27 (q, J 7.1 Hz, 2H, ОСН2СН3), 8.56 (s, 1H, H(5')), 8.60 (d, J 13.9 Hz, 1H, CH), 11.29 (d, J 13.9 Hz, 1H, NH), 14.13 (br.s, 1H, NH(1')); (E)-5c' (9 %) 1.25 (t, J 7.1 Hz, 3Н, ОСН2СН3), 4.26 (q, J 7.1 Hz, 2H, ОСН2СН3), 8.58 (s, 1H, H(5')), 8.77 (d, J 13.9 Hz, 1H, CH), 11.81 (d, J 13.9 Hz, 1H, NH), 14.22 (br.s, 1H, NH(1')) ppm. 19F NMR (DMSO-d6): δ 2c (80 %) 37.44 (m, AB-system, ΔAB 1.40 ppm, JAB 290.0 Hz, 2F, β-CF2), 46.26 (m, 2F, α-CF2), 82.34 (t, JF,F 11.6 Hz, 3F, CF3); (Z)-2c' (11%): 38.43 (m, 2F, β-CF2), 49.96 (m, 2F, α-CF2), 82.94 (t, JF,F 9.3 Hz, 3F, CF3); (E)-5c' (9 %): 39.64 (m, 2F, β-CF2), 49.61 (m, 2F, α-CF2), 82.92 (t, JF,F 9.3 Hz, 3F, CF3,) ppm. 13C NMR (DMSO-d6): δ 105.81-121.88 (m, С3F7 ((E)-5c', (Z)-5c', 5c)); 5c (80%) 14.03 (CH3), 59.89 (OCH2), 86.53 (t, JC,F 27.2 Hz, C(7)), 96.86 (C(6)), 139.09 (C(5)), 147.19 (C(3a)), 150.56 (C(2)), 163.98 (C(9)); (Z)-5c' (11 %) 13.74 (CH3), 60.86 (OCH2), 101.77 (C(2)), 144.52 (C(5')), 151.52 (C(4')), 157.15 (C(3')), 165.09 (C(1)), 179.43 (br.t, JC,F 25.4 Hz, C(3)); (E)-5c' (9 %) 13.85 (CH3), 60.69 (OCH2), 100.63 (C(2)), 144.73 (C(5')), 154.90 (C(4)), 156.69 (C(3')), 164.11 (C(1)), 180.74 (br.t, JC,F 25.0 Hz, C(3)) ppm.
Ethyl 7-(trifluoromethyl)-5H-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (6a).
Pyrimidine 5a (0.278 g, 1 mmol) gave by procedure B 0.247 g (95 %) of product 6a, mp 77-78 ºС. Anal. Calcd for C9H7F3N4O2: C, 41.55; H, 2.71; F, 21.91; N, 21.53. Found: C, 41.69; H, 2.80; F, 21.78; N, 21.69 %. IR: ν 3069, 3018 (C-H), 1719 (СO2Et), 1627, 1511 (C=C, C=N), 1191-1129 (C-F) cm-1. 1Н NMR (DMSO-d6): δ 1.37 (t, J 7.2 Hz, 3Н, ОСН2СН3), 4.41 (q, J 7.2 Hz, 2Н, ОСН2СН3), 9.05 (s, 1H, H(5)), 10.16 (s, 1H, H(2)) ppm. 19F NMR (DMSO-d6): δ 98.46 (s, СF3) ppm.
Ethyl 7-(1,1,2,2-tetrafluoroethyl)-5H-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (6b).
