Eco-efficient, Chemoselective, and Rapid Access to Aminals from Lactams Using RecyclableSilica-supported FeCl 3 Catalyst in Green Solvent Gunasekar Ramachandran, 1,2 Triveni Rajashekhar Mandlimath, 1 Venkatesan Sathesh, 1 Balijapalli Umamahesh, 1 and Kulathu I. Sathiyanarayanan* 1 1 Chemistry Division, School of Advanced Sciences, VIT University, Vellore-632014, India 2 Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Mohali, S A S Nagar Mohali PO, India (E-mail: sathiyanarayanank@vit.ac.in) Ahighlyefficient and environmentally benign protocol was developed for the synthesisof aminals using silica-supported iron(III) chloride as an active Lewis acid recyclable heteroge- neous catalyst from N-nucleophiles and active carboxaldehydes. This current modest protocolis cost-effective and an environ- mentally benign method for the synthesisof pharmaceutically and industrially useful scaffolds. Aminals, also named as N,N-acetals, are useful building blocks in many organic synthesis, 1a,1b especially as intermedi- ates for the construction of heterocyclic compounds. 1 Aminals in general contain two amide groups, where two nitrogen atoms were attached to the alkyl or aryl substituents. The stability of ketene aminals relies on the substituent on the nitrogen atom and the stability increases if the substituent on the nitrogen atom was aromatic group. 2 There isa lack of a synthetic method for such stable aminals, which clearly hold great potentialin organic synthesis. 3 In general, aminals exist in equilibrium, 4 and a classical method is used to shift the equilibrium toward the product side using various drying agents such as potassium carbonate 4a and boric anhydride, 4b or methods such as azeotropicdistillation with benzene 4c to make free from water. Thus, we have developed a synthetic methodology for the synthesisof stable aminals using FeCl 3 -SiO 2 as a recyclable heterogeneous catalyst using dimethyl carbonate as a green solvent. Recently, in green chemistry the use of solid-supported reagents has attracted considerable importance because of their ease of handling, reusability, convenient workup, and recoverability of catalysts by simple filtration. 5 Silica gel-supported iron(III) chloride has great advantages over various heterogeneous catalysts, such as easily available materialswith low cost, ease of preparation, and catalyst recycling. 6 In synthetic organic chemistry, the use of silica-supported iron(III) chloride has emerged as a poten- tiallyeffective catalyst for the generation of adiverse set of compounds. 7 Thus, these types of reactions have received great attention because of the formation of carbon-carbon and carbon-heteroatom bonds by a powerful one-pot method. This could be adopted in drug discovery as well as in total synthesis. 8 Use of simple starting materials helps to deliver most efficient bioactive compounds inasingle step. 9 γ-Butyrolactam and its derivatives are the most significant structural motifs that are found in natural products, which isof great interest for the synthetic community to develop a more appropriate synthetic route. 10 The γ-butyrolactam ring is implanted in numerous biological compounds as a subunit structure. Lactam derivatives are found in a numerous natural products such as lactacystin, salinosporamides A-B, dysibetaine, and cinnabaramides. 11 Drawing from the previous experiences for the synthesisof N,S-acetalsvia N-acylimininum ion intermediates, 12 we ex- tended this reaction to synthesize N,N-acetals(N-substituted lactams) from N-nucleophiles and active carboxaldehydes; we found that N,N-acetals could be purely isolated as a sole product from a simple and efficient greener method. For the first time, we describe the access to N,N-acetals by adding γ-butyrolactam to the N-acylimininum ion intermediate. We have used molecular iodine as a catalyst in the previous report for the synthesisof N,S- and N,N-acetals, 12 which are toxic. In order to avoid the toxic catalyst in the reaction, we have used the silica-supported iron(III) chloride (FeCl 3 -SiO 2 ) catalyst for the synthesisof ketene N,N-acetals. Encouraging results motivated us to synthesize electron- deficient N,N-acetals; because of the lack of methods to synthesize N,N-acetals such as compound 4, we optimized the reaction conditions to assess the efficiency of the catalyst for the reaction between γ-butyrolactam and benzaldehyde under various conditions. We found that it was best performed at 8 mol% of FeCl 3 -SiO 2 as the catalyst indimethyl carbonate (DMC) as the solvent. Initially, in this reaction, we used several metal chloride Lewis acid catalysts such as AlCl 3 , ZnCl 2 , HgCl 2 , FeCl 3 , and SnCl 2 . We achieved good yields while using 10 mol% of FeCl 3 . However, this reaction was more compli- cated during the work up because of the hygroscopic nature of FeCl 3 ;difficulties were also found in separating out the product from the adhesive iron solid. In an effort to minimize these problems, we prepared FeCl 3 -SiO 2 and used it as a catalyst for this reaction, which may increase the activity of Lewis acids. In the prepared FeCl 3 -SiO 2 catalyst, silanole groups of silica form a single-bond with iron(III) chloride. 6a The use of a solid- supported catalyst in the reaction becomes a clean one. If the reaction is carried out using 8 mol% of FeCl 3 -SiO 2 , we obtained better yields (92%). It was remarkable to note that the use of FeCl 3 -SiO 2 played an important role in this reaction. Thus, to evaluate the molar percentage of the catalyst required to produce excellent yield in shorter reaction times, we increased the mole percentage of FeCl 3 -SiO 2 ; however, itdid not further improve the yieldsignificantly on increasing the mol%.Finally, we reduced the mol% of the catalyst and obtained excellent yield while using 8 mol% of FeCl 3 -SiO 2 . The solvent effect was the next factor of consideration for better yield. Thus, initially, the experiments were carried out in various solvents such as dichloromethane (DCM), CH 3 CN, and THF using 8 mol% of FeCl 3 -SiO 2 as the catalyst (Table S1, Entries 13-20, Supporting Information (SI)). We obtained good yields while using DCM as the solvent. In order to replace DCM Received: June 25, 2014 | Accepted: July 12, 2014 | Web Released: July 23, 2014 CL-140624 Chem. Lett. 2014, 43, 1631–1633 | doi:10.1246/cl.140624 © 2014 The Chemical Society of Japan | 1631