OJMC  Vol.10 No.4 , December 2020
Ultrasound Promoted Synthesis and Antimicrobial Evaluation of Novel Seven and Eight-Membered 1,3-Disubstituted Cyclic Amidinium Salts
Abstract: Series of 1,3-dibenzyl-1H-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.

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,

Figure 1. Cyclic amidinium salts (CAS).

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. Experimental

2.1. Materials and Methods

2.1.1. 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, 4Harom.) 7.38 - 7.31 (m, 6Harom.), 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.

MP: 122˚C - 124˚C. 1H NMR δ ppm: 9.90 (s, 1H, NCHN), 7.30 (d, 4Harom., J = 7.7 Hz), 7.15 (d, 4Harom. 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, 4Harom., J = 8.5 Hz), 7.32 (d, 4Harom., 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, 2Harom.), 7.43 - 7041 (m, 2Harom.), 7.36 - 7.34 (m, 4Harom.), 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, 2Harom.), 7.32 (bs, 6Harom.), 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, 4Harom J = 7.2 Hz), 7.37 (dd, 4Harom 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, 2Harom., J = 7.6, 1.5 Hz), 7.47 (dd, 2Harom., J = 8.1, 1.5 Hz), 7.28 (dd, 2Harom., 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, 2Harom.), 7.44 - 7.43 (bs, 4Harom.), 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, 10Harom.), 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, 2Harom.), 7.42 (s, 2Harom.), 7.34 - 7.33 (4Harom.), 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, 2Harom., J = 7.7, 1.3 Hz), 7.44 (dd, 2Harom., J = 8.1, 1.3 Hz), 7.27(dd, 2Harom., 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, 2Harom., J = 2.0 Hz), 7.54 (dd, 2Harom, J = 8.2, 2.0 Hz), 7.43(d, 2Harom. 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 Discussion

3.1. 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.

Figure 2. Synthesis of cyclic amidinium salts 1 from aminals 2.

Figure 3. 1H-NMR spectrum of compound 1b.

Figure 4. 13C-NMR spectrum of compound 1b.

Figure 5. IR spectrum of compound 1b.

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.

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


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

Cite this paper: Blanco, M. , Reamírez, M. , Caterina, M. , Perillo, I. , Oppezzo, G. , Shmidt, M. , Gutkind, G. , Di Conza, J. 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. doi: 10.4236/ojmc.2020.104008.

[1]   Benhamou, L., Chardon, E., Lavigne, G., Bellemin-Laponnaz, S. and Cesar, V. (2011) Synthetic Routes to N-Heterocyclic Carbene Precursors. Chemical Reviews, 111, 2705-2733.

[2]   Perillo, I., Caterina, M.C., de los Santos, C. and Salerno, A. (2007) 1H and 13C nmr Analysis of a 1,2-diaryl-3-methyl-4,5-dihydro-1H-imidazolium Salts Series. Heterocycles, 71, 49-60.

[3]   García, M., Zani, M., Perillo, I. and Orelli, L. (2004) 1-Aryl-3-alkyl-1,4,5,6-tetrahy-dropyrimidinium Salts. Part 2. Reactions with Nucleophiles. Heterocycles, 63, 2557-2572.

[4]   Singh, K. and Singh, H. (2006) Coenzyme 5,10-Methylene and Methenyltetrahydrofolate Models in Organic Synthesis. Advances in Heterocyclic Chemistry, 91, 159-188.

[5]   Ozdemir, I., Yigit, M. and Cetinkaya, B. (2006) Novel Azolinium/Rhodium System Catalyzed Addition of Arylboronic Acids to Aldehydes. Heterocycles, 68, 1371-1379.

[6]   Perillo, I., Caterina, M.C. and Salerno, A. (2018) Synthesis and Properties of Seven-to Nine-Membered Ring Nitrogen Heterocycles. Cyclic Amidines and Cyclic Amidinium Salts. Arkivoc, 2018, 288-318.

[7]   Illuminati, G. and Mandolini, L. (1981) Ring Closure Reactions of Bifunctional Chain Molecules. Accounts of Chemical Research, 14, 95-102.

[8]   Yet, L. (2000) Metal-Mediated Synthesis of Medium-Sized Rings. Chemical Reviews, 100, 2963-3008.

[9]   Hoberg, J.O. (1998) Synthesis of Seven-Membered Oxacycles. Tetrahedron, 54, 12631-12970.

[10]   Andrew Evans, P. and Holmes, B. (1991) Synthesis of Monocyclic Medium Ring Lactams. Tetrahedron, 47, 9131-9166.

