Facile imine synthesis under green conditions using Amberlyst® 15

Introduction

Imines are fundamental intermediates in the synthesis of N-containing organic molecules which are biologically active (particularly alkaloids) or used in various industrial procedures (Kataja & Masson, 2014). Their formation via the condensation of amines with aldehydes or ketones is a reversible process (Kataja & Masson, 2014). In fact, the use of imines as intermediates in multicomponent reactions is very ubiquitous due to the same equilibrium which exists (Jin et al., 2014). Imine-based multicomponent reactions which have gained considerable attention in the past few years include: formation of quinolizidines and indolizidines via A³ coupling, other Mannich-type reactions (nitro-Mannich, aza-Friedel-Crafts, Petasis), and the intramolecular aza-Diels-Alder reaction (Rajesh, Purohit & Rawat, 2015; Kumar et al., 2014; Ramesh & Nagarajan, 2011).

In order to be able to drive the condensation process to completion, the classical method required azeotropic distillation by a Dean-Stark apparatus which obviously necessitated the use of excess amounts of solvents (Darling, 1966). Subsequently, alternative eco-friendly procedures were developed including the Schmidt reaction, the oxidative-dehydrogenation of amines and the oxidative coupling of alcohols and amines just to name a few (Adimurthy & Patil, 2013). Such procedures still may suffer from one or more of the following disadvantages: require expensive metallic catalysts, have a lower atom economy, require long reaction times, require the use of toxic solvents and show overall low environmental benignity (Darling, 1966; Adimurthy & Patil, 2013).

After the incorporation of the green chemistry principles into the synthetic chemistry modus operandi, following the works of Anastas & Warner (1998), the above mentioned syntheses were improved further and rendered more eco-friendly through the use of heterogeneous catalysts such as: sulfated-TiO₂, montmorillonite K-10 clay, sulfated nano-ordered silica and zeolites (Kumar et al., 2016; Atanassova et al., 2011; Naimi-Jamal, Ali & Dekamin, 2013; Amrutham et al., 2017). Further recently developed sustainable methodologies have been reported using irradiation techniques (Rizzuti et al., 2020). Moreover the addition of dehydrating agents such as phosphorous-pentoxide-silica have also been shown to drive the reaction to completion by removing the condensation product, ergo water (Naeimi et al., 2008). Obviously such agents require oven drying and reactivation for future re-use.

Another difficulty associated with this synthetic reaction is that in general, ketones are much less reactive when compared with aldehydes rendering ketimine synthesis even more unfavourable and non-green.

In the following research, in continuation of our interest in the application of heterogeneous catalysts (Bosica, 2021), herein we report how various heterogeneous catalysts and some desiccants were tried and compared in terms of activity and efficiency for the imine synthesis reaction. Amberlyst® 15, a cheap commercially available catalyst, is found to give the highest yields in short reaction times under neat conditions. In addendum, the unprecedented synthesis of the ketimine from the condensation of cyclohexanamine and cyclohexanone proved successful.

Experimental

Results and discussion

During the initial screening, the reaction between benzaldehyde (Scheme 1a) and t-butylamine (Scheme 2a) was chosen as the model reaction (Scheme 1). The latter was always performed at room temperature under quasi-solvent-free conditions in the presence/absence of a number of heterogeneous catalysts and desiccants. In addition, the molar ratios of the reagents and catalyst quantities were also varied. Table 1 shows the results of the preliminary catalyst/drying agent screening trials.

As evidenced, out of the catalysts and desiccants tried and tested, the best yields were obtained using Montmorillonite K-10, Amberlyst® 15 and acidic alumina. However, the work up of the reactions involving either MK-10 or acidic alumina required the addition of more solvent than that involving Amberlyst® 15 owing to their physical state (powder). Henceforth, Amberlyst® 15 (being in the form of macroporous beads) was selected for the subsequent optimization trials especially considering its ease of separation from the reaction mixture. In addition, it was discovered that a smaller amount of Amberlyst® 15 could result in even higher yields (Table 2) possibly owing to easier mechanical stirring and less product adsorption onto the catalyst beads.

