2 H -Pyrazol-3-ylamines as precursors for the synthesis of polyfunctionally substituted pyrazolo[1,5-a ]pyrimidines

Substituted aminopyrazoles ( 5a-d ) were synthesized and reacted with bidentate electrophiles to afford pyrazolo[1,5-a ]pyrimidines. The regioorientation of reagents has been determined by ( 15 N, 1 H) HMBC measurements as well as an X-ray crystal structure determination.


Introduction
2][3][4][5][6] The recent discovery of Zaleplon (1) as an ideal hypnotic drug has stimulated further interest in the pyrazolo [1,5a]pyrimidine chemistry. 7,8Pyrazolo [1,5-a]pyrimidines are readily obtained via reacting bidentate electrophiles with 3-amino-1H-pyrazoles. 9 If the reagent is symmetrical or a monocyclic intermediate is isolable, defining the exact structure of the reaction product does not make any significant problem.However, in some cases the only isolable products are the finally formed pyrazolo [1,5-a]pyrimidines. 10,11In such cases the identification of the exact regioorientation of the reactants could be only established with certainty by X-ray crystal structure determinations. 12n the past 9 we have described several synthetic approaches to pyrazolo [1,5-a]pyrimidines via reacting α,β-unsaturated nitriles and esters with 3-amino-1H-pyrazoles.The assigned structures were mainly based on the observed position of amino or carbonyl functions in 1 H NMR and IR spectra.Now we report on a more conclusive structure elucidation by applying ( 15 N, 1 H) HMBC experiments.

Results and Discussion
The aminopyrazole 5a, that has been selected as starting material, could be prepared via reacting 2 with hydrazine hydrate in a microwave oven in the presence of acetic acid.On the other hand 5b-d were prepared via coupling 3 with aromatic diazonium salts and subsequent refluxing of the so formed arylhydrazones 4b-d with hydrazine hydrate in ethanolic solution (Scheme 1).

Scheme 1
Compounds 5a-d reacted with benzylidenemalononitrile 6 to yield aminopyrazolo[1,5a]pyrimidines that may be formulated as 8a-d or isomeric 10a-d.Thus if the initial addition involves ring nitrogen atom N-2, as has been assumed earlier by Elnagdi et al. 10 , Michael adduct 7 would be formed.This then cyclizes to yield 8. On the other hand, if the exocyclic amino function reacts with the electrophilic carbon atom of 6, 9 would be formed.Its cyclization and autoxidation would then afford 10 (Scheme 1).Reacting 5a with 2 also afforded products that can be formulated as 11 or isomeric 12 (Scheme 2).
Figure 1 shows an 15 N, 1 H -heteronuclear multiple bond correlation (HMBC) of compound 11 measured in CD 3 SOCD 3 .Crosspeaks for all nitrogen atoms (N-1, N-4, N-7a and 7-NH 2 ) and the protons 2-H, 7-H and NH 2 can be observed provided that they are connected by not more than 4 bonds.The size of the coupling constants J ( 1 H, 15 4 J|.N-7a with two 3 J and one 4 J coupling gives the largest signal and N-4 with one 2 J and one 4 J coupling the smallest.The position of the amino group on C-7 is unambiguously determined by the 3 J coupling of its protons with the nodal nitrogen atom N-7a.The coupling 5 J (NH 2 , N-7a) of the alternative structure 12 (bearing the NH 2 group on C-5) would not be visible in the spectrum.On the other hand, large crosspeaks for 3 J (7-H, N-1) and 2 J (7-H, N-7a) should appear in the HMBC spectrum, when the isomer with a 5-NH 2 group would be present.Thus, structure 12 can be ruled out.Additionally to the ( 15 N, 1 H) HMBC spectrum, ( 13 C, 1 H) HSQC and ( 13 C, 1 H) HMBC spectra of 11 were measured.The three two-dimensional techniques permit a complete assignment of all 1 H, 13 C and 15   A rotational restriction of the amino group is unlikely.Therefore we have to consider a tautomeric equilibrium.Scheme 3 shows three possible tautomers 10b, 10b′ and 10b″.The ( 1 H, 15 N) HMBC spectrum contains signals for N-1, N-4 and N-7a.Whereas the δ values of N-1 and N-7a are very similar to the corresponding values of 11 and 10a, N-4 has now a δ value of 144 ppm, which is high-field shifted by almost 100 ppm in comparision to 11 and 10a.This effect can be explained by a rehybridization of N-4 from sp 2 to sp 3 .The ( 15 N, 1 H) HMBC measurement at room temperature in CD 3 SOCD 3 speaks for structure 10b′ as prevailing tautomer in solution in DMSO; for 10b a δ value of about 240 ppm could be expected for N-4.The 15 N chemical shift of one of the nitrogen atoms in the azo group (Figure 2) can be assigned by the 3 J ( 15 N, 1 H) coupling with the o-H of the benzene ring; its 15 N chemical shift of 471 ppm precludes a hydrazono group present in 10b″.The other nitrogen atom of the azo group can not be seen in the ( 15 N, 1 H) HMBC spectrum because of a minor polarization transfer.The nitrogen atom of the amino/imino group can also not be seen -due to an exchange mechanism, which includes a Z / E (syn/anti) isomerism at this center.Figure 2 shows the assignment of the 15 N, 1 H and 13 C NMR signals of 10b′.

Scheme 3
We could obtain an X-ray crystal structure 13 for the reaction product of 6 and 5c.As clearly indicated (cf.figure 3) and contradicting previous believes 10 the reaction product 10c is a 7aminopyrazolo[1,5-a]pyrimidine .milar to the behaviour of 5a-d toward 6, compound 5b also reacted with 3-(piperidin-1yl)acrylonitrile 13 to yield 14 (Scheme 4).

ISSN 1424-6376
Page 138 Two-dimensional NMR Bruker AMX 400 and Avance 600.Microwave irradiation was carried out using a commercial microwave oven (SGO 390 W).Crystal structures were performed using Envaf Nonius 591 Kappa CCD single crystal diffraction.Ms spectra were recorded on a Fison Instrument VG ProSpec Q.
3-Amino-4-phenyl-1H-pyrazole (5a) 14 One gram of 2 is placed in a 50 ml conical then treated with hydrazine hydrate (1 ml: 80%) then with acetic acid (2 ml) and DMF (2 ml).The reaction mixture was then heated in a domestic microwave oven at full power for 3 minutes.The resulting product was then triturated with water and the so formed solid was collected by filtration then crystallized from ethanol, (yield 67%, 0.5 g of 5a.The product was found identical (identity was made by mp 176-177 o C, lit. 14mp176 o C and mixed mp 175-176) with product obtained following literature procedure; MS (EI) m/z 159 (M + , 100%).
N signals to certain nuclei of 11 (Figure2).
NNC 6 H 4 -p-Cl All melting points are uncorrected.IR spectra were recorded in KBr with a Pye Unicam SP 1100 spectrophotometer.NMR spectra were recorded on a Bruker Avance DPX-300 MHz spectrometer.Coupling constants (J) are reported in Hz, and chemical shifts are reported in parts per million (δ) relative to DMSO-d 6 (2.49 ppm for 1 H and 39.5 ppm for 13 C).