[11]   Appukkuttan, P., Dehaen, W. and Van der Eycken, E. (2005) Microwave-Enhanced Synthesis of N-Shifted Buflavine Analogues via a Suzuki-Ring-Closing Metathesis Protocol. Organic Letters, 7, 2723-2726.

[12]   Appukkuttan, P., Dehaen, W. and Van der Eycken, E. (2007) Microwave-Assisted Transition-Metal-Catalyzed Synthesis of N-Shifted and Ring-Expanded Buflavine Analogues. Chemistry—A European Journal, 13, 6452-6460.

[13]   Sereda, O., Clemens, N., Heckel, T. and Wilhelm, R. (2012) Imidazolinium and Amidinium Salts as Lewis Acid Organocatalysts. Beilstein Journal of Organic Chemistry, 8, 1798-1803.

[14]   Zhou, H.-Y., Campbell, E.J. and Nguyen, S.-B.T. (2001) Imidazolinium Salts as Catalysts for the Ring-Opening Alkylation of meso Epoxides by Alkylaluminum Complexes. Organic Letters, 3, 2229-2231.

[15]   Jurcik, V. and Wilhelm, R. (2005) Imidazolinium Salts as Catalysts for the aza-Diels-Alder Reaction. Organic & Biomolecular Chemistry, 3, 239-244.

[16]   Jurcik, V. and Wilhelm, R. (2006) The Preparation of New Enantiopure Imidazolinium Salts and Their Evaluation as Catalysts and Shift Reagents. Tetrahedron: Asymmetry, 17, 801-810.

[17]   Yang, L.R., Wei, D., Mai, W.P. and Mao, P. (2013) Development on the Synthesis of Ring Expanded N-Heterocyclic Precursors. Chinese Journal of Organic Chemistry, 33, 943-953.

[18]   Douthwite, R.E. (2007) Metal-Mediated Asymmetric Alkylation Using Chiral N-Heterocyclic Carbenes Derived from Chiral Amines. Coordination Chemistry Reviews, 251, 702-717.

[19]   Valente, C., Calimsisiz, S., Hoy, K.H., Mallik, D., Sayah, M. and Organ, M.G. (2012) The Development of Bulky Palladium NHC Complexes for the Most-Challenging Cross-Coupling Reactions. Angewandte Chemie International Edition, 51, 3314-3332.

[20]   Clavier, H. and Nolan, S.P. (2010) Percent Buried Volume for Phosphine and N-Heterocyclic Carbene Ligands: Steric Properties in Organometallic Chemistry. Chemical Communications, 46, 841-861.

[21]   Díez-Gonzalez, S., Marion, N. and Nolan, S.P. (2009) N-Heterocyclic Carbenes in Late Transition Metal Catalysis. Chemical Reviews, 109, 3612-3676.

[22]   Samojlowicz, C., Bieniek, M. and Grela, K. (2009) Ruthenium-Based Olefin Metathesis Catalysts Bearing N-Heterocyclic Carbene Ligands. Chemical Reviews, 109, 3708-3742.

[23]   Lin, J.C.Y., Huang, R.T.W., Lee, C.S., Bhattacharyya, A., Hwang, W.S. and Lin, I.J.B. (2009) Coinage Metal-N-Heterocyclic Carbene Complexes. Chemical Reviews, 109, 3561-3598.

[24]   Dunsford, J.J., Tromp, D.S., Cavell, K.J., Elsevier, C.J. and Kariuki, B.M. (2013) N-Alkyl Functionalised Expanded Ring N-Heterocyclic Carbene Complexes of Rhodium(I) and Iridium(I): Structural Investigations and Preliminary Catalytic Evaluation. Dalton Transactions, 42, 7318-7329.

[25]   Dunsford, J.J., Tromp, D.S., Cavell, K.J. and Kariuki, B.M. (2012) Gold (I) Complexes Bearing Sterically Imposing, Saturated Six- and Seven-Membered Expanded Ring N-Heterocyclic Carbene Ligands. Organometallics, 31, 4118-4121.

[26]   Dunsford, J.J. and Cavell, K.J. (2014) Pd-PEPPSI-Type Expanded Ring N-Heterocyclic Carbene Complexes: Synthesis, Characterization, and Catalytic Activity in Suzuki-Miyaura Cross Coupling. Organometallics, 33, 2902-2905.

