Recoverable Phospha-Michael Additions Catalyzed by a 4-N,N

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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 addition 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

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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 forfor- 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 long-chained (4-Rf pyridine-CH2OCH (4-2-pyRf-CH where2OCH Rf 2=-py C11F where23), as Raf base= C11 catalyst,F23), as a worksbase catalyst,under thermomorphic works under thermomorphic conditions with conditions a feature with of homogeneously a feature of homogeneously catalyzing phospha-Michaelcatalyzing phospha-Michael addition at a addition high temperature at a high temperature in a neat reaction in a neat where reaction the wherereactants the servereactants as the serve solvent, as the forming solvent, heterogeneous forming heterogeneous precipitation precipitation at a lower at a temperature. lower temperature. The thermomorphicThe thermomorphic method method is an is alternative an alternative way way to use to use the the different different solubility solubility of of fluorous fluorous long-chainedlong-chained compounds compounds between between high high and and low low temperature temperature in in the the common common organic organic compoundscompounds [29–35]. [29–35]. In In this this me method,thod, a afluorous fluorous chain-containi chain-containingng pyridine-based pyridine-based catalyst catalyst couldcould be be soluble soluble at at high high temperatures temperatures during during the the catalytic catalytic reactions, reactions, but but insoluble insoluble at at room room temperaturetemperature for for the the recovery recovery of of catalysts catalysts via via a a simple simple liquid–solid liquid–solid separation separation [36–38]. [36–38].

(1)(1)

InIn this this work, work, two two kinds kinds of of basic basic pyridine-based pyridine-based organo-catalysts, organo-catalysts, which which are are the the DMAPDMAP.Hsac·Hsac adduct adduct and and a afluorous fluorous long-chained long-chained pyridine pyridine (py), (py), were were used used to to efficiently efficiently catalyzecatalyze phospha-Michael phospha-Michael addition addition reactions. reactions. To Toour our knowledge, knowledge, these these are two are twogood good ex- amplesexamples of recoverable of recoverable phospha-Michael phospha-Michael addition addition reaction reaction catalyzed catalyzed by by organo-bases, organo-bases, whichwhich are are DMAP DMAP.Hsac·Hsac adduct adduct in in neat neat condition condition and and a afluorous fluorous long-chained long-chained py py under under thermomorphicthermomorphic mode. mode. Taking Taking into into consideratio considerationn their their good good catalytic catalytic efficiency efficiency and and good good heterogenousheterogenous separation, separation, these these two two catalysts catalysts co coulduld be be regarded regarded as as very very good good alternatives alternatives toto most most homogeneous homogeneous catalysts. catalysts.

2. Results and Discussion

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2. Results and Discussion 2.1. Recoverable DMAP.HSac-Catalyzed Phospha-Michael Addition Reaction 2.1.2.1. RecoverableRecoverable DMAP DMAP·HSac-Catalyzed.HSac-Catalyzed Phospha-MichaelPhospha-Michael AdditionAddition ReactionReaction 2.1.1. Synthesis of DMAP.HSac (Catalyst A) 2.1.1.2.1.1. SynthesisSynthesis of of DMAP DMAP·HSac.HSac (Catalyst(Catalyst AA)) The preparation of DMAP.HSac (A) followed Lu’s literature procedure [28]. The re- TheThe preparationpreparation ofof DMAPDMAP·.HSacHSac ( (AA)) followed followed Lu’s Lu’s literature literature procedure procedure [28]. [28 ].The The reaction of DMAP with saccharin, as shown in Scheme 1, in tetrahydrofuran (THF) solvent reactionaction of of DMAP DMAP with with saccharin, saccharin, as as shown in Scheme1 1,, in in tetrahydrofuran tetrahydrofuran (THF) (THF) solvent solvent at 60 °C, took place ◦for 2 h in a nitrogen atmosphere to yield a white solid product of the atat 60 60 °C,C, tooktook placeplace forfor 22 h h in in a a nitrogen nitrogen atmosphere atmosphere to to yield yield a a white white solid solid product product of of the the adduct (A). adductadduct ( A(A).).

Scheme 1. Synthesis of the DMAP.HSac adduct (A). SchemeScheme 1. 1.Synthesis Synthesis of of the the DMAP DMAP·HSac.HSac adductadduct ((AA).). 2.1.2. Recoverable DMAP.HSac-Catalyzed· Phospha-Michael Addition Reaction 2.1.2.2.1.2. RecoverableRecoverable DMAP DMAPHSac-Catalyzed.HSac-Catalyzed Phospha-MichaelPhospha-Michael AdditionAddition ReactionReaction The DMAP.HSac adduct· A was then examined for the following neat phospha- TheThe DMAP DMAPHSac.HSac adduct adductA wasA was then then examined examined for the for following the following neat phospha-Michel neat phospha- Michel addition reactions, where A catalyzed addition of alkyl (R group) substituted di- additionMichel addition reactions, reactions, where A catalyzedwhere A additioncatalyzed of addition alkyl (R group)of alky substitutedl (R group) diorganophos-substituted diorganophosphite compounds [1a1a (R= isopropyl); 1b1b (R= methyl)] and tris(organo)phos- phiteorganophosphite compounds [ compounds(R= isopropyl); [1a (R= (R=isopropyl); methyl)] 1b and (R= tris(organo)phosphite methyl)] and tris(organo)phos- compound phite compound[2 (R[2 (R = ethyl)] = ethyl)] with with 2-benzylidinemelanonitrile-type 2-benzylidinemelanonitrile-type substrates substrates [3 [(X3 (X = H);= H);4 (X = CH3)] as Molecules 2021, 26, x FOR PEER REVIEW phite compound [2 (R = ethyl)] with 2-benzylidinemelanonitrile-type substrates5 of 14 [3 (X = H); 4 (X = CH3)] asindicated indicated in in Schemes Schemes2 2and and3. 3. 4 (X = CH3)] as indicated in Schemes 2 and 3.

