(E)-4,2′,4′-Trimethoxychalcone (Z)-N-Tosyl Hydrazone

Abstract

The synthesis and structural characterization of (E)-4,2′,4′-trimethoxychalcone (Z)-N-tosyl hydrazone, a conjugated tosylhydrazone derivative, is described. The compound was obtained via the condensation of (E)-1-(2,4-dimethoxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one with p-toluenesulfonylhydrazide in methanol under mild conditions, yielding a yellow solid in a 66% yield. The structure of the product was confirmed through ¹H NMR, ¹³C NMR, IR spectroscopy, mass spectrometry, and single-crystal X-ray diffraction analysis, which revealed a non-planar molecular conformation and a Z configuration for the C=N double bond. This work is part of our ongoing research on carbene-mediated transformations.

1. Introduction

N-Tosylhydrazones have long been recognized as valuable intermediates in organic synthesis, with a history of more than seventy years. These compounds, formed by the condensation of tosylhydrazine with aldehydes or ketones, have proven to be highly stable, crystalline, and non-toxic, making them attractive for various synthetic transformations [1]. Over the years, their role in organic chemistry has expanded significantly, providing access to diverse transformations such as olefination, cross-coupling, cycloaddition, and carbene chemistry [2].

Their application in organic synthesis began in 1952 when Bamford and Stevens introduced their use in the preparation of substituted alkenes under basic conditions [3]. One decade later, Caglioti reported their use in the reduction of aldehydes and ketones to methyl or methylene groups [4], and Closs et al. reported their use in the synthesis of cyclopropenes through thermal decomposition [5]. In 1967, two landmark reactions—the Shapiro reaction [6] and the Eschenmoser-Tanabe reaction [7,8]—were introduced, further solidifying the importance of these compounds. The former allowed for the transformation of aldehydes and ketones into alkenes, while the latter contributed to the synthesis of Muscone, a key fragrance ingredient. Subsequently, Kabalka et at. described in 1976 how unsaturated N-tosylhydrazones could facilitate double-bond migration alongside reduction [9,10,11]. Since these early discoveries, the scope of N-tosylhydrazones has expanded significantly, playing a crucial role in both transition metal-catalyzed and metal-free coupling reactions, enabling the formation of the key carbon–carbon (C–C) and carbon–heteroatom (C–X) [12] bonds essential for the synthesis of bioactive heterocyclic compounds [13].

Beyond these early reactions, N-tosylhydrazones have demonstrated their utility in [4 + 2] annulation reactions [14], and in 1,3-dipolar cycloadditions, both as inter [15,16] or intramolecular processes [17]. They have also been widely employed as synthetic intermediates due to their ability to serve as precursors to diazo compounds and carbenes or carbenoids [1,18,19,20], which facilitate multiple-bond formations in a single step due to the unique properties of carbenes [21] or the enantioselective synthesis of natural products through insertion of the metalocarbenoid into unactivated C-H bonds [22]. They have also been successfully used in the electrocatalytic synthesis of substituted pyrazoles [23], thiadiazoles [24], and other heterocyclic systems [25].

In recent years, N-tosylhydrazones have gained prominence as coupling partners in transition metal-catalyzed cross-coupling reactions [1,26]. These reactions have been particularly useful for forming polysubstituted olefins and represent an efficient alternative to unstable diazo compounds [27]. The ability of N-tosylhydrazones to generate carbenes in situ has broadened the scope of transition metal-mediated reactions, including catalytic migratory insertions and β-hydride eliminations, which are currently under active investigation for new synthetic methodologies.

Additionally, transition metal-free transformations of N-tosylhydrazones have gained attention due to their green chemistry attributes [28,29]. These reactions are not only highly versatile but also practical, as they do not require anhydrous solvents or inert atmospheres. In this context, N-tosylhydrazones have been employed as diazo precursors, free-carbene precursors, C1 equivalents, and surrogates for carbonyl compounds. Their nitrogen-rich structure has been leveraged in nitrogen heterocycle synthesis, offering novel synthetic strategies that allow Pd(0)-Catalyzed Carbene Insertion into Si–Si and Sn–Sn bonds [30], the preparation of sulfur-substituted quaternary carbon center atoms [31], or the light-promoted homologation of boronic acids [32].

Hydrazones, including N-tosylhydrazones, have shown significant promise in organocatalysis, where they participate in activation reactions under mild conditions [33]. The development of new reaction profiles has led to strategies such as nucleophilic formylation, acylation, cyanation, and cascade reactions involving hydrazones as both nucleophiles and electrophiles [34]. Furthermore, cycloaddition and cyclization reactions employing hydrazones have paved the way for the synthesis of multifunctional compounds and nitrogen-containing heterocycles [18,35,36,37,38]. The interplay between hydrazone-based reagents and organocatalysts—such as hydrogen-bonding donors, Brønsted acids, and N-heterocyclic carbenes (NHCs)—has led to innovative reaction mechanisms and stereochemical models. These advances have not only improved our understanding of hydrazone chemistry but have also opened new avenues for asymmetric synthesis, further demonstrating the versatility of N-tosylhydrazones [18].

