Reaction of acylpyruvic acid esters with hydrazides

Hydrazides reacted with acylpyruvic acid esters possessing a terminal straight chain alkyl substituent at the C=O bond distal from the ester group, giving 5-hydroxy-2-pyrazolines. Acylpyruvates with bulky terminal substituents underwent condensation at the C=O bond adjacent to the ester group, giving products with hydrazone or 5-hydroxy-2-pyrazoline structure and capable of displaying ring-chain equilibrium between these tautomers in solution.

The reaction of hydrazides with aroylpyruvic acid esters with the general formula MeO₂CCOCH₂COC₆H₄X proceeded with 100% regioselectivity at the C=O bond adjacent to the ester group, regardless of the electronic properties of aromatic ring substituent [1–3]. In the crystalline state, the resultant derivatives had either hydrazone or 5-hydroxy-2-pyrazoline structure, while forming tautomeric mixtures of these forms in solution [3, 4].

In the present work, we studied the reaction of aliphatic acylpyruvic acid esters RO₂CCOCH₂COR¹ 1a-f with hydrazides 2a-c. We were interested in the terminal alkyl substituent role in determining the regioselectivity of the reaction with hydrazides and tautomeric transformations in the products of these reactions.

Benzoylhydrazine 2b was used as the main nucleophilic reagent. The reaction was carried out under mild conditions, by mixing equimolar amounts of the reagents in ethanol or methanol and maintaining until the end of the reaction without using any acidic catalysts. At the end of the reaction as indicated by thin-layer chromatography, the solvent was removed at reduced pressure, and the residue was analyzed using ¹H or ¹³C NMR spectroscopy. In interpreting these spectral data, we should first take into account that the reaction could proceed through two pathways, while the condensation products, independently of which C=O bond reacted, could exist in several tautomeric forms similar to nitrogen derivatives of other 1,3-dicarbonyl compounds [4].

Let us examine the particular example of 2,4-dioxopentanoic acid methyl ester 1a reaction with benzoylhydrazine (2b). The crystalline material obtained at the reaction completion (compound 3a) exhibited a single set of ¹H NMR signals in chloroform solution. This finding primarily indicates that the reaction was 100% regioselective at one of the C=O bonds.

The presence of two asymmetric doublets at 3.01 and 3.25 ppm, forming a typical AB system (J _AB = 18.6 Hz) indicated cyclic 5-hydroxy-2-pyrazoline structure A ¹ or A ² having a chiral carbon atom C-5 in the ring. This accounted for the diastereotopic nature of the methylene protons at the carbon atom C-4, leading to the appearance of an AB system in the ¹H NMR spectrum. The ¹³C NMR spectrum corresponded to the cyclic structure of this condensation product. The presence of a signal at 89.7 ppm, which should be assigned to the quaternary carbon atom C-5 of the pyrazoline ring, was the most characteristic. The selection between structures A ¹ and A ² could be based on the IR spectral data. The ester C=O stretching band was found at 1764 cm^-1 in the IR spectrum for product 3a taken in a KBr pellet. This value corresponded to structure A ¹, in which the close-lying C(5)–O and C(5)–N bonds should shift the ester C=O stretching band towards shorter wavelengths in comparison with the ordinary position of this band in the spectra of acid esters (1735-1750 cm^-1) [5].

Thus, the reaction of acylpyruvate 1a with benzoylhydrazine (2b) occurred entirely at the distal C=O bond, and condensation product 3a had the 5-hydroxy-2-pyrazoline structure A ¹.

Solutions of product 3a did not exhibit any changes in their ¹H and ¹³C NMR spectra with time, and there were no new sets of resonance signals observed. This finding indicated a lack of tautomeric transformations between the cyclic structure and linear species, thus a clear preference for the 5-hydroxy-2-pyrazoline form A ¹.

Lengthening the chain of the terminal substituent (going to acylpyruvates 1b,c) did not alter the regioselectivity of the reactions with benzoylhydrazine (2b). Only products of condensation at the C=O bond adjacent to the alkyl group were formed. Derivatives 3b,c also had the 5-hydroxy-2-pyrazoline structure A ¹, which was entirely conserved in CDCl₃ solutions.

We also note that the products 3a-c did not undergo tautomeric transformations in DMSO-d₆, which is a dipolar basic solvent.

The regiodirection of the reaction with benzoylhydrazine (2b) changed when bulky branched substituents were present in the acylpyruvates. The reaction of acylpyruvates 1d-f with benzoylhydrazine (2b) gave only products from condensation at the C=O bond adjacent to the ester group (compounds 3d-f). Thus, the solution phase ¹H and ¹³C NMR spectra from the crystalline reaction product of acylpyruvate 1d (R¹ = i-Pr) had a single set of signals corresponding to the 5-hydroxy-2-pyrazoline structure (A ¹ or A ²). The ¹³C NMR signal for the C-5 carbon atom was found at 101.1 ppm, while the quaternary carbon atom 13C NMR signal for compounds 3a-c with structure A ¹ was located in a different region (89.5-90.0 ppm). This difference indicates that the product 3d most likely has the cyclic structure A ², which was confirmed by IR spectroscopy. The ester C=O stretching band in the IR spectrum of product 3d recorded in a KBr pellet was found at 1739 cm^-1. We recall that the analogous band, for example, in the case of compound 3a was found at 1764 cm^-1.

