Experimental investigation on the correlation between the physicochemical properties and catalytic activity of six DESs in Kabachnik-Fields reaction

Physicochemical properties of six Type IVDeep eutectic solvents formed from ZrOCl2.8H2O/ CeCl3.7H2O with urea, ethylene glycol & glycerol were compared. The study was performed by correlating the properties of DESs with their activity in Kabachnik-Fields reaction. Among the six DESs, lower density, viscosity, higher acidity & thermal stability were observed for DES 1(Deep eutectic solvent developed from ZrOCl2.8H2O and urea at 1: 5 ratio) and is reported as an excellent catalyst and reaction medium for the productive synthesis of α-aminophosphonates within a short period of time. One pot reaction of an aldehyde, dimethyl phosphite and amine (Kabachnik-Fields/ Phospha-Mannich reaction) took place at room temperature to give the corresponding α-aminophosphonates in good yield and the precipitation of these products in to water avoided the regular work up process. Catalyst was recycled up to five times without any loss in its activity.


Introduction
Due to the versatile activity, organophosphorous compounds have found extensive applications in industrial, agricultural, and medicinal fields and for transition-metal-catalyzed reactions, phosphine-containing compounds represent the conventional choice of ligands. [1][2][3][4] In recent years, α-aminophosphonates have obtained much attention and are major class of compounds in pharmaceutical chemistry, especially in the field of drug discovery, due to their biological activity and low mammalian toxicity. 5,6 Because of their effect as enzyme inhibitors, inhibitors of GABA receptors, α-aminophosphonates are very essential in the 2 development of antibiotics, antitumour agents, antihypertensive, antiviral species, anticlotting agent, antibody production etc. [7][8][9] The activities of α-aminophosphonates, such as HIV protease, 10 peptide mimics, 11 insecticides, herbicide and fungicides 12 etc. are also reported in the literature. They are phosphorous analogues of the corresponding α-aminoacids (bioisosterism), in which the carboxylic group (planar) is replaced by a phosphonic acid (tetrahedral functionality), acting as antagonist of amino acids. 13 The main synthetic routes for α-aminophosphonates are the Kabachnik-Fields reaction (condensation of amines, oxocompounds and >P(O)H species, such as dialkyl phosphites) and the Pudovik reaction of imines and >P(O)H reagents (Scheme 1). 7 The addition of phosphorus-hydrogen bond to electrophilic centers like C=O or C=N is a fascinating topic in synthetic organic chemistry. 14

Scheme 1 Common routes towards α-aminophosphonate synthesis
Of these, Kabachnik-Fields reaction is the most important pathway because of its one pot three component procedure and was observed when multicomponent processes were rather "exotic birds". 16 Three starting materials are involved in the reaction in which all of them are incorporated in the final product structure.

Experimental Preparation of DES
Preparation and recycling process of all the six deep eutectic solvents were done based on the procedure given in the previous papers. 35,36 General procedure for α-aminophosphonate synthesis A mixture of aldehyde (1 mmol), amine (1 mmol), dimethyl phosphite (DMP= 1 mmol) and DES was stirred at room temperature for the time as indicated in Table 2 & 3 (progress was monitored using TLC). After completion of the reaction, sufficient amount of distilled water was added and the αaminophosphonate precipitated was filtered and analysed by TLC, GCMS, FTIR, 1 H NMR, 13 C NMR and melting point measurements. was a contributing factor to the increase of density value as shown by the results. This is due to the formation of 3D network of hydrogen bonds through the interactions between glycerol and anions, which resulted in a closely packed structure and an increase in density. 41 Lowest density was observed when urea was paired with ZrOCl2.8H2O (Table 1, entry 1). In general, this difference in density of DESs is due to the varying degrees of hydrogen bonds in these systems.

Acidity
The knowledge of the acidity of DESs is very important for their application in different fields and is the main factor that determines their catalytic activity. The acidic or basic strength of the DESs is strongly dependent on the chemical nature of the HBDs and the metal salt hydrates. Here, the acidity of DESs was determined by FTIR study (using pyridine as probe (Py-IR)) and pH measurement (using pH meter). A peak at 1450 cm -1 indicated the Lewis acidity and peak at 1640 cm -1 & 1540 cm -1 indicated Brønsted acidity, Details are given in previous reports. 35  respectively) and were much lower than DES 1; but higher than DES 2 & DES 3. The results are given in Table 2.  The figures were published before in refs. [35] (DES 1 to DES 3) and [36] (DES 4 to DES 6). 3 The data were published before in refs. [35] (DES 1 to DES 3) and [36] (DES 4 to DES 6).

