A one-pot three-component synthesis of novel α-sulfamidophosphonates under ultrasound irradiation and catalyst-free conditions

Abstract

An efficient and convenient one-pot synthesis of novel α-sulfamidophosphonates is described via a three-component reaction. This reaction was carried out through a three component condensation reaction of sulfonamide, an aromatic aldehyde and triethylphosphite under conventional/ultrasonic techniques, catalyst-free and solvent-free conditions. This methodology was established with many advantages, including mild reaction conditions, short reaction times, good yields, simple work-up procedures, and environmental friendliness.

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Introduction

α-Aminophosphonate have found a wide range of applications in medicinal chemistry, and they are considered to be enzyme inhibitors,¹ antibiotics,² pharmacological agents,³ and peptidomimetics.⁴ But surprisingly α-sulfamidophosphonates, new sulfonamide derivatives, to the best of our knowledge, have not been described. In the literature novel phosphonates containing a sulfonamide moiety have been described and have interesting biological properties. They act as potent inhibitors of protein tyrosine phosphatase 1B and HIV protease inhibitors.^5,6

A number of synthetic methods for the construction of α-aminophosphonates derivatives have been reported. Generally, these methods could be performed in the catalysis of Bronsted or Lewis acids like BF₃/Et₂O, ZnCl₂, MgBr₂, SnCl₄, etc.^7–9 However, in spite of their potential utility, these methods typically suffer from more disadvantages such as high cost of the catalyst, use of a stoichiometric amount of reagent and occurrence of several side reactions. The first multicomponent synthesis of α-aminophosphonates has been achieved by Kabachnik–Fields^10–15 in the presence of different catalyst.

Multicomponent reactions are efficient and effective methods particularly well suited for diversity-oriented synthesis, they can be defined as convergent chemical processes where three or more reagents react together via a one-pot procedure in such a way that the final product retains significant portions of all starting materials.¹⁶ Such reactions present remarkable advantages for library synthesis aimed at carrying out structure–activity relationship (SAR) studies of drug-like compounds, in a single procedural step such as; high degree of atom economy, reduction in reaction steps and the number of workup, reduction in energy consumption.¹⁷ This methodological approach has now found various applications in synthesis of pharmaceutically active compounds, and marine alkaloids and derivatives.¹⁸

Many different process parameters such as temperature, pressure, solvent, catalyst type, Microwave and ultrasonic irradiations, and other factors can be utilized to modulate the selectivity of synthetic transformations.

One of the powerful tools used to connect economic features with the green concerns is performing organic reactions under ultrasound irradiation and solvent-free conditions.^19–21 This powerful technique became extremely efficient and attractive in synthetic organic chemistry, and is able to activate many reactions due to cavitational collapse. Ultrasound irradiation provides higher yields and selectivities, shorter reaction times and milder reaction conditions, nontoxic, environmentally friendly solvent, in a one-step reaction, without isolation of any intermediate thus reducing time, saving money, energy and raw materials. In this research, we report a highly efficient one-pot, three component condensation reaction for the synthesis α-sulfamidophosphonate derivatives 2 under ultrasound irradiation, catalyst and solvent-free conditions in high yields.

Results and discussion

Initially, the sulfonamides presented here were obtained in three steps from a simple and efficient methodology described by our group.^22–26

Herein we studied the one-pot synthesis of α-sulfamidophosphonates under solvent-free reaction conditions using ultrasound. Initially, benzaldehyde was reacted with structurally diverse sulfonamide and triethylphosphite in the absence of any solvent and any catalyst after 2–3 hours, the reaction was completed with an excellent yield (Scheme 1).

Scheme 1 One-pot synthesis of α-sulfamidophosphonate under ultrasound irradiations.

To find the effect of ultrasound, the same reaction was carried out under the same conditions in the absence of ultrasound irradiation. No reaction occurs after 5 h working time, this shows the essential role of ultrasound irradiation. This excellent result encourages us to extend this study to various structurally amines. To optimize our protocol, we also applied our reaction conditions to a number of primary and secondary aromatic and aliphatic (cyclic and acyclic) amines. The results of these studies are presented in Table 1, (entries 2a–q).

