An Easy Approach to Obtain Alcohol-Amines by Reduction of Alcohol Functionalized Imines ^†

Abstract

The reduction of functionalized imines to yield amines is often an intricate task, since most of the methods described in the literature to reduce imines to amines do not take into account that many reducing agents have also basic character. In this way, iminic compounds that have phenol functions usually produce the phenolic salt of the precursor when they are treated with a basic reducing agent, but not the desired amine. In this work, we describe an easy way of isolating very pure aminic compounds with alcoholic functions in its structure from the corresponding iminic compounds, by using NaBH₄ as a reducing agent, and avoiding tedious chromatography or multiple solvent extraction steps.

1. Introduction

Polydentate organic compounds containing amines in their structures are useful Lewis bases in coordination chemistry. Nevertheless, this kind of polydentate amine is often difficult to prepare. However, the analogous imine ligands are usually easier to obtain, by simple condensation of a carbonyl and an amine precursor [1,2]. Accordingly, an advantageous approach to isolate polydentate amines is by the reduction of the corresponding imine analogous.

The reduction of imines to isolate amines is a well-known field of study. In fact, it is one of the central reactions in organic chemistry, and the search for more efficient and practical synthetic methods for carrying out this reduction is a theme of constant interest [3,4,5]. Many reduction agents have been tested in order to produce the mentioned transformation, and H₂ [6], silanes [7,8], boranes [9], and borohydrides [10] are maybe the most popular ones. Among them, sodium borohydride is commonly chosen to reduced polydentate Schiff bases to amines, because it is cheap and its excess is easily destroyed by an acid medium [11,12]. Nevertheless, success in the reduction process depends on many factors. Thus, the basic character of this reduction agent and the fact that some of the NaBH₄ present in the reaction medium can be consumed by acid groups present in the Schiff base, like phenolic functions, are features that are often not considered, preventing the isolation of the desired amine. Besides, the time of the reaction, the election of the solvents of reaction and extraction are also critical. In addition, in numerous synthetic related methods, many steps for adjusting the pH of the medium, drying the reaction media, extracting and purifying the obtained amine are necessary, and sometimes the isolation of amines from imines becomes a cumbersome process.

With these considerations in mind, and as a result of many attempts of isolating a new alcohol-amine ligand from the corresponding imine, we describe herein an easy method to reduce an aromatic imine-alcohol precursor.

2. Materials and Methods

2.1. Materials and General Methods

All chemical reagents and solvents were purchased from commercial sources and used as received without further purification. Elemental analyses of C, H, and N were performed on a FISONS EA 1108 analyzer. Infrared spectra were recorded in the ATR mode on a Varian 670 FT/IR spectrophotometer in the range 4000–500 cm⁻¹. ¹H NMR spectra were recorded on a Bruker DPX-250 spectrometer, using DMSO-d₆ as a solvent. Selective NOEs spectra were recorded in DMSO-d₆ as a solvent on a Varian Inova 400 spectrometer.

2.2. Syntheses of the Alcohol-Imine and Its Reduction to Alcohol-Amine

Bis{2,6-bis[(2-hydroxy-5-methylphenyl)-iminomethyl]pyridine} (H₂L¹, Scheme 1) was obtained as a non-hydrated compound by a small modification of a procedure previously reported in the literature [13], by using absolute ethanol instead of ethanol, and by drying the compound in a laboratory oven. H₂L¹ was fully characterized by elemental analysis, IR and ¹H NMR spectroscopy. Yield: 79%. MW: 345.39. Anal. calcd. for C₂₁H₁₉N₃O₂: C 72.86, H 5.54, N 12.16%. Found: C 72.17, H 5.62, N 12.43%. IR (ATR, $\tilde{v}$/cm⁻¹): 3392, 3346 (OH), 1623 (C=N_imine), 1595 (C=N_Py). ¹H NMR (250 MHz, DMSO-d₆): δ 9.07 (s, 2H, OH), 8.79 (s, 2H, H4), 8.48 (d, 2H, H2,), 8.09 (t, 1H, H1), 7.16 (s, 2H, H6), 6.96 (d, 2H, H10), 6.83 (d, 2H, H9), 2.25 (s, 6H, CH₃).