Thermal stability
Similarly, the information about the thermal stability of DESs is very important for their application at higher temperatures and is dependent upon the hydrogen bond donors used. TG curve of six DESs are given below (Figure 2

Catalytic activity
To varify the applicability of DESs, Kabachnik-Fields reaction was performed with all the six DESs and the activity was correlated with the physicochemical properties of the six DESs.
Initially, a mixture of benzaldehyde (1 mmol), aniline (1 mmol) and dimethyl phosphite (1 mmol) was stirred at room temperature without any solvent and catalyst. The reaction did not progress even after 4 h, which indicated the necessity of a catalyst in this reaction (   The catalytic activities of DESs are mainly dependent upon their physicochemical properties like density, viscosity, acidity etc. Among the six DESs, quantitative conversion was observed using DES 1( with lower density, viscosity and higher acidity and thermal stability ) and was found to be the most effective catalyst compared to others and solid product was formed instantly by the addition of the catalyst which restricted further stirring.

Two pathways for Kabachnik-Fields reaction was introduced by Cherkasov et al. A)
nucleophilic addition of amine to aldehyde followed by the addition of phosphite to imine.
B) The second one involves the formation of αhydroxyphosphonate by the nucleophilic addition of dialkylphosphite to the carbonyl compound followed by the displacement of hydroxyl group by the amino group (Abramov reaction). 14 Keeping this in mind, benzaldehyde was treated with a) aniline b) dimethylphosphite in the presence of DES 1 in separate experiments to propose a plausible mechanism. Imine formation was observed in the former (GC-MS) and αhydroxyphosphonate was not observed in the latter (Scheme 2). In order to establish the result, the reaction was repeated using the aldehydes in Table 3, the outcome was the same. Hence, it was confirmed that the mechanism followed the pathway A (imine forming pathway). Also, the order of addition of reactants did not have any effect in the reaction, like product yield, purity etc. DES

Scheme 3 Mechanism for DES 1 catalysed Kabachnik-Fields reaction
Initially, DES interacted with the carbonyl group of the benzaldehyde to form an activated complex, followed by the generation of imine through the nucleophilic addition of aniline to the activated complex. In the presence of the catalyst, the carbon of imine was attacked by phosphite and the desired αaminophosphonate was formed with the regeneration of the catalyst. With these conditions in hand, the attention was focussed to assess the functional group resilience of this reaction with DES 1. For that, various aldehydes, amines and dimethyl phosphite were subjected to a one pot three component reaction catalysed by DES 1. Corresponding αaminophosphonates were formed in good to excellent yield and the outcome is summarised in Table 4. 12  Both electron withdrawing/ donating groups on the aromatic aldehyde reacted efficiently with excellent yield. The reaction conditions were very gentle and αaminophosphonates were formed without the formation of any side products (with all the substrates used, αhydroxyphosphonates were not formed due to the rapid formation of iminium species).Various aromatic amines reacted neatly with excellent yields.
At first, the reaction was performed by using benzaldehyde/ monosubstituted benzaldehydes with aniline/ substituted anilines; excellent yields were obtained for all the derivatives (both electron donating and electron withdrawing), the results are tabulated in  8 Here, the synthesis of the catalyst was a tedious process (the crucial synthesis of Fe3O4 nanoparticles was followed by the synthesis of Fe3O4@ZrO2/SO4 2-) and also required higher temperature and time ( Here also, more steps were involved in the catalyst preparation process (three steps were involved here; first, synthesis of Fe3O4, then synthesis of silica-coated Fe3O4 and finally synthesis of Fe3O4@SiO2-PTA). In addition to this, prolonged reaction time was required for the synthesis of αaminophosphonates (Table 5, Entry 2). The study was extended to other catalysts mentioned in Table 5. An organocatalyst, pentafluorophenylammonium triflate (PFPAT) was also used as catalyst in Kabachnik-Fields reaction in 2014. 19 The reaction was completed within 60 min with the use of volatile organic solvent (Toluene). The details are given in Here also the reaction was completed after 1h with the use of acetonitrile as solvent (

Recyclability of DES 1
After completion of the reaction, the product was washed with water and filtered off and the catalyst obtained in the water layer was recycled 35,36 and reused up to 5 runs without any noticeable loss in catalytic activity and the results are summarised in Table 6. which led to the preparation of task specific DES. By this way, DES with lower viscosity could be prepared, which was one of the main issues related with DESs in organic synthesis.
Among the six DESs, lower density, viscosity and higher acidity and thermal stability was observed for DES 1 (ZrOCl2.8H2O with urea at 1:5 ratio) and was found to be a magnificent catalyst for Kabachnik Fields reaction and could replace many harmful catalysts and volatile solvents. The dominance of this method includes simple procedure, benign reaction conditions, free from organic solvents, broad application scope, cost effectiveness, outstanding yield, easy separation of products and renewability of the catalyst (reusability has been achieved up to 5 runs, without any influence in its activity). In addition to this, the wide substrate scope was scrutinised by synthesising 22 different αaminophosphonate derivatives in the present work. The products were characterised by TLC, GCMS, 1 HNMR, 13 CNMR, and melting point measurements (Supporting Information File).