The ¹H and ¹³C NMR spectra of product 3d solutions did not change over time. The possible linear tautomeric structures were not favored, compared to the 5-hydroxy-2-pyrazoline form A ².

Thus, the presence of a relatively bulky isopropyl substituent was sufficient to completely alter the regiodirection of the acylpyruvate reaction with hydrazides. Hence, it was not surprising that the pyruvates 1e,f having even bulkier sec-butyl and tert-butyl groups as the terminal substituents yielded the derivatives 3e,f, which were products of condensation at the C=O bond adjacent to the ester group. However, the products 3e,f deserve a separate discussion.

The ¹H and ¹³C NMR spectra of derivative 3e in CDCl₃ recorded immediately after dissolution corresponded to the 5-hydroxy-2-pyrazoline form A ², represented by two diastereomers due to two chiral centers. This was indicated by the doubling of several ¹H and ¹³C NMR signals. For example, the ¹³C NMR signals at 100.9 and 101.0 ppm corresponded to the C-5 carbon atoms of the diastereomeric heterocycles.

Partial transformation of compound 3e into a hydrazone form, most likely with Z-configuration B _Z ² permitting the formation of an intramolecular chelate hydrogen bond, gradually occurred in solution. The NH proton and carbonyl oxygen atom of the ester group participated in the formation of this intramolecular hydrogen bond. The ¹H NMR singlets appearing at 3.87 and 13.52 ppm indicated the formation of a hydrazone tautomer. The signal at 3.87 ppm should be assigned to methylene group protons, while the signal at 13.52 ppm with only half the intensity of the former signal belonged to the amide NH proton. The relatively downfield position of the amide proton signal was a direct indication of a strong intramolecular chelate hydrogen bond and, thus, Z-configuration of the hydrazone tautomer B _Z ².

A peculiar ring-chain-ring equilibrium was established for compound 3e in CDCl₃ solution after 3 days, featuring two 5-hydroxy-2-pyrazoline forms differing in the chiral center configurations, namely, (RR,SS)-A ² and (RS,SR)-A ², and the Z-hydrazone form B _Z ². The fraction of form B _Z ² was only about 5%. The ratio of the diastereomers in the tautomer A ² was 3:2. These diastereomers converted into each other through E-isomer B _E ² of the hydrazone form, in which the suitable structural fragments could approach, permitting reversible cyclization. This E-isomer was not detected by ¹H NMR spectroscopy but was predicted to be a necessary intermediate species in the observed equilibrium.

The hydrazone form B ² in DMSO-d₆ solution was not detected in the ¹H and ¹³C NMR spectra of compound 3e. Formally, we can discuss a ring-ring equilibrium of two cyclic 5-hydroxy-2-pyrazoline forms A ² differing in the configuration of the asymmetric centers.

Compound 3f, which was obtained from the condensation of benzoylhydrazine (2b) with acylpyruvate 1f containing a terminal tert-butyl group, had the hydrazone structure B ² in crystalline state. The IR spectrum of this compound recorded in a KBr pellet had absorption bands in the stretching region at 1706 and 1744 cm^-1, indicating that the crystalline product 3f existed in the hydrazone form B ². The band at 1706 cm^-1 should be assigned to a ketonic C=O stretching band, while the band at 1744 cm^-1 should be assigned to an ester C=O stretching band. The solid phase ¹³C NMR spectrum of product 3f exhibited a set of resonance signals corresponding to hydrazone structure B ². The signal at 211.5 ppm quite likely belonged to the carbon atom of the ketonic C=O bond.

The ¹H NMR spectrum of compound 3f in CDCl₃ recorded immediately after preparation of the solution contained two sets of resonance signals. One set was that of the cyclic form A ², while the other corresponded to one of the diastereomers of hydrazone form B ². The intensity ratio of these two sets stopped changing after a few minutes. Equilibrium was apparently very soon established between the two forms. Such a behavior would be possible if the crystalline compound 3f had the E-hydrazone structure B _E ², in which the arrangement of the functional groups, NH bond, and ketonic C=O bond provided for reversible cyclization to give the 5-hydroxy-2-pyrazoline structure A ².

