4,5-Dimethylfuro[3,4-d]pyridazin-1(2H)-one

Abstract

The synthesis of previously unknown 4,5-dimethylfuro[3,4-d]pyridazin-1(2H)-one has been proposed and structurally characterized via a single-crystal X-ray diffraction analysis, ¹H, ¹³C–{¹H}, ¹H–¹³C HMQC, and ¹H–¹³C HMBC NMR spectroscopy, and IR spectroscopy.

1. Introduction

The furan ring is a component of many medications with a wide spectrum of action [1,2,3,4]. The development of methods for obtaining new furan derivatives is one of the most dynamic areas of modern organic and medicinal chemistry [5,6]. Of particular interest in this case are condensed biheterocyclic systems containing a furan and another heterocycle [7,8,9,10,11]. Thus, based on tetrasubstituted furans containing ester and acetyl groups in positions 3 and 4, the corresponding furo[3,4-d]piridazines were obtained in a reaction with hydrazine (1,2-binucleophile) [11,12]. In this article, we will focus on the synthesis of a new fused biheterocycle—4,5-dimethylfuro[3,4-d]pyridazin-1(2H)-one—and the characterization of its fine structure using NMR (nuclear magnetic resonance), FTIR (Fourier-transform infrared spectroscopy), and an X-ray diffraction analysis. This study will contribute to our understanding of the properties of furo-containing biheterocycles and may have important implications for the development of new biologically active substances.

2. Results and Discussion

We have proposed a method for the synthesis of an original biheterocycle, 4,5-dimethylfuro[3,4-d]pyridazin-1(2H)-one 2, based on the reaction of acetyl-containing furan-3-carboxylates 1a, b [13] with hydrazine hydrate. It turned out that boiling furancarboxylates 1a, b with an excess of hydrazine hydrate in acetic acid (method A) leads to the preparation of the target 4,5-dimethylfuro[3,4-d]pyridazin-1(2H)-one 2 with yields up to 32%. Changing the synthesis conditions, namely, the reaction of furan-3-carboxylate 1b with an excess of hydrazine hydrate in ethanol solution in the presence of catalytic amounts of trifluoroacetic acid at room temperature (method B), led to the formation of biheterocycle 2 with a yield of 44% (Scheme 1).

The synthesized 4,5-dimethylfuro[3,4-d]pyridazin-1(2H)-one 2 can exist in the form of lactim or lactam tautomeric (Figure 1). Studying the structure of biheterocycle 2 using IR and ¹H, ¹³C–{¹H} NMR spectroscopy, as well as an X-ray structural analysis, unambiguously confirmed that its molecule exists in the lactam form in solution and in the solid phase.

Indeed, the IR spectrum of biheterocycle 2 contains an intense band at 1668 cm⁻¹ (C=O), which belongs to the valence vibrations of the amide carbonyl group, as well as a broadened band of the amino group of the amide fragment at 3167 cm⁻¹ (NH).

The ¹³C–{¹H} NMR spectrum of biheterocycle 2 contains a carbon atom signal at 157.92 ppm (C=O), characteristic of the carbonyl group of the amide fragment. In addition, the cross peak 11.44 (NH)/140.51 (C⁴) in the ¹H–¹³C HMBC experiment spectrum also confirms the existence of the synthesized bicycle 2 in solution in the lactam form.

The assignment of signals of protons and carbon atoms in the ¹H and ¹³C NMR spectra was carried out using heteronuclear (¹H–¹³C HMQC, ¹H–¹³C HMBC) experiments. The key cross peaks used for interpretation in the ¹H–¹³C HMBC spectra are as follows: 2.34 (C⁴CH₃)/115.26 (C^4a)/140.51 (C⁴); 2.61 (C⁵CH₃)/115.26 (C^4a)/150.92 (C⁵); 8.43 (C⁷H)/115.26 (C^4a)/117.71 (C^7a)/150.92 (C⁵); and 11.44 (NH)/117.71 (C^7a)/140.51 (C⁴) (Figure 2).