2 2.5 80 97 19.4 3 3 80 99 (96) 19.8 4 3 80 99 19.8 5 3 80 96 (95) 19.2 6 3 80 96 19.2 7 3 80 95 19

8 3.5 80 97 19.4 Scheme 2. SchemeThe DMAP 2. The·HSac DMAP (A)-catalyzed.HSac (A)-catalyzed phospha-Michael phospha-Michael addition addition of diisopropyl of diisopropyl phosphite phosphite (1a) with (1a benzyliden) Reaction conditions:Scheme T 2=. 80The °C, DMAP cat. A.HSac (5 mol%), (A)-catalyzed 1a (0.23 mL, phospha-Michael 1.37 mmol), 4 (115addition mg, 0.68of diisopropyl mmol), phosphite (1a) emalononitrile-typewith benzylidenemalononitrile-type substrates [3 (X =a H); 4 (X = CHsubstrates)]. [3b (X = H); 4 (X = CH3)]. solvent free reaction.with benzylidenemalononitrile-type Measured by GC/MS;3 isolated substrates yield in [3 parenthesis. (X = H); 4 (X = CH3)]. a. A-catalyzed phospha-Michael addition of diisopropyl phosphite (1a) and benzylidenemalono- a. A-catalyzed phospha-Michael addition of diisopropyl phosphite (1a) and benzylidenemalononitrile (3) nitrile (3)

Table 1. Recycling results of A-catalyzed phospha-Michael addition of diisopropyl phosphite (1a) Table 1. Recycling results of A-catalyzed phospha-Michael addition of diisopropyl phosphite (1a) with benzylidenemalononitrile (3) at 80 °C. with benzylidenemalononitrile (3) at 80 °C. Cycle No. Time (h) Temp. (°C) Yield (%)a TON Cycle No. Time (h) Temp. (°C) Yield (%)a TON 1 1 80 99 (97)b 19.8 1 1 80 99 (97)b 19.8 2 1 80 99 19.8 2 1 80 99 19.8 3 1 80 99 (96) 19.8 Scheme 3. A-catalyzedScheme 3. phospha-MichaelA-catalyzed 3phospha-Michael addition of dimethyladdition1 of phosphite dimethyl80 (phosphite1b ) with 2-benzylidenemalononitrile-type(1b) with99 (96) 2-benzyli- 19.8 denemalononitrile-type4 substrates1 [3 (X = H); 804 (X = CH3)]. 99 19.8 substrates [3 (X = H); 4 (X = CH3)]. 4 1 80 99 19.8 5 1 80 99 (95) 19.8 5 1 80 99 (95) 19.8 c. A-catalyzed6 phospha-Michel1 addition of 80dimethyl phosphite98 (1b ) and 2-benzylidenemalono-19.6 a. A-catalyzed6 phospha-Michael1 addition of diisopropyl80 phosphite (981a ) and benzylidenemalonon-19.6 nitrile7 (3) 1.5 80 99 19.8 itrile7 (3) 1.5 80 99 19.8 8 1.5 80 99 19.8 Table 4. RecyclingAs results shown8 of A in-catalyzed Scheme phospha-Michael1.52, the DMAP ·HSac addi80tion (A )-catalyzedof dimethyl phosphite phospha-Michael99 (1b) 19.8 addition Reaction conditions: temp (T) = 80 °C, cat. A (5 mol%), 1a (0.25 mL, 1.5 mmol), 3 (115 mg, 0.75 with 2-benzylidenemalononitrilereactionReaction ofconditions: diisopropyl ( 3temp). phosphite (T) = 80 °C, ( 1acat.) withA (5 mol%), 2-benzylidenemalononitrile 1a (0.25 mL, 1.5 mmol), 3 ((1153) was mg,selected 0.75 mmol), solvent free reaction. a Measured by GC/MS; b isolated yield in parenthesis. tommol), demonstrate solvent free the reaction. feasibility a Measured of recycling by GC/MS; usage b withisolatedA as yield a catalyst in parenthesis. using a solvent free a Cycle No.method, at Time 80 ◦C (h) mainly for Temp. 1 h. In(°C) this time, Yield the reaction(%) was successfully TON carried out As shown in Scheme 2, the DMAP.HSac (A)-catalyzed phospha-Michael addition re- 1 to affordAs shown the product1 in Scheme in quantitative 2, the80 DMAP conversions,.HSac (100A)-catalyzed (96) asb shown phospha-Michael in Scheme 20 2 and addition Table1 .reaction of diisopropyl phosphite (1a) with 2-benzylidenemalononitrile (3) was selected to 2 action of diisopropyl1 phosphite 80 (1a ) with 2-benzylidenemalononitrile 99 19.8 ( 3) was selected to demonstrate the feasibility of recycling usage with A as a catalyst using a solvent free 3 demonstrate the1 feasibility of recycling 80 usage 99with (95) A as a catalyst 19.8 using a solvent free 4 1 80 97 19.4 5 1 80 99 (94) 19.8