2. Results and Discussion

As a part of our interest in the total synthesis of natural products [22,39,40,41] through the Rh- or Ir-catalyzed C-H insertion of metalocarbenoids, we required the conjugated tosylhidrazone 2. The synthesis of (E)-4,2′,4′-trimethoxychalcone (Z)-N-tosyl hydrazone (2) was achieved through the reaction between (E)-1-(2,4-dimethoxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (1) and TsNHNH₂ in methanol at 65 °C for 15 min. Subsequently, the mixture was stirred for 15 h at room temperature. After the formation of a yellow solid, it was vacuum-filtered and purified by column chromatography yielding the target molecule (2) with a 66% yield (Scheme 1). A small amount of 2 was further recrystallized in ethanol.

The structural identity of compound (2) was confirmed using spectroscopic techniques, including ¹H NMR, ¹³C NMR, IR spectroscopy, and mass spectrometry, ensuring the successful formation of the desired hydrazone derivative.

The structure of (E)-4,2′,4′-trimethoxychalcone (Z)-N-tosyl hydrazone (2) was unambiguously confirmed by single-crystal X-ray analysis (Figure 1). The single crystals of 2 were grown by recrystallization of the title compound in ethanol.

Compound (2) crystallizes in the triclinic space group P-1. Opposite to the parent chalcone (1), in which two phenyl rings are co-planar [42], the molecule exhibits a non-planar conformation between the two aromatic rings and the propene unit, with a dihedral angle C2′-C1′-C=N-Cα of 92.202 degrees. In fact, it can be appreciated that both nitrogen atoms, the propene unit and one of the aromatic rings, are in the same plane. XR also reveals a Z configuration for the C=N double bond.

These structural parameters confirm the formation of the expected compound, with a well-defined crystal structure. The refinement statistics and residual electron density values indicate a high-quality crystal data set, supporting the molecular conformation and packing arrangement.

The hydrogen bond distance between the hydrogen on N2 and oxygen O2′ is 3.383Å, which is an intramolecular weak or electrostatic interaction. No intermolecular hydrogen bonds can be appreciated (see Supporting Information, Figure S9). Figures S10 and S11 show a molecular packing based on Van der Waals forces. In a single molecule, one of the chalcone rings is orthogonal to the rest of the structure. The molecular packing arranges all the 1,3-dioxygenated rings to be parallel (the horizontal planes in Figure S10). In addition, monooxygenated rings are also located in parallel planes (horizontal planes in Figure S11) and the methylsubstituted rings of the tosyl group are also in a different plane (the vertical planes in Figure S11). In 2014, Blatova et al. published a nice work on the topological analysis of molecular packings and intermolecular bonding patterns in sulfonamides [43]. The authors tested the crystal structures of 1463 sulfonamide derivatives taken from the Cambridge Structural Database. A comparison of the structure packing of 2 with their results confirms that the peculiar shape of 2 falls into the category named ‘butterfly’ packing by the authors, a form that is topologically less dense than other close packings.

In conclusion, (E)-4,2′,4′-trimethoxychalcone (Z)-N-tosyl hydrazone (2) was synthesized and its structure was confirmed by a combination of ¹H NMR, ¹³C NMR, IR spectroscopy, and mass spectrometry, and by X-ray diffraction data.

3. Materials and Methods

The reactions were monitored by thin-layer chromatography performed using 0.2 mm thick Scharlau Si UV254 TLC silica gel plates with an aluminum support. Spot detection was achieved by two methods—exposing the plate to 254 nm ultraviolet light using a BIOTRÓN A/70 lamp, or by immersing the plate in a phosphomolybdic acid solution (7% in ethanol)—followed by development by heating. Throughout the process, the reactions were monitored by thin-layer chromatography until the limiting reagent disappeared. The infrared spectra were recorded on a Bruker Alpha spectrometer using a single-reflection ATR platinum module. The ¹H-NMR and ¹³C-NMR spectra were acquired on a Bruker Avance HD 300, operating at 300 MHz for ¹H-NMR and 75 MHz for ¹³C-NMR. The measurements were performed using a 5 mm GA(Z)-QNP probe (1H and 13C) (Bruker 300) equipped with magnetic field gradients. The spectra were recorded in CDCl₃ (Eurisotop) with a deuteration degree of 99.9%. The chemical shifts (δ) are reported in parts per million (ppm), and the coupling constants are expressed in hertz (Hz). The signal multiplicities are designated s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and dd (double doublet). To determine the carbon substitution degree, the DEPT 135 pulse sequence was employed. Additionally, in some cases, signal assignments were assisted by two-dimensional experiments such as HSQC (Heteronuclear Single Quantum Correlation) and HMBC (Heteronuclear Multiple Bond Correlation). High-resolution and accurate mass measurements were carried out using a Bruker MaXis Impact (positive electrospray ionization). The melting point were determined on a Stuart SMP 30 apparatus and were left uncorrected. The X-ray diffraction investigation of compound (2) was conducted using an automatic diffractometer Bruker APEX-II CCD (MoKα radiation, ω- and φ-scanning). The empirical absorption correction and systematic error correction were performed using Olex2 program. The structure was deciphered by direct methods. All calculations were performed using the SHELX XS software package.

