Synthesis and Characterization of Novel Pyridinium Salts of (E)-2-(Pyridin-4-ylmethylene)hydrazine-1-carboximidamide

Abstract

We report the synthesis and characterization of the novel pyridinium salts from (E)-2-(pyridin-4-ylmethylene)hydrazine-1-carboximidamide. The pyridinium salts were obtained via the reaction of guanylhydrazone derived from pyridine-4-carbaldehyde with phenacyl bromides. Structural characterization was carried out using IR, ¹H, and ¹³C NMR spectroscopy and mass spectrometry.

1. Introduction

Phenacyl bromides have long been employed in heterocyclic chemistry, particularly in the synthesis of fused ring systems and five- or six-membered heterocycles [1,2]. Imidazo[1,2-a]pyridines, for example, are readily synthesized by the reaction of 2-aminopyridines, aldehydes, and phenacyl bromides [3]. Similarly, the condensation of amidines with phenacyl bromides was reported for the preparation of 2,4-disubstituted imidazoles [4].

Reactions of phenacyl bromides with pyridine leading to pyridinium salts, which are used for synthesis of chalcogeno-indolizines [5] and 1-styrylpyridinium salts [6].

However, the phenacyl bromides and pyridines were used for the preparation of indolizine C-nucleoside analogs [7], indolizines, pyrrolo[1,2-a]quinolines, and pyrrolo[2,1-a]isoquinolines [8,9] in multicomponent reactions.

Guanylhydrazones have also been used as versatile precursors in imidazole chemistry. For instance, 2-bromoacetophenone reacts with guanylhydrazones to synthesize 2-amino-1-arylidenaminoimidazoles [10,11].

Imidazole, a five-membered aromatic ring containing nitrogen, was discovered in the 1840s and plays a role as an important pharmacophore in drug discovery. This ring is present in several natural compounds, such as histidine, histamine, and natural alkaloids, as well as in synthetic drugs like cimetidine and losartan [12,13].

Since the discovery of imidazole, the research and development of compounds with an imidazole ring have been a major focus of research with a reported variety of activities, such as antibacterial [14], antifungal [15], antitumor [16], antiviral [17], anti-inflammatory [13], antihypertensive [18], and antiplatelet [10,19].

Different synthetic strategies have been reported for imidazoles [11,20,21,22].

A series of quinoxaline derivatives containing 2-aminoimidazole groups were reported to display promising anticancer activity [23].

In this study, we investigated the reaction of guanylhydrazone derived from pyridine-4-carbaldehyde with phenacyl bromides and report novel pyridinium salts derived from this reaction for the first time (Scheme 1).

2. Results and Discussion

Guanylhydrazones precursors were first prepared from pyridine-4-carbaldehyde and thiophene-2-carbaldehyde using aminoguanidine bicarbonate as the starting material according to previously reported methods [10,24]. After the addition of concentrated HCl to aminoguanidine bicarbonate, the appropriate aldehydes were added. The mixtures were treated with 40% NaOH and stirred for 24 h. The resulting guanylhydrazones were isolated as precipitates. For cyclization and formation of the imidazole ring, the guanylhydrazones were reacted with equimolar amounts of phenacyl bromide derivatives in ethanol.

The structures of the obtained compounds were characterized by MS, Fourier transform infrared (FT-IR), ¹H-NMR, and ¹³C-NMR (Supplementary Materials).

Characterization results revealed that treatment with phenacyl bromide derivatives in ethanol led to divergent reactivity, suggesting the involvement of multiple reaction pathways. Reaction of 1a resulted in nucleophilic substitution rather than cyclization. Here, the pyridine nitrogen atom attacked the electrophilic carbon of phenacyl bromides, affording pyridinium salts (3a and 3b). In the ¹H-NMR spectrum of compound 3a, a singlet peak at δ 6.50 ppm, integrating two protons, was observed, indicating the presence of a CH₂ group. In addition, the protons of the guanidine group were observed (δ 8.13 and 12.49 ppm), which indicates that the guanidine moiety remained unreacted. The ¹³C-NMR spectrum peak at δ 191.75 ppm confirmed the presence of a carbonyl group in the structure of compound 3a. The ¹H-NMR spectrum of 3b displayed a singlet at δ 6.19 ppm (CH₂ group) along with a broad singlet at δ 6.83 ppm (NH protons of guanidine), indicating that the guanidine moiety remained unreacted. The ¹³C-NMR spectrum showed a peak at δ 191.30 ppm, consistent with the carbonyl carbon.