6 1.5 80 95 19 7 1.5 80 96 19.2 8 2 80 98 19.6 Reaction conditions: T = 80 °C, cat. A (5 mol%), 1b (0.14 mL, 1.5 mmol), 3 (115 mg, 0.75 mmol), solvent free reaction. a Measured by GC/MS; b isolated yield in parenthesis.

Table 4 shows the result of the reactivity and recycling of the A-catalyzed phospha- Michael addition reaction of dimethyl phosphite (1b) with 2-benzylidenemalononitrile (3). The results of Table 1 show a slightly shorter reaction time at later stages of recycling than those of Table 4. The change of the isopropyl group to methyl group on the phosphite substrate (see Schemes 2 and 3) did not show much change in the rate of the reaction. Thus, this change does not have a significant effect on the nucleophilicity of the phosphite substrate. d. A-catalyzed phospha-Michael addition of dimethyl phosphite (1b) and 2-(4-methylbenzylidene)malononitrile (4)

Table 5. Recycling results of A-catalyzed phospha-Michael addition of dimethyl phosphite (1b) with 2-(4-methylbenzylidene)malononitrile (4).

Cycle No. Time (h) Temp. (°C) Yield (%)a TON 1 2 80 100 20

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At the end of each cycle, the product mixtures were cooled to room temperature, and non-polar solvent (e.g., ether) was added to the reaction tube and centrifuged, and the catalyst was recovered by decantation. The recovered catalyst A was dried under vacuum and proceeded to the next cycle. The products were quantiﬁed with GC/MS analysis by comparison to internal standard (anisole). As shown in Table1, A-catalyzed phospha- Michael addition of 1a with 3 could give rise to good yield and recycling results for a total of eight times without using any solvent.

Table 1. Recycling results of A-catalyzed phospha-Michael addition of diisopropyl phosphite (1a) with benzylidenemalononitrile (3) at 80 ◦C.

Cycle No. Time (h) Temp. (◦C) Yield (%) a TON 1 1 80 99 (97) b 19.8 2 1 80 99 19.8 3 1 80 99 (96) 19.8 4 1 80 99 19.8 5 1 80 99 (95) 19.8 6 1 80 98 19.6 7 1.5 80 99 19.8 8 1.5 80 99 19.8 Reaction conditions: temp (T) = 80 ◦C, cat. A (5 mol%), 1a (0.25 mL, 1.5 mmol), 3 (115 mg, 0.75 mmol), solvent free reaction. a Measured by GC/MS; b isolated yield in parenthesis.

The phospha-Michel addition reaction of 1a with 3 showed high yield and good recycling result for eight cycles by using 5 mol% catalyst at 80 ◦C. By further lowering the catalytic loading to 1 mol% at 100 ◦C, a higher yield was still obtained within 1 h (see Table2 ). Additionally, catalyst A, which is thermally robust and is stable even when temperature is higher than 100 ◦C, was effectively recycled for the increased number of cycles (16 cycles) almost without a loss in catalytic activity. The average yield for all the con- secutive runs was 99%, which clearly demonstrates the practical reusability of this catalyst. Thus, it can be said that catalyst A showed a robust catalytic activity with a TON = ca 100 and a TOF = ca 100 and also with excellent recovery and good thermal stability.

Table 2. Recycling results of A-catalyzed phospha-Michael addition of diisopropyl phosphite (1a) with benzylidenemalononitrile (3) at 100 ◦C.

Cycle No. Time (h) Temp. (◦C) Yield (%) a TON 1 1 100 100 (98) b 100 2 1 100 100 100 3 1 100 99 (97) 99 4 1 100 100 100 5 1 100 99 (98) 99 6 1 100 100 100 7 1 100 100 100 8 1 100 100 100 9 1 100 99 99 10 1 100 100 100 11 1 100 100 100 12 1 100 100 100 13 1 100 100 100 14 1 100 100 100 15 1 100 100 100 16 1 100 100 100 Reaction conditions: T = 100 ◦C, cat. A (1 mol%), 1a (0.25 mL, 1.5 mmol), 3 (115 mg, 0.75 mmol), solvent free reaction. a Measured by GC/MS; b isolated yield in parenthesis. Molecules 2021, 26, 1159 5 of 14

b. A-catalyzed phospha-Michael addition of diisopropyl phosphite (1a) with 2-(4-methylbenzylidene)malononitrile (4) The catalyst A -catalyzed phospha-Michael addition reaction of diisopropyl phosphite (1a) with 2-(4-methylbenzylide)nemalononitrile (4) proceeded with a good yield at 80 ◦C in 2.5–3.5 h. However, the introduction of the electron donating group (X = CH3) into the benzene ring of compound 4 reduced the rate of the reaction, leading to increased reaction time (Table3) compared to the unsubstituted one ( 3, X = H).

