HETEROCYCLES

Paper | Regular issue | Vol. 83, No. 7, 2011, pp. 1567-1585
Received, 10th March, 2011, Accepted, 25th April, 2011, Published online, 10th May, 2011.
DOI: 10.3987/COM-11-12206

■ Reactions and Tautomeric Behavior of 1-(2-Pyridinyl)-1H-pyrazol-5-ols

Peter Pfaffenhuemer, Christian Laggner, Stefan Deibl, Barbara Datterl, and Wolfgang Holzer*

Department of Drug and Natural Product Synthesis, Faculty of Life Sciences, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria

Abstract

The tautomeric behavior of 1-(2-pyridinyl)-2-pyrazolin-5-one (1a) and its 3-methyl derivative (1b) in different solvents was investigated by means of NMR spectroscopy (1H, 13C, 15N). Moreover, studies regarding the reactions of the title compounds with trimethylsilyldiazomethane, carboxylic acid chlorides, different orthoesters, dimethylformamide diethyl acetal and benzaldehyde are presented. Involvement of pyridine-N atoms in hydrogen bondings was investigated by means of 15N-NMR spectroscopy.

INTRODUCTION
Pyrazolones (2-pyrazolin-5-ones) are compounds of significant importance due to their role as core structural element in a number of drug molecules, complexing agents, dyestuffs and agrochemicals.1-5 Moreover, pyrazolones are inasmuch interesting structures as they are capable of prototropic tautomerism. In principle, for compounds unsubstituted at pyrazole C-4, OH (A), CH (B), and NH (C) forms are possible (Figure 1), designated as 1H-pyrazol-5-ols, 2,4-dihydro-3H-pyrazol-3-ones and 1,2-dihydro-3H-pyrazol-3-ones according to Chemical Abstracts nomenclature. The tautomerism of pyrazolones has been the subject of a considerable number of studies,6,7 in recent years we have also presented some contributions concerning the tautomerism, reactivity and synthetic potential of pyrazolones and 4-acylpyrazolones.8-15 In continuation of these studies we here want to present investigations with 2-pyrazolin-5-ones having a 2-pyridinyl moiety attached to pyrazole N-1, i.e. compounds of type 1 (Figure 1). Such compounds have been very rarely studied and provide the possibility to form additional tautomeric forms characterized by intramolecular hydrogen bonds between the pyridine nitrogen atom and the OH proton (form A’) or the NH proton (form C’) (Figure 1). Naturally, also the tautomerism of 4-acyl derivatives of compounds 1 is expected to be more complex compared to that of congeners carrying an 1-phenyl group instead of an 1-(2-pyridinyl) moiety. Moreover, preliminary tests showed different reactivities of the title compounds 1a and 1b compared to their 1-phenyl congeners 1-phenyl-2-pyrazolin-5-one and 3-methyl-1-phenyl-2-pyrazolin-5-one.

RESULTS AND DISCUSSION
Synthesis of title compounds 1
The synthesis of pyrazolones 1 was accomplished by known methods. Reaction of diethyl ethoxymethylenemalonate (2) with 2-hydrazinopyridine (3) in aqueous potassium carbonate led to ester 4, which was transformed into the corresponding acid 5 by heating with 4M sodium hydroxide (Scheme 1).16 Decarboxylation of the latter afforded 1a, which was purified by sublimation.16 Pyrazolone 1b resulted from reaction of ethyl acetoacetate with 2-hydrazinopyridine.17,18 For the investigation of tautomeric equilibria the concept of fixed or blocked derivatives is important – compounds in which the moveable proton is replaced by a methyl group. Such blocked derivatives are not capable of tautomerism and can act as model compounds for comparison purposes.6,7,19 Thus, pyrazolones 1a,b as well as 4 were reacted with trimethylsilyldiazomethane in order to obtain the corresponding O-methyl derivatives 6a,b and 8. The formation of corresponding N-methyl products was not observed during these reactions. This regioselective behavior can be rationalized by the ‘soft-hard’ reagent rule: the substituted diazomethane is a hard electrophile and thus attacks the harder nucleophilic site, i.e. the pyrazolone O-atom.19 N-Methyl derivative 7b, obtained by reaction of 1b with dimethyl sulfate, is already described in the literature.20

Tautomeric behavior of pyrazolones 1a,b in solution
For pyrazolone 1a in CDCl3 solution a single signal set was observed, which can be attributed best to the OH-form fixed by an intramolecular hydrogen bond between OH and pyridine-N (form A’ in Figure 1). The 1H, 13C and 15N-NMR chemical shifts for 1a and its fixed derivative 6a are given in Figure 2. The shifts of

1a and 6a (in CDCl3) resemble closely, except that of the pyridine N-atom which is markedly shifted downfield when switching from 1a (δ –129.6 ppm) to 6a (δ –93.1 ppm). This explicit difference can be explained by the involvement of the concerning pyridine N-atom of 1a in an intramolecular hydrogen bond (Figures 1 and 2). The so-caused stress of the nitrogen’s lone-pair leads to a decrease of its chemical shift.21-23 In 6a (and also in 8) such an interaction is not possible and hence the pyridine-N atom appears at markedly larger chemical shifts (6a: δ –93.1 ppm; 8: δ –87.5 ppm). In contrast, the 1H and 13C-NMR spectra of 1a in DMSO-d6 solution (0.2 M) at 25 °C show broad to very broad lines indicating a dynamic behavior and preventing the detection of signals due to quaternary carbon atoms as well as of nitrogen atoms. However, due to the similarity of chemical shifts in DMSO-d6 compared to those found for CDCl3 it is assumed that 1a is also present in the OH form in DMSO-d6 solution at room temperature (Figure 1).
The structure of 1b in the solid state has been determined by X-ray crystallography and showed the compound to exist as 5-methyl-2-(2-pyridinyl)-1,2-dihydro-3H-pyrazol-3-one (NH-form C, Figure 1) stabilized by intermolecular hydrogen bonds of N1-H···O=C type.24,25 For 1b in CDCl3 solution, 1H and 13C-NMR chemical shifts are provided in several publications,18,26 however without signal assignment. These data denote the presence of only one signal set with one proton attached to pyrazole C-4. This hints either to the presence of the OH-form or the NH-form, or to a mixture of both forms being in fast exchange. The results of our 1H-, 13C- and 15N-NMR recordings with 1b in CDCl3 solution are displayed in Figure 2 (lower trace). According to our data, 1b exists as a ~ 10:1 mixture of OH-form and CH form in CDCl3 (0.2 M solution) at 25 °C. The two signal sets can be easily distinguished considering the pyrazole C-4 signals in the 1H-coupled 13C-NMR spectrum. The main form shows a double quartet (1J(C4,H4) = 177.3 Hz, 3J(C4,Me) = 3.4 Hz) whereas the C-4 signal of the minor component is split into a triple quartet (1J(C4,H4) = 133.7 Hz, 3J(C4,Me) = 2.9 Hz). As found with 1a, also for the OH-form of 1b in CDCl3 the presence of an intramolecular hydrogen bond is assumed as in principle the same phenomena were observed as described above (for instance pyridine-N: 6b δ – 94.4 ppm, 1b δ – 130.5 ppm). In contrast, in DMSO-d6 solution only a single signal set is present. However, some broad signals (pyridine H-3, pyrazole C-O, pyrazole C-4) hint to an explicit dynamic behavior. A marked saturation transfer between the acidic proton and the H-4 signal indicates the involvement of the CH-isomer into the exchange process, the lack of an NOE between pyridine H-3 and the acidic proton rules out the presence of significant amounts of NH-form (form C in Figure 1).