Pyrimidine 5b (0.310 g, 1 mmol) gave by procedure B 0.228 g (78 %) of product 6b, mp 93-95 ºС. Anal. Calcd for C10H8F4N4O2: C, 41.11; H, 2.76; F, 26.01; N, 19.17. Found: C, 41.25; H, 2.81; F, 25.89; N, 18.95 %. IR: ν 3118, 3079, 3029 (C-H), 1707 (СO2Et), 1620, 1506 (C=C, C=N), 1164-1071 (C-F) cm-1. 1Н NMR (DMSO-d6): δ 1.36 (t, J 7.1 Hz, 3Н, ОСН2СН3), 4.41 (q, J 7.1 Hz, 2Н, ОСН2СН3), 7.19 (t.t, JH,F 51.8, 6.0 Hz, 1Н, (CF2)2H), 9.02 (s, 1H, H(5)), 10.12 (s, 1H, H(2)) ppm. 19F NMR (DMSO-d6) δ: 24.69 (d.m, JF,H 51.8 Hz, 2F, СF2H), 48.38 (m, 2F, СF2) ppm.
Ethyl 7-(1,1,2,2,3,3,3-heptafluoropropyl)-5H-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (6c).
Pyrimidine 5c (0.378 g, 1 mmol) gave by procedure B 0.234 g (65 %) of product 6с, mp 125-126 ºС. Anal. Calcd for C11H7F7N4O2: C, 36.68; H, 1.96; F, 36.92; N, 15.55. Found: C, 36.36; H, 2.00; F, 36.94; N, 15.28 %. IR: ν 3049, 3104 (C-H), 1727 (СO2Et), 1622, 1502 (C=C, C=N), 1236-1124 (C-F) cm-1. 1Н NMR (СDCl3): δ 1.43 (t, J 7.2 Hz, 3Н, ОСН2СН3), 4.49 (q, J 7.2 Hz, 2Н, ОСН2СН3), 8.78 (s, 1H, H(5)), 9.39 (s, 1H, H(2)) ppm. 19F NMR (CDCl3): δ 39.12 (m, 2F, β-СF2), 54.73 (m, 2F, α-СF2), 81.86 (t, JF,F 10.0 Hz, 3F, СF3) ppm.

Ethyl 7-hydroxy-2-methyl-7-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate (7а).
The ester 1a (0.720 g, 3 mmol) gave by procedure A 0.664 g (76 %) of product 7a, mp 193-195 ºС. Anal. Calcd for C11H12F3N3O3: C, 45.37; H, 4.15; F, 19.57; N, 14.43. Found: C, 45.41; H, 4.08; F, 19.49; N, 14.46 %. IR: ν 3300, 3119 (NH, OH), 3007, 2961 (C-H), 1669 (СO2Et), 1628, 1601 (C=C, C=N), 1200-1080 (C-F) cm-1. 1Н NMR (DMSO-d6): δ 1.22 (t, J 7.0 Hz, 3Н, ОСН2СН3), 2.14 (s, 3H, CH3), 4.13 (m, AB-system, ΔAB 0.05 ppm, JAB 10.8, J 7.0 Hz, 2H, ОСН2СН3), 5.64 (s, 1H, H(3)), 7.83 (с, 1H, H(5)), 7.85 (br.s, 1H, OH), 10.82 (br.s, 1Н, NH(4)) ppm. 19F NMR (DMSO-d6) δ: 84.24 (s, CF3) ppm.
Ethyl 7-(1,1,2,2,3,3,3-heptafluoropropyl)-7-hydroxy-2-methyl-4,7-dihydropyrazolo[1,5-a]pyrimidine -6-carboxylate (7b).