Table 3. Recycling results of A-catalyzed phospha-Michael addition of diisopropyl phosphite (1a) with 2-(4-methylbenzylidene)malononitrile (4).

Cycle No. Time (h) Temp. (◦C) Yield (%) a TON 1 2.5 80 99 (99) b 19.8 2 2.5 80 97 19.4 3 3 80 99 (96) 19.8 4 3 80 99 19.8 5 3 80 96 (95) 19.2 6 3 80 96 19.2 7 3 80 95 19 8 3.5 80 97 19.4 Reaction conditions: T = 80 ◦C, cat. A (5 mol%), 1a (0.23 mL, 1.37 mmol), 4 (115 mg, 0.68 mmol), solvent free reaction. a Measured by GC/MS; b isolated yield in parenthesis.

c. A-catalyzed phospha-Michel addition of dimethyl phosphite (1b) and 2-benzylidenemalononitrile (3) Table4 shows the result of the reactivity and recycling of the A-catalyzed phospha- Michael addition reaction of dimethyl phosphite (1b) with 2-benzylidenemalononitrile (3). The results of Table1 show a slightly shorter reaction time at later stages of recycling than those of Table4. The change of the isopropyl group to methyl group on the phosphite substrate (see Schemes2 and3) did not show much change in the rate of the reaction. Thus, this change does not have a signiﬁcant effect on the nucleophilicity of the phosphite substrate.

Table 4. Recycling results of A-catalyzed phospha-Michael addition of dimethyl phosphite (1b) with 2-benzylidenemalononitrile (3).

Cycle No. Time (h) Temp. (◦C) Yield (%) a TON 1 1 80 100 (96) b 20 2 1 80 99 19.8 3 1 80 99 (95) 19.8 4 1 80 97 19.4 5 1 80 99 (94) 19.8 6 1.5 80 95 19 7 1.5 80 96 19.2 8 2 80 98 19.6 Reaction conditions: T = 80 ◦C, cat. A (5 mol%), 1b (0.14 mL, 1.5 mmol), 3 (115 mg, 0.75 mmol), solvent free reaction. a Measured by GC/MS; b isolated yield in parenthesis.

d. A-catalyzed phospha-Michael addition of dimethyl phosphite (1b) and 2-(4-methylbenzylidene) malononitrile (4) In Table5, the recycling results of the A-catalyzed phospha-Michael addition of dimethyl phosphite (1b) with 2-(4-methylbenzylidene)malononitrile (4) are presented. This reaction proceeded with good yield, mainly for 2 h at 80–100 ◦C. However, the introduction of the electron donating group (X = CH3) into the malononitrile substrate (4, X = CH3) reduced the rate of the reaction, leading to an increased reaction time and temperature (Table5) compared to the unsubstituted substrate ( 3, X = H). Molecules 2021, 26, 1159 6 of 14

Table 5. Recycling results of A-catalyzed phospha-Michael addition of dimethyl phosphite (1b) with 2-(4-methylbenzylidene)malononitrile (4).

Cycle No. Time (h) Temp. (◦C) Yield (%) a TON 1 2 80 100 20 2 2 80 100 (96) b 20 3 2 80 100 (96) 20 4 2 80 100 (97) 20 5 2 80 100 20 6 2 80 100 20 7 2 100 100 20 8 4 100 90 18 Reaction conditions: T = 80–100 ◦C, cat. A (5 mol%), 1b (0.12 mL, 1.37 mmol), 4 (115 mg, 0.68 mmol), solvent free reaction. a Measured by GC/MS; b isolated yield in parenthesis.

Molecules 2021, 26, x FOR PEER REVIEW 6 of 14 e. A-catalyzed phospha-Michael addition of triethyl phosphite (2) and 2-benzylidenemalononitrile (3) As shown in Table6, the A-catalyzed phospha-Michael addition of triethyl phosphite (2) with 2-benzylidenemalononitrile2 2 (3) demonstrated 80 good 100 product (96)b yield and20 catalytic recovery3 in 1 h for the ﬁrst2 four cycles. However, 80 it was found 100 (96) that the catalytic 20 perfor- mance of4 the recovered cat.2 A slightly diminished 80 after each100 (97) step to the 8th 20cycle. In Scheme4,5 the different kind2 of phosphite ( 2) 80 used in this reaction 100 is seen to yield 20 an alkyl substituted6 product. 2 80 100 20 7 2 100 100 20 Table 6. Recycling8 results of4A -catalyzed phospha-Michael 100 addition 90 of triethyl phosphite 18 (2) 2- benzylidenemalononitrileReaction conditions: T = 80–100 (3). °C, cat. A (5 mol%), 1b (0.12 mL, 1.37 mmol), 4 (115 mg, 0.68 mmol), solvent free reaction. a Measured by GC/MS; b isolated yield in parenthesis. Cycle No. Time (h) Temp. (◦C) Yield (%) a TON In Table1 5, the recycling1 results of the 80A-catalyzed phospha-Michael100 (96) b addition20 of dimethyl phosphite2 (1b) with1 2-(4-methylbenzylidene)malononitrile 80 100 (4) are presented. 20 This 3 1 80 100 (97) 20 reaction proceeded with good yield, mainly for 2 h at 80–100 °C. However, the introduc- 4 1 80 100 20 tion of the5 electron donating2 group (X = CH 803) into the malononi 100 (97)trile substrate (4, 20 X = CH3) reduced6 the rate of the reaction,2 leading to 100 an increased reaction 100 time and temperature 20 (Table 5)7 compared to the 2unsubstituted substrate 100 (3, X = H). 100 20 8 4 100 75 15 e. A-catalyzed phospha-Michael◦ addition of triethyl phosphite (2) and 2-benzylidenemalononitrile Reaction(3) conditions: T = 80–100 C, cat. A (5 mol%), 2 (0.25 mL, 1.5 mmol), 3 (115 mg, 0.75 mmol), solvent free reaction. a Measured by GC/MS; b isolated yield in parenthesis.