The lactam molecular and crystal structures of 4,5-dimethylfuro[3,4-d]pyridazin-1(2H)-one (2) have been determined via an X-ray analysis. Light-brown crystals were grown from a saturated ethanol solution by slow solvent evaporation.

The title compound (2) crystallizes in the monoclinic space group P2₁/c. Figure 3 represents the molecular structures of 4,5-dimethylfuro[3,4-d]pyridazin-1(2H)-one.

The molecule has a planar conformation, and the deviation of atoms from the least-square plane is lower than 0.039(3) Å. The pyridazinone fragment exists in the lactam form.

The distribution of bond lengths in a molecule indicates the presence of a conjugation in it, which ensures the planar conformation of the entire molecule (see Supplementary Materials Table S2).

The crystal structure of compound 2 is primarily determined by intermolecular hydrogen bonds (N2-H2….O12′ (−x,−1/2 + y,1/2 − z)) and stacking interactions between planar conjugated molecules. The hydrogen bond parameters are as follows: N2-H2 0.87(3), N2….O12′ 2.787(4), H2….O12′ 1.97(3) Å, and angle N2-H2….O12′ 156(3)°. Due to these H-bonds, ribbons are formed along the b axis of the crystal (Figure 4).

Figure 5 shows a fragment of the packaging of crystal 2, which demonstrates interplanar interactions, due to which the formation of double layers is observed. The interplanar distances are 3.19(1) Å, and the angle between the planes of molecules is 0.16(12)°.

3. Materials and Methods

Alkyl 4-acetyl-5-methylfuran-3-carboxylates (1a, b) [13] were prepared according to published methods. All reagents were of commercial grade and used without purification.

Method A: To a solution of 0.2 g (1.09 mmol) of methyl 4-acetyl-5-methylfuran-3-carboxylate 1a [13] in 5 mL of glacial acetic acid, 0.275 g (5.5 mmol) of hydrazine hydrate was added. The reaction mixture was refluxed for 1 h. Then the solvent was evaporated and the residue was crystallized from ethanol. Yield 0.017 g (10%), light-brown crystals, mp. 273–275 °C (EtOH).

IR: 1345, 1546, 1617, 1668 (C=O), 3167 (NH).

¹H NMR: 2.34 (3H, s, C⁴CH₃), 2.61 (3H, s, C⁵CH₃), 8.43 (1H, s, C⁷H), 11.44 (1H, s, NH). (Atom labeling shown in Figure 2).

¹³C{¹H} NMR: 13.87 [C⁵CH₃], 19.92 [C⁴CH₃], 115.26 (C^4a), 117.71 (C^7a), 140.51 (C⁴), 150.92 (C⁵), 157.92 (C=O).

Found, %: C 58.53; H 4.91, N 17.06. C₈H₈N₂O₂. Calculated, %: C 58.23; H 4.84, N 16.94.

To a solution of 0.2 g (1.02 mmol) of ethyl 4-acetyl-5-methylfuran-3-carboxylate 1b [13] in 5 mL of glacial acetic acid, 0.255 g (5.1 mmol) of hydrazine hydrate was added. The reaction mixture was refluxed for 1 h. Then the solvent was evaporated and the residue was crystallized from ethanol. Yield 0.054 g (32%), light-brown crystals, mp. 273–275 °C (EtOH).

Method B: To a solution of 0.15 g (0.077 mmol) of ethyl 4-acetyl-5-methylfuran-3-carboxylate 1b [13] in 5 mL of ethanol, 0.077 g (1.53 mmol) of hydrazine hydrate and catalytic amount of trifluoroacetic acid were added. The reaction mixture was kept for 2 h at room temperature. Then the solvent was evaporated and the residue was crystallized from ethanol. Yield 0.055 g (44%), light-brown crystals, mp. 273–275 °C (EtOH).