In the case of thiophene guanylhydrazone, 1b, cyclization occurred, yielding imidazole derivative 4b, confirmed by a characteristic singlet at δ 7.91 ppm (H-5 of imidazole) in its ¹H-NMR spectrum [10,23].

In summary, the spectroscopic data confirmed the formation of the novel pyridinium salts (3a and 3b), which, to the best of our knowledge, are reported here for the first time by disclosed reaction.

3. Materials and Methods

3.1. General

FT-IR and IR spectra were recorded on a Agilent Cary 630 FTIR (Santa Clara, CA, USA) and a Perkin Elmer IR spectrophotometer (Norwalk, CT, USA), respectively. ¹H-NMR (400 MHz and 500 MHz) and ¹³C-NMR (100 MHz) spectra were recorded on a Bruker spectrometer (Bruker Biosciences, Billerica, MA, USA).

Mass spectra were acquired using a 6410 Agilent LC-MS triple quadrupole mass spectrometer (Santa Clara, CA, USA) equipped with an electrospray ionization (ESI) interface in positive mode. An Electrothermal 9100 melting point apparatus (Electrothermal, Staffordshire, UK) was used to obtain the melting points of derivatives. Costech 4010 elemental analyzer (Milan, Italy) was used for elemental analysis (C, H, and N). For all the compounds, the calculated values agreed with the measured values to within 0.4%.

3.2. Synthesis

3.2.1. (E)-4-((2-Carbamimidoylhydrazineylidene)methyl)-1-(2-oxo-2-phenylethyl)pyridin-1-ium bromide (3a)

A mixture of (E)-2-(pyridin-4-ylmethylene)hydrazine-1-carboximidamide 1a (163 mg, 1 mmol) and 2-bromo-1-phenylethan-1-one 2a (197 mg, 1 mmol) in ethanol (2 mL) and in the presence of two drops of NaOH (5%) was refluxed for 5 min and stirred at 25 °C for 24 h. The obtained precipitate was filtered and washed with a mixture of water and acetic acid (Yield: 49%, 177 mg).

C₁₅H₁₆BrN₅O; red brown solid; Melting point (m.p.): 198–201 °C; IR (KBr, cm⁻¹): 3304, 3333 (NH₂), 1709 (C=O); MS (ESI): [M]⁺ = 282.1; ¹H-NMR (500 MHz, DMSO-d₆, δ, ppm): 6.50 (2H, s, CH₂), 7.61–7.64 (2H, m, H-3′ and H-5′), 7.74–7.77 (1H, m, H-4′), 8.04 (2H, d, J = 7.5 Hz, H-2′and H-6′), 8.13 (3H, bs, NH), 8.39 (1H, s, HC=N), 8.70 (2H, d, J = 6.5 Hz, pyridine H-3 and H-5), 9.06 (2H, d, J = 6.5 Hz, pyridine H-2 and H-6), 12.49 (1H, s, NH); ¹³C-NMR (100 MHz, DMSO-d₆, δ, ppm): 65.1, 122.0, 128.7, 129.6, 134.1, 135.1, 136.0, 145.1, 153.2, 163.0, 191.7; Anal. calcd for C₁₅H₁₆BrN₅O: C 49.74, H 4.45, N 19.33, found: C 49.83, H 4.45, N 19.28.

