A new, efficient and recyclable [Ce(L-Pro)]₂(Oxa) heterogeneous catalyst used in the Kabachnik–Fields reaction

Abstract

Herein we introduce a new catalyst for the Kabachnik–Fields reaction, [Ce(L-Pro)]₂(Oxa), using a very accessible, simple and efficient methodology for α-aminophosphonate synthesis using an aromatic aldehyde, an aromatic amine and diphenyl phosphite. This procedure was developed using a low catalyst loading of cerium(III) prolinate and it has allowed for the recycling of the catalyst.

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Introduction

Organophosphorus compounds are useful building blocks for medicinal applications. Among them, aminophosphonic acids are a class of organic compounds that have attracted the attention of many research groups around the world because this class has frequently presented some biological properties such as antibacterial, antithrombotic, and anti-inflammatory properties, and can be used as anticancer drugs, pesticides and HIV protease inhibitors.^1,2 Besides, the synthesis of aminophosphonic derivatives has achieved considerable importance due to their structural analogy with aminoacids.³ For this reason, several methodologies have been developed for the synthesis of α-aminophosphonates. Among them, the Kabachnik–Fields reaction is one of the easiest and most direct approaches, as it is carried out using an aldehyde, an amine and diphenyl phosphite.⁴ Usually, this reaction could be catalysed by Lewis acids, such as SnCl₂, SnCl₄, ZnCl₂ and MgBr₂, but these reactions cannot be done in one-pot.⁵ Among the many synthetic approaches for α-aminophosphonate synthesis, the nucleophilic addition of phosphites to imines is the most useful method. However, many imines are hygroscopic and are not stable for isolation.⁶ Moreover, this procedure usually involves long reaction times, difficult procedures, low yields, the use of stoichiometric amounts of catalyst and difficulties with separation and recycling, and generally only dialkyl phosphites are used as phosphorus reagents.^7,8 Due to the biological potential of α-aminophosphonates, the development of a new and simple method that enables the use of many types of phosphorus reagent, mainly less reactive types such as aryl phosphites, and applies a reusable catalyst in a one-pot methodology has become necessary.^9,10 It is observed that lanthanides have greater effects on the α-aminophosphonate reaction.¹¹ The first example using lanthanide complexes for the synthesis of α-aminophosphonates was described by Shibasaki¹² et al. using lanthanum–potassium–BINOL, however, the authors unfortunately described the use of high catalyst loading (5–20 mol%). Furthermore, it is widely known that lanthanoid complexes used as catalysts represent an efficient method to produce high yields and high enantiomeric excess in reactions of α-aminophosphonates.¹³ For these reasons, it is important to develop a new, efficient and green catalyst which may be used in the Kabachnik–Fields reaction. Our research group has worked on the application of some hybrid heterogeneous catalysts in many organic reactions, e.g. thio-Michael reactions, but all the catalysts contained zinc metal.¹⁴ In order to modify the catalyst we herein present oxalate cerate (III) – N,O-(L)-prolinate or [Ce(L-Pro)]₂(Oxa) (Fig. 1) as a heterogeneous catalyst in the Kabachnik–Fields reaction. In other words, herein, we report an eco-friendly, easy and efficient methodology for the synthesis of α-aminophosphonates using [Ce(L-Pro)]₂(Oxa) as the catalyst. This catalyst can be separated using filtration and can be reused in the reaction and it is almost insoluble in any solvent.

Fig. 1 Proposed structure of [Ce(L-Pro)]₂(Oxa).

Experimental section

General methods

All chemical reagents and solvents were used without any specific treatment. The respective reactions were monitored using thin layer chromatography (TLC) MACHEREY-NAGEL (SIL G/UV₂₅₄). The purification of the compounds was performed through recrystallization from chloroform/hexane at 65 °C. ¹H and ¹³C NMR spectra were recorded in CDCl₃ on a Bruker spectrometer (300 MHz and 75 MHz, respectively). The infrared spectra were recorded on a FT/IR 4100 type A spectrometer of Jasco.

Preparation of the catalyst

[Ce(L-Pro)]₂(Oxa) was synthesized from proline (2.7 mmol) in methanol (15 mL) and aqueous sodium hydroxide solution (2.7 mmol in 1 mL) at room temperature for 10 minutes. After that, cerium(III) chloride (1.4 mmol) was added and the reaction mixture was stirred for 45 minutes and a few drops of sodium oxalate solution (0.1 g mL⁻¹) were added as a precipitating agent. The semi-solid was centrifuged, washed with methanol and dried overnight at 40 °C and a pale yellow semi-solid was obtained.