SchemeScheme 4.4. A A-catalyzed-catalyzed phospha-Michael phospha-Michael addition addition of oftriethyl triethyl phosphite phosphite (2) (with2) with 2-benzyli- 2-benzylidene malononitriledenemalononitrile (3). (3).

TableIn 6. summary, Recycling results in the ofA -catalyzedA-catalyzed phospha-Michel phospha-Michael addition of of triethyl phosphite phosphite reagents (2) 2- (1a, 1bbenzylidenemalononitrileor 2) with 2-benzylidenemalononitrile-type (3). substrates (3 or 4), the methyl, ethyl and isopropyl substituents of the phosphite did not show a signiﬁcant difference in their yields andCycle reaction No. times. However, Time (h) after several Temp. recycles, (°C) the Yield triethyl (%) substituteda TON phosphite did not maintain1 its reaction1 speed as the 80 previous cycles 100 (see (96) Tableb 6). Additionally, 20 for the phosphorus-acceptor2 1 saturated bond 80 containing 2-benzylidenemalononitrile-type 100 20 3 1 80 100 (97) 20 4 1 80 100 20 5 2 80 100 (97) 20 6 2 100 100 20 7 2 100 100 20 8 4 100 75 15 Reaction conditions: T = 80–100 °C, cat. A (5 mol%), 2 (0.25 mL, 1.5 mmol), 3 (115 mg, 0.75 mmol), solvent free reaction. a Measured by GC/MS; b isolated yield in parenthesis.

As shown in Table 6, the A-catalyzed phospha-Michael addition of triethyl phosphite (2) with 2-benzylidenemalononitrile (3) demonstrated good product yield and catalytic recovery in 1 h for the first four cycles. However, it was found that the catalytic perfor- mance of the recovered cat. A slightly diminished after each step to the 8th cycle. In Scheme 4, the different kind of phosphite (2) used in this reaction is seen to yield an alkyl substituted product. In summary, in the A-catalyzed phospha-Michel addition of phosphite reagents (1a, 1b or 2) with 2-benzylidenemalononitrile-type substrates (3 or 4), the methyl, ethyl and