A mixing test with a sample obtained by methods A and B did not result in a depression in the melting point.

Elemental analysis was performed with a Euro Vector EA 3000 analyzer (CHN Dual). Melting points were determined on a PTP-M melting point apparatus.

IR spectra (Figure S1) were registered on Shimadzu IR Prestige-21 spectrometers with samples in KBr pellets. ¹H, ¹³C–{¹H} NMR spectra (Figures S2 and S3), ¹H–¹³C HMQC (Figure S4), and ¹H–¹³C HMBC (Figure S5) experiments were performed using a Jeol ECX400A spectrometer (400 MHz for ¹H nuclei and 100 MHz for ¹³C nuclei) in DMSO-d₆. The residual signals of the solvent (DMSO-d₆: 2.50 ppm for ¹H nuclei and 39.6 ppm for ¹³C nuclei) were used as internal standard.

X-ray diffraction analysis was performed at 108 K on a Bruker D8 QUEST automatic three-circle diffractometer (graphite monochromator, λMoK_α = 0.71073 Å, ω- and φ-scan with a step of 0.5°) at the Distributed Spectral-Analytical Center of Shared Facilities for Study of Structure, Composition and Properties of Substances and Materials of FRC Kazan Scientific Center of RAS.

An X-ray diffraction analysis of 2 was performed on a Bruker D8 QUEST automatic three-circle diffractometer with a PHOTON III two-dimensional detector and an I_S DIAMOND microfocus X-ray tube (Mo K_α radiation, λ = 0.71073 Å) at cooling conditions. Data collection and the processing of diffraction data were performed using APEX3 software package. Structure 2 was solved by the direct method using the SHELXT program [14]. It was refined by the full-matrix least-squares method over F² using the SHELXL program [15]. Crystal 2 was found to be two-component twin and twin rot matrix (−0.694 0 −0.424)/(0 −1 0)/(−1.223 0 0.694), with the estimated BASF line = 0.46. Final model was refined using a combined diffraction data set (HKLF 5), with parameter BASF refined to 0.33285. All calculations were performed in the WinGX software package [16]. The calculations of the geometry of molecules and intermolecular interactions in crystals were carried out using the PLATON program [17]. The drawings of molecule were performed using the MERCURY [18] programs. Non-hydrogen atoms were refined using the anisotropic approximation. The position of the hydrogen atom H(N2) was determined using difference Fourier map. The remaining hydrogen atoms were placed in geometrically calculated positions, and all hydrogen atoms were included in the refinement in the “riding” model.

Crystal 2 monoclinic at 108(2) K a = 7.024(4), b = 7.659(4), c = 13.714(7) Å, β = 98.312(17)^o, V = 730.1(6) ų, Z = 4 ρ _calc 1.493 g/cm³, and μ 0.110 mm⁻¹. Reflections collected: 19508, independent reflections: 1464, and observed reflections: I ≥ 2σ(I) 831. Final R-factors were as follows: R factors [I >= 2σ (I)] R₁ = 0.0802, wR₂ = 0.1895, R factors (all reflections) R₁ = 0.1442, wR₂ = 0.2182, and GOOF on F² 1.003

Crystallographic data, experimental parameters, and refinement of the condensed biheterocyclic structure were deposited at the Cambridge Crystallographic Data Center; registration numbers and the most important characteristics are provided in Tables S1–S3 (see Supplementary Materials).

4. Conclusions

A method has been proposed for the synthesis under mild conditions of a previously unknown representative of biheterocyclic compounds—4,5-dimethylfuro[3,4-d]pyridazin-1(2H)-one—with a free α-position of the furan ring based on the reaction of acetyl-containing furan-3-carboxylates with excess hydrazine hydrate. Its fine structure is characterized via NMR and IR spectroscopy, as well as an X-ray diffraction analysis. The existence of its molecule in lactam form in solution and in the solid phase has been established.