Table 1 One-pot synthesis of α-sulfamidophosphonate under ultrasound irradiation^a

Entry	Amine	Compound	Time (hours)	Yield (%)	M.p. (°C)
a Conditions: aldehyde (1 mmol), sulfonamide (1 mmol), triethylphosphite (1 mmol), 40 kHz, r.t.
2a			2	95	152–154
2b			2	89	143–145
2c			2.5	90	138–140
2d			3	87	—
2e			3	85	145–147
2f			1.5	92	109–111
2g			2	91	116–118
2h			2	84	—
2i			3	70	156–158
2j			3	65	—
2k			3	75	—
4l			3	80	147–149
2m			3	73	—
2n			1.5	82	131–133
2o			2	88	136–138
2p			2.5	86	135–137
2q			1.5	94	137–139

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Mechanistic proposal

The presented results demonstrate the specific ultrasonic effect on multicomponent reactions giving pure product with quantitative yields in a few minutes. The ultrasonic energy applying to the reaction generates the acoustic cavitation mechanical effect when sonic waves propagate through the medium. In solids, both longitudinal and transverse waves can be transmitted whereas in liquids only longitudinal waves can be transmitted. Vibrations of molecules generate compressions and rarefactions which give rise to the phenomenon of bubble formation and collapse in the reaction mixture [sulfonamide, amine and triethylphosphite] and facilitate the nucleophilic attack of the amino functional on the carbonyl group. During cavitation, the chemical bonds break, and H₂O and EtOH were eliminated to afford the α-sulfamidophosphonate according to the mechanism below (Scheme 2).

Scheme 2 Mechanistic proposal for synthesis of α-sulfamidophosphonate.

Experimental

Materials

The chemicals used in this work were obtained from Fluka and Merck Chemical Company and were used without purification.

Apparatus

Melting points were measured in open capillary tubes on an electro thermal apparatus and uncorrected. Mass spectra were recorded on a Shimadzu QP 1100 Ex mass spectrometer operating at an ionization potential of 70 eV. IR spectra were recorded as KBr pellets on a Perkin Elmer 781 spectrophotometer and an Impact 400 Nicolet FT-IR spectrophotometer. ¹H NMR, ¹³C NMR and ³¹P NMR spectra were recorded in DMSO-d₆ or CDCl₃ solvents on a 250, 300 or 400 MHz Bruker spectrometer with tetramethylsilane as internal reference.

Ultrasound assisted reactions were carried out using a FUNGILAB ultrasonic bath with a frequency of 40 kHz and a nominal power of 250 W. The reactions were carried out in an open glass tube (diameter: 25 mm; thickness: 1 mm; volume: 20 mL) at room temperature. All reactions were monitored by thin layer chromatography (TLC) on silica Merck 60 F254 percolated aluminum plates.

General procedure

In a 10 mL round bottom flask taken a mixture of aldehyde (1 mmol) and sulfonamide (1 mmol) at room temperature and then triethylphosphite (1 mmol) was added. Then reaction mixture was subjected to the ultrasonication for appropriate time. After completion of the reaction, as indicated by TLC, silica gel; dichloromethane : methanol (9 : 1), a (4 : 1) mixture of diethyl ether and n-hexane was added and the mixture was cooled to 6 °C overnight. The product was finally filtered and dried.

Conclusions

In conclusion, we have developed a facile and efficient one-pot, three-component synthesis of α-sulfamidophosphonates under ultrasound irradiation, solvent- and catalyst-free conditions at room temperature in high yields. This reaction system provides a novel method for the synthesis of biologically important α-sulfamidophosphonates. The method offers several advantages including high yield of products and easy experimental work-up procedure.

Acknowledgements

This work was supported financially by The General Directorate for Scientific Research and Technological Development (DG-RSDT), Algerian Ministry of Scientific Research, Applied Organic Laboratory (FNR 2000).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Spectral data for the synthesis of novel α-sulfamidophosphonate prepared in this work. See DOI: 10.1039/c5ra03473f

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