Reaction of 1a,b with carboxylic acid chlorides
For the introduction of an acyl or aroyl group in position 4 of a pyrazolone system, the standard procedure consists in reaction of the pyrazolone with an appropriate acid chloride in the presence of excess calcium hydroxide in boiling 1,4-dioxane (‘Jensen’-method) (Scheme 2).27 However, we observed that this approach is not suitable when using 1a or 1b as starting pyrazolones. Thus, reaction of 1a or 1b with benzoyl chloride under the above mentioned conditions did not afford the desired 4-benzoylpyrazol-5-ols of type 9, instead the isomeric O-benzoyl products 10a,b were isolated as the sole reaction products. Such a reaction behavior has been also found with 1-phenyl-3-trifluoromethyl-1H-pyrazol-5-ol.14 The structure of compounds 10 easily follows from the NMR spectra, they show the presence of a C-H moiety within the pyrazole system, relative small 13C-NMR chemical shifts of pyrazole C-5 (~145 ppm) and the ester C=O atom (~163 ppm).

Reaction of 1a,b with orthoesters and benzamidine
An alternative method for the introduction of an aroyl or acyl substituent into position 4 of a 2-pyrazolin-5-one should be condensation with appropriate orthoesters, primarily leading to enol ethers of type 11 (Scheme 3). The latter can be easily hydrolized into the corresponding enols which tautomerize into the desired ketones (Scheme 3). This approach has been demonstrated by means of some examples,14,28,29 however it is very limited to a few available orthoesters.
Hence, the reaction of 1a and 1b with trimethyl orthoacetate, trimethyl orthopropionate, trimethyl orthobenzoate and trimethyl orthoformate was investigated in a series of experiments under different reaction conditions. These consisted in heating of molar amounts of the neat reactants to temperatures between 100 and 180 °C for times between 2 minutes and several hours, or performing the reaction in boiling toluene. It turned out that these reactions are very difficult to control and do not take place uniformly. Whereas upon somewhat too low temperatures and/or too short reaction times no conversion was observed, higher temperatures and longer reaction times led to complete decomposition. In general, with 1a no defined reaction products could be obtained at all. Whereas heating of 1b with triethyl orthopropionate to 120–150 °C without a solvent led to decomposition, in boiling toluene the formation of some condensation product 11b was observed (Scheme 3). The latter was isolated for spectroscopic investigations, but rather quickly converted into ketone 12b upon standing. Whereas heating of 1b with trimethyl orthobenzoate in boiling toluene brought no reaction, with neat diethyl orthobenzoate at 200 °C condensation was observed. After refluxing the obtained material with ethanol for one hour the desired 4-benzoylpyrazol-5-ol 9b was obtained in acceptable yield (45%) (Scheme 3).

Alternatively, an access to 9b is possible by melting 1b together with benzamidine hydrochloride at 220 °C (as described for a similar example in lit.,30) which produces 14b. The latter was converted into 9b by refluxing in aqueous/ethanolic NaOH. Detailed NMR spectroscopic investigations revealed 14b to exist exclusively as an enamine (as given in Scheme 3) and not in the corresponding imino form. This finding is supported by the following facts (Figure 3). The methyl protons (δ 1.66 ppm) are significantly shifted upfield compared to those in corresponding 1b or 6b (δ ~2.2 ppm) and exhbit a marked NOE to the protons H-2,6 of the phenyl ring. Furthermore, the existence of an amino function is proved by an 15N,1H-HSQC spectrum, showing two different amino protons attached to the nitrogen atom resonating at –269.7 ppm (in CDCl3). The non-equivalence of the diastereotopic amino protons can be explained by restricted rotation around the C-N bond (vinylogous carboxamide substructure), the involvement of one NH proton into an intramolecular hydrogen bond to the pyrazolone O-atom explains its markedly larger chemical shift (δ 10.30 ppm) compared to the other being not affected (δ 6.65 ppm). Interestingly, in the course of NOE-difference experiments no chemical exchange between the two amino protons was observed, indicating strong hydrogen bonding and also highly restricted rotation around the C-N bond under the recording conditions (Figure 3). In addition, considering the chemical shift of the pyridin-N atom in 14b (δ –99.5 ppm) involvement of this nitrogen into an intramolecular hydrogen bond as found in 1a or of 1b in CDCl3 (OH-form) is improbable.
For 9b, in principle numerous different tautomeric forms are possible. Considering the reflexions given above, the presence of 9b as OH-isomer stabilized by an intramolecular hydrogen bond between OH and pyridine-N atom (Figure 3) is supposable. This again is supported by the relatively small chemical shift of the pyridine-N atom (δ –134.2 ppm), closely resembling those of 1a and 1b in CDCl3 and being in clear contrast to the corresponding pyridine-N chemical shifts in related derivatives without such an interaction, for instance in 6b and 8 (δ ~ –90 ppm, see Figure 2). Moreover, structure 9b is confirmed by a midsize NOE observed on the signal of pyridine H-6 (8.21ppm) upon irradiation of the OH transition (Figure 3). Another midsize NOE detected between methyl protons and H-2,6 of C-phenyl gives a hint that also that rotamer depicted in Figure 3 contributes to the overall situation.

Furthermore, reaction of 1b with trimethyl orthoformate expectedly led to the dimeric product 13b, resulting from addition of a second unit of 1b to the primarily formed condensation product. In all NMR spectra of 13b the two 1-(2-pyridinyl)pyrazole units are completely equivalent, what can be explained by fast exchange of tautomers X and Y (Scheme 3) or by the presence of a species of type Z. Investigations with closely related compounds including also X-ray crystal structure analysis revealed forms of type Z to be valid.14,31-33 Such species are stabilized by a strong intramolecular hydrogen bond with double minimum potential. The extraordinaryly large chemical shift of the OH proton in 13b (δ 17.87 ppm in CDCl3) hints to a comparable situation. On basis of the above considerations, especially due to the chemical shift of the pyridine-N atom in 13b (δ –92.9 ppm, in CDCl3) it can be concluded that the latter is not involved in hydrogen bonding.

Reaction of 1a,b with N,N-dimethylformamide diethyl acetal
It is known from the literature that the active methylene group in 4-position of 2-pyrazolin-5-ones smoothly reacts with dimethylformamide acetals to form the corresponding 4-enaminopyrazolones.12,34,35 Thus, 1a and 1b were heated with one equivalent of dimethylformamide diethyl acetal (DMFDEA) in boiling toluene to afford the colored condensation products 15a and 15b in good yields (Scheme 4).