A third set of signals appeared after some time in the solution phase spectrum of compound 3f, indicating formation of the hydrazone Z-isomer B _Z ². The signal for methylene group protons at 3.94 ppm and NH proton at 13.51 ppm belonged to the diastereomer formed. The downfield position of the signal at 13.51 ppm is due to a strong intramolecular hydrogen bond, as noted above, possible only for the Z-configuration of the hydrazone fragment in form B _Z ².

The appearance of the spectrum ceased to change after 72 h, and equilibrium was established between the cyclic form A ² and the hydrazone diastereomers B _Z ² and B _E ². The B _Z ² diastereomer was the main component comprising 85% of the equilibrium mixture, while the B _E ² diastereomer comprised 10% and the fraction of 5-hydroxy-2-pyrazoline form A ² was 5%.

Hence, the crystalline derivative 3f existed as hydrazone B _E ² with E-configuration at the C=N bond. A rapid equilibration to the cyclic form A ² occurred in CDCl₃, facilitated by a favorable arrangement of the nucleophilic and electrophilic sites. The subsequent transformation to Z-hydrazone form B _Z ² was slow, since a change in the C=N bond configuration was required. The predominance of this form in the observed three-component equilibrium was caused by its greater stability due to a chelate intramolecular hydrogen bond.

When DMSO-d₆ was used as the solvent, no changes in the ring-chain equilibrium were observed, but the E-diastereomer B _E ² became dominant within the hydrazone form (68%), while the fraction of Z-diastereomer B _Z ² was 9% and the fraction of 5-hydroxy-2-pyrazoline form A ² was 23%. The predominance of the E-hydrazone diastereomer within the linear tautomer should be ascribed to its greater polarity relative to the Z-isomer and, thus, better solvation by the dipolar solvent. The possibility of forming strong intermolecular hydrogen bonds between the NH group of diastereomer B _E ² and highly basic dimethyl sulfoxide molecules may have also contributed to the stabilization of form B _E ².

Comparison of products 3d-f obtained by condensation of benzoylhydrazine 2b with acylpyruvates 1d-f at the C=O bond adjacent to the ester group clearly revealed a strong dependence of the ring-chain equilibrium between 5-hydroxy-2-pyrazoline form A ² and linear hydrazone tautomer B ² on the bulk of the terminal substituent in the structure of the starting pyruvates. The presence of an isopropyl substituent in compound 3d did not guarantee the appearance of the linear tautomer in solutions, while the introduction of a somewhat bulkier sec-butyl group (compound 3e) was sufficient to make the hydrazone tautomer B ² competitive. A tert-butyl group in the acylpyruvate structure provided for almost complete predominance of hydrazone form B ² in the solution of derivative 3f.

Changing the hydrazide component could also have a serious effect on tautomeric behavior of the acylpyruvate derivatives. This effect was shown in the case of products from the acylpyruvate 1d-f condensation with picolinic acid hydrazide 2c. As expected, the reaction led to derivatives 3g-i, formed by condensation at the C=O bond adjacent to the ester group.

A spectroscopic study of compound 3g showed that this acylpyruvate derivative with a terminal isopropyl group had Z-hydrazone structure B _Z ² in the crystalline state, while a ring-chain equilibrium was observed in CDCl₃ solution with the hydrazone diastereomers B _Z ² (87%) and B _E ² (4%), along with the 5-hydroxy-2-pyrazoline form A ² (9%). Derivatives 3h,i, obtained by the condensation of acylpyruvates 1e (R¹ = s-Bu) and 1f (R¹ = t-Bu) also had the Z-hydrazone structure B _Z ² in the crystalline state, while equilibrium mixtures of the hydrazone isomers B _E ² and B _Z ² formed in CDCl₃. The Z-diastereomer with an intramolecular chelate hydrogen bond was the prevalent species (at least 95%).

Comparison of the tautomeric behavior of compounds 3d-f (R² = Ph) and 3g-i (R² = 2-Py) showed that in the series of products from acylpyruvate condensation with hydrazides, replacement of a phenyl ring in the hydrazide structure with a 2-pyridyl ring strongly favored the linear tautomer B ². This behavior may be related to stabilization of form B ² for the condensation products of the acylpyruvates with picolinic acid hydrazide due to an intramolecular hydrogen bond between the NH proton and the 2-pyridyl ring nitrogen atom.

The regiodirection in acylpyruvate reactions with hydrazides should be interpreted within the general framework for describing reactions of 1,3-dicarbonyl compounds with hydrazines [6–10].

Hydroxyhydrazides C ¹ and C ² must have initially formed in equilibrium with the starting reagents. The irreversible elimination of water from these intermediates led to the hydrazones B ¹ and B ², which may partially or completely convert into 5-hydroxy-2-pyrazolines A ¹ and A ².

