1. Introduction

OJMC

Open Journal of Medicinal Chemistry

2164-3121

Scientific Research Publishing

10.4236/ojmc.2020.104008

OJMC-106129

Articles

Chemistry&Materials Science

Ultrasound Promoted Synthesis and Antimicrobial Evaluation of Novel Seven and Eight-Membered 1,3-Disubstituted Cyclic Amidinium Salts

María

M. Blanco

¹María

A. Reamírez

¹María

C. Caterina

¹Isabel

A. Perillo

¹Guido

A. Oppezzo

¹María

S. Shmidt

¹Gabriel

O. Gutkind

²José

Di Conza

²Alejandra

Salerno

¹^*

Departamento de Microbiología, Inmunología y Biotecnología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina

Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina

28122020

100413915216, October 202025, December 2020 28, December 2020

2014

This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

Series of 1,3-dibenzyl-1 H-4,5,6,7-tetrahydro-1,3-diazepinium and 1,4,5,6,7,8-hexahydro-1,3-diazocinium salts derivatives were efficiently synthesized in excellent yields by dehydrogenation of the corresponding N, N ' -dibenzyl aminals employing N-bromosuccinimide (NBS) as dehydrogenating agent under ultrasound irradiation. The present methodology has proven to be simple, efficient and environmentally benign. All novel compounds were identified and characterized by ¹H and ¹³C NMR spectra. The synthesized compounds were screened for their antimicrobial activities.

Medium Ring Amidinium Salts Ultrasonic Assisted Synthesis Antimicrobial Green Chemistry

1. Introduction

Cyclic amidinium salts (CAS) with a fully saturated backbone (I) have attracted a great deal of interest in recent years. Most CAS (I) investigated so far are five- or six-membered rings derived from imidazole (1H-4,5-dihydroimidazolium salts) or pyrimidine (1,4,5,6-tetrahydropyrimidinium salts) (I, n = 0 and 1 respectively) [1] - [5]. However, higher homologues, such as 1H-4,5,6,7-tetrahydro-1,3-diazepinium and 1,4,5,6,7,8-hexahydro-1,3-diazocinium salts (I, n = 2 and 3) have been less studied [6]. It is known that medium-size rings are generally more difficult to synthesize than their lower counterparts [7] [8] [9] [10] since the synthetic strategies employed have to overcome unfavorable transannular interactions leading to large enthalpies of activation [11] [12] (Figure 1).

CAS I possess soft Lewis acidic character due to the contribution of the fully saturated mesomeric structure Ib and they have also found applications on their own as organocatalysts [13] [14] [15] [16].

2-Unsubstituted salts (I, R² = H), are conventional synthetic precursors, of NHCs (N-heterocyclic carbenes) [1] [17] [18] [19]. These compounds are of special interest due to their electron richness. Consequently, they have been widely applied as ligands in transition-metal catalysis and organometallic chemistry [20] - [28] and as organocatalysts in their own right [29] [30]. In particular, tetrahydrodiazepinium salts (I, n = 2) have been synthesized to be employed as precursor of ring expanded NHCs (RE-NHCs), which are stronger σ-donating ligands [24] [25] [26] [27] [31] [32] [33] [34]. A few years ago was reported the synthesis of the first eight-membered ring 8-NHC through the reaction of the corresponding cyclic amidinium salt (I, n = 3) with KHMDS (potassium hexamethyldisilylamide) [35].

Green chemistry focuses on research that attempts to reduce or eliminate the negative environmental impacts [36]. In accordance with green chemistry requirements, ultrasound irradiation has emerged as an efficient technique for reagent activation in organic reactions and has been considered as a clean and useful methodology in organic synthesis for the last years [37] [38]. In this context, many organic reactions can be carried out under ultrasound irradiation and compared with classical synthetic procedures [39] - [44].

On the other hand, the search for compounds with antibacterial activity has gained increasing importance in recent time, due to growing worldwide concern over the increase in the rate of infection by antibiotic-resistant microorganisms [45]. One of the groups with good antimicrobial activity is cationic nitrogen containing molecules as acyclic [46] and cyclic [47] [48] quaternary ammonium compounds (QACs). In this line, cyclic amidinium salts as pyrimidinium [49] and imidazolium [50] and their silver complex were investigated as antibacterial agents [51].