Careful NMR spectroscopic investigations revealed 15a to have E-configuration regarding the exocyclic double bond, whereas 15b has the opposite Z-configuration (Scheme 4, Figure 4). These findings are based on NOE-difference experiments, chemical shift considerations and bearing in mind some diagnostic 13C,1H coupling constants (Figure 4). Hence, for 15a a clear NOE between pyrazole CH and NMe protons and no NOE between pyrazole CH and alkene-H is observed, quite contrary to 15b (NOE between C-methyl and alkene-H, no NOE between C-methyl and NMe protons, Figure 4). The alkene-H in 15a exhibits a markedly larger chemical shift (δ 7.53 ppm) compared to that in 15b (δ 7.00 ppm) due to the magnetic anisotropy effect of the cis-positioned C=O moiety. The pyrazolone C=O atom in 15b is more shielded (δ 162.6 ppm) than that in 15a (δ 166.4 ppm) what can be attributed to γ-effects caused by the amino-N atom in cis position (Figure 4). Moreover, the configurational differences between 15a and 15b are impressively confirmed on the basis of the vicinal coupling constants 3J(C=O,=CH) and 3J(C5,=CH) which show opposite trends (Figure 4). A characteristic feature with both compounds is the non-equivalence of the two methyl groups attached to the amino nitrogen atom leading to distinctly separated signals in the 1H and 13C-NMR spectra. This phenomenon can be explained by hindered rotation around the C–N bond which has partial double bond character (vinylogous carboxamide character of compounds 15).

Investigations concerning the hydrolytic cleavage of the exocyclic C-N bond in compounds 15 in order to access the corresponding 5-hydroxypyrazole-4-carbaldehydes and regarding the chemistry of the latter compounds are in progress and will be published elsewhere.

Reaction of 1a,b with benzaldehyde
Another possibility for C–C bond formation at position 4 of the pyrazolone system consists in condensation with aldehydes, which again utilizes the CH acidity of pyrazolones.3 However, reaction of 1a or 1b did not afford the corresponding 1:1 condensation products but led to dimeric species of type 16 (Scheme 5). Obviously, under the employed conditions the primary product is very reactive and immediately adds a second pyrazolone unit to afford compounds 16. In contrast to dimer 13b, the pyridine-N atom in 16a (or 16b) is involved into an intramolecular hydrogen bond what is reflected by the corresponding 15N chemical shifts (16a: δ –129.4 ppm ; 16b: δ –130.6 ppm, in CDCl3) (Scheme 5).

EXPERIMENTAL
Melting points were determined on a Reichert-Kofler hot-stage microscope and are uncorrected. MS spectra were obtained on a Shimadzu QP 1000 instrument (EI, 70 eV), HRMS spectra (EI) on a Finnigan MAT 8230 instrument. IR spectra were recorded on a Perkin-Elmer FTIR 1605 spectrophotometer. The NMR spectra were obtained on a Varian UnityPlus 300 spectrometer (299.95 MHz for 1H, 75.43 MHz for 13C) or on a Bruker Avance 500 (500.14 MHz for 1H, 125.77 MHz for 13C) spectrometer. The center of the solvent signal was used as an internal standard which was related to TMS with δ 7.26 ppm (1H in CDCl3), δ 2.49 ppm (1H in DMSO-d6), δ 77.0 ppm (13C in CDCl3), δ 39.5 ppm (13C in DMSO-d6). 15N-NMR spectra (gs-HMBC, gs-HSQC) (50.69 MHz) were obtained on a Bruker Avance 500 spectrometer using a ‘directly’ detecting broadband observe (BBFO) probe and were referenced against neat, external nitromethane. Digital resolutions were 0.25 Hz/data point in the 1H and 0.4 Hz/data point in the 1H-coupled 13C-NMR spectra (gated decoupling). Except as noted otherwise the NMR spectra were taken at 25 °C. Unequivocal assignment of signals was carried out by the combined application of standard NMR spectroscopic techniques such as 1H-coupled 13C-NMR spectra, APT, HMQC, gs-HSQC, gs-HMBC, COSY, TOCSY, NOESY and NOE-difference spectroscopy.36 Moreover, in some cases experiments with selective excitation (DANTE) of certain 1H-resonances were performed, such as long-range INEPT37 and 2D(δ,J) long-range INEPT.38 Especially the latter experiments were indispensable for the unambiguous mapping of long-range 13C,1H coupling constants. Reliable and unambiguously assigned chemical shift data such as those presented here can be considered as important reference material for NMR prediction programs, such as CSEARCH39/NMRPREDICT40 and ACD/C + H predictor41 – programs which have become very popular in the last few years, particularly for predicting 13C-NMR chemical shifts.

1-(2-Pyridinyl)-1H-pyrazol-5-ol (1a)16
1H-NMR (CDCl3): δ (ppm) 12.69 (s, 1H, OH), 8.28 (m, 1H, py H-6), 7.92 (m, 1H, py H-3), 7.90 (m, 1H, py H-4), 7.47 (d, 1H, H-3, 3J(H3,H4) = 2.0 Hz), 7.18 (m, 1H, py H-5), 5.59 (d, 1H, H-4, 3J(H4,H3) = 2.0 Hz); 13C-NMR (CDCl3): δ (ppm) 156.7 (C5, 2J(C5,H4) = 5.8 Hz, 3J(C5,H3) = 5.8 Hz), 154.5 (py C-2), 145.2 (py C-6), 142.0 (C-3, 1J = 185.0 Hz, 2J(C3,H4) = 4.9 Hz), 140.0 (py C-4), 120.1 (py C-5), 112.2 (py C-3), 88.2 (C-4, 1J = 179.2 Hz, 2J(C4,H3) = 10.3 Hz); 15N-NMR (CDCl3): δ (ppm) −112.4 (N-2), −129.6 (py N), −186.2 (N-1).
1H-NMR (DMSO-d6): δ (ppm) 12.38 (br s, 1H, OH), 8.43 (m, 1H, py H-6), 8.00 (br s, 1H, py H-4), 7.95 (br s, 1H, py H-3), 7.59 (br s, 1H, H-3), 7.31 (br s, 1H, py H-5), 5.51 (br s, 1H, H-4); 13C-NMR (DMSO-d6): δ (ppm) 146.8 (py C-6), 141.3 (C-3), 139.9 (py C-4), 120.8 (py C-5), 112.3 (py C-3), 88.5 (C-4), signals of C-5 and py C-2 were not found.

