molecules Article Recoverable Phospha-Michael Additions Catalyzed by a 4-N,N-Dimethylaminopyridinium Saccharinate Salt or a Fluorous Long-Chained Pyridine: Two Types of Reusable Base Catalysts Eskedar Tessema 1,†, Vijayanath Elakkat 1,† , Chiao-Fan Chiu 2,3,*, Jing-Hung Zheng 1, Ka Long Chan 1, Chia-Rui Shen 4,5, Peng Zhang 6,* and Norman Lu 1,7,* 1 Institute of Organic and Polymeric Materials, National Taipei University of Technology, Taipei 106, Taiwan; [email protected] (E.T.); [email protected] (V.E.); [email protected] (J.-H.Z.); [email protected] (K.L.C.) 2 Department of Pediatrics, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan 3 Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan 4 Department of Medical Biotechnology and Laboratory Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; [email protected] 5 Department of Ophthalmology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan 6 Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221-0172, USA 7 Development Center for Smart Textile, National Taipei University of Technology, Taipei 106, Taiwan Citation: Tessema, E.; Elakkat, V.; * Correspondence: [email protected] (C.-F.C.); [email protected] (P.Z.); Chiu, C.-F.; Zheng, J.-H.; Chan, K.L.; [email protected] (N.L.) Shen, C.-R.; Zhang, P.; Lu, N. † These authors contributed equally to this work. Recoverable Phospha-Michael Additions Catalyzed by a Abstract: Phospha-Michael addition, which is the addition reaction of a phosphorus-based nucle- 4-N,N-Dimethylaminopyridinium ophile to an acceptor-substituted unsaturated bond, certainly represents one of the most versatile and Saccharinate Salt or a Fluorous powerful tools for the formation of P-C bonds, since many different electrophiles and P nucleophiles Long-Chained Pyridine: Two Types can be combined with each other. This offers the possibility to access many diversely functionalized of Reusable Base Catalysts. Molecules products. In this work, two kinds of basic pyridine-based organo-catalysts were used to efficiently 2021, 26, 1159. https://doi.org/ catalyze phospha-Michael addition reactions, the 4-N,N-dimethylaminopyridinium saccharinate 10.3390/molecules26041159 (DMAP·Hsac) salt and a fluorous long-chained pyridine (4-Rf-CH2OCH2-py, where Rf = C11F23). Academic Editor: Alessandra Puglisi These catalysts have been synthesized and characterized by Lu’s group. The phospha-Michael addi- tion of diisopropyl, dimethyl or triethyl phosphites to α, β-unsaturated malonates in the presence of ◦ Received: 5 February 2021 those catalysts showed very good reactivity with high yield at 80–100 C in 1–4.5 h with high catalytic Accepted: 19 February 2021 recovery and reusability. With regard to significant catalytic recovery, sometimes more than eight Published: 22 February 2021 cycles were observed for DMAP·Hsac adduct by using non-polar solvents (e.g., ether) to precipitate out the catalyst. In the case of the fluorous long-chained pyridine, the thermomorphic method was Publisher’s Note: MDPI stays neutral used to efficiently recover the catalyst for eight cycles in all the reactions. Thus, the easy separation of with regard to jurisdictional claims in the catalysts from the products revealed the outstanding efficacy of our systems. To our knowledge, published maps and institutional affil- these are good examples of the application of recoverable organo-catalysts to the DMAP·Hsac adduct iations. by using non-polar solvent and a fluorous long-chained pyridine under the thermomorphic mode in phospha-Michael addition reactions. Keywords: phospha-Michael; recoverable; fluorous; DMAP; long-chained; pyridine; catalysis; Copyright: © 2021 by the authors. adduct; thermomorphic; phosphite Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons 1. Introduction Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ The chemistry of phosphonates has inspired an increasing interest following their 4.0/). synthetic and biological reputation. As a result, the development of new methodologies for Molecules 2021, 26, 1159. https://doi.org/10.3390/molecules26041159 https://www.mdpi.com/journal/molecules Molecules 2021, 26, 1159 2 of 14 Molecules 2021, 26, x FOR PEER REVIEW 2 of 14 their preparation is an important goal in organic synthesis [1–4]. To date, intensive studies studies have been reported in their synthetic application in biomedical fields, such as pep- have been reported in their synthetic application in biomedical fields, such as peptide tidemimicking mimicking [5], [5], enzyme enzyme inhibition inhibition [6 ],[6], metabolic metabolic inquiries inquiries [7 [7],], pharmacological pharmacological activity activ- itystudy study [8 ][8] and and biological biological activities activities [9 [9].]