Molecules 2021, 26, 1159 7 of 14

substrates (3 or 4), the unsubstituted compound 3 showed a shorter reaction time than the CH3 substituted compound 4. Here, the electron releasing CH3 group was found to retard the speed of the reaction. Hosseini-Sarvari and Etemad reported a nanosized zinc oxide catalyzed similar reaction by using [P(O)(OEt)2] phosphite substrate showing a similar trend of shorter reaction time for the unsubstituted malononitrile substrate (2.5 h) than the methyl substituent (5 h) [23,25]. For the base A-catalyzed reactions of diorganophosphite compounds (1a or 1b) with 2-benzylidenemalononitrile-type substrates (3 or 4), the reactions followed the cited reaction mechanism [39,40], demonestrating the base assisted P-H bond cleavage and adding Molecules 2021, 26, x FOR PEER REVIEW 7 of 14 the H and P-containing moiety into the two sides of the double bond (see Figure S1 in SM). However, the A-catalyzed similar reaction of tris(organo)phosphite (2) with 2- benzylidenemalononitrile (3) followed a different mechanism through the O-C bond cleav- isopropylage of one substituents -OC2H5 group of the to phosphite add the phosphonate did not show group a significant [P(O)(O difference C2H5)2] in and their the yields ethyl andgroups reaction into thetimes. two However, sides of the after double several bond recycles, (Scheme the4 ).triethyl substituted phosphite did not maintain its reaction speed as the previous cycles (see Table 6). Additionally, for the 2.1.3. Kinetic Study of A-Catalyzed Phospha-Michael Addition Reaction of Diisopropyl phosphorus-acceptor saturated bond containing 2-benzylidenemalononitrile-type sub- Phosphite (1a) with Benzylidenemalononitrile (3) strates (3 or 4), the unsubstituted compound 3 showed a shorter reaction time than the The phospha-Michael addition of diisopropyl phosphite (1a) with benzylidenemalonon- CH3 substituted compound 4. Here, the electron releasing CH3 group was found to retard itrile (3) was also studied kinetically at 80 ◦C (see Figure1). The reaction showed a drastic the speed of the reaction. Hosseini-Sarvari and Etemad reported a nanosized zinc oxide increase in product concentration within the initial 10 min to 54 %, and the reaction reached catalyzed similar reaction by using [P(O)(OEt)2] phosphite substrate showing a similar 100 % yield after 1 h. The integrated rate law derived from the concentration of reactant 3 trend of shorter reaction time for the unsubstituted malononitrile substrate (2.5 h) than vs. time showed the ln[reactant 3] = −kt + ln[reactant 3] plot with a rate constant k = 0.057 the methyl substituent (5 h) [23,25]. o and R2 = 0.97, where [reactant 3] = 3 M and ln[reactant 3] = 1.074, as shown in Figure S2 For the base A-catalyzed reactionso of diorganophosphiteo compounds (1a or 1b) with (in supplementary material). This kinetically monitored reaction showed the turnover 2-benzylidenemalononitrile-type substrates (3 or 4), the reactions followed the cited reac- frequency (TOF) to be 19.8 h−1 at 1 h. However, for the same reaction, only about 50% tion mechanism [39,40], demonestrating the base assisted P-H bond cleavage and adding product yield was found after 90 min without using catalyst A or by using saccharine as the H and P-containing moiety into the two sides of the double bond (see Figure S1 in a catalyst (see in Figure1). Likewise, Sobani and her coworkers reported the reaction of SM). However, the A-catalyzed similar reaction of tris(organo)phosphite (2) with 2-ben- diethyl phosphite with 2-benzylidenemalononitrile (3) in the absence of the catalyst to give zylidenemalononitrilea yield of 60% in 24 h. ( The3) followed reactions a withoutdifferent a mechanism catalyst led through to the formation the O-C bond of the cleavage desired ofproduct one -OC in2 lowH5 group yields to after add a the long phosphonate reaction time group [25]. [P(O)(O Furthermore, C2H5)2 Sarvari] and the and ethyl coworkers groups intoreported the two that sides the reaction of the double of diethyl bond phosphite (Scheme with 4). the electron withdrawing group substituted 2-[(4-chlorophenyl) methylene]malononitrile in the absence of the catalyst gave no 2.1.3.product Kinetic after Study 24 h [ 23of]. A Overall,-Catalyzed these Phospha-Michael control experiments Addition showed Reaction the same of Diisopropyl trend, which Phosphiteindicated that(1a) withoutwith Benzylidenemalononitrile a catalyst, the phospha-Michael (3) addition reactions were either very slow or showed no reaction.

100

80 Catalyst A Without a catalyst Saccharin 60

0 0 102030405060708090 Time (min) FigureFigure 1. KineticKinetic study of phospha-Michael additionaddition ofof diisopropyldiisopropyl phosphite phosphite ( 1a(1a)) with with benzylidene- benzyli- denemalononitrilemalononitrile (3) with (3) with and withoutand without a catalyst a catalystA. (Note: A. (Note: saccharin saccharin as a catalystas a catalyst was alsowas tested,also tested, but it butshowed it showed no catalytic no catalytic effect.) effect.)

The phospha-Michael addition of diisopropyl phosphite (1a) with benzylidenemalononitrile (3) was also studied kinetically at 80 °C (see Figure 1). The reaction showed a drastic increase in product concentration within the initial 10 min to 54 %, and the reaction reached 100 % yield after 1 h. The integrated rate law derived from the concentration of reactant 3 vs. time showed the ln[reactant 3] = −kt + ln[reactant 3]o plot with a rate constant k = 0.057 and R2 = 0.97, where [reactant 3]o = 3 M and ln[reactant 3]o = 1.074, as shown in Figure S2 (in supplementary material). This kinetically monitored reaction showed the turnover frequency (TOF) to be 19.8 h−1 at 1 h. However, for the same reaction, only about 50% product yield was found after 90 min without using catalyst A or by using saccharine as a catalyst (see in Figure 1). Likewise, Sobani and her coworkers reported the reaction of diethyl phosphite with 2-benzylidenemalononitrile (3) in the absence of the catalyst to give a yield of 60% in 24 h. The reactions without a catalyst led to the formation of the desired product in low yields after a long reaction time [25]. Furthermore, Sarvari and

Molecules 2021, 26, 1159 8 of 14 Molecules 2021, 26, x FOR PEER REVIEW 8 of 14

coworkers reported2.2. Recoverable that the reaction Fluorous of Long-Chained diethyl phosphite Pyridine-Catalyzed with the electron Phospha-Michael withdrawing Addition Reaction group substituted2.2.1. 2-[(4- Synthesischlorophenyl) of RfCH2 OCHmethylene]malononitrile2-py (Catalyst B) in the absence of the catalyst gave no productThe after synthesis 24 h [23]. of ROverall,fCH2OCH these2-py control (catalyst experimentsB) proceeds showed through the same two steps, as re- trend, which portedindicated in that the literaturewithout a [ 41cataly]. Thest, the initial phospha-Michael step starts from addition the deprotonation reactions of readily Molecules 2021, 26, x FOR PEER REVIEW available ﬂuorinated alcohols. Thus, R -CH OH, where R = C F ,8 was of 14 treated with were either very slow or showed no reaction. f 2 f 11 23 30% CH3ONa/CH3OH to give the corresponding alkoxides whose nucleophilic attack 2.2. Recoverableon Fluorous 4-(BrCH Long-Chained2)-py·HBr gave Pyridine-Catalyzed rise to the synthesis Phospha-Michael of ﬂuorous Addition long-chained Reaction pyridine B, [4- (R CH OCH )-py)] (see Scheme5). 2.2.1.coworkers Synthesis reported off Rf2CH that2OCH the2 2reaction-py (Catalyst of diet Bhyl) phosphite with the electron withdrawing group substituted 2-[(4-chlorophenyl) methylene]malononitrile in the absence of the catalyst gave no product after 24 h [23]. Overall, these control experiments showed the same trend, which indicated that without a catalyst, the phospha-Michael addition reactions were either very slow or showed no reaction.

