N-Acetylation of methyl hydrazones with acetic acid in presence of PdCl2

Abstract Organic compounds such as acetic anhydride or acetyl chloride are generally used to form amide bonds by the acetylation of a nitrogen atom. However, it is not possible to use this traditional method for hydrazine derivatives. In this article, a new synthesis method has been developed for the formation of a new amide bond via the acetylation of methyl hydrazones with acetic acid. In the development of this unprecedented synthesis method, more than one catalyst was used as the Lewis acid. PdCl2 was identified as the most suitable catalyst for this reaction. In addition, more than one solvent experiment was carried out for the optimization of this method and experiments were carried out to provide the most optimal conditions for catalyst loading. In addition, the applicability of this method to various hydrazone derivatives was tested. The structures of nine new amide bond-containing acetylated methyl hydrazones prepared by this synthesis method were elucidated using 1D-NMR, 2D-NMR, LCMS and X-Ray. Graphical Abstract


Introduction
The acylation of amino groups is an important reaction in the field of organic chemistry. These reactions create amide bonds used in synthesizing bioactive compounds like amino acids, beta-lactams, and alkaloids in medicinal chemistry [1,2] and in the protection of amino groups in multistep reactions. [3] Many methods and strategies for N-acylating amines have been developed over the years owing to the significance of the amide bond. Although many studies on oxidative amidation reactions of alcohols and aldehydes have been carried out in recent years, [4] the formation of amide bonds in the reaction of carboxylic acids with amine derivatives is currently being studied using new techniques. These are, amide bond formation from carboxylic acids with Cu(OTf), [5] N-formylation of amine derivative in the presence of indium [6] and the direct amidation of phenylacetic acid with benzylamine can be exemplified as a catalysis reaction with ZrCl 4 . [7] As can be seen, many new acylation methods on amines have been studied and continue to be studied. However, the literature has no new and effective synthesis method for the acetylation of N-methyl hydrazones. Hydrazones and acyl hydrazones are bioactive molecules. These compounds have anti-tumor, [8] analgesic, [9] anti-inflammatory, [10] anti-oxidant, [11] anti-depressant [12] and anti-convulsant [13] properties. Therefore, due to the biological properties of amide bonds and the important medicinal properties of acetyl hydrazones, this study attempted to form a new amide bond by acetylation of methyl hydrazones.
Many studies on the chemistry of heteroatoms, such as acetyl acetylation and cyclization, have been carried out and continue to be carried out in our group. [14][15][16] Acetylation is one of them. Acetylation of amines is usually carried out using acetic anhydride or acetyl chloride. However, when this traditional method was used to acetylate hydrazones, it was found to fail. [17] In the first step of the study to develop a new method of synthesis, we have synthesized methyl hydrazone derivatives (1). These methyl hydrazones were then reacted with acetic acid (2) in toluene in presence of PdCl 2 to form acetyl methyl hydrazones (3) containing new amide bonds.
Palladium is one of the most widely used catalysts for the formation of C-H, C-C, C-O, C-N, C-S bonds in organic synthesis. Palladium activates carbon-halogen bonds by the addition of an oxidant when it has zerovalent. [18] However, in this study, a new methodology for the acetylation of hydrazones was proposed using PdCl 2 as the Lewis acid, which is not available in the literature.
A search of the literature reveals only one method for the direct acetylation of methyl hydrazone. [19] Using this method, acetylation of benzaldehyde methylhydrazone is obtained with a 35% yield as a by-product. In this synthesis, benzaldehyde was dissolved in 20 ml of acetic acid and then reacted in the presence of bromine. If we compare this method with our proposed method. In this method, the acetylation product of methyl hydrazone is formed as a by-product with a yield of 35%. According to our proposed method, the acetylation product of methyl hydrazone is formed as a single product with an 81% yield.

