In the field of organic syntheses, the development of environmentally friendly methods based on the concept of green chemistry has been always required. In response to this requirement, we reported solvent- and catalyst-free syntheses of imines using the pressure reduction technique as a key technology. We found that this reaction proceeded very rapidly in the initial stage, but its rate decreased with the passage of time. It was also found that the reaction of benzaldehyde with aniline had a specificity that the phase transition occurred. In this method, the desired imines could be obtained in good to excellent yields, but target compounds had to be given by purifications using organic solvents. Therefore, we tried to develop the perfect synthetic method of imine derivatives without organic or inorganic solvents. We selected two methods and took them into this investigation. One was exactly mixing (1:1, substance ratio) aldehydes and amines and the other was employing lower pressure (>0.1 mmHg, previous method: 1.0 mmHg) at the pressure reducing technique. When this improved synthetic method was performed, it was revealed that pure target imines were obtained in excellent yields without any purification.
From the viewpoint of green chemistry, it was considered that using organic solvents in organic syntheses aimed at formation convenient compounds was not environmentally friendly, in recent years. Several attempts have been made to avoid using organic solvents in organic synthetic methods. Among them, the method attracting attention was to use water instead of an organic solvent [
In this paper, we will report the details of the improved reaction method.
Standard bench top techniques were employed for handling air-sensitive reagent. Liquid aromatic aldehydes and all amines were distilled under argon before use. p-Bromobenzaldehyde and p-chlorobenzaldehyde were purified by recrystallization before use. All reactions were carried out under nitrogen atmospheres. All yields of target compounds were isolated yields. ULVAC G-50DA (ULVAC KIKO Inc.) was used for carrying out this reducing pressure operation. IR spectra were recorded on an FT/IR-610 (JASCO) spectrophotometer. 1H-NMR, 13C-NMR and 19F-NMR spectra were measured on Bruker BioSpin AVANCE III 400 Nanobay spectrometer at 400.1, 100.6 and 376.5 MHz, respectively. Chemical shifts were given in ppm relative to TMS (1H and 13C) or CFCl3 (19F).
To a stirring p-tolualdehyde (1.20 g, 10.0 mmol) was added dropwise o-toluidine (1.07 g, 10.0 mmol) at 25˚C After 1.5 hours, the reaction system was connected to a vacuum pump, the pressure was reduced to >0.1 mmHg (13.3 Pa) and stirred for 3.0 hours to give the desired pure compound (Compound 1) as a pale yellow clear oil in 99% yield (2.06 g) without any purification. All physical properties of this product were completely consistent with literature values [
p-Tolualdehyde (1.20 g, 10.0 mmol) reacted with m-toluidine (1.07 g, 10 mmol) to give the corresponding pure compound (Compound 2) in 99% yield (2.06 g) as a colorless crystal in the same manner of procedure 1. All physical properties of this product were completely consistent with literature values [
p-Tolualdehyde (1.20 g, 10.0 mmol) reacted with p-toluidine (1.07 g, 10 mmol) to give the corresponding pure compound (Compound 3) in 98% yield (2.05 g) as a colorless crystal in the same manner of procedure 1. All physical properties of this product were completely consistent with literature values [
p-Anisaldehyde (1.36 g, 10.0 mmol) reacted with o-toluidine (1.07 g, 10 mmol) to give the corresponding pure compound (Compound 4) in 99% yield (2.24 g) as a colorless crystal in the same manner of procedure 1. All physical properties of this product were completely consistent with literature values [
p-Anisaldehyde (1.36 g, 10.0 mmol) reacted with m-toluidine (1.07 g, 10 mmol) to give the corresponding pure compound (Compound 5) in 99% yield (2.24 g) as a colorless crystal in the same manner of procedure 1. All physical properties of this product were completely consistent with literature values [
p-Anisaldehyde (1.36 g, 10.0 mmol) reacted with p-toluidine (1.07 g, 10 mmol) to give the corresponding pure compound (Compound 6) in 98% yield (2.21 g) as a colorless crystal in the same manner of procedure 1. All physical properties of this product were completely consistent with literature values [
To a stirring p-tolualdehyde (1.20 g, 10.0 mmol) was added dropwise benzylamine (1.07 g, 10.0 mmol) at 25˚C. After 2.0 hours, the reaction system was connected to a vacuum pump, the pressure was reduced to >0.1 mmHg (13.3 Pa) and stirred for 3.0 hours to give the desired pure compound (Compound 7) as a white solid in 97% yield (2.03 g) without any purification. All physical properties of this product were completely consistent with literature values [
p-Anisaldehyde (1.36 g, 10.0 mmol) reacted with benzylamine (1.07 g, 10 mmol) to give the corresponding pure compound (Compound 8) in 100% (2.25 g) as a colorless crystal in the same manner of procedure 2. All physical properties of this product were completely consistent with literature values [