The actual concentration of hydroxyhydrazide C ¹ may have been insignificant but the significantly easier irreversible elimination of water from this species enabled the predominant or even exclusive formation of condensation product at the C=O bond adjacent to the alkyl substituent. The concentration of hydroxyhydrazide C ¹ was maintained by the reversibility of the initial reaction steps. The reaction of acylpyruvates 1a-c with benzoylhydrazine 2b proceeded precisely in this manner. The small effective bulk of terminal n-alkyl groups permitted the competitive appearance of hydroxyhydrazide C ¹, opening a pathway to the formation of the corresponding final products. In this case, we may assert that the regioselectivity was determined at the second step by water elimination rate from the hydroxyhydrazides C ¹ and C ². Increasing the bulk of the terminal substituent in the starting acylpyruvates (compounds 1d-f) may completely suppress formation of initial hydroxyhydrazide C ¹, such that the reaction is forced through an alternative pathway, giving condensation products at the C=O bond adjacent to the ester group.

In addition, we examined the reaction of acylpyruvate 1f with formylhydrazine 2a, in which a hydrogen atom served as the substituent in the hydrazide component. The solution phase ¹H and ¹³C NMR spectra of completed reaction mixture had two sets of resonance signals corresponding to two 5-hydroxy-2-pyrazoline structures 3j,k, formed in a 2:3 ratio.

Spectral assignment of these regioisomers was carried out by comparison with the spectra of previously examined products 3a-i.

Decreasing the bulk of the substituent in the hydrazide component somewhat enhanced the formation of hydroxyhydrazide C ¹, originating from the initial hydrazide addition to the C=O bond adjacent to the tert-butyl, thus leading to regioisomeric condensation products. These regioisomers could not be isolated as pure compounds by either recrystallization or thin-layer chromatography.

This study quite clearly demonstrated the crucial influence of structural features on the regiodirection in reactions of asymmetric 1,3-dicarbonyl compounds with two different C=O bonds with nitrogen nucleophiles.

Experimental

The IR spectra were recorded on a PerkinElmer Spectrum FT-IR instrument in KBr pellets. The ¹H and ¹³C NMR spectra were recorded on a Bruker DX-300 spectrometer (300 and 75 MHz, respectively) in CDCl₃. The ¹H NMR spectrum of ester 3e was also recorded in DMSO-d₆. The residual solvent signals (7.26 and 2.50 ppm for the ¹H nuclei and 77.0 ppm for the ¹³C nuclei) were used as internal standard. The solid phase ¹³C NMR spectrum was recorded on a Bruker AV-500 spectrometer (125 MHz). The elemental analysis was performed on a Hewlett-Packard 185B CHN analyzer. The melting points were determined on a Thiele apparatus. The reaction progress and purity of the products were monitored by thin-layer chromatography on Silufol UV-254 plates with chloroform as the eluent and iodine vapor for visualization.

The starting acylpyruvate 1a-f were obtained by a reported method involving the condensation of oxalic acid esters with methyl alkyl ketones [11]. Formylhydrazine (2a), benzoylhydrazine (2b), and picolinic acid hydrazide (2c) were obtained from Sigma-Aldrich and were recrystallized prior to use.

Reaction of Acylpyruvic Acid Esters with Hydrazides (General Method). A solution of acylpyruvate 1a-f (1.5 mmol) in absolute alcohol (25 ml) was mixed with a solution of hydrazide 2a-c (1.5 mmol) in absolute alcohol (25 ml). (Methanol was used as the solvent for methyl esters 1a-c, while ethanol was used for the ethyl esters 1d-f). The mixture was stirred for an additional 2 h and then left at room temperature until completion of the reaction. The solvent was removed under reduced pressure. The residue was dried in vacuum and recrystallized from hexane. All the products formed colorless crystals.

Methyl 1-Benzoyl-5-hydroxy-3-methyl-4,5-dihydro-1 H -pyrazole-5-carboxylate (3a). Yield 0.315 g (80%); mp 166-167°С. IR spectrum, ν, cm^-1: 1764 (СО₂Mе). ¹Н NMR spectrum, δ, ppm (J, Hz): 2.11 (3Н, s, 3-СН₃); 3.01 (1Н, d, J _АВ = 18.6) and 3.25 (1Н, d, J _АВ = 18.6, 4-СН₂); 3.87 (3Н, s, ОСН₃); 4.99 (1Н, s, ОН); 7.43-7.96 (5Н, m, Н Ph). ¹³C NMR spectrum, δ, ppm: 16.3 (3-СН₃); 48.8 (4-СН₂); 54.1 (ОСН₃); 89.7 (С-5); 128.2 (2С), 130.5 (2С), 132.0, 133.2 (С Ph); 155.0 (C-3); 167.1, 171.0 (COPh, CO₂Me). Found, %: С 59.59; H 5.35; N 10.62. С₁₃H₁₄N₂O₄. Calculated, %: С 59.54; H 5.38; N 10.68.