3-Methyl-1-(2-pyridinyl)-1H-pyrazol-5-ol (1b)17,18
1H-NMR (CDCl3): δ (ppm) (major isomer) 12.70 (s, 1H, OH), 8.21 (m, 1H, py H-6), 7.83 (m, 1H, py H-3), 7.82 (m, 1H, py H-4), 7.09 (m, 1H, py H-5), 5.41 (s, 1H, H-4), 2.24 (s, 3H, 3-Me); δ (ppm) (minor isomer) 8.51 (m, 1H, py H-6), 7.99 (m, 1H, py H-3), 7.44 (m, 1H, py H-4), 7.11 (m, 1H, py H-5), 3.48 (s, 2H, H-4), 2.22 (s, 3H, 3-Me); 13C-NMR (CDCl3): δ (ppm) (major isomer) 156.9 (C5, 2J(C5,H4) = 5.5 Hz), 151.5 (C-3, 2J(C3,3-Me) = 6.8 Hz, 2J(C3,H4) = 4.4 Hz), 145.0 (py C-6), 139.8 (py C-4), 119.4 (py C-5), 111.7 (py C-3), 88.3 (C-4, 1J = 177.3 Hz, 3J(C4,3-Me) = 3.4 Hz), 14.6 (3-Me, 1J = 127.5 Hz), py C-2 was not unambiguously assigned; δ (ppm) (minor isomer) 170.9 (C-5 = C=O), 154.5 (C-3), 148.6 (py C-6), 138.0 (py C-4), 120.7 (py C-5), 114.0 (py C-3), 43.1 (C-4, 1J = 133.7 Hz, 3J(C4,3-Me) = 2.9 Hz), 17.1 (3-Me, 1J = 129.2 Hz), py C-2 was not found; 15N-NMR (CDCl3): (major isomer) δ (ppm) −116.9 (N-2), −130.5 (py N), −190.0 (N-1); 15N-NMR (CDCl3): (minor isomer) δ (ppm) −59.1 (N-2), py N and N-1 were not found.
1H-NMR (DMSO-d6): δ (ppm) 12.17 (s, 1H, OH), 8.39 (m, 1H, py H-6), 8.17 (m, 1H, py H-3), 7.91 (m, 1H, py H-4), 7.21 (m, 1H, py H-5), 5.20 (s, 1H, H-4), 2.15 (s, 3H, 3-Me); 13C-NMR (DMSO-d6): δ (ppm) 160.3 (br, C-5), 149.8 (C-3, 2J(C3,3-Me) = 6.5 Hz, 2J(C3,H4) = 6.5 Hz), 147.0 (py C-6), 139.3 (py C-4), 120.0 (py C-5), 111.4 (py C-3), 91.0 (br, C-4), 12.8 (3-Me, 1J = 128.5 Hz), py C-2 was not found; 15N-NMR (DMSO-d6): δ (ppm) −112.5 (py N), −196.5 (N-1), N-2 was not found.

2-(5-Methoxy-1H-pyrazol-1-yl)pyridine (6a)
To a solution of 1a (161 mg, 1 mmol) in a mixture of EtOAc (7.5 mL) and MeOH (2.5 mL) was added a solution of trimethylsilyldiazomethane (2.0 M in hexane, 1.63 mL, 3.25 mmol) within a peroid of 10 min and the mixture was stirred for further 15 min. Then the solvents were removed under reduced pressure and the residue was subjected to column chromatography (eluent: EtOAc) to afford 67 mg (38%) of 6a as a brownish oil. 1H-NMR (CDCl3): δ (ppm) 8.49 (ddd, 1H, py H-6, 3J(H5,H6) = 4.9 Hz, 4J(H4,H6) = 1.9 Hz, 5J(H3,H6) = 0.9 Hz), 7.74 (m, 1H, py H-4, 3J(H3,H4 = 8.3 Hz, 3J(H4,H5) = 7.3 Hz, 4J(H4,H6) = 1.9 Hz), 7.67 (ddd, 1H, py H-3, 3J(H3,H4) = 8.3 Hz, 4J(H3,H5) = 1.1 Hz, 5J(H3,H6) = 0.9 Hz), 7.49 (d, 1H, H-3, 3J(H3,H4) = 1.9 Hz), 7.15 (ddd, 1H, py H-5, 3J(H4,H5) = 7.3 Hz, 3J(H5,H6) = 4.9 Hz, 4J(H3,H5) = 1.1 Hz), 5.64 (d, 1H, H-4, 3J(H4,H3) = 1.9 Hz), 3.93 (s, 3H, OMe); 13C-NMR (CDCl3): δ (ppm) 156.2 (C5, 2J(C5,H4) = 5.7 Hz, 3J(C5,H3) = 5.9 Hz, 3J(C5,OMe) = 4.9 Hz), 151.2 (py C-2), 148.3 (py C-6, 1J = 180.5 Hz, 2J(C6,H5) = 3.6 Hz, 3J(C6,H4) = 7.4 Hz), 140.5 (C-3, 1J = 186.5 Hz, 2J(C3,H4) = 4.1 Hz), 138.0 (py C-4, 1J = 163.8 Hz, 2J(C4,H5) = 1.2 Hz, 3J(C4,H6) = 6.8 Hz), 121.4 (py C-5, 1J = 165.1 Hz, 2J(C5,H4) = 0.9 Hz, 3J(C5,H6) = 8.0 Hz, 3J(C5,H3) = 6.4 Hz), 116.2 (py C-3, 1J = 169.5 Hz, 2J(C3,H4) = 1.3 Hz, 3J(C3,H5) = 6.8 Hz, 4J(C3,H6) = 1.3 Hz), 86.3 (C-4, 1J = 178.2 Hz, 2J(C4,H3) = 10.7 Hz), 59.1 (OMe, 1J = 146.3 Hz); 15N-NMR (CDCl3): δ (ppm) −93.1 (py N), −100.2 (N-2), −181.2 (N-1); MS (m/z, %): 175 (M+, 25), 146 (25), 79 (26), 78 (100), 63 (69); HRMS: Calcd for C9H9N3O: 175.0746. Found: 175.0744.

2-(5-Methoxy-3-methyl-1H-pyrazol-1-yl)pyridine (6b)42
Similarly as described for the preparation of 6a, from 1b (175 mg, 1 mmol) and trimethylsilyldiazomethane (2.0 M in hexane, 1.63 mL, 3.25 mmol) 81 mg (43%) of 6b were obtained as a yellowish oil. 1H-NMR (CDCl3): δ (ppm) 8.45 (ddd, 1H, py H-6, 3J(H5,H6) = 4.9 Hz, 4J(H4,H6) = 1.9 Hz, 5J(H3,H6) = 0.9 Hz), 7.66 (m, 1H, py H-4, 3J(H3,H4 = 8.3 Hz, 3J(H4,H5) = 7.3 Hz, 4J(H4,H6) = 1.9 Hz), 7.60 (ddd, 1H, py H-3, 3J(H3,H4) = 8.3 Hz, 4J(H3,H5) = 1.1 Hz, 5J(H3,H6) = 0.9 Hz), 7.06 (ddd, 1H, py H-5, 3J(H4,H5) = 7.3 Hz, 3J(H5,H6) = 4.9 Hz, 4J(H3,H5) = 1.1 Hz), 5.45 (s, 1H, H-4), 3.86 (s, 3H, OMe), 2.22 (s, 3H, 3-Me); 13C-NMR (CDCl3): δ (ppm) 156.3 (C5, 2J(C5,H4) = 5.7 Hz, 3J(C5,OMe) = 4.9 Hz), 150.9 (py C-2), 149.7 (C-3, 2J(C3,3-Me) = 6.7 Hz, 2J(C3,H4) = 3.6 Hz), 148.3 (py C-6, 1J = 180.2 Hz, 2J(C6,H5) = 3.6 Hz, 3J(C6,H4) = 7.4 Hz), 137.8 (py C-4, 1J = 163.5 Hz, 2J(C4,H5) = 1.2 Hz, 3J(C4,H6) = 6.7 Hz), 120.7 (py C-5, 1J = 165.1 Hz, 2J(C5,H4) = 1.0 Hz, 3J(C5,H6) = 8.1 Hz, 3J(C5,H3) = 6.3 Hz), 115.5 (py C-3, 1J = 169.2 Hz, 2J(C3,H4) = 1.3 Hz, 3J(C3,H5) = 6.8 Hz, 4J(C3,H6) = 1.4 Hz), 86.4 (C-4, 1J = 176.3 Hz, 3J(C4,3-Me) = 3.4 Hz), 58.9 (OMe, 1J = 146.2 Hz), 14.4 (3-Me, 1J = 127.5 Hz, 3J(3-Me,H4) = 0.7 Hz); 15N-NMR (CDCl3): δ (ppm) −94.4 (py N), −105.7 (N-2), −185.7 (N-1); MS (m/z, %): 189 (M+, 59), 188 (26), 160 (31), 119 (42), 118 (30), 117 (59), 111 (27), 93 (28), 83 (21), 79 (33), 78 (100), 67 (21), 52 (36), 51 (81).