[27]   Kolychev, E.L., Asachenko, A.F., Dzhevakov, P.B., Bush, A.A., Shuntikov, V.V., Khrustalev, V.N. and Nechaev, M.S. (2013) Expanded Ring Diaminocarbene Palladium Complexes: Synthesis, Structure, and Suzuki-Miyaura Cross-Coupling of Heteroaryl Chlorides in Water. Dalton Transactions, 42, 6859-6866.

[28]   Gilani, M.A., Rais, E. and Wilheim, R. (2015) Chiral Imidazolinium Salts with TIPS Groups for the Palladium-Catalyzed α-Arylation and as Chiral Solvating Agents. Synlett, 26, 1638-1641.

[29]   Marion, N., Díez-Ganzález, S. and Nolan, S.P. (2007) N-Heterocyclic Carbenes as Organocatalysts. Angew. Angewandte Chemie International Edition, 46, 2988-3000.

[30]   Fevre, M., Pinaud, J., Gnanou, Y., Vignolle, J. and Taton, D. (2013) N-Heterocyclic Carbenes (NHCs) as Organocatalysts and Structural Components in Metal-Free Polymer Synthesis. Chemical Society Reviews, 42, 2142-2172.

[31]   Binobaid, A., Iglesias, M., Beetstra, D., Dervisi, A., Fallis, I., Cavell, K.J. (2010) Donor-Functionalised Expanded Ring N-Heterocyclic Carbenes: Highly Effective Ligands in Ir-Catalysed Transfer Hydrogenation. European Journal of Inorganic Chemistry, 2010, 5426-5431.

[32]   Dunsford, J.J. and Cavell, K.J. (2011) Expanded Ring N-Heterocyclic Carbenes: A Comparative Study of Ring Size in Palladium (0) Catalysed Mizoroki-Heck Coupling. Dalton Transactions, 40, 9131-9135.

[33]   Karaca, E.O., Akkoc, M., Oz, O., Altin, S., Dorcet, V., Roisnel, N., Gurbuz, N., Celic, O., Bayri, A., Bruneau, C., Yasar, S. and Ozdemir, I. (2017) Ring-Expanded Iridium and Rhodium N-Heterocyclic Carbene Complexes: A Comparative DFT Study of Heterocycle Ring Size and Metal Center Diversity. Journal of Coordination Chemistry, 70, 1270-1284.

[34]   Dunsford, J.J., Cade, I.A., Fillman, K.L., Neidig, M.I. and Ingleson, M.J. (2014) Reactivity of (NHC)2FeX2 Complexes toward Arylborane Lewis Acids and Arylboronates. Organometallics, 33, 370-377.

[35]   Lu, W.Y., Cavell, K.J., Wixey, J.S. and Kariuki, B. (2011) First Examples of Structurally Imposing Eight-Membered-Ring (Diazocanylidene) N-Heterocyclic Carbenes: Salts, Free Carbenes, and Metal Complexes. Organometallics, 30, 5649-5655.

[36]   Anastas, P.T. and Waener, J.C. (1998) Green Chemistry: Theory and Practice. Oxford University Press, New York.

[37]   Mason, T.J. and Cintas, P.J. (2002) Handbook of Green Chemistry and Technology. Blackwell Science, Oxford.

[38]   Mason, T.J. (2007) Sonochemistry and the Environment—Providing a “Green” Link between Chemistry, Physics and Engineering. Ultrasonics Sonochemistry, 14, 476-483.

[39]   Luche, J.L. (1998) Synthetic Organic Sonochemistry. Springer, Boston.

[40]   Mason, T.J. and Peters, D. (2002) Practical Sonochemistry: Power Ultrasound Uses and Applications. 2nd Edition, Woodhead Publishing, London.

[41]   Li, J.T., Yin, Y., Li, L. and Sun, M.X. (2010) A Convenient and Efficient Protocol for the Synthesis of 5-aryl-1,3-diphenylpyrazole Catalyzed by Hydrochloric Acid under Ultrasound Irradiation. Ultrasonics Sonochemistry, 17, 11-13.

[42]   Li, J.T., Wang, S.X., Chen, G.F. and Li, T.S. (2005) Some Applications of Ultrasound Irradiation in Organic Synthesis. Current Organic Synthesis, 2, 415-436.

[43]   Mason, T. (1997) Ultrasound in Synthetic Organic Chemistry. Chemical Society Reviews, 26, 443-451.

[44]   Lindley, J. and Mason, T.J. (1987) Sonochemistry. Part 2: Synthetic Applications. Chemical Society Reviews, 16, 275-311.