Methyl 1-Benzoyl-3-ethyl-5-hydroxy-4,5-dihydro-1 H -pyrazole-5-carboxylate (3b). Yield 0.269 g (65%); mp 128-129°С. ¹Н NMR spectrum, δ, ppm (J, Hz): 1.22 (3Н, t, J = 7.3, СН₂СН ₃); 2.45 (2Н, q, J = 7.3, СН ₂СН₃); 3.01 (1Н, d, J _АВ = 18.6) and 3.24 (1Н, d, J _АВ = 18.6, 4-СН₂); 3.87 (3Н, s, ОСН₃); 4.97 (1Н, s, ОН); 7.43-8.01 (5Н, m, Н Ph). ¹³C NMR spectrum, δ, ppm: 10.9 (СН₂ СН₃); 23.9 (СН₂СН₃); 47.2 (4-СН₂); 54.0 (ОСН₃); 89.6 (С-5); 128.1 (2С), 130.6 (2С), 132.0, 133.2 (С Ph); 159.4 (C-3); 167.1, 171.1 (COPh, CO₂Me). Found, %: С 60.79; H 5.80; N 10.07. С₁₄H₁₆N₂O₄. Calculated, %: С 60.86; H 5.84; N 10.14.

Methyl 1-Benzoyl-5-hydroxy-3-propyl-4,5-dihydro-1 H -pyrazole-5-carboxylate (3c). Yield 0.248 g (57%); mp 117-118°С. ¹Н NMR spectrum, δ, ppm (J, Hz): 1.02 (3Н, t, J = 7.3, СН₂СН₂СН ₃); 1.61-1.73 (2Н, m, СН₂СН ₂СН₃); 2.41 (2Н, t, J = 7.1, СН ₂СН₂СН₃); 3.00 (1Н, d, J _АВ = 18.5) and 3.23 (1Н, d, J _АВ = 18.5, 4-СН₂); 3.87 (3Н, s, ОСН₃); 4.96 (1Н, s, ОН); 7.43-7.99 (5Н, m, Н Ph). ¹³C NMR spectrum, δ, ppm: 14.1 (СН₂СН₂ СН₃); 20.1 (СН₂ СН₂СН₃); 32.4 (СН₂СН₂СН₃); 47.3 (4-СН2); 54.0 (ОСН₃); 89.6 (С-5); 128.1 (2С), 130.6 (2С), 132.0, 133.2 (С Ph); 159.3 (C-3); 167.1, 171.1 (COPh, CO₂Me). Found, %: С 62.10; H 6.32; N 9.57. С₁₅H₁₈N₂O₄. Calculated, %: С 62.06; H 6.25; N 9.65.

Ethyl 1-Benzoyl-5-hydroxy-5-(1-methylethyl)-4,5-dihydro-1 H -pyrazole-3-carboxylate (3d). Yield 0.386 g (85%); mp 107-108°С. IR spectrum, ν, cm^-1: 1739 (СО₂Et). ¹Н NMR spectrum, δ, ppm (J, Hz): 0.92 (3Н, d, J = 6.6) and 1.12 (3Н, d, J = 6.6, СН(СН ₃)₂); 1.36 (3Н, t, J = 7.1, ОСН₂СН ₃); 2.97-3.06 (1Н, m, СНMе₂); 3.02 (1Н, d, J _АВ = 19.2) and 3.23 (1Н, d, J _АВ = 19.2, 4-СН₂); 4.34 (2Н, q, J = 7.1, ОСН ₂СН₃); 4.65 (1Н, br. s, ОН); 7.45-7.88 (5Н, m, Н Ph). ¹³C NMR spectrum, δ, ppm: 14.5 (СН₃); 17.1 (СН₃); 18.4 (СН₃); 34.9 (СНMе₂); 40.0 (4-СН₂); 62.4 (ОСН₂СН₃); 101.1 (С-5); 128.3 (2С), 130.6 (2С), 132.4, 133.6 (С Ph); 146.8 (C-3); 161.9, 170.4 (COPh, CO₂Et). Found, %: С 63.10; H 6.59; N 9.17. С₁₆H₂₀N₂O₄. Calculated, %: С 63.14; H 6.62; N 9.20.