General procedure for the preparation of α-aminophosphonates

Aldehyde (2.2 mmol), aniline (2 mmol), diphenyl phosphite (2 mmol) and the [Ce(L-Pro)]₂(Oxa) catalyst (1 mol%) were added to toluene (10 mL) with magnetic stirring at room temperature. The progress of the reaction was monitored using TLC (eluent: EtOAc/hexane, 10 : 90). After the reaction was complete the catalyst was separated using filtration.

After the product was purified through recrystallization (chloroform/hexane) the α-aminophosphonates were obtained.

Results and discussion

First of all, we performed the synthesis of the catalyst using the same procedure described by Darbem¹⁴, here using a cerium salt (CeCl₃·H₂O) (see the ESI for more information about the synthesis†). After the reaction the semi-solid was analysed using FTIR and XRD and the data is presented in Fig. 2 and 3, respectively.

Fig. 2 IR spectrum of Ce[(L-Pro)₂(Oxa)] in KBr.

Fig. 3 X-ray diffraction patterns of proline (a), cerium chloride (b), sodium oxalate (c) and [Ce(L-Pro)]₂(Oxa) (d).

From the analysis of the FTIR spectrum, we observed that ν_C=O for [Ce(L-Pro)]₂(Oxa) was shifted to a higher frequency (1636 cm⁻¹) which indicated that oxygen (sp³) was bonded to the cerium atom and this interaction increased the bond order of the carbonyl group. Furthermore, we observed a decrease in frequency for ν_C–O in the cerium complex, from 1380 for proline to 1322 cm⁻¹ for [Ce(L-Pro)]₂(Oxa), which indicated the same interaction previously described. At the end, we observed that the band at 780 cm⁻¹ indicates the interaction between nitrogen and cerium. It is worth mentioning that the band at 3427 cm⁻¹ is due to the presence of water in the catalyst structure. All these results are in concordance with the literature data for similar compounds containing cerium.¹³ We also obtained the X-ray diffraction patterns from the analysis of all the starting materials and [Ce(L-Pro)]₂(Oxa) and the data is presented in Fig. 3. The results enabled us to observe that even proline and sodium oxalate are very well crystallized, and these diffraction peaks can be indexed as the references.¹³ The starting materials and the catalyst presented a different pattern with X-ray diffraction, which indicated the success of the synthesis. Besides, from the analysis of literature for a similar compound containing cerium and a different amino acid in the structure, we observed that the X-ray data was very similar.^15,16

After this analysis, we used [Ce(L-Pro)]₂(Oxa) in the Kabachnik–Fields reaction with the aim to identify the optimum catalytic system. So, we carried out the standard reaction using aniline, benzaldehyde, diphenyl phosphite and [Ce(L-Pro)]₂(Oxa) in different solvents using the methodology described by Zhu and co-workers.¹³ As shown in Table 1, the solvent has impacted directly on the yields. Moreover, we observed that [Ce(L-Pro)]₂(Oxa) was compatible with many low polarity solvents. Thus, we established toluene as the best solvent for this reaction (96% yield).

Table 1 Optimization of the syntheses of α-aminophosphonates^a

Solvent	Time	Yield^b
a Reaction conditions: benzaldehyde (2.2 mmol), aniline (2.0 mmol) and diphenylphosphite (2.0 mmol) and 1 mol% catalyst at room temperature.b Yield of isolated product.
Toluene	10	96
DCM	10	90
CH3CN	10	55
THF	60	80
No solvent	60	0