Syntheses of bis{2,6-bis[(2-hydroxy-5-methylphenyl)-aminomethyl]pyridine (H₄L², Scheme 1). This ligand was obtained by a modification of a method previously reported [14], and that is detailed as follows: To a suspension of H₂L¹ (0.214 g, 0.616 mmol) in methanol (20 mL), NaBH₄ (0.050 g, 1.232 mmol) is added in small portions during 30 min, and a very pale yellow solution is obtained. The solution is concentrated to dryness and the oily residue obtained is dissolved in 15 mL of 10% H₃PO₄. The solution is basified with NaOH 10% up to pH = 7, and a yellow solid precipitate. The mixture is extracted with ethyl acetate (150 mL), and the organic phase is dried with Na₂SO₄ during 1 h, and filtered. The solution is concentrated to dryness, and the obtained yellow residue is treated with hexane. After stirring the mixture for 30 min, a pale yellow solid precipitate; this is filtered and dried in air. Yield: 0.11 (51%). MW: 349.43. Anal. calcd. for C₂₁H₂₃N₃O₂: C 72.18, H 6.63, N 12.03%. Found: C 71.90, H 6.87, N 11.89%. IR (ATR, $\tilde{v}$/cm⁻¹): 3437 (OH), 3267 (NH), 1600 (C=N_Py). ¹H NMR (250 MHz, DMSO-d₆): δ 9.05 (s, 2H, OH), 7.67 (t, 1H, H1), 7.19 (d, 2H, H2), 6.56 (d, 2H10), 6.24–6.20 (m, 4H, 2H6 + 2H9), 5.45 (s, 2H, NH), 4.37 (s, 4H, CH₂), 2.07 (s, 6H , CH₃).

3. Results and Discussion

3.1. Synthesis

H₄L² could be obtained from H₂L¹, according to Scheme 1, after various attempts to reduce the imine bond of H₂L¹ with different reducing agents, and under different reaction conditions. Accordingly, the treatment of diimine H₂L¹ with NaBH₄ in 1:4 molar ratio, followed by acidification with hydrochloric acid, in line with a synthetic method previously described [15], was unsuccessful. Nevertheless, a second approach using NaBH₄, followed by treatment with phosphoric acid, and with control of the reaction time, allows isolating the alcohol-amine H₄L² with high purity. This method supposes a modification of an already related one [14], where both diimine precursor and NaBH₄ are mixed in 1:1 molar ratios. In our case study, when the diimine H₂L¹ is treated with the reducing agent in 1:1 molar ratio, H₂L¹ does not lose its yellow color, suggesting that the reduction of the imine group does not take place. Nevertheless, if H₂L¹ and NaBH₄ are mixed in 1:2 molar ratios, the reduction proceeds.

H₄L² was unequivocally identified by a combination of elemental analysis, IR and ¹H NMR spectroscopy techniques.

3.2. Spectroscopic Characterization

IR Spectroscopy

The IR spectroscopy was a useful technique for detecting the reduction of the imine group of H₂L¹. Thus, when the IR spectrum of H₄L² was compared with that of H₂L¹, some changes that became apparent unequivocally point to the reduction of the imine group. In this sense, the following facts are observed:

• The ν(C=N_imine) band, present in the spectrum of H₂L¹ at 1623 cm⁻¹, is absent in the spectrum of H₄L².
• The spectrum of H₄L² shows a sharp band at 3437 cm⁻¹, which can be assigned to an N-H vibration, and that is absent is the spectrum of H₂L¹.

Accordingly, both facts, i.e., the disappearance of the imine vibration and the appearance of a new band assigned to an N-H vibration, agree with the reduction of the imine group and the isolation of the alcohol-amine H₄L².

The ¹H NMR studies are even more conclusive. First of all, the ¹H NMR spectra of both H₂L¹ and H₄L² suggest their isolation with high purity. In addition, the comparison of the ¹H NMR spectra of both samples (Figure 1) shows some remarkable differences, which agree with the reduction of the imine functional group by NaBH₄. In this way, the following is observed:

• The singlet at 8.79 (2H) ppm, assigned to the imine nitrogen atoms H₄ in the spectrum of H₂L¹, is absent in the spectrum of H₄L².
• All the aromatic hydrogen atoms are displaced to a higher field in the spectrum of H₄L² with respect to that of H₂L¹, in agreement with less delocalization of the charge.
• The spectrum of H₄L² shows two new singlets with respect to that of H₂L¹. These singlets are located at 5.45 (2H) and 4.37 (4H) ppm, and can be assigned to the protons of NH and CH₂ groups, respectively.

Therefore, the ¹H NMR spectra clearly confirm the isolation of the desired alcohol-amine. In addition, selective NOE experiments were performed for H₄L², with the aim of unequivocally assigning the three kinds of aromatic protons that lead to doublet signals (H2, H9, and H10, Figure 1), information that has also been useful to assign the protons in the region 8.5–6.8 for H₂L¹. Accordingly, selective irradiation of the triplet peak corresponding to H1 allows identifying the doublet at 7.19 ppm as that corresponding to H2. In the same way, selective irradiation of H8, allows locating both H9 protons in the multiplet at 6.20–6.24 ppm. Therefore, the only remaining doublet at 6.56 ppm is assigned to H10.