The synthetic methods for cyclic amidinium salts of medium size ring, are in general extensions of the methods employed for lower homologues as imidazolinium and tetrahydropirimidinium salts. The literature describes general strategies that involve cyclic and acyclic compounds as precursors [6]. In line with our ongoing work in the use of green chemistry tools [52] - [56] for heterocyclic chemistry,

we report herein an eco-friendly approach for the synthesis of 1,3-dibenzyl tetrahydro-1,3-diazepinium (1, n = 2) and hexaydro-1,3-diazocinium salts (1, n = 3) with potential microbiological activity, under ultrasound irradiation.

2. Experimental2.1. Materials and Methods2.1.1. Chemistry. General Data

Melting points were taken on a Büchi capillary apparatus and are uncorrected. ¹H and ¹³C NMR spectra were measured in DCCl₃ solutions on a Bruker Avance II 500 MHz spectrometer at room temperature in 5 mm tubes. Standard concentration of the samples was 2 and 10 mg/mL for ¹H and ¹³C respectively. Chemical shifts are reported in ppm (δ) relative to TMS as an internal standard. Coupling constant (J) values are given in Hz. Splitting multiplicities are reported as singlet (s), broad signal (bs), doublet (d), triplet (t), broad triplet (bt), multiplet (m), double doublet (dd), double triplet (dt) and pentuplet (p). High resolution mass spectra (HMRS), were acquired with a model GCT (Waters, Milford, MA, USA), operating at 8000 resolving power (50% valley definition) using heptacose (m/z 219) as the reference compound. IR spectra were recorded on a Perkin Elmer Spectrum One FT-IR spectrometer.

Ultrasonic irradiation experiments were performed using a VCX 750 Vibra-Cell high intensity ultrasonic processor (Sonics & Materials, USA) equipped with an immersion ultrasonic probe, which was made of titanium alloy T1-6AL-4V, and with the tip diameter of 13 mm. The frequency is 20 KHz and the net power output is 750 W. The variable power output control allows the ultrasonic vibrations at the probe tip to be set to any desired amplitude. With the amplitude control set at 100%, the amplitude at the tip with diameter of 13 mm is 124 μm. In our work, the amplitude control was set at 35%.

2.1.2. Antimicrobial Activity

Antimicrobial activity was tested by the disk diffusion method, with Antibiotic Medium number 1 (pH 6.5) and 11 (pH 7.9). The assayed microorganisms were B. subtilis ATCC 6633 CCM-A-10, S. aureus ATCC 6538P CCM-A-424, E. coli ATCC 11105 CCM-A-424 and A. niger ATCC 16404. MIC determination was performed following the agar dilution method recommendations as proposed by CLSI (MO7-A10) [57].

2.2. Synthesis and Characterization of Cyclic Amidinium Salts 1

Aminals 2 were synthesized by reaction of N,N’-disubstituted alkylenediamines with formaldehyde under microwave irradiation [52]. Compounds 2a [58] b,c,e,g-l were previously described [58]. Aminals 2d,f were obtained in the same way and were used as precursors of the salts 1d,f without previous purification.

2.2.1. Conventional Synthesis

To a stirred solution of corresponding aminal 2 (0.01 mol) in ethyl ether (5 mL) at room temperature, the dehydrogenating agent (0.02 mol) was added in portions while the reaction was monitored by TLC. After complete disappearance of the starting material, salts 1 precipitate in variable times. The solid products were collected and recrystallized from anhydrous methanol and the oils were purified by column chromatography (n-hexane-ethyl acetate 1:1). Required times and yields are indicated in Table 1.

2.2.2. Reaction under Ultrasound Irradiation

A mixture of the corresponding aminal 2 (0.01 mol) in ethyl ether (5 mL) and the dehydrogenating agent (NBS, 0.02 mol) was taken in a flask. The reaction mixture was sonicated by an ultrasonic probe in ice bath for the specified period until complete consumption of starting materials (monitored by TLC). Compounds 1 were isolated and purified as was indicated in conventional synthesis. Required times and yields are indicated in Table 1.

2.2.3. Data of the New Compounds

- 1,3-Dibenzyl-1H-4,5,6,7-tetrahydro-1,3-diazepinium bromide (1a).

This compound was obtained as oil. ¹H NMR δ ppm: 9.52 (s, 1H, NCHN), 7.43 - 7.42 (m, 4H_arom.) 7.38 - 7.31 (m, 6H_arom.), 4.94 (s, 4H, NCH₂Ar), 3.62 (bs, 4H, NCH₂), 1.83 (p, 4H, CH₂CH₂, J = 2.9 Hz). ¹³C NMR δ ppm: 159.7, 134.6, 130.1, 129.9, 127.1, 62.1, 50.4, 25.7. IR (film) ν: 3030, 2940, 1674, 1455, 1090, 748, 705 cm⁻¹. MS: m/z 278 (M-1-Br). HRMS: 278.17821. Calcd. for C₁₉H₂₂N₂: 278.17830.