The ester 1c (1.021 g, 3 mmol) gave by procedure A 0.822 г (70 %) of product 5c, mp 128-130 ºС. Anal. Calcd for C13H12F7N3O3: C, 39.91; H, 3.09; F, 33.99; N, 10.74. Found: C, 40.11; H, 3.21; F, 34.07; N, 10.72 %. IR: ν 3241, 3212, 3133 (NH, OH), 3077, 2990 (C-H), 1682 (СO2Et), 1637, 1606 (C=C, C=N), 1265-1088 (C-F) cm-1. 1Н NMR (DMSO-d6): δ 7b (40 %) 1.22 (t, J 7.1 Hz, 3Н, ОСН2СН3), 4.13 (m, AB-system, ΔAB 0.03 ppm, JAB 10.8, J 7.1 Hz, 2H, ОСН2СН3), 5.66 (s, 1H, H(3)), 7.85 (d, J 5.0 Hz, 1H, Н(5)), 7.94 (s, 1H, OH), 10.90 (d, J 5.0 Hz, 1H, NH(4)); (Z)-7'b (26 %) 1.25 (t, J 7.0 Hz, 3Н, ОСН2СН3), 4.25 (q, J 7.0 Hz, 2H, ОСН2СН3), 6.12 (s, 1H, H(4')), 8.49 (d, J 14.3 Hz, 1H, CH); 11.10 (d, J 14.3 Hz, 1Н, NH), 12.48 (s, 1H, NH(1')); (E)-7'b (34 %) 1.24 (t, J 7.0 Hz, 3Н, ОСН2СН3), 4.18 (q, J 7.0 Hz, 2H, ОСН2СН3), 6.20 (s, 1H, H(4')), 8.66 (d, J 14.5 Hz, 1H, CH), 11.87 (d, J 14.5 Hz, 1Н, NH), 12.55 (s, 1H, NH(1')) ppm. 19F NMR (DMSO-d6): δ 7b (40 %) 37.14 (m, AB-system, ΔAB 1.10 ppm, JAB 288.5 Hz, 2F, β-CF2), 46.13 (m, AB-system, ΔAB 1.36 ppm, JAB 278.6 Hz, 2F, α-CF2), 82.33 (t, JF,F11.5 Hz, 3F, CF3); (Z)-7'b (26 %) 38.73 (m, 2F, β-CF2), 50.23 (m, 2F, α-CF2), 83.00 (t, JF,F 9.2 Hz, 3F, CF3); (E)-7'b (34 %) 39.59 (m, 2F, β-CF2), 49.79 (m, 2F, α-CF2), 82.93 (t, JF,F 9.2 Hz, 3F, CF3) ppm.
Diethyl 7-hydroxy-7-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarboxylate (7c). The ester 1a (0.720 g, 3 mmol) gave by procedure A 0.702 g (67 %) of product 7a, mp 216 – 218 ºС. Anal. Calcd for C13H14F3N3O5: C, 44.71; H, 4.04; F, 16.32; N, 12.03. Found: C, 44.73; H, 3.86; F, 15.99; N, 11.90 %. IR: ν 3287, 3133 (NH, OH), 2971 (C-H), 1690, 1672 (СO2Et), 1607 (C=C, C=N),1230-1104 (C-F). 1Н NMR (DMSO-d6): δ 1.24, 1.29 (both t, J 7.0 Hz, 3Н each, 2 ОСН2СН3), 4.18 (m, AB-system, ΔAB 0.05 ppm, JAB 10.8, J 7.0 Hz, 2H, ОСН2СН3), 4.25 (q, J 7.0 Hz, 2H, ОСН2СН3), 7.79 (d, J 5.1 Hz, 1 H, Н(5)), 7.92 (s, 1H, H(2)), 8.48 (d, JH,F 0.9 Hz, 1H, OH), 10.69 (d, J 5.1 Hz, 1H, NH(4)) ppm. 19F NMR (DMSO-d6): δ 84.01 (d, JF,H 0.9 Hz, CF3) ppm.
Diethyl 7-hydroxy-7-(1,1,2,2-tetrafluoroethyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarboxylate (7d).