1,5-Dimethyl-2-(2-pyridinyl)-1,2-dihydro-3H-pyrazol-3-one (7b)20
1H-NMR (DMSO-d6): δ (ppm) 8.45 (m, 1H, py H-6), 7.89 (m, 1H, py H-3), 7.78 (m, 1H, py H-4), 7.11 (m, 1H, py H-5), 5.33 (s, 1H, H-4), 3.29 (s, 3H, NMe), 2.23 (s, 3H, 5-Me); 13C-NMR (DMSO-d6): δ (ppm) 166.3 (C-3), 158.4 (C-5), 148.7 (py C-2), 148.0 (py C-6), 138.0 (py C-4), 129.2 (py C-5), 117.6 (py C-3), 97.9 (C-4), 36.3 (NMe), 12.9 (5-Me).

Ethyl 5-methoxy-1-(2-pyridinyl)-1H-pyrazole-4-carboxylate (8)
Similarly as described for the preparation of 6a, from 4 (233 mg, 1 mmol) and trimethylsilyldiazomethane (2.0 M in hexane, 1.63 mL, 3.25 mmol) 88 mg (36%) of 8 were obtained as a yellowish oil. 1H-NMR (CDCl3): δ (ppm) 8.58 (m, 1H, py H-6), 7.96 (s, 1H, H-3), 7.84 (m, 1H, py H-4), 7.65 (m, 1H, py H-3), 7.30 (m, 1H, py H-5), 4.32 (q, 2H, OCH2, 3J = 7.2 Hz), 4.22 (s, 3H, OMe), 1.37 (t, 3H, Me, 3J = 7.2 Hz); 13C-NMR (CDCl3): δ (ppm) 162.1 (C=O, 3J(CO,CH2) = 3.2 Hz), 156.4 (C-5), 150.5 (py C-2), 148.8 (py C-6, 1J = 181.2 Hz, 2J(C6,H5) = 3.5 Hz, 3J(C6,H4) = 7.6 Hz), 142.4 (C-3, 1J = 192.1 Hz), 138.3 (py C-4, 1J = 165.8 Hz, 3J(C4,H6) = 6.7 Hz), 122.8 (py C-5, 1J = 165.2 Hz, 2J(C5,H4) = 1.0 Hz, 2J(C5,H6) = 8.2 Hz, 3J(C5,H3) = 6.4 Hz), 117.6 (py C-3, 1J = 170.0 Hz, 3J(C3,H5) = 6.9 Hz), 101.5 (C-4, 2J(C4,H3) = 8.7 Hz), 63.4 (OMe, 1J = 147.8 Hz), 60.2 (OCH2, 1J = 147.4 Hz, 2J(CH2,CH3) = 4.5 Hz), 14.3 (Me, 1J = 127.0 Hz, 2J(CH3,CH2) = 2.6 Hz); 15N-NMR (CDCl3): δ (ppm) −87.5 (py N), −96.5 (N-2), −169.7 (N-1); IR (KBr): ν (cm-1) 1716 (C=O); MS (m/z, %): 247 (M+, 48), 218 (40), 202 (56), 201 (24), 200 (30), 174 (25), 145 (22), 125 (33), 92 (27), 79 (67), 78 (100), 53 (36), 51 (47). HRMS: Cald for C12H13N3O3: 247.0956. Found: 247.0959.

[5-Hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazol-4-yl](phenyl)methanone (9b)
Method a: Under a nitrogen atmosphere, a mixture of 1b (876 mg, 5 mmol) and triethyl orthobenzoate (4.5 mL, 4.46 g, 19.9 mmol) was heated to 200 °C for 40 min. After cooling to room temperature, 96% EtOH (15 mL) was added and the mixture was heated to reflux for 1 h. Then the solvents were removed under reduced pressure, the residue was digested with ice-cold EtOAc (35 mL) and washed with cold Et2O to afford 999 mg (52%) of colorless crystals of mp 182–183 °C.
Method b: Under a nitrogen atmosphere, a mixture of 1b (526 mg, 3 mmol) and benzamidine hydrochloride (705 mg, 4. mmol) was heated to 220 °C for 40 minutes. After cooling to room temperature, 96% EtOH (12 mL) and 2M NaOH (5 mL) was added and the mixture was heated to reflux for 12 h. Then H2O was added (40 mL), the mixture was extracted with CH2Cl2 (2 × 15 mL). The aqueous phase was brought to pH 5 by addition of 2M HCl and then exctracted with CH2Cl2 (3 × 30 mL). The combined organic phases were washed with brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was digested with ice-cold Et2O (5 mL) to afford, after drying, 260 mg (31%) of 9b. 1H-NMR (CDCl3): δ (ppm) 12.96 (s, 1H, OH), 8.21 (m, 1H, py H-6), 7.94 (m, 1H, py H-3), 7.92 (m, 1H, py H-4), 7.81 (m, 2H, Ph H-2,6), 7.54 (m, 1H, Ph H-4), 7.45 (m, 2H, Ph H-3,5), 7.20 (m, 1H, py H-5), 2.49 (s, 3H, 3-Me); 13C-NMR (CDCl3): δ (ppm) 189.6 (C=O), 158.1 (C-5), 153.7 (C-3, 2J(C3,3-Me) = 7.0 Hz), 153.5 (py C-2), 144.6 (py C-6), 140.4 (py C-4), 139.3 (Ph C-1), 131.7 (Ph C-4), 128.8 (Ph C-2,6), 127.8 (Ph C-3,5), 120.4 (py C-5), 112.7 (py C-3), 103.5 (C-4, 3J(C4,3-Me) = 2.3 Hz), 15.1 (3-Me, 1J = 129.0 Hz); 15N-NMR (CDCl3): δ (ppm) −114.1 (N-2), −134.2 (py N), N1 was not found; MS (m/z, %): 279 (M+, 54), 278 (100), 202 (46), 134 (29), 105 (32), 77 (45). Anal. Calcd for C16H13N3O2: C, 68.81; H, 4.69; N, 15.04. Found: C, 68.76; H, 4.80; N, 15.03.