Results and discussion
Initially, we completed the derivatization step by synthesizing different methyl hydrazone derivatives (1). [20] These compounds were prepared by dissolving aldehydes (1Eq.) in 15 ml of EtOH, adding then methylhydrazine (1Eq.) and refluxing for 30 min. The crude product was collected and after the necessary purification, the methyl hydrazone derivatives were prepared for the second stage reaction. For the acetylation of methyl hydrazones derivative (1a), various catalysts such as Yb(TFA) 3 , AuCl 3 , PdCl 2 and solvents such as THF, CH 2 Cl 2 , CH 3 CN, toluene have been tried out. (Table 1). Catalyst efficiency was analyzed from 20 mol % to 3 mol % catalyst loading.
The optimization of the acetylation reaction of methyl hydrazones (1) has shown that it is impossible to carry out the reaction without using a catalyst. It was observed that of the catalysts evaluated, PdCl 2 was the most suitable for this reaction. When PdCl 2 was used to catalyze the reaction, toluene was found to be the most suitable solvent. (Table 1) Furthermore, we observed that the catalyst loading for this reaction can be reduced from 20 mol % to 10 mol %. When this reaction was not carried out in the N 2 atmosphere, it was observed that the yield decreased. The reason for this is that O 2 reduces the activity of PdCl 2 . In the acetylation reaction of methyl hydrazones, optimum conditions were achieved when methyl hydrazone derivative (1a) was reacted with acetic acid (2) in toluene under PdCl 2 catalyzed and N 2 atmosphere.
Compound 3a's structure was clarified by 1D and 2D NMR. From the APT spectrum of this compound, we determined that the carbonyl carbon at 172.92 ppm, the N ¼ C-H carbon at 138.71 ppm, the aromatic carbons at 134.79, 129.61, 128.74, 126.94 ppm and the methyl carbons at 27.48, 21.58 ppm are resonated. The HSQC spectrum also showed which carbon belonged to which proton. In the HMBC spectrum of this compound, the carbonyl group was correlated with two methyl groups. The -N¼C-H group was correlated with the nitrogen-bonded methyl group. As a result of all 1D and 2D NMR analyses, the structure was proposed and its compatibility with the NMR results was verified.
Compound 3b was then subjected to X-ray analysis to be completely certain of its structure. X-ray analysis indicated that the proposed structure was consistent with the X-ray structure (Fig. 1). The exact structure of the (E) N-methyl-N'-(2-chlorophenylmethylene)acetohydrazide (3b) was confirmed by X-ray diffraction analysis (Fig. 1). Compound 3b crystallizes in the triclinic space group P-1with two molecules in the unit cell. The structure is almost planer, N1 ¼ C7 double bond is 1.271(3) Å while C-N single amide bonds are in the range of 1.366-1.378(3) Å. The crystal structure is in a layered structure and the distance between the layers is approximately 3.5 Å. C1-Cl bond distance is 1.740(5) Å. In the solid state, the compound 3b is stabilized via effective intermolecular C5-HÁÁÁCl halogen bonds [DÁÁÁA ¼ 3.762(3) Å] which leads to the formation of the polymeric structure.  Aromatic and heteroaromatic aldehydes were used to test the reproducibility of the amide bond formation reaction upon the acetylation of methyl hydrazone derivatives (3) ( Table 2). This derivatization achieved the acetylation of nine hydrazones and the formation of new amide bonds in good yields.
The applicability of this new method for acetylating methyl hydrazone derivatives to phenyl hydrazone derivative (4) was tested. For this purpose, the reaction of phenylhydrazone derivative (4) with acetic acid (2) under the same conditions has been shown to lead to the acetylation of the corresponding hydrazone (5) in 71% yield (Scheme 1). Synthesis of compound 5 by another method is available in the literature. [21] The proposed mechanism for the PdCl 2 -catalyzed acetylation reaction is described in Scheme 2. First of all, PdCl 2 coordinates with the acetic acid and methyl hydrazone then activate the acetic acid and methyl hydrazone. The methyl hydrazone then attacks the carbonyl carbon of acetic acid to form the corresponding intermediate. Finally, the acetylated hydrazone is synthesized by eliminating PdCl 2 and water from the intermediate. [22,23]

Conclusion
In summary, we have developed a new and potent method for the acetylation of methyl hydrazones and the formation of a new amide bond using acetic acid as the acetylating agent, which was not previously available in the literature. Optimization studies of this reaction have used different catalysts and different solvents. It was decided that Scheme 1. Acetylation of phenyl hydrazine Scheme 2. Proposed mechanism for the PdCl2-catalyzed acetylation reaction of methyl hydrazone toluene/PdCl 2 was the most suitable catalyst and solvent for the proposed methodology. This method is considered to be suitable for synthesis on a large scale.

Experimental
General procedure for the synthesis of 3a-i Palladium (II) chloride (17.3 mg, 10 mol %) was added to a solution of methyl hydrazone derivative (1a) (1 Eq.) in toluene (15 mL). Acetic acid (2) (1.2 Eq.) was then added and the resulting mixture was heated at reflux temperature for 18 h under an N 2 atmosphere. After complete conversion (monitored by TLC) the reaction mixture was filtered and then evaporated. The residue was eluted with ethyl acetate to give (E) N-methyl-N'-(phenylmethylene)acetohydrazide (3a), which were chromatographed on silica gel (20 g

Disclosure statement
No potential conflict of interest was reported by the author(s).

Supporting Information Summary
Supporting Information is included in full experimental detail (1H-NMR, 13C-NMR spectra, LC-MS, IR). This material can be found via the "Supplementary Content" section of this article's webpage.