The ester 1b (0.817 g, 3 mmol) gave by procedure A 0.890 g (78 %) of product 7d, mp 178-180 ºС. Anal. Calcd for C14H15F4N3O5: C, 44.10; H, 3.97; F, 19.93; N, 11.02. Found: C, 43.97; H, 3.82; F, 19.82; N, 11.16 %. IR: ν 3272, 3132 (NH, OH), 2998 (C-H), 1689, 1673 (СO2Et), 1608 (C=C, C=N),1229-1079 (C-F). 1Н NMR (DMSO-d6): 7d (81 %) 1.24, 1.29 (both t, J 7.1 Hz, 3Н each, 2 ОСН2СН3), 4.16 (m, AB-system, ΔAB 0.03 ppm, JAB 10.8, J 7.1 Hz, 2H, ОСН2СН3), 4.27 (m, AB-system, ΔAB 0.02 ppm, JAB 10.8, J 7.1 Hz, 2H, ОСН2СН3), 6.68 (d.d.d.d, JH,F 53.5, 51.5, 10.9, 1.6 Hz, 1H, (CF2)2H), 7.76 (s, 1H, H(5)), 7.91 (d, J 6.3 Hz, 1H, Н(2)), 8.33 (s, 1H, OH), 10.65 (br.s, 1H, NH(4)); (Z)-7'd (7 %) 1.26, 1.38 (both t, J 7.1 Hz, 3Н each, 2 ОСН2СН3), 4.30, 4.24 (both q, J 7.1 Hz, 2H each, 2 ОСН2СН3), 6.68 (t.t, JH,F 51.5, 7.2 Hz, 1H, (CF2)2H), 8.39 (br.s, 1H, H(5')), 8.67 (br.d, J 13.7 Hz, 1H, CH), 11.84 (br.d, J 13.7 Hz, 1Н, NH), 13.38 (br.s, 1Н, NH(1')); (Е)-7'd (12 %): 1.28, 1.34, (both t, J 7.1 Hz, 3Н each, 2 ОСН2СН3), 4.21, 4.32 (both q, J 7.1 Hz, 2H each, 2 ОСН2СН3), 6.99 (t.t, JH,F 52.7, 7.3 Hz, 1H, (CF2)2H), 8.42 (br.s, 1Н, H(5')), 8.83 (d, J 14.3 Hz, 1H, CH), 12.43 (d, J 14.3 Hz, 1Н, NH), 13.49 (br.s, 1Н, NH(1')) ppm. 19F NMR (DMSO-d6): δ 7d (19 %) 26.01 (d.d.t, JF,F 293.4, 9.1, JF,H 53.5 Hz, 1F, CF2H), 31.23 (d.d.d, JF,F 293.4, 10.7, JF,H 51.5 Hz, 1F, CF2H), 32.29 (d.m, JF,F 260.8 Hz, 1F, CF2), 41.79 (d.d, JF,F 260.8, 9.1 Hz, 1F, CF2); (Z)-7'd (25 %) 23.90 (d.m, JF,H 51.5 Hz, 2F, CF2H), 42.98 (m, 2F, CF2); (Е)-7'd (56 %) 25.17 (d.m, JF,H 52.7 Hz, 2F, CF2H), 41.32 (m, 2F, CF2) ppm.
Ethyl 2-methyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-6-carboxylate (8a).
Pyrimidine 7a (0.291 g, 1 mmol) gave by procedure B 0.235 g (86 %) of product 8a, mp 94-95 ºС. Anal. Calcd for C11H10F3N3O2: C, 48.36; H, 3.69; F, 20.86; N, 15.38. Found: C, 48.26; H, 3.53; F, 20.68; N, 15.68 %. IR: ν 3115, 3097 (C-H), 1717 (СO2Et), 1618, 1553 (C=C, C=N), 1192-1116 (C-F) cm-1. 1Н NMR (DMSO-d6): δ 1.42 (t, J 7.1 Hz, 3Н, ОСН2СН3), 2.59 (s, 3H, CH3), 4.44 (q, J 7.1 Hz, 2Н, ОСН2СН3), 6.75 (s, 1H, H(3)), 9.26 (s, 1H, H(5)) ppm. 19F NMR (DMSO-d6): δ 96.73 (s, CF3) ppm.
Diethyl 7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3,6-dicarboxylate (8b).