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Great news related to the reaction time also surprised us. Zhu¹¹ described the Kabachnik–Fields reaction using diethyl phosphite (a better nucleophile than diphenyl phosphite used by us) in 6 h and our procedure required only 10 minutes (Table 1). We also studied the effect of the catalyst loading on the yield of the standard reaction (Table 2). We observed that the best catalyst loading was 1 mol% (96% yield). However, the reaction did not afford any product without the catalyst (blank reaction). Furthermore, the increase in the catalyst loading did not furnish a substantial increase in the yield. Besides, we did not observe any sub-product resulting from a Pudovik reaction. After establishing all the general procedures for the Kabachnik–Fields reaction using [Ce(L-Pro)]₂(Oxa) as a heterogeneous catalyst, we extended the same protocol to several other reactions aiming to obtain some α-aminophosphonates using various substituted benzaldehydes and substituted anilines, and diphenyl phosphite (Table 3). Concerning the benzaldehyde derivatives, we observed that withdrawing groups bonded at the para position furnished α-aminophosphonates in a shorter reaction time, whereas the donor groups furnished them in long ones. This was expected because a withdrawing group confers a lower electron density to the carbonyl carbon compared to the donor ones and this makes the carbonyl group more reactive (more electrophilic). So, the imine will be obtained quickly in such cases and also, consequently, the α-aminophosphonates. This can be confirmed from the analysis of both entries 2 and 8 (nitro substituted), in which the change of the position of the nitro group from para to meta doubled the reaction time. Regarding aniline derivatives, we observed that donor groups bonded at the para position (entries 18–20), contrary to what we expected, produced the α-aminophosphonate in longer reaction times than anilines containing withdrawing groups at the para position (entries 13–17).

Table 2 Examination of the catalyst loadings for the Kabachnik–Fields reaction using [Ce(L-Pro)]₂(Oxa) as a catalyst^a

Catalyst loading (% mol)	Yield^b (%)
a Reaction conditions: benzaldehyde (2.2 mmol), aniline (2.0 mmol) and diphenyl phosphite (2.0 mmol) at room temperature.b Yields after recrystallization.c No reaction.
0	—^c
1	96
2	97

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Table 3 Kabachnik–Fields reactions using [Ce(L-Pro)]₂(Oxa) as a catalyst

Entry	Aldehyde	Amine	Product	Time (min)	Yield^a (%)
a Yields after recrystallization.
1				10	96
2				10	99
3				10	96
4				10	93
5				10	91
6				60	94
7				60	94
8				20	97
9				5	96
10				20	89
11				60	98
12				20	96
13				20	91
14				5	96
15				5	96
16				20	96
17				5	89
18				50	89
19				60	99
20				60	98

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As observed from the proposed mechanism (Scheme 1), we concluded, with respect to cycle #1, that the catalyst affected this cycle making this step faster. We determined this when we used [Ce(L-Pro)]₂(Oxa) as catalyst in the imine reactions. In this case, the catalyst accelerated the reaction affording the imine in a shorter reaction time when compared to data described in the literature. For the second cycle, the catalyst affected the reaction by increasing the positive charge on the imine carbon as shown in intermediate #8.

Scheme 1 Proposed mechanism of the Kabacnick–Fields reaction catalyzed by [Ce(L-Pro)]₂(Oxa).

So, the strong withdrawing groups (NO₂ and F) will make this interaction more difficult than the moderate groups (Cl, Br and I) but both will activate C=N. On the other hand, donor groups, despite the fact that they decrease the electronic potential of the nitrogen lone pair (more basic), will not increase the electrophilicity of the carbonyl carbon in comparison to the previous ones (NO₂, F, Cl, Br and I). For this reason, for withdrawing groups, the Kabachnik–Fields reaction using [Ce(L-Pro)]₂(Oxa) will be carried out in a shorter time than for the ones with electron donor groups. We also performed the recycling of the catalyst for the reaction using para-anisaldehyde, aniline and diphenyl phosphite (entry 6, Table 3 – see the procedure in the ESI†). From the analysis of the data, we concluded that the catalyst efficiency decreased with every reuse (Table 4, entries 1–3). But as the described process uses only 1 mol% of the catalyst, its reusability does not depreciate the methodology.

Table 4 Kabachnik–Fields reaction with [Ce(L-Pro)]₂(Oxa) recycling

Cycle	Yield^a (%)	Δyield (per cycle)
a Yields after recrystallization.
#1	94	—
#2	80	14
#3	65	15

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Aiming to analyse the catalyst structure to try and obtain some information able to confirm what is responsible for the decrease in the yields of the sequential catalysis cycles, we performed SEM and EDS for the catalyst before and after the reaction (Fig. 4). The data indicated that there were no changes in the morphology nor in the atomic percentage. Besides, we observed that there was a reduction in the catalyst loading per cycle (around 18%).

Fig. 4 SEM and EDS for [Ce(L-Pro)]₂(Oxa) before the reaction (A1, A2 and A3) and after the reaction (B1, B2 and B3).

Therefore, as we carried out the subsequent cycles in the same flask without any further catalyst charge and maintained the same starting material amounts used in the first cycle, we can assume that this reduction is strongly associated with the decrease in the subsequent reaction yields.