[45]   Zinner, S.H. (2005) The Search for New Antimicrobials: Why We Need New Options. Expert Review of Anti-Infective Therapy, 3, 907-913.

[46]   Skrzypczak, A., Brycki, B., Mirska, I. and Pernak, J. (1997) Synthesis and Antimicrobial Activities of New Quats. European Journal of Medicinal Chemistry, 32, 661-668.

[47]   Dega-Szafran, Z. and Dulewicz, E. (2007) Synthesis and Characterization of 1-carbalkoxymethyl-4-hydroxy-1-methylpiperidinium Chlorides. Arkivoc, 2017, 90-102.

[48]   Brycki, B., Szulc, A. and Kowalczyk, I. (2010) Study of Cyclic Quaternary Ammonium Bromides by B3LYP Calculations, NMR and FTIR Spectroscopies. Molecules 15, 5644-5657.

[49]   Kourany-Lefoll, E., Pais, M., Sevenet, T., Guittet, E, Montagnac, A., Fontaine, C., Guenard, D., Adeline, M.T. and Debitus, C. (1992) Phloeodictines A and B: New Antibacterial and Cytotoxic Bicyclic Amidinium Salts from the New Caledonian Sponge, Phloeodictyon sp. Journal of Organic Chemistry, 57, 3832-3835.

[50]   Butorac, R.R., Al-Deyab, S.S. and Cowley, A.H. (2011) Syntheses, Structures and Antimicrobial Activities of bis(Imino)acenaphthene (BIAN) Imidazolium Salts. Molecules, 16, 3168-3178.

[51]   Johnson, N.A., Southerland, M.R. and Youngs, W.J. (2017) Recent Developments in the Medicinal Applications of Silver-NHC Complexes and Imidazolium Salts. Molecules, 22, 1263.

[52]   Ramirez, M.A., Ortiz, G., Levin, G., McCormack, W., Blanco, M.M., Perillo, I.A. and Salerno, A. (2014) Rapid and Efficient Synthesis of Five- to Eight-Membered Cyclic Aminals under Ultrasound Irradiation. Tetrahedron Letters, 55, 4774-4776.

[53]   Ramirez, M.A., Ortiz, G.M., Salerno, A., Perillo, I.A. and Blanco, M.M. (2012) A Novel Alkylation Procedure Using MW Irradiation for the Synthesis of 1,2,3-trisubstituted 1,4,5,6,7,8-hexahydro-1,3-diazocinium Salts from Their Corresponding 1,2-diaryldiazocines. Tetrahedron Letters, 53, 1367-1369.

[54]   Reverdito, A.M., Perillo, I.A. and Salerno, A. (2012) Synthesis and Synthetic Applications of 1-Aryl-2-alkyl-4,5-dihydro-1H-imidazoles. Synthetic Communications, 42, 2083-2097.

[55]   Caterina, M.C., Corona, M.V., Perillo, I.A. and Salerno, A. (2009) An Efficient Synthesis of 1-acyl-3-arylimidazolidines Catalyzed by Montmorillonite K-10 Clay under Microwave Irradiation. Heterocycles, 78, 771-781.

[56]   Shmidt, M.S., Reverdito, A.M., Kremenchuzky, L. Perillo, I.A. and Blanco, M.M. (2008) Simple and Efficient Microwave Assisted N-alkylation of Isatin. Molecules, 13, 831-840.

[57]   Patel, J.B., Cockerill, F.R., Bradford, P.A., Eliopoulos, G.M., Hindler, J.A., Jemkins, S.G., Lewis, J.S., Limbago, B., Miller, L.A., Nicolau, D.P., Powell, M., Swenson, J.M., Traczrwski, M.M., Turnidge, J.D., Weinstein, M.P. and Zimmer, B.L. (2015) Methods for Dilution Antimicrobial Susceptibility Test for Bacteria That Grow Aerobically, Approved Standard. Vol. 35, Tenth Edition, Clinical and Laboratory Standards Institute, Wayne.

[58]   Westman, J., Toft-Gard, R., Lauth, M. and Teglund, S. (2007) Hexahydropyrimidine, Tetrahydro Imidazole or Octahydroazepan Derivatives. WO Patent 2007/139492 A1.

[59]   Caterina, M.C., Figueroa, M.A., Perillo, I.A. and Salerno, A. (2006) 1,3-Dibromo-5,5-dimethylhydantoin as a New Imidazolidine Dehydrogenating Agent: Synthesis of 4,5-dihydro-1H-imidazolium Salts. Heterocycles, 68, 701-712.