1-(2-Pyridinyl)-1H-pyrazol-5-yl benzoate (10a)
Under anhydrous conditions, to a suspension of 1a (161 mg, 1 mmol) and Ca(OH)2 (148 mg, 12 mmol) in dry 1,4-dioxane (2 mL) a solution of benzoyl chloride (141 mg, 1 mmol) in dry 1,4-dioxane (2 mL) was added. The reaction mixture was heated at reflux for 2 h under stirring. After cooling to room temperature, the mixture was treated with 2 M HCl (8 mL), stirred for 1 h, and poured into H2O (20 mL). Then the mixture was neutralized with aqueous Na2CO3 and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water, dried (Na2SO4) and evaporated under reduced pressure. The residue was subjected to column chromatography (silica gel, eluent: EtOAc–CH2Cl2, 1:1) to afford 91 mg(34 %) of colorless crystals of mp 69 °C. 1H-NMR (CDCl3): δ (ppm) 8.21 (m, 3H, py H-6 and Ph H-2,6), 7.86 (m, 1H, py H-3), 7.80 (m, 1H, py H-4), 7.70 (d, 1H, H-3, 3J(H3,H4) = 1.8 Hz), 7.66 (m, 1H, Ph H-4), 7.52 (m, 2H, Ph H-3,5), 7.15 (m, 1H, py H-5), 6.37 (d, 1H, H-4, 3J(H3,H4) = 1.8 Hz); 13C-NMR (CDCl3): δ (ppm) 163.4 (C=O), 151.9 (py C-2), 147.9 (py C-6), 145.6 (C-5), 140.5 (C-3, 1J = 188.4 Hz, 2J(C3,H4) = 4.6 Hz), 138.4 (py C-4), 133.9 (Ph C-4), 130.6 (Ph C-2,6), 128.62 (Ph C-1), 128.56 (Ph C-3,5), 121.7 (py C-5), 115.4 (Py C-3), 98.3 (C-4, 1J = 182.3 Hz, 2J(C4,H3) = 10.4 Hz; 15N-NMR (CDCl3): δ (ppm) −93.3 (N-2), −94.9 (py N), −174.3 (N-1); IR (KBr): ν (cm-1) 1747 (C=O); MS (m/z, %): 265 (M+, 7), 105 (100), 77 (20), 51 (11). Anal. Calcd for C15H11N3O2: C, 67.92; H, 4.18; N, 15.84. Found: C, 68.08; H, 4.26; N, 15.56.

3-Methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl benzoate (10b)
Similarly as described for the preparation of 10a, from 1b (175 mg, 1 mmol) and benzoyl chloride (141 mg, 1 mmol) 168 mg (60%) of 10b were obtained as colorless crystals of mp 59–61 °C. 1H-NMR (CDCl3): δ (ppm) 8.20 (m, 2H, Ph H-2,6), 8.19 (m, 1H, py H-6), 7.80 (m, 1H, py H-3), 7.75 (m, 1H, py H-4), 7.65 (m, 1H, Ph H-4), 7.51 (m, 2H, Ph H-3,5), 7.09 (m, 1H, py H-5), 6.19 (s, 1H, H-4), 2.37 (s, 3H, Me); 13C-NMR (CDCl3): δ (ppm) 163.3 (C=O), 151.8 (py C-2), 149.8 (C-3, 2J(C3,3-Me) = 6.8 Hz, 2J(C3,H4) = 4.1 Hz), 147.9 (py C-6), 145.5 (C-5), 138.2 (py C-4), 133.8 (Ph C-4), 130.5 (Ph C-2,6), 128.7 (Ph C-1), 128.6 (Ph C-3,5), 121.2 (py C-5), 115.1 (Py C-3), 98.2 (C-4, 1J = 180.3 Hz, 3J(C4,3-Me) = 3.4 Hz), 14.6 (3-Me, 1J = 127.8 Hz); 15N-NMR (CDCl3): δ (ppm) −95.4 (py N), −98.2 (N-2), −178.8 (N-1); IR (KBr): ν (cm-1) 1755 (C=O); MS (m/z, %): 279 (M+, 5), 105 (100), 78 (22), 77 (67), 51 (35). Anal. Calcd for C16H13N3O2: C, 68.81; H, 4.69; N, 15.04. Found: C, 68.95; H, 4.87; N, 15.03.

Reaction of 1b with triethyl orthopropionate – compounds 11b and 12b
A mixture of 1b (175 mg, 1 mmol) and triethyl orthopropionate (176 mg, 1 mmol) in toluene (2 mL) was was heated to reflux for 1 h. Then the solvent was removed under reduced pressure and the residue was washed with diisopropyl ether to afford 36 mg (14%) of (4E)-4-(1-ethoxypropylidene)- 5-methyl-2-(2-pyridinyl)-2,4-dihydro-3H-pyrazol-3-one (11b) as red crystals of mp 92 °C. The product hydrolized to 1-[5-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazol-4-yl]-1-propanone (12b) on treatment with 96% EtOH to give 23 mg (10%) of colorless crystals of mp 115–118 °C (EtOH).
Compound 11b: 1H-NMR (CDCl3): δ (ppm) 8.50 (m, 1H, py H-6), 8.14 (m, 2H, py H-3, py H-4), 7.04 (m, 1H, py H-5), 4.37 (q, 2H, OCH2, 3J = 7.0 Hz), 3.21 (q, 2H, CCH2, 3J = 7.5 Hz), 2.39 (s, 3H, 5-Me), 1.47 (t, 3H, OCH2CH3, 3J = 7.0 Hz), 1.28 (t, 3H, CCH2CH3, 3J = 7.5 Hz); 13C-NMR (CDCl3): δ (ppm) 182.3 (C=C-O), 165.7 (C-3), 149.8 (C-5, 2J(C5,5-Me) = 7.6 Hz), 149.8 (py C-2), 148.5 (py C-6), 137.6 (py C-4), 119.7 (py C-5), 114.0 (py C-3), 107.3 (C-4), 64.7 (OCH2), 20.6 (CCH2), 17.9 (5-Me, 1J = 129.3 Hz), 14.8 (OCH2CH3), 11.6 (CCH2CH3).
Compound 12b: 1H-NMR (CDCl3): δ (ppm) 8.28 (m, 1H, py H-6), 7.91 (m, 2H, py H-3, py H-4), 7.20 (m, 1H, py H-5), 2.84 (q, 2H, CH2, 3J = 7.2 Hz), 2.47 (s, 3H, 3-Me), 1.16 (t, 3H, CH2CH3, 3J = 7.2 Hz), OH was not unambiguously assigned; 13C-NMR (CDCl3): δ (ppm) 195.7 (C=O), 159.1 (C-5), 152.9 (C-3), 150.5 (py C-2), 144.8 (py C-6), 140.3 (py C-4), 120.4 (py C-5), 112.6 (py C-3), 104.1 (C-4), 34.5 (CH2, 1J = 126.4 Hz, , 2J(CH2,CH3) = 7.0 Hz), 15.5 (3-Me, 1J = 128.9 Hz), 8.0 (CH2CH3, 1J = 127.5 Hz, 2J(CH3,CH2) = 4.4 Hz); MS (m/z, %): 231 (M+, 19), 202 (100), 134 (20), 104 (40), 93 (16), 78 (11), 67 (13), 49 (27). HRMS: Cald for C12H13N3O2: 231.1008. Found: 231.1003.