- 1,3-Di-(4-methylbenzyl)-1H.4,5,6,7-tetrahydro-1,3-diazepinium bromide (1b).

Table 1 Synthesis of cyclic amidinium salts 1a-l under sonication and conventional conditions

Comp. 1	Ar	n	Conventional (ethyl ether)		Ultrasonic irradiation Sonicator (HIU)
Comp. 1	Ar	n	Time (min)	Yield (%)	Time (min)	Yield (%)
a	C₆H₅	2	25	34	2	85
b	4-CH₃C₆H₄	2	30	36	1	87
c	4-ClC₆H₄	2	29	32	1	91
d	2-ClC₆H₄	2	25	25	2	94
e	3-ClC₆H₄	2	30	42	1	88
f	4-NO₂C₆H₄	2	20	35	1	95
g	2,3-Cl₂C₆H₃	2	25	30	3	89
h	3,4-Cl₂C₆H₃	2	35	51	3	98
i	C₆H₅	3	25	50	2	87
j	3-ClC₆H₄	3	30	51	2	80
k	2,3-Cl₂C₆H₃	3	25	52	4	85
l	3,4-Cl₂C₆H₃	3	30	55	5	80

MP: 122˚C - 124˚C. ¹H NMR δ ppm: 9.90 (s, 1H, NCHN), 7.30 (d, 4H_arom., J = 7.7 Hz), 7.15 (d, 4H_arom. J = 7.7 Hz), 4.89 (s, 4H, NCH₂Ar), 3.54 (bt, 4H, NCH₂), 2.32 (s, 6H, CH₃), 1.79 (bp, 4H, CH₂CH₂). ¹³C NMR δ ppm: 159.6, 139.7, 131.6, 130.7, 129.7, 61.6, 30.1, 25.6, 22.1. IR (film) ν: 3022, 2936, 1609, 1489, 1030, 919, 757 cm⁻¹. MS: m/z 306 (M-1-Br). HRMS: 306.20895. Calcd. for C₂₁H₂₆N₂: 306.20960.

- 1,3-Di(4-chlorobenzyl)-1H-4,5,6,7-tetrahydro-1,3-diazepinium bromide (1c).

MP: 200˚C - 202˚C. ¹H NMR δ ppm: 10.04 (s, 1H, NCHN), 7.43 (d, 4H, 4H_arom., J = 8.5 Hz), 7.32 (d, 4H_arom., J = 8.5 Hz), 4.94 (s, 4H, NCH₂Ar), 3.54 (bt, 4H, NCH₂), 1.83 (p, 4H, CH₂CH₂, J = 2.9 Hz). ¹³C NMR δ ppm: 160.3, 136.0, 133.1, 131.3, 130.3, 61.1, 50.4, 25.7. IR (film) ν: 2941, 2870, 1668, 1492, 815, 801 cm⁻¹. MS: m/z 346 (M-1-Br). HRMS: 346.10049. Calcd. for C₁₉H₂₀Cl₂N₂: 346.10035.

- 1,3-Di(2-chlorobenzyl)-1H-4,5,6,7-tetrahydro-1,3-diazepinium bromide (1d).

This compound was obtained as oil. ¹H NMR δ ppm: 9.26 (s, 1H, NCHN), 7.70 - 7.68 (m, 2H_arom.), 7.43 - 7041 (m, 2H_arom.), 7.36 - 7.34 (m, 4H_arom.), 5.05 (s, 4H, NCH₂Ar), 3.69 (bt, 4H, NCH₂), 1.90 (p, 4H, CH₂CH₂, J = 2.8 Hz). ¹³C NMR δ ppm: 160.0, 134.5, 132.3, 131.3, 130.7, 130.1, 127.8, 58.4, 49.4, 24.6. IR (film) ν: 2932, 2864, 1615, 1586, 1443, 766, 700 cm⁻¹. MS: m/z 346 (M-1-Br^.). HRMS: 346.10120. Calcd. for C₁₉H₂₀Cl₂N₂: 346.10035.

- 1,3-Di(3-chlorobenzyl)-1H-4,5,6,7-tetrahydro-1,3-diazepinium bromide (1e).