. These These transformations, transformations, however, however, require require the the use use of ofa a base base catalyst catalyst to to promote promote tautomeric tautomeric equilibria equilibria of of H-phosphonates H-phosphonates in in favor favor of of a reactivea reac- tiveform form of phosphitesof phosphites [10 ].[10]. AmongAmong the the main main methods methods of of the the synthesis synthesis of of phosphonates phosphonates through through C-P C-P bond bond for- for- mationmation is is the the addition addition of of phosphite phosphite nucleo nucleophilephile across across the the carbon–carbon carbon–carbon double double bond, bond, whichwhich is is called called the the phospha-Michael phospha-Michael reaction reaction [11,12]. [11,12 This]. This reaction reaction has hasbeen been catalyzed catalyzed by metalby metal oxides oxides [13], acids [13], [14], acids bases [14], [15,16], bases [radical15,16], initiator radical initiator[17,18] transition [17,18] transition metal catalysts metal [19], tetramethylguanidine [20], microwave [21], HClO4.-SiO2 [22], nano-sized ZnO [23], catalysts [19], tetramethylguanidine [20], microwave [21], HClO4.-SiO2 [22], nano-sized sodiumZnO [23 stearate], sodium [24], stearate and so [on.24], Although and so on. phospha-Michael Although phospha-Michael addition could addition proceed could by theseproceed catalyzed by these methods, catalyzed many methods, of these reagents many of cannot thesereagents be reused, cannot and in be many reused, instances, and in longmany reaction instances, time; long drastic reaction reaction time; conditions drastic reaction; and sometimes, conditions; according and sometimes, to the nature according of theto thecatalyst, nature tedious of the work-up catalyst, tediousis needed. work-up Theref isore, needed. the development Therefore, theof a development new method ofto a overcomenew method these to shortcomings overcome these still shortcomings remains an ongoing still remains challenge an ongoingfor the synthesis challenge of forthese the significantsynthesis scaffolds. of these significant Recently, scaffolds.some recovera Recently,ble catalyst some recoverablesystems have catalyst also been systems reported have toalso be active, been reported such as magnetically to be active, suchrecyclable as magnetically heterogeneous recyclable organic heterogeneous base [25] and organic3-ami- nopropylatedbase [25] and silica 3-aminopropylated gel [26]. silica gel [26]. ReportedReported here, here, the the 4- 4-NN,N,N-dimethylaminopyridinium-dimethylaminopyridinium saccharinate saccharinate (DMAP (DMAP.Hsac)·Hsac) salt salt waswas used used as as a acatalyst catalyst in in the the current current work. work. This This salt salt was was synthesized synthesized by by the the reversible reversible acid-baseacid-base reaction reaction of ofthe the basic basic 4-N,N 4-N-dimethylaminopyridine,N-dimethylaminopyridine (DMAP) (DMAP) with with the acidic the acidic sac- charinesaccharine (Hsac). (Hsac). During During the equilibrium, the equilibrium, there is there always is always a very small a very amount small amountof free DMAP of free presentDMAP in present the solution in the solution(see Equation (see Equation 1), and this 1), andfree thisDMAP free can DMAP homogeneously can homogeneously and ef- fectivelyand effectively catalyze catalyze the phospha-Michael the phospha-Michael addition additionreactions reactions[27]. Additionally, [27]. Additionally, this salt of this 4- N,Nsalt-dimethylaminopyridinium of 4-N,N-dimethylaminopyridinium saccharinate saccharinate (DMAP.Hsac), (DMAP which·Hsac), is an ionic which compound, is an ionic iscompound, usually insoluble is usually in most insoluble non-polar in most solvents. non-polar It can solvents. be easily Itprecipitated can be easily out precipitated to achieve theout phase to achieve separation the phase by adding separation the non-polar by adding so thelvents. non-polar (e.g., solvents.ether, hexane (e.g., ether,etc.) [27,28]. hexane Thisetc.) special [27,28 ].solubility This special property solubility of DMAP property.Hsac ofmakes DMAP the·Hsac adduct makes act as the a adductgood catalytic act as a bridgegood catalyticbetween bridgeheterogeneous between heterogeneousand homogeneous and catalysis, homogeneous as the catalysis, addition as of the non-polar addition solventof non-polar makes solventthe catalyst makes precipitate the catalyst out. precipitate Likewise, out.in the Likewise, 2nd part in of the this 2nd research, part of the this fluorousresearch, long-chained the fluorous pyridine