(4Z)-4-{[5-Hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazol-4-yl]methylene}-5-methyl-2-(2-pyridinyl)-2,4-dihydro-3H-pyrazol-3-one (13b)
A mixture of 1b (175 mg, 1 mmol) and triethyl orthoformate (106 mg, 1mmol) was heated to 140 °C for 1 h. The solid material obtained after cooling was washed with diisopropyl ether and recrystallized from EtOH to afford 61 mg (34%) of orange needles, mp 237 °C. 1H-NMR (CDCl3): δ (ppm) 17.87 (1H, OH), 8.60 (m, 2H, py H-6), 7.99 (m, 2H, py H-3), 7.81 (m, 2H, py H-4), 7.29 (s, 1H, CH), 7.23 (m, 2H, py H-5), 2.42 (s, 6H, 3-Me); 13C-NMR (CDCl3): δ (ppm) 162.2 (C-5, 3J(C5,CH) = 10.0 Hz), 153.5 (C-3, 2J(C3,3-Me) = 6.9 Hz, 3J(C3,CH) = 5.7 Hz), 149.5 (py C-2), 148.9 (py C-6), 138.9 (alkene C-H, 1J = 148.2 Hz), 138.1 (py C-4), 122.0 (py C-5), 116.1 (py C-3), 109.7 (C-4, 3J(C4,3-Me) = 2.4 Hz, 2J(C4,CH) = 2.4 Hz), 13.0 (3-Me, 1J = 128.7 Hz); 15N-NMR (CDCl3): δ (ppm) −92.9 (py N), −93.6 (N-2), −180.4 (N-1); IR (KBr): ν (cm-1) 3430 (OH), 1628 (C=O); MS (m/z, %): 360 (M+, 40), 345 (88), 343 (76), 230 (20), 79 (46), 78 (100). Anal. Calcd for C19H16N6O2: C, 63.33; H, 4.47; N, 23.32. Found: C, 63.27; H, 4.41; N, 23.21.

(4Z)-4-[Amino(phenyl)methylene]-5-methyl-2-(2-pyridinyl)-2,4-dihydro-3H-pyrazol-3-one (14b)
Under a nitrogen atmosphere, a mixture of 1a (350 mg, 2 mmol) and benzamidine hydrochloride (329 mg, 2.1 mmol) was heated to 220 °C for 1 h. After cooling to room temperature, 96% EtOH (3 mL) was added and the mixture was refluxed for 5 min, before it was stored in the deep freezer for some hours. The precipitate was filtered off and washed with a few ice-cold EtOH to afford 14b•HCl as a yellow powder. The latter was dissolved in H2O (20 mL), the solution was neutralized with aqueous NaHCO3 and extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were washed with brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was recrystallized from MeCN to give 178 mg (32 %) of apricot-colored crystals with mp 223–228 °C. 1H-NMR (CDCl3): δ (ppm) 10.30 (s, 1H, NH···O), 8.39 (m, 1H, py H-6), 8.17 (m, 1H, py H-3), 7.71 (m, 1H, py H-4), 7.53 (m, 1H, Ph H-4), 7.46 (m, 2H, Ph H-3,5), 7.43 (m, 2H, Ph H-2,6), 7.03 (m, 1H, py H-5), 6.65 (s, 1H, NH), 1.66 (s, 3H, 5-Me); 13C-NMR (CDCl3): δ (ppm) 166.5 (C-3), 165.4 (N-C-Ph), 150.6 (py C-2), 149.1 (C-5, 2J(C5,5-Me) = 7.0 Hz), 148.4 (py C-6), 137.7 (py C-4), 134.2 (Ph C-1), 131.0 (Ph C-4), 128.7 (Ph C-3,5), 127.6 (Ph C-2,6), 119.8 (py C-5), 113.9 (py C-3), 99.8 (C-4), 16.3 (5-Me, 1J = 128.7 Hz); 15N-NMR (CDCl3): δ (ppm) −99.5 (N-1 and py N), −269.7 (NH2), N-2 was not found; MS (m/z, %): 279 (M+, 9), 278 (54), 277 (100), 134 (11), 104 (12), 78 (16), 66 (16). Anal. Calcd for C16H14N4O: C, 69.05; H, 5.07; N, 20.13. Found: C, 68.94; H, 5.19; N, 20.34.

(4E)-4-[(Dimethylamino)methylene]-2-(2-pyridinyl)-2,4-dihydro-3H-pyrazol-3-one (15a)
A mixture of 1a 161 mg (1 mmol) and dimethylformamide diethyl acetal (147 mg, 1 mmol) in toluene (5 mL) was heated to reflux for 3 h. On cooling, an orange solid precipitated which was filtered off and recrystallized from toluene to afford 172 mg (80%) of orange-yellow crystals, mp 193 °C. 1H-NMR (CDCl3): δ (ppm) 8.48 (m, 1H, py H-6), 8.25 (m, 1H, py H-3), 7.76 (s, 1H, H-5), 7.71 (m, 1H, py H-4), 7.53 (s, 1H, =CH), 7.05 (m, 1H, py H-5), 3.32 (s, 3H, NMe cis to =CH), 3.24 (s, 3H, NMe trans to =CH); 13C-NMR (CDCl3): δ (ppm) 166.4 (C-3, 3J(C3,H5) = 4.7 Hz, 3J(C3,=CH) = 3.9 Hz), 150.8 (=CH, 1J = 168.3 Hz, 3J(=CH,NMecis) = 4.0 Hz, 3J(=CH,NMetrans) = 3.4 Hz), 150.8 (py C-2, 3J(C2,H6) = 12.3 Hz, 3J(C2,H4) = 9.1 Hz, 4J(C2,H5) = 1.1 Hz), 148.4 (py C-6, 1J = 179.4 Hz, 2J(C6,H5) = 3.6 Hz, 3J(C6,H4) = 7.6 Hz), 138.4 (C-5 1J = 189.2 Hz, 3J(C5,=CH) = 7.4 Hz), 137.7 (py C-4, 1J = 162.1 Hz, 2J(C4,H5) = 1.2 Hz, 3J(C4,H6) = 6.7 Hz), 119.9 (py C-5, 1J = 164.5 Hz, 2J(C5,H6) = 8.0 Hz, 3J(C5,H3) = 6.6 Hz), 114.0 (py C-3, 1J = 169.7 Hz, 2J(C3,H4) = 1.8 Hz, 3J(C3,H5) = 6.7 Hz, 4J(C3,H6) = 1.8 Hz), 100.1 (C-4, 2J(C4,H5) = 11.2 Hz, 2J(C4,=CH) = 1.8 Hz), 47.2 (NMe cis to =CH, 1J = 139.8 Hz, 3J(NMe,=CH) = 5.2 Hz, 3J(NMe,NMe) = 3.2 Hz), 40.6 (NMe trans to =CH, 1J = 139.4 Hz, 3J(NMe,=CH) = 7.3 Hz, 3J(NMe,NMe) = 3.5 Hz); 15N-NMR (CDCl3): δ (ppm) −90.2 (N-1), −99.2 (py N), −180.5 (N-2), −269.9 (NMe2); IR (KBr): ν (cm-1) 1684 (C=O). MS (m/z, %): 216 (M+, 100), 201 (39), 145 (40), 82 (20), 78 (22), 51 (16), 42 (44). Anal. Calcd for C11H12N4O: C, 61.10; H, 5.59; N, 25.91. Found: C, 60.89; H, 5.35; N, 25.68.