Ethyl 1-Benzoyl-5-hydroxy-5-(1-methylpropyl)-4,5-dihydro-1 H -pyrazole-3-carboxylate (3e). Yield 0.429 g (90%); mp 103-104°С. IR spectrum, ν, cm^-1: 1740 (СО₂Et). ¹Н NMR spectrum (CDCl₃), δ, ppm (J, Hz): form А ² (95%): 0.88-0.92 (3Н, m, СН₃); 0.98-1.02 (3Н, m, СН₃); 1.34 (3Н, t, J = 7.3, ОСН₂СН ₃); 1.39-1.46 (1Н, m) and 1.89-1.98 (1Н, m, СН(Mе)СН ₂Mе); 2.65-2.76 (1Н, m, СН(Mе)Et); 3.02 (1Н, d, J _АВ = 18.9) and 3.18 (1Н, d, J _АВ = 18.9, 4-СН₂); 4.33 (2Н, q, J = 7.3, ОСН ₂СН₃); 4.65 (1Н, br. s, ОН); 7.44-7.88 (5Н, m, Н Ph); form В _Z ² (5%): 3.87 (2H, br. s, СН₂); 13.52 (1Н, br. s, NH); other signals overlap with signals of form А ². ¹Н NMR spectrum (DMSO-d₆), δ, ppm (J, Hz): form А ², diastereomer I (65%): 0.78 (3Н, d, J = 6.5, СНСН ₃); 0.85-1.01 (4Н, m, СНСН _АСН ₃); 1.18-1.29 (1Н, m, СНСН _ВСН₃); 1.22 (3Н, t, J = 7.3, ОСН₂СН ₃); 1.78-1.83 (1Н, m, СН(Mе)Et); 2.75 (1Н, d, J _АВ = 18.9) and 3.23 (1Н, d, J _АВ = 18.9, 4-СН₂); 4.22 (2Н, q, J = 7.3, ОСН ₂СН₃); 6.85 (1Н, br. s, ОН); 7.46-7.61 (5Н, m, Н Ph); diastereomer II (35%): 2.77 (1Н, d, J _АВ = 18.7) and 3.21 (1Н, d, J _АВ = 18.7, 4-СН₂); 6.81 (1Н, s, ОH); other signals overlap with signals of diastereomer I. ¹³C NMR spectrum, δ, ppm: diastereomer I: 12.7 (СН₃); 14.5 (СН₃); 15.1 (СН₃); 24.1 (CHСН₂); 40.4 (4-СН₂); 42.1 (CH); 62.3 (ОСН₂СН₃); 100.9 (С-5); 128.3 (2С), 130.6 (2С), 132.4, 133.6 (С Ph); 146.9 (C-3); 161.9, 170.4 (COPh, CO₂Et); diastereomer II: 12.3 (СН₃); 13.7 (СН₃); 15.1 (СН₃); 25.5 (СНСН₂); 40.7 (4-СН₂); 41.8 (CH); 62.3 (ОСН₂СН₃); 101.0 (С-5); 128.2 (2С), 130.5 (2С), 132.0, 133.6 (С Ph); 146.9 (C-3); 161.9, 170.4 (COPh, CO₂Et). Found, %: С 64.08; H 6.90; N 8.88. С₁₇H₂₂N₂O₄. Calculated, %: С 64.13; H 6.97; N 8.80.

Ethyl 2-[( E )-2-Benzoylhydrazino]-5,5-dimethyl-4-oxohexanoate (3f). Yield 0.234 g (49%); mp 154-155°С. IR spectrum, ν, cm^-1 (form В _Е ²): 1744 (СО₂Et), 1706 (СОBu-t). ¹Н NMR spectrum, δ, ppm (J, Hz): form А ² (10%): 1.11 (9Н, s, С(СН₃)₃); 1.32 (3Н, t, J = 7.3, ОСН₂СН ₃); 3.14 (1Н, d, J _АВ = 18.9) and 3.44 (1Н, d, J _АВ = 18.9, 3-СН₂); 4.27 (2Н, q, J = 7.3, ОСН ₂СН₃); 6.13 (1Н, s, ОН); 7.44-7.85 (5Н, m, Н Ph); form В _Z ² (85%): 1.23 (9Н, s, С(СН₃)₃); 1.32 (3Н, t, J = 7.3, ОСН₂СН ₃); 3.94 (2Н, br. s, 3-СН₂); 4.30 (2Н, q, J = 7.3, ОСН ₂СН₃); 7.51-7.95 (5Н, m, Н Ph); 13.51 (1Н, br. s, NH); form В _Е ² (5%): 1.25 (9Н, s, С(СН₃)₃); 1.32 (3Н, t, J = 7.3, ОСН₂СН ₃); 4.04 (2Н, br. s, 3-СН₂), 4.35 (2Н, q, J = 7.3, ОСН ₂СН₃); 7.54-8.05 (5Н, m, Н Ph); NH proton signal is not localized. ¹³С NMR spectrum (crystalline state), δ, ppm: form В _E ²: 14.7 (OСН₂ СН₃); 25.6 (С(СН₃)₃); 37.4 (С(СН₃)₃); 44.6 (3-СН₂); 61.4 (OСН₂СН₃); 128.9 (2С), 129.8 (2С), 132.7, 133.3 (С Ph); 144.1 (C=N); 162.2, 164.1 (COPh, CO₂Et); 211.5 (COBu-t). ¹³С NMR spectrum (DMSO-d₆), δ, ppm: form В _E ²: 15.7 (ОСН₂ CH₃); 26.8 (С(СН₃)₃); 42.9 (3-СН₂); 44.7 (С(СН₃)₃); 66.2 (OСН₂СН₃); 128.1 (2С), 129.3 (2С), 132.7, 133.0 (С Ph); 135.5 (C=N); 162.0, 163.1 (COPh, CO₂Et); 212.6 (COBu-t). Found, %: С 64.21; H 6.89; N 8.71. С₁₇H₂₂N₂O₄. Calculated, %: С 64.13; H 6.97; N 8.80.