One of the main limitations of the condensation of primary amines and aldehydes/ketones is the equilibrium which exists between the products and the substrates. This explains why in the initial trials the amine was used in excess, ergo, to shift the equilibrium forward. Yet, as outlined in Table 3, the yields remained practically the same even when the latter mentioned excess was decreased to 0.1 equivalents only.

Subsequently, having identified the ideal conditions (neat, room temperature, 0.2 g per 5 mmol Amberlyst® 15, 0.1 equivalent excess of amine), the substrate scope could be expanded by varying the aldehydes and the amines. In general, the best outcomes were obtained (Table 4) when using aromatic aldehydes and aliphatic primary amines due to the higher reactivity of the aldehydes as opposed to ketones and the greater nucleophilic character of aliphatic amines as opposed to aromatic amines.

Table 4:

Condensation of primary aliphatic amines with aromatic aldehydes using Amberlyst® 15 as catalyst.

Entrya	Aldehyde/Ketone	Amine	Product	Time (h)	Yield (%)b
1	1a	2a	3a	2	99
2	1b	2a	3b	3	96
3	1c	2a	3c	4.5	93
4	1d	2a	3d	4.5	98
5	1e	2a	3e	3	97
6	1f	2a	3f	2	97
7c	1g	2a	3g	80	NYd
8	1h	2a	3h	80	NYd
9	1a	2b	3i	1	99
10	1i	2b	3j	1	97
11	1c	2b	3k	3	93
12	1d	2b	3l	2.5	92
13c	1a	2c	3m	1	98
14c	1a	2d	3n	1	99

DOI: 10.7717/peerj-ochem.7/table-4

Notes:

a All reactions carried out under solventless conditions at RT using 0.2 g Amberlyst® 15 on a 5 mmol scale using an amine equivalent excess of 0.1.

b Yield of pure isolated product collected after work-up and purification.

c Reactions carried out in a 1:1.5 aldehyde/ketone:amine molar ratio.

d No pure product collected.

Positively, despite their inherent lack of reactivity, aromatic amines also gave appreciable yields as outlined in Table 5. Not only, but the primary aliphatic amine, c-hexylamine, was able to react successfully with the cyclic ketone, cyclohexanone (Scheme 2) to give the product (Scheme 3s) in 85% yield.

Table 5:

Condensation of aromatic primary amines with aromatic aldehydes.

Entrya	Aldehyde	Amine	Product	Time (h)	Yield (%)b
1	1a	2e	3o	3	72
2	1b	2e	3p	2.5	81
3	1c	2e	3q	4	75
4c	1e	2f	3r	3	90

DOI: 10.7717/peerj-ochem.7/table-5

Notes:

a All reactions carried out under solventless conditions using 0.2 g Amberlyst® 15 on a 5 mmol scale using an aldehyde/ketone:amine molar ratio of 1:1.1.

b Yield of pure isolated product collected by recrystallization from ethanol.

c Reactions carried out using a 1:1.5 aldehyde/ketone:amine ratio.

Lastly, the catalyst exhibited good recyclability because the model reaction could be repeated up to five times with the same catalyst with the yield decreasing by 10% between the first and last trial (Fig. 1). The latter decrease is most probably a result of sulfonic acid group inactivation by the reaction with the amine reactant.

Conclusions

The heterogeneous, safe-to-handle, relatively-cheap and commercially-available Amberlyst® 15 was found to be the ideal catalyst for the synthesis of various imines using both aliphatic and aromatic amines and aromatic aldehydes (72–99% yields, 17 examples) in significantly short reaction times (2–4 h) at room temperature in neat conditions. The catalyst morphology, i.e., being in the form of macroporous beads, enabled it to be easily recovered with minimal solvent use during work up and reused for up to five times.

Supplemental Information