(4Z)-4-[(Dimethylamino)methylene]-5-methyl-2-(2-pyridinyl)-2,4-dihydro-3H-pyrazol-3-one (15b)
Similarly as described for the preparation of 15a, from 1b (175 mg, 1 mmol) and dimethylformamide diethyl acetal (147 mg, 1 mmol) 174 mg (76%) of 15b were obtained as yellow crystals of mp 181 °C (toluene) (lit.43: mp 180 °C). 1H-NMR (CDCl3): δ (ppm) 8.49 (m, 1H, py H-6), 8.16 (m, 1H, py H-3), 7.67 (m, 1H, py H-4), 7.01 (m, 1H, py H-5), 7.00 (s, 1H, =CH), 3.83 (s, 3H, NMe trans to =CH), 3.29 (s, 3H, NMe cis to =CH), 2.21 (s, 3H, 5-Me); 13C-NMR (CDCl3): δ (ppm) 162.6 (C-3, 3J(C3,=CH) = 8.5 Hz), 152.3 (=CH, 1J = 162.5 Hz, 3J(=CH,NMe) = 3.8 Hz), 151.6 (C-5, 2J(C5,5-Me) = 6.9 Hz, 3J(C5,=CH) = 4.1 Hz), 151.0 (py C-2), 148.4 (py C-6), 137.4 (py C-4), 119.4 (py C-5), 114.1 (py C-3), 99.2 (C-4, 2J(C4,=CH) = 2.4 Hz, 3J(C4,5-Me) = 2.4 Hz), 48.0 (NMe cis to =CH, 1J = 139.3 Hz, 3J(NMe,=CH) = 5.5 Hz, 3J(NMe,NMe) = 3.8 Hz), 43.4 (NMe trans to =CH, 1J = 140.3 Hz, 3J(NMe,=CH) = 7.7 Hz, 3J(NMe,NMe) = 3.0 Hz), 13.6 (5-Me, 1J = 127.8 Hz); 15N-NMR (CDCl3): δ (ppm) −98.8 (py N), −100.6 (N-1), −182.0 (N-2), −264.7 (NMe2); IR (KBr): ν (cm-1) 1671 (C=O). MS (m/z, %): 230 (M+, 100), 215 (76), 188 (28), 186 (26), 145 (38), 107 (30), 96 (29), 78 (57), 53 (31), 51 (24).

4,4'-(Phenylmethylene)bis[1-(2-pyridinyl)-1H-pyrazol-5-ol] (16a)
A mixture of 1a (161 mg, 1 mmol) and benzaldehyde (106 mg, 1 mmol) in toluene (1 mL) was stirred at 80 °C for 3 h. Then the solvent was largely removed under reduced pressure and the residue was cooled to 5 °C. The precipitated crystals were washed with cold ether and dried to give 123 mg (60%) of colorless crystals, mp 179 °C. 1H-NMR (CDCl3): δ (ppm) 12.63 (s, 2H, OH), 8.22 (m, 2H, py H-6), 7.90 (m, 2H, py H-3), 7.85 (m, 2H, py H-4), 7.44 (s, 2H, H-3), 7.40 (m, 2H, Ph H-2,6), 7.31 (m, 2H, Ph H-3,5), 7.21 (m, 1H, Ph H-4), 7.13 (m, 2H, py H-5), 5.24 (s, 1H, CH); 13C-NMR (CDCl3): δ (ppm) 154.5 (py C-2), 152.7 (C-5), 145.1 (py C-6), 143.2 (Ph C-1), 142.3 (C-3, 1J = 184.4 Hz, 3J(C3,CH) = 5.0 Hz), 139.8 (py C-4), 128.3 (Ph C-3,5), 127.9 (Ph C-2,6), 126.2 (Ph C-4), 120.0 (py C-5), 112.1 (py C-3), 104.1 (C-4, 2J(C4,H-3) = 8.6 Hz, 2J(C4,CH) = 8.6 Hz), 33.8 (CH, 1J =127.4 Hz); 15N-NMR (CDCl3): δ (ppm) −116.4 (N-2), −129.4 (py N), −186.4 (N-1); IR (KBr): ν (cm-1) 1599; MS (m/z,%): 410 (M+, 3), 250 (61), 249 (68), 221 (45), 220 (51), 161 (72), 120 (43), 115 (37), 94 (25), 79 (69), 78 (100), 67 (21), 52 (30), 51 (42). Anal. Calcd for C23H18N6O2: C, 67.31; H, 4.42; N, 20.48. Found: C, 67.25; H, 4.35; N, 20.26.

4,4'-(Phenylmethylene)bis[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ol] (16b)
Similarly as described for the preparation of 16a, from 1b (175 mg, 1 mmol) and benzaldehyde (106 mg, 1 mmol) were obtained 158 mg (72 %) of colorless crystals, mp 168–173 °C. 1H-NMR (CDCl3): δ (ppm) 12.68 (broad s , 2H, OH), 8.16 (m, 2H, py H-6), 7.85 (m, 2H, py H-3), 7.80 (m, 2H, py H-4), 7.34 (m, 2H, Ph H-2,6), 7.30 (m, 2H, Ph H-3,5), 7.22 (m, 1H, Ph H-4), 7.06 (m 1H, py H-5), 5.28 (s, 1H, CH), 2.10 (s, 3H, 3-Me); 13C-NMR (CDCl3): δ (ppm) 154.4 (py C-2), 153.5 (C-5, 3J(C5,CH) = 5.6 Hz), 151.4 (C-3), 144.9 (py C-6), 141.4 (Ph C-1), 139.6 (Ph C-4), 128.2 (Ph C-2,6), 128.0 (Ph C-3,5), 126.0 (Ph C-4), 119.2 (py C-5), 111.7 (py C-3), 101.0 (C-4), 33.7 (CH, 1J = 124.3 Hz, 3J(CH,PhC-2,6) = 4.0 Hz), 13.7 (3-Me, 1J = 127.5 Hz); 15N-NMR (CDCl3): δ (ppm) −121.1 (N-2), −130.6 (Py N), −199.1 (N-1); IR (KBr): ν (cm-1) 1599; MS (m/z,%): 438 (M+, 1), 264 (24), 263 (81), 262 (23), 248 (32), 234 (39), 221 (30), 220 (34), 175 (100), 160 (22), 134 (37), 128 (47), 127 (23), 91 (27), 79 (78), 78 (78), 52 (35), 51 (44). Anal. Calcd for C25H22N6O2: C, 68.48; H, 5.06; N, 19.17. Found: C, 68.50; H, 5.13; N, 18.88.

ACKNOWLEDGEMENTS
We are grateful to Dr. L. Jirovetz for recording the MS spectra.

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