Pyrimidine 7c (0.349 g, 1 mmol) gave by procedure B 0.298 g (90 %) of product 8b, mp 95-97 ºС. Anal. Calcd for C13H12F3N3O4: C, 47.14; H, 3.65; F, 17.21; N, 12.69. Found: C, 47.11; H, 3.63; F, 17.18; N, 12.64 %. IR: ν 3062 (C-H), 1712 (СO2Et), 1623, 1562 (C=C, C=N), 1219-1156 (C-F) cm-1. 1Н NMR (DMSO-d6): δ 1.34, 1.36 (both t, J 7.1 Hz, 3Н each, 2 ОСН2СН3), 4.34, 4.39 (both q, J 7.1 Hz, 2Н each, 2 ОСН2СН3), 8.96 (s, 1H, H(2)), 9.97 (s, 1H, H(5)) ppm. 19F NMR (DMSO-d6): δ 98.52 (s, CF3) ppm.

Diethyl-7-(1,1,2,2-tetrafluoroethyl)pyrazolo[1,5-a]pyrimidine-3,6-dicarboxylate (8c).
Pyrimidine 7d (0.381 g, 1 mmol) gave by procedure B 0.283 g (78 %) of product 8c, mp 107-109 ºС. Anal. Calcd for C14H13F4N3O4: C, 46.13; H, 3.61; F, 20.92; N, 11.57. Found: C, 46.43; H, 3.61; F, 20.88; N, 11.59 %. IR: ν 2996 (C-H), 1727, 1719 (СO2Et), 1624, 1598 (C=C, C=N), 1207-1092 (C-F) cm-1. 1Н NMR (CDCl3): δ 1.42, 1.43 (both t, J 7.1, 7.2 Hz, 3Н each, 2 ОСН2СН3), 4.47, 4.49 (both q, J 7.1, 7.2 Hz, 2Н each, 2 ОСН2СН3), 7.09 (t.t, JH,F 53.3, 5.8 Hz, 1Н, (CF2)2H), 8.68 (s, 1H, H(5)), 8.84 (s, 1H, H(2)) ppm. 19F NMR (CDCl3): δ 24.83 (d.m, JF-H 53.3 Hz, 2F, CF2H), 44.49 (m, 2F, CF2) ppm.
Diethyl 4-hydroxy-4-(trifluoromethyl)-1,4-dihydroimidazo[1,5-a]pyrimidine-3,8-dicarboxylate (9a).
The ester 1a (0.720 g, 3 mmol) gave by procedure C 0.754 g (72 %) of product 9a, mp 185-186 ºС. Anal. Calcd for C13H14F3N3O5: C, 44.71; H, 4.04; F, 13.32; N, 12.03. Found: C, 44.92; H, 3.90; F, 16.28; N, 11.91 %. IR: ν 3248 (NH, OH); 2999 (C-H), 1719, 1698 (СO2Et), 1639, 1611 (C=C, C=N); 1194-1138 (C-F) cm-1. 1Н NMR (DMSO-d6): δ 9a (72 %) 1.24, 1.29 (both t, J 7.0 Hz, 3Н each, 2 ОСН2СН3), 4.16 (m, AB-system, ΔAB 0.05 ppm, JAB 10.8, J 7.0 Hz, 2H, ОСН2СН3), 4.28 (q, J 7.0 Hz, 2H, ОСН2СН3), 7.74 (s, 1H, H(6)), 7.78 (d, J 6.3 Hz, 1H, Н(2)), 8.95 (s, 1H, OH), 10.62 (d, J 6.3 Hz, 1H, NH(1)); (Z)-9'a (10 %) 1.28, 1.38 (both t, J 7.0 Hz, 3Н each, 2 ОСН2СН3), 4.36, 4.12 (both q, J 7.0 Hz, 2H each, 2 ОСН2СН3), 7.90 (br.s, 1H, H(2')), 8.83 (d, J 13.9 Hz, 1H, CH), 11.84 (d, J 13.9 Hz, 1Н, NH), 13.47 (s, 1H, NH(1')); (Е)-9'a (18 %): 127, 1.41 ((both t, J 7.0 Hz, 3Н each, 2 ОСН2СН3), 5.89, 4.22 (both q, J 7.0 Hz, 2H each, 2 ОСН2СН3), 7.94 (br.s, 1Н, H(2')), 8.66 (d, J 13.7 Hz, 1H, CH), 12.51 (d, J 13.7 Hz, 1Н, NH), 13.56 (s, 1H, NH(1')) ppm. 19F NMR (DMSO-d6): δ 9a (72 %) 81.38 (s, CF3); (Z)-9'a (10 %) 91.82 (s, CF3); (Е)-9'a (18 %) 90.83 (s, CF3) ppm.