Conclusions

We have successfully developed a new versatile catalyst, [Ce(L-Pro)]₂(Oxa), for the Kabachnik–Fields reaction which afforded high yields of α-aminophosphonates through the use of a very accessible, simple and efficient methodology with minimal catalyst loading and short reaction times. In relation to its reusability, it was possible only for some cycles but this does not depreciate the procedure.

Acknowledgements

The authors (N. L. C. D. and C. D. G. S) thank Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq/Brazil) for financial support (Process: 314140/2014-0 and 400706/2014-8 CNPq – Brazil) and scholarships. The authors (N. L. C. D. and M. P. D. R) thank Fundação de Apoio ao Desenvolvimento do Ensino and Ciência e Tecnologia do Estado de Mato Grosso do Sul (FUNDECT/Brazil) for financial support and fellowship (Processo Chamada FUNDECT/CAPES no. 02/2014 – Mestrado em Mato Grosso do Sul). Furthermore, the author (A. R. O) thanks Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/Brazil) for her scholarships.

Notes and references

1. (a) R. Ghosh, S. Maiti, A. Chakraborty and D. K. Maitil, J. Mol. Catal., 2003, 210, 53; (b) P. A. Bartlett, J. E. Hanson and P. P. Giannousis, J. Org. Chem., 1990, 55, 6268; (c) P. Kafarski and B. Lejczak, Phosphorus, Sulfur Silicon Relat. Elem., 1991, 63, 1993; (d) M. C. Allen, W. Fuhrer, B. Tuck, R. Wade and J. M. Wood, J. Med. Chem., 1989, 32, 1652; (e) E. W. Logusch, D. M. Walker, J. F. McDonald, G. C. Leo and J. E. Franz, J. Org. Chem., 1988, 53, 4069; (f) A. Peyman, K.-H. Budt, J. Spanig, B. Stowasser and D. Ruppert, Tetrahedron Lett., 1992, 33, 4549; (g) A. Peyman, W. Stahl, K. Wagner, D. Ruppert and K.-H. Budt, Bioorg. Med. Chem. Lett., 1994, 4, 2601.
2. Z. Rashid, H. Naieimi and R. Ghahremanzadeh, RSC Adv., 2015, 5, 99148.
3. Y. Zhanga and C. Zhu, Catal. Commun., 2012, 28, 134.
4. S. Rostamniaa and H. Xin, J. Mol. Liq., 2014, 195, 30.
5. S. Sobhania, E. Safaeib, M. Asadic and F. Jalilia, J. Org. Chem., 2008, 693, 3313.
6. M. H. Sarvari, Tetrahedron, 2008, 64, 5443.
7. V. H. Tillu, D. K. Dumbreb, R. D. Wakharkara and V. I. Choudhary, Tetrahedron Lett., 2011, 52, 863.
8. (a) H. Ghafuri, A. Rashidizadeha and H. R. E. Zanda, RSC Adv., 2016, 00, 1; (b) E. Mollashahi, H. Gholami, M. Kangani and M. T. Maghsoodlou, Heteroat. Chem., 2015, 0, 1.
9. F. Xu, Y. Luo, J. Wu, W. Shen and H. Chen, Heteroat. Chem., 2006, 17, 389.
10. S. Sobhani, Z. M. Falatooni and M. Honarmand, RSC Adv., 2014, 4, 15797.
11. M. Shibasaki and N. Yoshikawa, Chem. Rev., 2002, 102, 2187.
12. M. Shibasaki and H. Gröger, in Lanthanides: Chemistry and Use in Organic Synthesis, ed. S. Kobayashi, Springer, Heidelberg, 1999, p. 199 and references inside there.
13. X. Zhu, S. Wang, S. Zhou, Y. Wei, L. Zhang, F. Wang, Z. Feng, L. Guo and X. Mu, Inorg. Chem., 2012, 51, 7134.
14. M. P. Darbem, A. R. Oliveira, C. R. Winck, A. W. Rinaldi and N. L. C. Domingues, Tetrahedron Lett., 2014, 55, 5179.
15. (a) S. Myung, M. Pink, M. H. Baik and D. E. Clemmer, Acta Crystallogr., 2005, 61, o506–o508; (b) D. A. Reed and M. M. Olmstead, Acta Crystallogr., 1981, B37, 938.
16. B. Ptaszyński and A. Zwolińska, Pol. J. Environ. Stud., 2001, 10(4), 257.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra27064b

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