This compound was obtained as oil. ¹H NMR δ ppm: 9.06 (s, 1H, NCHN), 7.36 (bs, 2H_arom.), 7.32 (bs, 6H_arom.), 4.76 (s, 4H, NCH₂Ar), 3.61 (bs, 4H, NCH₂), 1.85 (p, 4H, CH₂CH₂, J = 2.9 Hz). ¹³C NMR δ ppm: 158.9, 135.5, 134.9, 130.6, 129.2, 128.5, 126.7, 60.5, 49.5, 24.5. IR (film) ν: 2930, 1673, 1431, 785, 682 cm⁻¹. MS: m/z 346 (M-1-Br^.). HRMS: 346.10087. Calcd. for C₁₉H₂₀Cl₂N₂: 346.10035.

- 1,3-Di(4-nitrobenzyl)-1H-4,5,6,7-tetrahydro-1,3-diazepinium bromide (1f).

This compound was obtained as oil. ¹H NMR δ ppm: 9.78 (s, 1H, NCHN), 7.45 (d, 4H_arom J = 7.2 Hz), 7.37 (dd, 4H_arom J = 7.2 Hz), 4.93 (s, 4H, CH₂Ar), 3.58 (bt, 4H, NCH₂N), 1.79 (bt, 4H, CH₂N). ¹³C NMR δ ppm: 158.7, 133.6, 129.2, 128.9, 128.8, 60.0, 49.3, 24.4. IR (film) ν: 3109, 2853, 1607, 1539, 1345, 835 cm⁻¹. MS: m/z 368 (M-1-Br^.). HRMS: 368.14722. Calcd. for C₁₉H₂₀N₄O₄: 368.14845.

- 1,3-Di(2,3-dichlorobenzyl)-1H-4,5,6,7-tetrahydro-1,3-diazepinium bromide (1g).

MP: 182˚C - 184˚C. ¹H NMR δ ppm: 9.42 (s, 1H, NCHN), 7.69 (dd, 2H_arom., J = 7.6, 1.5 Hz), 7.47 (dd, 2H_arom., J = 8.1, 1.5 Hz), 7.28 (dd, 2H_arom., J = 8.1, 7.6 Hz Hz), 5.10 (s, 4H, NCH₂Ar), 3.67 (bt, 4H, NCH₂), 1.90 (p, 4H, CH₂CH₂, J = 2.9 Hz). ¹³C NMR δ ppm: 161.3, 134.9, 134.3, 133.6, 132.4, 131.3, 129.2, 59.8, 50.8, 25.5. IR (film) ν: 2930, 1674, 1424, 788, 737 cm⁻¹. MS: m/z 414 (M-1-Br^.). HRMS: 414.02358. Calcd. for C₁₉H₁₈Cl₄N₂: 414.02241.

- 1,3-Di(3,4-dichlorobenzyl)-1H-4,5,6,7-tetrahydro-1,3-diazepinium bromide (1h).

MP: 163˚C - 165˚C. ¹H NMR δ ppm: 9.87 (s, 1H, NCHN), 7.53 (bs, 2H_arom.), 7.44 - 7.43 (bs, 4H_arom.), 4.93 (s, 4H, NCH₂Ar), 3.57 (bt, 4H, NCH₂), 1.90 (p, 4H, CH₂CH₂, J = 2.8 Hz). ¹³C NMR δ ppm: 160.7, 134.7, 134.4, 134.2, 132.6, 131.6, 129.3, 60.9, 50.7, 25.7. IR (film) ν: 2934, 2859, 1611, 1470, 837, 732 cm⁻¹. MS: m/z 414 (M-1-Br^.). HRMS: 414.02310. Calcd. for C₁₉H₁₈Cl₄N₂: 414.02241.

- 1,3-Dibenzyl-1,4,5,6,7,8-hexahydro-1,3-diazocinium bromide (1i).

MP: 187˚C - 189˚C. ¹H NMR δ ppm: 10.32 (s, 1H, NCHN), 7.50 - 7.36 (m, 10H_arom.), 5.02 (s, 4H, NCH₂Ar), 3.70 (bs, 4H, NCH₂), 1.54 (bs, 4H, CH₂CH₂N), 1.45 (bs, 2H, CH₂CH₂CH₂). ¹³C NMR δ ppm: 154.9, 134.9, 130.2, 130.1, 130.0, 62.7, 48.6, 29.1, 20.1. IR (film) ν: 3055, 2938, 1618, 1585, 778, 700 cm⁻¹. MS: m/z 292 (M-1-Br^.). HRMS: 292.19421. Calcd. for C₂₀H₂₄N₂: 292.19395.

