Journal of Organometallic Chemistry 892 (2019) 24e33 Contents lists available at ScienceDirect Journal of Organometallic Chemistry journal homepage: www.elsevier.com/locate/jorganchem Cross-linked polystyrene/titanium tetrachloride as a tightly bound complex catalyzed the modified Mannich reaction for the synthesis of piperidin-4-ones * Ali Rahmatpour , Reza Emen, Ghazal Amini Polymer Research Laboratory, Faculty of Chemistry, Shahid Beheshti University, P. O. Box: 19839-4716, Tehran, Iran article info abstract Article history: Cross-linked polystyrene beads were prepared, characterized and the resulting polymer carrier was Received 7 December 2018 functionalized with titanium tetrachloride (TiCl4) via complexation of polystyrene with TiCl4 to afford the Received in revised form corresponding cross-linked polystyrene-TiCl4 stable complex (PSt/TiCl4) in an one step reaction and 17 February 2019 characterized by FT-IR, UV, TGA, DSC, XRD, SEM, BET. This tightly bound coordination complex was used Accepted 5 April 2019 as a water tolerant, heterogeneous, recoverable and reusable Lewis acid catalyst for the synthesis of Available online 16 April 2019 substituted piperidin-4-ones via the modified Mannich multi-component condensation of ketones, ar- omatic aldehydes, and ammonium acetate in 1:2:1 M ratio under mild conditions. The rate of reactions Keywords: Polymer/Lewis acid coordination complex was found to decrease with an increasing percentage of crosslinking and the mesh size of the copolymer Polystyrene-supported catalyst beads. The catalyst is water tolerant, stable and can be easily recovered and reused at least four times Substituted piperidin-4-one without any loss of activity. Multi-component reaction © 2019 Elsevier B.V. All rights reserved. 1. Introduction homogeneous environment, it has drawbacks such as its corrosive nature, moisture sensitivity, less stability at room temperature, Heterogeneous catalysis is a clean and environment-friendly handling difficulty, a hazardous nature, and can not be recovered. catalytic method. The possibility of performing multicomponent Immobilized TiCl4 catalyst is expected to solve these problems. The reactions with a heterogeneous catalyst could enhance their effi- heterogenisation of inorganic reagents and catalysts in an inert ciency from an economic as well as ecological point of view [1]. matrix that are useful in organic reactions is an important goal in Although various catalysts have been developed to realize organic clean technology [7]. Polystyrene (frequently as a cross-linked transformation under homogeneous conditions, it is still difficult to resin) is one of the most popular polymer supports, due to its achieve recovery and reuse of the catalysts in many cases. Prepar- availability, facile functionalization and chemical inertness [8]. ative procedures using polymer-supported catalysts have several There are several different ways by which active homogeneous advantages beacause of their nature; the most important proper- catalysts have been heterogenized for use in organic synthesis. ties of such catalysts are as active as their homogeneous counter- Perhaps a most attractive method known to date is immobilization parts while having the distinguishing characteristics of being easily of active catalysts on an inert organic polymer matrix [8]. One of the separable from the reaction media, reusability, higher selectivity, interesting aspects of such immobilized catalysts is that they swell enhanced stability, easier handling, non-toxicity, non-corrosive- under certain solvent conditions and thus provide a near homo- ness, and simple workup procedures [2,3]. geneous environment for the reactants while retaining all the ad- Over the past few years, TiCl4 has been reported as an efficient vantages of a heterogeneous catalysts. The aim of this study was to catalyst for organic synthesis and industrially organic compounds, heterogenize and immobilize strong Lewis acid titanium tetra- which exhibits, in numerous cases, a stronger activity than other chloride directly by supporting it on cross-linked polystyrene with known metal chlorides, in particular those of transition elements specified morphology in an one step reaction without functionali- [4e6]. Even though free TiCl4 has many advantages in a zation of the polymer matrix. We have recently reported the synthesis and use of polymer- supported Lewis acids as efficient catalysts for a variety of organic * Corresponding author. transformations [9e14]. Cross-linked polystyrene-supported E-mail address: [email protected] (A. Rahmatpour). https://doi.org/10.1016/j.jorganchem.2019.04.004 0022-328X/© 2019 Elsevier B.V. All rights reserved. A. Rahmatpour et al. / Journal of Organometallic Chemistry 892 (2019) 24e33 25 titanium tetrachloride (PS/TiCl4), which is a tightly bound and directly immobilization of TiCl4 on PS with specified crosslinking stable complex between TiCl4 and polystyrene-divinylbenzene degree, mesh size, and morphology prepared by carrying out cross- copolymer. The use of the PSeTiCl4 complex catalyst has several linking suspension