3.2.2. (E)-4-((2-Carbamimidoylhydrazineylidene)methyl)-1-(2-oxo-2-(p-tolyl)ethyl)pyridin-1-ium bromide (3b)

A mixture of (E)-2-(pyridin-4-ylmethylene)hydrazine-1-carboximidamide 1a (163 mg, 1 mmol) and 2-bromo-1-(p-tolyl)ethan-1-one 2b (211 mg, 1 mmol) in ethanol (2 mL) and in the presence of two drops of NaOH (5%) was refluxed for 5 min and stirred at 25 °C for 24 h. The obtained precipitate was filtered and washed with hot water and hexane (Yield: 56%, 210 mg).

C₁₆H₁₈BrN₅O; red brown solid; Melting point (m.p.): 216–219 °C; FT-IR (KBr, cm⁻¹): 3380 (NH₂), 1692 (C=O); MS (ESI): [M]⁺ = 296.1; ¹H-NMR (400 MHz, DMSO-d₆, δ, ppm): 2.44 (3H, s, CH₃), 6.19 (2H, s, CH₂), 6.83 (4H, bs, NH), 7.47 (2H, d, J = 8.0 Hz, H-3′ and H-5′), 7.96–7.99 (3H, m, H-2′, H-6′ and N=CH), 8.26 (2H, d, J = 6.4 Hz, pyridine H-3 and H-5), 8.57 (2H, d, J = 6.8 Hz, pyridine H-2 and H-6); ¹³C-NMR (100 MHz, DMSO-d₆, δ, ppm): 21.8, 64.8, 121.6, 128.8, 130.1, 131.7, 135.3, 144.9, 145.8, 153.5, 164.0, 191.3; Anal. calcd for C₁₆H₁₈BrN₅O: C 51.08, H 4.82, N 18.61, found: C 51.11, H 4.83, N 18.56.

3.2.3. (E)-1-((Thiophen-2-ylmethylene)amino)-4-(p-tolyl)-1H-imidazol-2-amine (4b)

Compound 4b was prepared according to a previously reported method [10]. A mixture of (E)-2-(thiophen-2-ylmethylene)hydrazine-1-carboximidamide 1b (168 mg, 1 mmol) and 2-bromo-1-(p-tolyl)ethan-1-one 2b (211 mg, 1 mmol) in ethanol (2 mL) and in the presence of two drops of NaOH (5%) was refluxed for 5 min and stirred at 25 °C for 24 h. The obtained precipitate was filtered and washed with hot water and hexane (Yield: 41%, 118 mg).

C₁₅H₁₄N₄S; brown solid; Melting point (m.p.): 202–203 °C; FT-IR (KBr, cm⁻¹): 3399 (NH₂), 1613 (C=N); MS (ESI): [M + H]⁺ = 283.1; ¹H-NMR (400 MHz, DMSO-d₆, δ, ppm): 2.29 (3H, s, CH₃), 5.97 (2H, s, NH₂), 7.16 (2H, d, J = 8.0 Hz, H-3′ and H-5′), 7.20 (1H, t, J = 4.8 Hz, thiophene H-4); 7.55 (1H, d, J = 2.8 Hz, thiophene H-5), 7.58 (2H, d, J = 8.0 Hz, H-2′ and H-6′), 7.77 (1H, d, J = 5.2 Hz, thiophene H-3), 7.91 (1H, s, H-imidazole), 8.76 (1H, s, N=CH); ¹³C-NMR (100 MHz, DMSO-d₆, δ, ppm): 21.3, 101.5, 124.5, 128.6, 129.5, 130.3, 132.1, 135.9, 137.1, 138.7, 142.2, 149.5.

4. Conclusions

The reaction of equimolar amounts of guanylhydrazone, derived from pyridine-4-carbaldehyde with phenacyl bromides, afforded, for the first time, a pyridinium salt rather than an imidazole derivative. Structural elucidation by various spectroscopic techniques confirmed the structure. This reaction may lead to the formation of an imidazole ring at the guanyl moiety when carried out with more than two equivalents of phenacyl bromide. This work expands the scope of guanylhydrazone reactivity with α-haloketones and introduces a novel pyridinium salt.