Ethyl 5-Methyl-4-oxo-2-[( Z )-2-(2-pyridylcarbonyl)hydrazono]hexanoate (3g). Yield 0.384 g (84%); mp 127-128°С. IR spectrum, ν, cm^-1 (form В _Z ²): 1707, 1696 (СО₂Et, СOPr-i). ¹Н NMR spectrum, δ, ppm (J, Hz): form А ² (9%): 3.06 (1Н, d, J _АВ = 18.9) and 3.26 (1Н, d, J _АВ = 18.9, 3-СН₂); other signals in common with the major tautomer or not localized; form В _Z ² (87%): 1.04 (6Н, d, J = 6.9, (СН(СН ₃)₂); 1.22 (3Н, t, J = 7.3, СН₂СН ₃); 2.51-2.65 (1Н, m, СН(СН₃)₂); 3.77 (2Н, s, 3-СН₂); 4.22 (2Н, q, J = 7.3, ОСН ₂СН₃); 7.38 (1H, ddd, J = 7.7, J = 4.7, J = 1.4, Н Py); 7.77 (1H, td, J = 7.8, J = 1.6, Н Py); 8.18 (1H, br. d, J = 7.6, H Py); 8.55-8.59 (1H, m, H Ру); 14.11 (1Н, br. s, NH); form В _Е ² (4%): 4.01 (2Н, s, 3-СН₂); 11.86 (1Н, br. s, NH); other signals in common with major tautomer or not localized. ¹³C NMR spectrum, δ, ppm (form В _Z ²): 14.3 (ОСН₂ СН₃); 18.6 (СН(СН₃)₂); 41.2 (СН(СН₃)₂); 46.1 (СН₂); 62.4 (ОСН₂СН₃); 123.9, 127.4, 137.8, 149.1, 149.3 (С Pу); 137.8 (C=N); 161.8, 162.1 (COPу, CO₂Et); 210.8 (COPr-i). Found, %: С 59.02; H 6.20; N 13.71. С₁₅H₁₉N₃O₄. Calculated, %: С 59.01; H 6.27; N 13.76.

Ethyl 5-Methyl-4-oxo-2-[( Z )-2-(2-pyridylcarbonyl)hydrazono]heptanoate (3h). Yield 0.429 g (90%); mp 103-104°С. IR spectrum, ν, cm^-1 (form В _Z ²): 1706, 1696 (СО₂Et, СOBu-s). ¹Н NMR spectrum, δ, ppm (J, Hz): form В _Z ² (96%): 0.93 (3H, t, J = 7.3, ОСН₂СН ₃); 1.15 (3H, d, J = 7.3, СН(Et)СН ₃); 1.35 (3H, t, J = 7.3, ОСН₂СН ₃); 1.39-1.50 (3Н, m) and 1.68-1.80 (3Н, m, CH(Mе)СН ₂Mе); 2.50-2.61 (1Н, m, СН(Mе)Et); 3.88 (1Н, d, J _АВ = 18.2) and 3.90 (1Н, d, J _АВ = 18.2, 3-СН₂); 4.35 (2Н, q, J = 7.3, ОСН ₂СН₃); 7.51 (1H, br. dd, J = 6.9, J = 5.1, H Py); 7.90 (1H, td, J = 7.1, J = 1.4, H Py); 8.31 (1H, d, J = 7.2, H Py); 8.70 (1H, br. d, J = 5.1, H Ру); 14.24 (1Н, br. s, NH); form В _Е ² (4%): 3.98 (1Н, d, J _АВ = 16.0) and 4.01 (1Н, d, J _АВ = 16.0, 3-СН₂); 11.83 (1Н, br. s, NH); other signals in common with the major tautomer or not localized. ¹³C NMR spectrum, δ, ppm (form В _Z ²): 12.0 (СН₃); 14.3 (СН₃); 16.3 (СН₃); 24.2 (CH(Mе)СН₂); 46.9 (3-СН₂); 48.1 (CH(Mе)Et); 62.5 (OСН₂СН₃); 123.8, 127.4, 137.8, 149.1, 149.3 (С Pу); 137.9 (C=N); 161.8, 162.1 (COPу, CO₂Et); 210.8 (COBu-s). Found, %: С 60.28; H 6.67; N 13.08. С₁₆H₂₁N₃O₄. Calculated, %: С 60.18; H 6.63; N 13.16.