copolymerization using xanthan gum/or guar advantages over a conventional acid catalyst, such as its ease of gum from bioresources as new alternative synthetic suspension handling (as a bench-top catalyst), stability, cost efficiency, recy- stabilizer is also described. A tightly bound complex PS/TiCl4 clability, and tunable Lewis acidity. combines the advantages of being both a Lewis acid and a dehy- Nitrogen containing heterocyclic compound especially piper- drating agent. idin-4-ones presumably gaining considerable importance owing to their varied biological properties such as antiviral, antifungal, anti- 2. Experimental section tumour, analgesic activities [15e17]. Substituents (presence phenyl or para substituted phenyl groups) at C-2 and C-6 positions of the 2.1. Preparation of cross-linked polystyrene copolymer beads piperidin-4-one ring moiety have a wide range of antimicrobial activity. Into a 250 mL three-necked round-bottomed flask equipped Multicomponent reactions (MCRs) are chemical trans- with a mechanical stirrer, nitrogen gas inlet, and reflux condenser formations in which three or more reactants form a product that is placed in a thermostated water bath, a mixture of distilled derived from all of the inputs in a single operation without isolating water (500 parts) containing GG or XG/PVA (2 wt% in relation to the the intermediates and therefore reducing the reaction times and monomers) and NaCl (1% w/v in relation to water volume) was first e energy input [18 20]. These type of reactions introduce the most of introduced into the flask and stirred at room temperature for diversity in one step, making full use of the many building blocks 30 min. While stirring, nitrogen was purged from the mixture, the available today from commercial vendors. The interest in MCRs has suspending medium was then heated to the reaction temperature. boosted during the past two decades since are a very useful tool for A mixture of the monomers (St and several weight ratios of DVB fi the ef cient synthesis of small molecule libraries. The search and cross-linker, 4, 6, 8, 10%) were first mixed well with the porogen discovery for new as well as improvement of known MCRs is still in (toluene-heptane (3:2) mixture) to form an organic phase in which, demand as the best tools in combinatorial chemistry. One of these the initiator, AIBN, was added in the amount of 1 mol% of mono- MCRs is the preparation of piperidin-4-one derivatives by a three- mers. The organic phase mixture was then added dropwise to the component reaction using ketones, aromatic aldehydes, and aqueous phase, through a dropping funnel to the flask for about ammonium acetate (in 1:2:1 M ratio) reported by Noller et al. [21]. 30 min (The volume ratio between the two phases (organic/ A few number of methods are available for the synthesis of aqueous) was kept constant at 1/5). The stirring rate was kept at e substituted piperidin-4-ones [22 27] and a few catalysts are also 350e400 rpm and the polymerization was allowed to proceed at available up to now to improve the yield and reaction conditions of 80 C for 18 h. After the polymerization, the copolymer beads were fi the modi ed Mannich reaction. The main disadvantage of almost filtered out on a Buchner funnel under vacuum, and treated in 1 N all conventional methods is that the catalysts are destroyed in the HCl at boiling temperature for 15 min, washed twice with hot work-up procedure and their recovery and reuse is often impos- water, and then vacuum filtered to remove the stabilizer. The sible, and most importantly, the conventional method of synthesis copolymer beads were extracted thoroughly with acetone for a few of polysubstituted piperidin-4-one derivatives necessitate a tedious hours in a soxhlet apparatus to remove porogen and residual work-up procedure, including the conversion of the product to its monomers, and then were washed twice with acetone, two times hydrochloride salt. Thus, the development of new methods that with methanol to ensure complete removal of impurities. Finally, utilize eco-friendly protocols are highly desirable. the samples were dried in a vacuum oven at 50 C for at least 8 h. As part of our continuing interest in heterogeneous catalysis in The overall conversion of the monomers to solid copolymer was fi organic transformations, we report herein an ef cient and eco- determined gravimetrically. Of these beads the 50e80 mesh size friendly procedure for the synthesis of substituted piperidin-4- (or 170e290 mm) beads were used in the subsequent studies. one derivatives from the modified Mannich condensation of ke- tones, aromatic aldehydes, and ammonium acetate catalyzed by a 2.2. Preparation of crosslinked polystyrene-titanium tetrachloride tightly bound DVB-PS/TiCl complex as a reusable heterogeneous 4 complex (PS/TiCl ) Lewis acid catalyst in ethanol for the first time (Scheme 1). In this 4 study, the preparation of DVB-crosslinked PSeTiCl complex by 4 The carrier beads of cross-linked polystyrene (8% DVB, grain size Scheme 1. Synthesis of substituted piperidin-4-one derivatives catalyzed by PS/TiCl4 complex. 26 A.