2.2. Recoverable Fluorous Long-Chained Pyridine-Catalyzed Phospha-Michael Addition Reaction

2.2.1. Synthesis of RfCH2OCH2-py (Catalyst B)

Scheme 5. Synthesis ofScheme RfCH2OCH 5. Synthesis2-py catalyst of R fBCH. 2OCH2-py catalyst B.

The synthesis of RfCH2OCH2-py (catalyst B) proceeds through two steps, as reported 2.2.2. Recoverable Fluorous Rf-py-Catalyzed Phospha-Michael Addition in the literature [41]. The initial step starts from the deprotonation of readily available a. B-catalyzed phospha-Michael addition of diisopropyl phosphite (1a) with 2-benzylidenemalono- fluorinated alcohols. Thus, Rf-CH2OH, where Rf = C11F23, was treated with 30% nitrile (3). CH3ONa/CH3OH to give the corresponding alkoxides whose nucleophilic attack on 4- (BrCH2)-py.HBr gaveIn Scheme rise to6, thethe Bsynthesis-catalyzed of phospha-Michael fluorous long-chained addition pyridine of diisopropyl B, [4- phosphite (1a) f 2 2 with 2-benzylidenemalononitrile (3) was selected to demonstrate the feasibility of recycling (RSchemeCH OCH 5. Synthesis)-py)] (see of R SchemefCH2OCH 5).2-py catalyst B. usage with B as a catalyst using a solvent free method, at 80 ◦C for 1 h. At the end of each cycle, the product mixtures were cooled to room temperature, resulting in catalyst 2.2.2. RecoverableThe synthesis fluorous of RfCH R2OCHf-py-catalyzed2-py (catalyst phospha-Michael B) proceeds through addition two steps, as reported precipitation due to their thermomorphic behavior where the solubility of the catalyst in the literature [41]. The initial step starts from the deprotonation of readily available increased dramatically with the increasing temperature [36,38]. Finally, after centrifugation, fluorinated alcohols. Thus, Rf-CH2OH, where Rf = C11F23, was treated with 30% the catalyst was recovered by decantation. The recovered catalyst B was dried under CH3ONa/CH3OH to give the corresponding alkoxides whose nucleophilic attack on 4- vacuum and proceeded to the next cycle. The products were quantiﬁed with GC/MS (BrCH2)-py.HBr gave rise to the synthesis of fluorous long-chained pyridine B, [4- analysis through comparison to the internal standard (e.g., anisole). As shown in Table7, (RfCH2OCH2)-py)] (see Scheme 5). the B-catalyzed phospha-Michael addition reaction of 1a with 3 could give rise to good recycling results for a total of eight times without using any solvent. 2.2.2. Recoverable fluorous Rf-py-catalyzed phospha-Michael addition

Scheme 6. The B-catalyzed phospha-Michael addition of diisopropyl phosphite (1a) with 2-benzylidenemalononitrile-type substrates [3 (X = H), or 4 (X = CH3)]. a. B-catalyzed phospha-Michael addition of diisopropyl phosphite (1a) with 2- benzylidenemalononitrile (3).

Table 7. Recycling results of B-catalyzed phospha-Michael addition of diisopropyl phosphite (1) with 2-benzylidenemalononitrile (3) at 80 °C. Scheme 6. TheSchemeB-catalyzed 6. The phospha-Michael B-catalyzed phospha-Michael addition of diisopropyl addition phosphite of diisopropyl (1a) with 2-benzylidenemalononitrile-type phosphite (1a) substrates [3 (X =Cycle H), or No.4 (X = CH3)]. Time (h) Temp. (°C) Yield (%)a TON with 2-benzylidenemalononitrile-type substrates [3 (X = H), or 4 (X = CH3)]. 1 1 80 100 20 a. B-catalyzedb. phospha-MichaelB-catalyzed phospha-Michael addition additionof diisopropyl diisopropyl phosphite (1a()1a with) 2-(4-methylbenzylidene)with 2- 2 malononitrile1 (4) 80 100 20 benzylidenemalononitrile3 1 (3). 80 100 20 The B-catalyzed phospha-Michael addition of diisopropyl phosphite (1a) with 2-(4- 4 1 80 100 20 Table 7. Recyclingmethylbenzylidene)malononitrile results of B-catalyzed phospha-Michael (4) was additi successfullyon of diisopropyl carried phosphite out under (1 thermomorphic) 5 1 80 99 19.8 with 2-benzylidenemalononitrileconditions at 5 mol% (3) at catalyst80 °C. loading as shown in Scheme6 above (Table8). However, 6 1 80 98 19.6 Cycle No.an elongated Time reaction (h) time Temp. was observed (°C) compared Yield (%) toa the reactionTON using unsubstituted 7 2-benzylidenemalononitrile1 (380). It followed the98 same trend compared19.6 to the similar A- 1 1 80 100 20 8 catalyzed reaction1 mentioned80 above (see Table3).96 19.2 2 1 80 100 20 3 1 80 100 20 4 1 80 100 20 5 1 80 99 19.8 6 1 80 98 19.6 7 1 80 98 19.6 8 1 80 96 19.2