Ethyl 5,5-Dimethyl-4-oxo-2-[( Z )-2-(2-pyridylcarbonyl)hydrazono]hexanoate (3i). Yield 0.374 g (78%); mp 134-135°С. IR spectrum (form В _Z ²), ν, cm^-1: 1714 (СО₂Et), 1696 (СОBu-t). ¹Н NMR spectrum, δ, ppm (J, Hz): form В _Z ² (95%): 1.22 (9Н, s, С(СН₃)₃); 1.34 (3Н, t, J = 7.3, ОСН₂СН ₃); 3.97 (2Н, br. s, 3-СН₂); 4.34 (2Н, q, J = 7.3, ОСН ₂СН₃); 7.50 (1H, br. dd, J = 7.9, J = 4.4, H Py); 7.91 (1H, br. t, J = 8.0, H Py); 8.31 (1H, d, J = 8.0, H Py); 8.70 (1H, br. d, J = 4.4, H Ру); 14.26 (1Н, br. s, NH); form В _Е ² (5%): 1.26 (9Н, s, С(СН₃)₃); 1.40 (3Н, t, J = 7.3, ОСН₂СН ₃); 4.07 (2Н, br. s, 3-СН₂), 4.40 (2Н, q, J = 7.3, ОСН ₂СН₃); ); 7.50 (1H, br. dd, J = 7.9, J = 4.4, H Py); 7.91 (1H, br. t, J = 8.0, H Py); 8.31 (1H, d, J = 8.0, H Py); 8.61 (1H, br. d, J = 4.4, H Ру); 11.81 (1H, br. s, NH). ¹³С NMR spectrum (form В _Z ²), δ, ppm: 14.3 (ОСН₂ СН₃); 26.9 (С(СН₃)₃); 43.3 (3-СН₂); 44.6 (С(СН₃)₃); 62.4 (OСН₂СН₃); 123.9, 127.4, 137.8, 149.1, 149.4 (С Py); 138.4 (C=N); 161.8, 162.1 (COPy, CO₂Et); 212.5 (COBu-t). Found, %: С 60.20; H 6.64; N 12.91. С₁₆H₂₁N₃O₄. Calculated, %: С 60.18; H 6.63; N 13.16.

Ethyl 1-Formyl-5-hydroxy-3-(1,1-dimethylethyl)-4,5-dihydro-1 H -pyrazole-5-carboxylate (3j) and Ethyl 1-Formyl-5-hydroxy-5-(1,1-dimethylethyl)-4,5-dihydro-1 H -pyrazole-3-carboxylate (3k). The reaction of ester 1f with formylhydrazine (2a) gave a 2:3 mixture of regioisomers A ¹ (ester 3j) and A ² (ester 3k) as indicated by ¹H NMR spectroscopy. The mixture could not be separated into pure compounds by recrystallization or thin-layer chromatography. The total yield of these regioisomers was 0.211 g (58%). Mp 74-75°С. Compound 3j. ¹Н NMR spectrum, δ, ppm (J, Hz): 1.24 (9Н, s, С(СН₃)₃); 1.31 (3Н, t, J = 6.6, ОСН₂СН ₃); 3.02 (1Н, d, J _АВ = 18.5) and 3.28 (1Н, d, J _АВ = 18.5, 4-СН₂); 4.32 (2Н, q, J = 6.6, ОСН ₂СН₃); 4.55 (1Н, br. s, ОН), 8.67 (1Н, s, СНО). ¹³C NMR spectrum, δ, ppm: 14.4 (ОСН₂ СН₃); 25.3 (С(СН₃)₃); 30.1 (С(СН₃)₃); 44.6 (С-4); 62.7 (OСН₂СН₃); 87.3 (С-5); 154.8 (С-3); 160.5 (СНО); 164.6 (CO₂Et). Compound 3k. ¹Н NMR spectrum, δ, ppm (J, Hz): 1.04 (9Н, s, С(СН₃)₃); 1.40 (3Н, t, J = 7.3, ОСН₂СН ₃); 3.14 (1Н, d, J _АВ = 19.8) and 3.42 (1Н, d, J _АВ = 19.8, 4-СН₂); 4.38 (2Н, q, J = 7.3, ОСН ₂СН₃); 4.55 (1Н, br. s, ОН), 8.91 (1Н, s, СНО). ¹³C NMR spectrum, δ, ppm: 14.5 (ОСН₂ СН₃); 28.3 (С(СН₃)₃); 34.5 (С(СН₃)₃); 45.7 (С-4); 63.8 (OСН₂СН₃); 102.6 (С-5); 148.8 (С-3); 161.4 (СНО); 170.0 (CO₂Et). Found, %: С 54.42; H 7.41; N 11.43. С₁₁H₁₈N₂O₄. Calculated, %: С 54.53; H 7.49; N 11.56.