Diethyl 4-hydroxy-4-(1,1,2,2-tetrafluoroethyl)-1,4-dihydroimidazo[1,5-a]pyrimidine-3,8-dicarboxy- late (9b).
The ester 1b (0.817 g, 0.003 mol) gave by procedure C 0.766 g (67 %) of product 9b, mp178-180 ºС. Anal. Calcd for C14H15F4N3O5: 44.10; H, 3.97; F, 19.93; N, 11.02. Found: C, 44.31; H, 3.83; F, 19.91; N, 10.96 %. IR: ν 3242 (NH), 3015 (C-H), 1724, 1674 (СO2Et), 1634, 1609 (C=C, C=N), 1254-1114 (C-F) cm-1. 1Н NMR (DMSO-d6): δ 9b (19 %): 1.25, 1.30 (both t, J 7.1, 3Н each, ОСН2СН3), 4.16, 4.28 (both q, J 7.1 Hz, по 2H, ОСН2СН3), 6.67 (d.d.d.d, JH,F 52.0, 51.2, 8.5, 4.2 Hz, 1Н, (CF2)2H), 7.67 (d, J 3.7 Hz, 1H, H(2)), 7.76 (s, 1H, H(6)), 8.82 (d, J 3.7 Hz, 1H, NH(1)), 10.55 (br.s, 1H, OH); (Z)-9'b (25 %) 1.29, 1.38 (both t, J 7.2, 7.0 Hz, 3Н each, ОСН2СН3), 4.29, 4.36 (both q, J 7.2, 7.0 Hz, 2Н each, ОСН2СН3), 6.67 (t.t, JH,F 52.1, 5.9 Hz, 1Н, (CF2)2H), 7.89 (с, 1Н, СН(2')), 8.80 (d, J 13.7 Hz, 1Н, СН), 11.69 (d, J 13.7 Hz, 1Н, NH), 13.51 (br. s, 1H, NH(1')); (Е)-9'b (56 %): 1.28, 1.40 (both t, J 7.2, 7.0 Hz, 3Н each, ОСН2СН3), 4.39, 4.23 (both q, J 7.0, 7.2 Hz, 2Н each, ОСН2СН3), 7.00 (t.t, JH,F 52.3, 5.9 Hz, 1Н, (CF2)2H), 7.93 (s, 1Н, CН(2')), 8.93 (d, J 13.7 Hz, 1Н, СН), 12.56 (d, J 13.7 Hz, 1Н, NH), 13.51 (br.s, 1H, NH(1')) ppm. 19F NMR (DMSO-d6): δ 9b (19 %) 26.85 (d.d.m, JF,F 296.6, JF,H 52.0 Hz, 1F, CF2H), 30.21, (d.d.m, JF,F 296.6, JF,H 51.2 Hz, 1F, CF2H), 33.50 (d.m, JF,F 262.0 Hz, 1F, CF2), 38.16 (d.m, JF,F 262.0 Hz, 1F, CF2); (Z)-9'b (25 %) 23.80 (d.t, JF-H 52.1, 8.2 Hz, 2F, CF2H), 43.11 (m, 2F, CF2); (Е)-9'b (56 %) 25.27 (d.t, JF,H 52.3, JF,F 7.9 Hz, 2F, CF2H), 41.43 (m, 2F, CF2) ppm.

ACKNOWLEDGEMENTS
This study was financially supported by the Grant for young scientists and postgraduates of the Ural branch of the Russian Academy of Sciences for 2008 and by the Program for the support of leading scientific schools (Grant no. 3758.2008.3).

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