(E)-4,2′,4′-Trimethoxychalcone (Z)-N-Tosyl Hidrazone (2)

To obtain (E)-4,2′,4′-trimethoxychalcone (Z)-N-tosyl hydrazone (2), a standard hydrazone formation reaction was carried out starting from (E)-1-(2,4-dimethoxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (1), which was prepared following a procedure from the literature [44]. The enone (1) was dissolved in methanol (8.5 mL), and to this solution, p-toluenesulfonylhydrazide (TsNHNH₂) (2.16 g, 12 mmol, 1.5 eq) was added. The reaction mixture was heated at 65 °C for 15 min to facilitate the nucleophilic attack of the hydrazine on the carbonyl group.

Subsequently, the reaction was stirred at room temperature for 15 h to ensure complete conversion of the starting material. The solvent was then evaporated under reduced pressure to remove methanol, leaving behind the crude hydrazone product.

To remove the excess TsNHNH₂ and any by-products, purification was performed using column chromatography with a hexane/ethyl acetate (8:2) mixture as the eluent. This purification step allowed the isolation of (E)-4,2′,4′-trimethoxychalcone (Z)-N-tosyl hydrazone (2) as a yellow solid (2.11 g, 5.39 mmol, 66%). A small amount was recrystallized from ethanol: mp 142.2 °C; IR νmax (cm⁻¹): 3213, 2930, 2834, 1602, 1500, 1251, 1210, 1161, 1101, 1028, 917 (Figure S6).

¹H NMR (300 MHz, CDCl₃) δ 7.84 (d, J = 8.3 Hz, 2H, H2″-H6″), 7.51 (s, 1H, NH), 7.37–7.27 (m, 4H, H3″-H5″, H2-H6, and residual CHCl₃), 7.00 (d, J = 16.2 Hz, 1H, Hβ), 6.92 (d, J = 8.3 Hz, 1H, H6′), 6.87–6.79 (m, 2H, H3-H5), 6.62 (dd, J = 8.4, 2.3 Hz, 1H, H5′), 6.56 (d, J = 2.2 Hz, 1H, H3′), 6.26 (d, J = 16.2 Hz, 1H, Hα), 3.90 (s, 3H, MeO-C2′), 3.81 (s, 3H, MeO-C4′), 3.61 (s, 3H, MeO-C4), 2.45 (s, 3H, Me-Ar) (Figure S1).

¹³C NMR (75 MHz, CDCl₃) δ 162.48 (C, C4′), 160.04 (C, C4), 157.14 (C, C2′), 154.16 (C, C=N), 143.80 (C, C4″), 136.31 (C, C1″), 135.97 (CH, Cα), 130.89 (CH, C6′), 129.52 (CH, C3″-C5″), 128.92 (C, C1), 128.42 (CH, C2-C6), 127.79 (CH, C2″-C6″), 126.52 (CH, Cβ), 114.12 (CH, C3-C5), 111.03 (C, C1′), 106.01 (CH, C5′), 99.22 (CH, C3′), 55.58 (CH₃, MeO-C4′,MeO-C2′), 55.30 (CH₃, MeO-C4), 21.59 (CH₃, MeO-Ar) (Figure S2).

HRMS ESI: exact mass found 467.16321 (exact mass calculated for C₂₅H₂₆N₂O₅S 467.16352) (Figure S7).

Crystal Data for C₂₅H₂₆N₂O₅S (M = 466.54 g/mol): triclinic, space group P-1 (no. 2), a = 7.8005(3) Å, b = 11.8282(4) Å, c = 13.3285(5) Å, α = 79.7430(10)°, β = 78.8290(10)°, γ = 80.7900(10)°, V = 1177.10(7) ų, Z = 2, T = 100.00 K, μ(MoKα) = 0.176 mm⁻¹, Dcalc = 1.316 g/cm³. In total, 45,700 reflections measured (4.36° ≤ 2Θ ≤ 50.046°); 4144 unique (R_int = 0.0607, R_sigma = 0.0265), which were used in all calculations. The final R₁ was 0.0606 (I > 2σ(I)) and wR₂ was 0.1448 (all data). CCDC 2439942 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge at https://doi.org/10.5517/ccdc.csd.cc2mwyt9 from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44-1223-336033; E-mail: deposit@ccdc.cam.ac.uk.