p-Fluorobenzaldehyde (1.24 g, 10.0 mmol) reacted with benzylamine (1.07 g, 10 mmol) to give the corresponding pure compound (Compound 9) in 99% (2.11 g) as a pale yellow clear oil in the same manner of procedure 2. All physical properties of this product were completely consistent with literature values [
p-Chlorobenzaldehyde (1.41 g, 10.0 mmol) reacted with benzylamine (1.07 g, 10 mmol) to give the corresponding pure compound (Compound 10) in 99% (2.27 g) as a colorless crystal in the same manner of procedure 2. All physical properties of this product were completely consistent with literature values [
p-Bromobenzaldehyde (1.85 g, 10.0 mmol) reacted with benzylamine (1.07 g, 10 mmol) to give the corresponding pure compound (Compound 11) in 100% (2.74 g) as a colorless crystal in the same manner of procedure 2. All physical properties of this product were completely consistent with literature values [
We found that target imines were obtained in excellent yields easily when aldehydes and amines were mixed without a solvent and a catalyst. Some results of reactions of p-tolualdehyde or p-anisaldehyde with various type toluidines were summarized in
p-Tolualdehyde reacted with o-toluidine for 1.5 h without any solvent followed by the vacuum operation (3.0 h) to give the corresponding imine (Compound 1) in 99% yield (entry 1). In this reaction method, any purification, for example, a column chromatography with organic solvents and so on, of the target compound was not needed. The corresponding pure imine (by 1H-NMR analysis, purity: over 99.5%) was obtained. This methodology could be applied to the case of m-toluidine and p-toluidine. When p-tolualdehyde and m-toluidine were stirred under nitrogen for 1.5 h, the target compound (Compound 2) was obtained, quantitatively (entry 2) after the vacuum operation. We also found that p-tolualdehyde reacted with p-toluidine, in the same manner, to give the target imine (Compound 3) in excellent yield (entry 3). Interestingly, an aldehyde that was inert to a nucleophilic reaction could be also used as a starting material for this synthetic method. p-Anisaldehyde was inactive for the nucleophilic reaction because it had a strong electron-donating group (methoxy group) at p-position. When this type of reaction using p-anisaldehyde and o-toluidine as starting materials was carried out, the target compound (Compound 4) was obtained in 99% yield (entry 4). m-Toluidine and p-toluidine also reacted with p-anisaldehyde smoothly, and products (Compounds 5 and 6) were given in 99% yield and 98% yield (entries 5 and 6). It was reported that Compound 1 was obtained in the highest yield (96%) when formic acid, water, and ethanol were used as a catalyst and solvents in the previous study [
Some aldehydes were examined as starting materials for this imine formation and results were shown in
When aromatic aldehydes having weak or strong electron-donating groups, such as methyl group and methoxy group, were employed as substrates, pure target imines (Compounds 7 and 8) were obtained in 97% yield and 100% yield (entries 1 and 2). This phenomenon indicated that the ability of electron-donation of a substituent at p-position of the aromatic aldehyde did not affect the yield of an imine at all. Halogenated aromatic aldehydes were also used as starting compounds in this synthetic method. The fluorinated imine derivative (Compound 9) was given in excellent yield by the reaction of p-fluorobenzaldehyde and benzylamine (entry 3). Furthermore, p-chlorobenzaldehyde and p-bromobenzaldehyde could be used as substrates in this reaction system to give target compounds (Compounds 10 and 11) in 99% yield and 100% yield (entries 4 and 5). In previous synthetic methods of Compounds 7, 8, 9, 10 and 11, these compounds were obtained in over 90% yields [
It was revealed that our methodology was superior to the previous one for the synthesis of an imine derivative, because of two reasons that were led from facts in
In this paper, we reported that perfect solvent- and catalyst-free syntheses of imine derivatives use the pressure reduction technique. This synthetic reaction proceeded under mild conditions, and desired imines were obtained in excellent yields. In this synthetic method, there were two important key-techniques. When aldehydes and amines were mixed exactly 1:1 (substance ratio) and reduced the pressure of the reaction pod under >0.1 mmHg at the end of this reaction, target imines were obtained, quantitatively. The scope and limitation of this synthetic method are now unknown. Further investigation is in progress.
The authors declare no conflicts of interest regarding the publication of this paper.
Suzuki, S., Ito, H., Ishizuka, S., Nonaka, R., Noike, M., Kodama, T., Funaki, K., Taguchi, M., Kagaya, T., Sato, S., Redler, G. and Yokoyama, Y. (2019) Perfect Solvent- and Catalyst-Free Syntheses of Imine Derivatives Using the Pressure Reduction Technique. Green and Sustainable Chemistry, 9, 105-118. https://doi.org/10.4236/gsc.2019.94008