A one-pot three-component synthesis of novel a- sulfamidophosphonates under ultrasound irradiation and catalyst-free conditions† Billel Belhani, a Malika Berredjem, * a Marc Le Borgne, b Zouhair Bouaziz, b Jacques Lebreton c and Nour-Eddine Aouf a An efficient and convenient one-pot synthesis of novel a-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. Introduction a-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 pepti- domimetics. 4 But surprisingly a-sulfamidophosphonates, new sulfonamide derivatives, to the best of our knowledge, have not been described. In the literature novel phosphonates contain- ing a sulfonamide moiety have been described and have inter- esting 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 a-aminophosphonates derivatives have been reported. Generally, these methods could be performed in the catalysis of Bronsted or Lewis acids like BF 3 /Et 2 O, ZnCl 2 , MgBr 2 , SnCl 4 , 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 rst multicomponent synthesis of a-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 dened as convergent chemical processes where three or more reagents react together via a one-pot procedure in such a way that the nal product retains signicant portions of all starting materials. 16 Such reactions present remarkable advan- tages 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, reduc- tion in energy consumption. 17 This methodological approach has now found various applications in synthesis of pharma- ceutically active compounds, and marine alkaloids and derivatives. 18 Many different process parameters such as temperature, pressure, solvent, catalyst type, Microwave and ultrasonic irra- diations, 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 reac- tions 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 a-sulfamidophosphonate derivatives 2 under ultrasound irra- diation, catalyst and solvent-free conditions in high yields. a Laboratory of Applied Organic Chemistry, Synthesis of Biomolecules and Molecular Modelling Group, Sciences Faculty, Chemistry Department, BadjiMokhtar – Annaba University, Box 12, 23000 Annaba, Algeria. E-mail: malika.berredjem@univ-annaba. org; mberredjem@yahoo.fr b Universit´ e de Lyon, Universit´ e Lyon 1, Facult´ e de Pharmacie e ISPB, EA 4446 Biomol´ ecules Cancer et Chimior´ esistances, SFR Sant´ e Lyon-Est, CNRS UMS3453 e INSERM US7, 8 Avenue Rockefeller, F-69373 Lyon Cedex 8, France c Universit´ e de Nantes, UMR CNRS 6230, Chimie Et Interdisciplinarit´ e: Synth` ese, Analyse, Mod´ elisation (CEISAM), UFR des Sciences et des Techniques, 2, rue de la Houssini` ere, BP 92208, 44322 Nantes Cedex 3, France † Electronic supplementary information (ESI) available: Spectral data for the synthesis of novel a-sulfamidophosphonate prepared in this work. See DOI: 10.1039/c5ra03473f Cite this: RSC Adv. , 2015, 5, 39324 Received 25th February 2015 Accepted 21st April 2015 DOI: 10.1039/c5ra03473f www.rsc.org/advances 39324 | RSC Adv., 2015, 5, 39324–39329 This journal is © The Royal Society of Chemistry 2015 RSC Advances PAPER