- 1,3-Di(3-chlorobenzyl)-1,4,5,6,7,8-hexahydro-1,3-diazocinium bromide (1j).

MP: 273˚C - 275˚C. ¹H NMR δ ppm: 10.48 (s, 1H, NCHN), 7.52 (bs, 2H_arom.), 7.42 (s, 2H_arom.), 7.34 - 7.33 (4H_arom.), 5.07 (s, 4H, NCH₂Ar), 3.72 (bs, 4H, NCH₂), 1.66 (p, 4H, CH₂CH₂N, J = 6.2 Hz), 1.53 (p, 2H, CH₂CH₂CH₂, J = 6.2 Hz). ¹³C NMR δ ppm: 159.5, 135.6, 134.7, 130.6, 129.5, 129.0, 127.4, 60.6, 47.9, 27.9, 19.7. IR (film) ν: 2930, 1674, 1471, 820, 733. MS: m/z 360 (M-1-Br^.). HRMS: 360.11655 Calcd. for C₂₀H₂₂Cl₂N₂: 360.11600.

- 1,3-Di(2,3-dichlorobenzyl)-1,4,5,6,7,8-hexahydro-1,3-diazocinium bromide (1k).

This compound was obtained as oil. ¹H NMR δ ppm: 9.30 (s, 1H, NCHN), 7.62 (dd, 2H_arom., J = 7.7, 1.3 Hz), 7.44 (dd, 2H_arom., J = 8.1, 1.3 Hz), 7.27(dd, 2H_arom., J = 8.1, 7.7 Hz), 5.04 (s, 4H, NCH₂Ar), 3.80 (bs, 4H, NCH₂), 1.54 (bs, 4H, CH₂CH₂N), 1.47 (bs, 2H, CH₂CH₂CH₂). ¹³C NMR δ ppm: 159.8, 134.6, 134.2, 133.6, 132.2, 131.4., 129.0, 60.8, 48.7, 29.1, 21.0. IR (film) ν: 2933, 1671, 1422, 1049, 782, 753 cm⁻¹. MS: m/z 428 (M-1-Br^.). HRMS: 428.03872. Calcd. for C₂₀H₂₀Cl₄N₂: 428.03806.

- 1,3-Di(3,4-dichlorobenzyl)-1,4,5,6,7,8-hexahydro-1,3-diazocinium bromide (1l).

MP: 228˚C - 230˚C. ¹H NMR δ ppm: 10.40 (s, 1H, NCHN), 7.57 (d, 2H_arom., J = 2.0 Hz), 7.54 (dd, 2H_arom, J = 8.2, 2.0 Hz), 7.43(d, 2H_arom. J = 8.2 Hz), 5.01 (s, 4H, NCH₂Ar), 3.67 (bs, 4H, NCH₂), 1.63 (p, 4H, CH₂CH₂N, J = 6.2 Hz), 1.51 (p, 2H, CH₂CH₂CH₂, J = 6.2 Hz)_. ¹³C NMR δ ppm: 159.7, 134.8, 134.5, 134.1, 132.2, 131.8, 129.7, 61.3, 48.8, 29.0, 20.8. IR (film) ν: 2936, 1611, 1469, 838, cm⁻¹. MS: m/z 428 (M-1-Br^.). HRMS: 428.03791. Calcd. for C₂₀H₂₀Cl₄N₂: 428.03806.

3. Results and Discussion3.1. Preparation of Cyclic Amidinium Salts (1)

The compounds synthesized in this work were obtained by dehydrogenation of the corresponding aminals 2 (n = 2,3, hexahydro-1,3-diazepines and octahydro-1,3-diazocines respectively). The required aminals 2 were synthesized by our improved method involving the reaction of N,N'-disubstituted alkylenediamines with formaldehyde under microwave irradiation [52].

In order to set dehydrogenation conditions we used the diazepine derivative 2c and test several dehydrogenating agents and solvents following the method described for the synthesis of five membered cyclic amidinium salts [59]. Dehydrogenations with NBA, NBS, and DBDMH (1,3-dibromo-5,5-dimethylhydantoin) were carried out at room temperature (20˚C) by stirring a mixture of the aminal and the reagent. Conversions were achieved in as few minutes. Ether solvents (ethyl ether, dimethoxyethane, and THF) were preferred due to the insolubility of products in such media. NBS in ethyl ether afforded the best results, with higher yields and purer reaction products (Figure 2).

