ULTRASOUND-ASSISTED SYNTHESIS OF NOVEL 3-(PYRIDINYLAMINO)-1-FERROCENYLPROPAN-1-ONES

In this work we will report the formulation of novel 3-(pyridinylamino)-1-ferrocenylpropan-1-ones. A fruitful azaMichael addition of pyridinamine moiety to a conjugated enone, 1-ferrocenylpropenone, has been accomplished by an ultrasonic irradiation of the mixture of these reactants. As the catalyst montmorillonite K-10 has been used and the reaction has been carried out as solvent-free, yielding ferrocene containing Mannich bases, compounds considered as important precursors in organic synthesis. The reaction score has been evaluated on three examples. The prepared products have been purified by column chromatography. In addition, a detailed characterization of the obtained 3-(pyridin-2-ylamino)-1-ferrocenylpropan-1-on and 3-(pyridin-3-ylamino)-1-ferrocenylpropan-1-on has been completed by IR and NMR spectroscopy, as well as elemental analyses.


INTRODUCTION 
Ferrocene has been discovered in 1951 (Kealy & Pauson, 1951), and since then its derivatives have been found applications in many areas, among which the most important are in material science, asymmetric catalysis, bioorganometallic chemistry, medicinal chemistry, and organic synthesis (Köpf-Maier et al., 1984;Houlton et al., 1991;Kowalski, 2018). The application of ferrocene derivatives in the medicinal investigations proved to be a fertile area of bioorganometallic chemistry. Although ferrocene is not biologically active, it possesses a unique feature to strongly affect the activity of the structures to which is bound for (Togni, 1996). The incorporation of ferrocene nucleus into biologically relevant molecules can significantly enhance molecular properties such as solubility, hydrophobicity, and lipophilicity of ''parent compounds'' (Jaouen, 2006;Gambino & Otero, 2012;Salas et al., 2013;Biot et al., 2012;Supan et al., 2012). In such a way, some ferrocenyl derivatives like ferroquine and ferrocifen occupied an important position in pharmaceutical and medicinal chemistry. Likewise, the presence of the organoiron unit in bioactive skeletons increases their original antimalarial and antitumoral activity. Thus, the ferrocene moiety was recognized as an attractive pharmacophore in drug design (N'Da, & Smith, 2014) and a multitude of reports dealing with derivatives of this metallocene have been appeared in the literature.
In agreement with above statement, herein, we report the ultrasound-assisted synthesis between three different pyridinamine and 1-ferrocenylpropenone. All formulated compounds have been washed by column chromatography and their predicted structure have been verified with spectroscopic data ( 1 H-NMR, 13 C-NMR, and IR), as well as by elemental analyses. Also, this synthetic approach gives rise to favorable starting materials for advance synthesis of Fc-containing compounds.

Materials and measurements
All chemicals were commercially available and used as received, except the solvents, which were purified by distillation. Ultrasonic cleaner Elmasonic S 10 (Elma, Germany), 30W was used for the ultrasonically supported synthesis. Chromatographic O N L I N E F I R S T separations were carried out using silica gel 60 (Merck, 230-400 mesh ASTM), whereas silica gel 60 on Al plates, (Merck, layer thickness 0.2 mm) was used for TLC. Melting points were determined on a Mel-Temp capillary melting points apparatus, model 1001, and the given values have been uncorrected. The 1 H-and 13 C-NMR spectra of the samples in CDCl3 have been recorded on a Varian Gemini ( 1 H-at 200 MHz, 13 C-at 50 MHz) NMR spectrometer. Chemical shifts are reported in ppm (δ) values relative to TMS (δH 0 ppm) in 1 H-, 13 C-NMR spectra. The coupling constants (J) are reported in Hz. Multiplicities of proton resonance are designated as singlet (s), a doublet (d), a doublet of doublets (dd), a triplet (t), a pseudo triplet (pseudo t), doublet of doublets of doublets (ddd), a quartet (q) and a multiplets (m). IR measurements were carried out with a Perkin-Elmer FTIR 31725-X spectrophotometer. Microanalyses of carbon, hydrogen and nitrogen were carried out with a Carlo Erba 1106 model microanalyzer; these results agreed satisfactorily with the calculated values.