Having set up the conditions, compounds 2a-n were dehydrogenated at room temperature by stirring a mixture with NBS in anhydrous ethyl ether (Figure 2). In this medium, salts generally precipitate as long as they were formed. Under those conditions the reactions proceeded with different yields (Table 1). Diazepinium salts 1a-h were obtained with low yields (25% - 51%) and required 20 - 35 min for complete consumption of the starting material. On the other hand, diazocinium salts 1i-l were obtained with moderate yields (50% - 55%) and required 25 - 30 min.

In order to optimize the dehydrogenation reaction of aminals described above, we explored the use of ultrasound irradiation as promoting agent. The reactions were carried out in ice bath with high intensity ultrasonic (HIU) probe system. In all cases, the experimental results show that yields of compounds 1a-l improved under sonication (80% - 94%) and the reaction times decreased (1 - 5 min) if compared to conventional heating (Table 1).

Unlike other medium size cyclic amidinium salts [53] the compounds were generally isolated as hygroscopic solids, melting above 100˚ and, therefore, they are not ionic liquids. This would be related with the structural symmetry of salts 1.

The analysis of the NMR and IR spectra of compounds 1 confirmed their identity. The most valuable spectroscopic feature for assessing the success of the dehydrogenation was the appearance of the a strongly deshielded H-2 signal at ca. 9 - 10 ppm, results from the electron deficiency of the heterocyclic ring, caused by the cationic character of the amidinium system Ib. On the other hand, infrared spectra confirmed their ionic structure, as it can be seen from the amidinium band at ca. 1600 - 1620 cm⁻¹. The ¹³C-NMR spectra characteristically show the C-2 signal at approximately 160 ppm. The ¹H and ¹³C NMR and IR spectra of a representative compound are shown in Figures 3-5.

3.2. Biological Evaluation

The synthesized salts were screened for their in vitro antimicrobial activity using the disk diffusion method employing Gram positive (Staphylococcus aureus, Bacilus subtilis) and Gram-negative bacteria (Escherichia coli) and funji (Aspergillus niger). Those compounds which presented any inhibition zone were evaluated by their minimal inhibitory concentration (MIC). Results are shown in Table 2.

According to the antimicrobial activity results, the derivatives without substitution in the aromatic nucleus (1a,i) and the nitroderivative 1f do not present antimicrobial activity with any of the microorganisms tested. The N-monosubstituted aryl compounds (1b-e,j) have low antimicrobial activity against Staphylococcus aureus, Bacilus subtilis and Escherichia coli. Compounds with two chloro atoms in the aryl groups (1g,h,k,l) were those with the highest antibacterial activity showing also antifungal activity against Aspergillus niger.

4. Conclusions

In conclusion, we have developed a simple and efficient procedure for the synthesis of 1,3-dibenzyl-tetrahydro-1,3-diazepinium (1, n = 2) and hexahydro-1,3-diazocinium (1, n = 3) salts, a new family of medium ring nitrogen heterocyclic salts. The method involves the dehydrogenation of aminals employing a cheap commercially available reagent under ultrasound irradiation as promoting agent. This approach has several and important advantages including methodologically easy reactions, milder conditions, shorter reaction times and

Table 2 Synthesis of cyclic amidinium salts 1a-l under sonication and conventional conditions

Comp. 1	E. coli	S. aureus	B. subtilis	A. niger
a	-	-	-	-
b	>256	256	>256	-
c	>256	>256	>256	-
d	-	-	-	-
e	-	>256	-	-
f	-	-	-	-
g	128	32	128	>256
h	256	32	64	128
i	-	-	-	-
j	>256	>256	>256	-
k	128	16	16	>256
l	>256	32	32	128

higher yields, and provides biologically interesting nitrogen containing heterocycles in good yields.

Acknowledgements

This work was financially supported by the Universidad de Buenos Aires, Argentina, UBACyT 2017–2019 N˚ 20020160100062BA.

Conflicts of Interest

The authors declare no conflicts of interest regarding the publication of this paper.

Cite this paper

Blanco, M.M., Reamírez, M.A., Caterina, M.C., Perillo, I.A., Oppezzo, G.A., Shmidt, M.S., Gutkind, G.O., Conza, J.D. and Salerno, A. (2020) Ultrasound Promoted Synthesis and Antimicrobial Evaluation of Novel Seven and Eight-Membered 1,3-Disubstituted Cyclic Amidinium Salts. Open Journal of Medicinal Chemistry, 10, 139-152. https://doi.org/10.4236/ojmc.2020.104008

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