Synthesis
As it has been declared in the introduction in the last decade our research group stated reaction conditions for the synthesis of 3-arylamino-1-ferrocenylpropan-1-ones in high yields. This reaction has yielded numerous compounds, which have been demonstrated to be both biological active agents and excellent starting materials (Damljanović et al., 2011;Pejović et al., 2012b;Minić et al., 2015;Minić et al., 2017;Minić et al., 2018;Minić et al., 2019;Minić et al., 2020a), see Scheme 1. Consequently, for required synthesis within this work we agreed to apply these already know reaction conditions (see Scheme 2). A test tube containing a well homogenized mix of 1-ferrocenylpropenone (240 mg, 1 mmol), the analogous pyridinamine (2a, 2 mmol) and montmorillonite K-10 (100 mg, O N L I N E F I R S T CHEMISTRY 0.42 m-eq.) has been placed in the ultrasonic cleaner for 1h irradiations in the absence of solvent at ambient temperature. Later, the crude product has been purified by column chromatography (SiO2/n-hexane-MeOH, 9 : 1, v/v) to give 3-(pyridin-2-ylamino)-1-ferrocenylpropan-1-on (3a) in only 10% yield. This result shows us that the reaction certainly occurs, but also that we need to and established the optimal parameters. Therefore, we set reaction under no different conditions, but this time reaction outcome has been monitored by TLC. Indeed, based on TLC plate, for the reaction to be fully done it was necessary much more time around 8 hours. Usual workup of the reaction and column chromatography (SiO2/n-hexane-MeOH, 9 : 1, v/v), provided compound 3a in 60% yield based on 1-ferrocenylpropenone.

Scheme 2. Synthesis of novel 3-(pyridinylamino)-1-ferrocenylpropan-1-ones (3a-c).
Reaction score has been evaluated on two additional examples and we discovered very interesting results (see Table  1). Under submitted conditions 3-(pyridin-3-ylamino)-1ferrocenylpropan-1-on (3b) has been smoothly prepared in good yield 75% (see Table 1, entry 2), but when we used pyridine-4amine as starting substrate the reaction has not proceed (see Table 1, entry 3). The explanation for these outcomes must be the different influence of electronic properties depending on the position of nitrogen atom in pyridinamine ring.

Spectral characterization
The newly obtained compounds 3a and 3b described in this paper have been found to be stable at the ambient temperature for a prolonged time and could safely be handled in air, but like other Fc derivatives, they should be stored in closed containers. To validate their structure detailed characterized by standard spectroscopic techniques (IR, 1 H-and 13 C-NMR), as well as elemental analyses has been done. All spectral data were completely consistent with the planned structures (for more data see Experimental part).
The IR spectra of compounds 3a and 3b contained characteristic vibrations of the N-H bonds at 3234 cm -1 . The strong band at 1670 cm -1 relating to absorptions of the C=O bond. Three sets of signals have been observed in the 1 H-NMR spectra. The first belongs to protons of the methylene groups, the second to protons of the ferrocene moiety and the third to the aromatic protons (see Figure 1).
Supplementary, signals assigned to the corresponding carbons of the synthesized compounds 3a and 3b appear in the expected regions of the 13 C NMR spectra. The corresponding signals originated from the carbonyl group (δ(C) around 203 ppm), aromatic core above 108 ppm, ferrocene moiety between 69 and 79 ppm and aliphatic carbons at ca 37 ppm. (for more data see Experimental part, Figure

CONCLUSION
In a nutshell, within this study first time synthesis of 3-(pyridin-2-ylamino)-1-ferrocenylpropan-1-on and 3-(pyridin-3ylamino)-1-ferrocenylpropan-1-on has been submitted. Proposed structures of prepared molecules were undoubtedly confirmed by spectroscopic techniques (IR and NMR), as well as by elemental analyses. Added investigation to broaden this methodology for the synthesis of other ferrocenes is under development of our research group. In supplement, the synthesized molecules correspond to be interesting starting material for biological evaluation.