Molecules 2021, 26, x FOR PEER REVIEW 9 of 14

Reaction conditions: T = 80 °C, cat. B (5 mol%), 1a (0.25 mL, 1.5 mmol), 3 (115 mg, 0.75 mmol), sol- Molecules 2021, 26, 1159vent free reaction. a Measured by GC/MS. 9 of 14

In Scheme 6, the B-catalyzed phospha-Michael addition of diisopropyl phosphite (1a) with 2-benzylidenemalononitrile (3) was selected to demonstrate the feasibility of recycling usage withTable B as 7. Recyclinga catalyst results using ofa Bsolvent-catalyzed free phospha-Michael method, at 80 °C addition for 1 h. of diisopropylAt the end phosphiteof (1) with ◦ each cycle, the2-benzylidenemalononitrile product mixtures were (cooled3) at 80 toC. room temperature, resulting in catalyst precipitation due toCycle their No. thermomorphic Time (h)behavior where Temp. the (◦C) solubility Yield of the (%) catalysta in- TON creased dramatically with the increasing temperature [36,38]. Finally, after centrifugation, 1 1 80 100 20 the catalyst was recovered by decantation. The recovered catalyst B was dried under vac- 2 1 80 100 20 uum and proceeded to3 the next cycle. The1 products were quantified 80 with GC/MS 100 analysis 20 through comparison to4 the internal standard1 (e.g., anisole). 80 As shown in Table 100 7, the B- 20 catalyzed phospha-Michael5 addition reaction1 of 1a with 3 could 80 give rise to good 99 recycling 19.8 results for a total of eight6 times without 1using any solvent. 80 98 19.6 7 1 80 98 19.6 b. B-catalyzed phospha-Michael8 addition1 diisopropyl 80phosphite (1a) 96with 2-(4- 19.2 methylbenzylidene)malononitrileReaction conditions: T = ( 804) ◦C, cat. B (5 mol%), 1a (0.25 mL, 1.5 mmol), 3 (115 mg, 0.75 mmol), solvent free reaction. a Measured by GC/MS. Table 8. Recycling results of B-catalyzed phospha-Michael addition of diisopropyl phosphite (1a) with 2-(4-methylbenzylidene)malononitrileTable 8. Recycling results of (B4).-catalyzed phospha-Michael addition of diisopropyl phosphite (1a) with 2-(4-methylbenzylidene)malononitrile (4). Cycle No. Time (h) Temp. (°C) Yield (%)a TON 1 Cycle No.4.5 Time (h)80 Temp.98 (◦ C)(98)b Yield (%)19.6a TON 2 1 4.5 4.580 80 98 98 (98)19.6b 19.6 3 2 4.5 4.580 8098 (96) 9819.6 19.6 4 3 4.5 4.580 8097 98 (96)19.4 19.6 5 4 4.5 4.580 8097 (95) 9719.4 19.4 5 4.5 80 97 (95) 19.4 6 4.5 80 96 19.2 6 4.5 80 96 19.2 7 7 4.5 4.580 8094 9418.8 18.8 8 8 4.5 4.580 8094 9418.8 18.8 Reaction conditions:Reaction T = conditions: 80 °C, cat. T B =, 804-23F-py,◦C, cat. B (5, 4-23F-py, mol%), (51a mol%), (0.23 mL,1a (0.23 1.37 mL, mmol), 1.37 mmol), 4 (1154 mg,(115 mg,0.68 0.68 mmol), solvent mmol), solvent free reaction.reaction.a Measureda Measured by GC/MS;by GC/MS;b isolated b isolated yield yield in parenthesis. in parenthesis.

The B-catalyzedc. B-catalyzed phospha-Michael phospha-Michael addition addition of diisopropyl of dimethyl phosphite phosphite ((1b1a)) withwith 2-benzylidenemalono- 2-(4- methylbenzylidene)malononitrilenitrile (3) (4) was successfully carried out under thermomorphic conditions at 5 mol%The catalystB-catalyzed loading phospha-Michael as shown in Scheme addition 6 above of dimethyl (Table phosphite8). However, (1b )an with 2-benzylid- elongated reactionenemalononitrile time was observed (3) (see Schemecompar7ed) was to alsothe reaction found to using be effective unsubstituted with good 2- recoveries, as benzylidenemalononitrileshown in Table (3).9 It. Thefollowed reaction the timesame recorded trend compared for this reactionto the similar is almost A-cata- the same as the lyzed reactiontime mentioned for A-catalyzed above (see similar Table reaction. 3).

Scheme 7.Scheme B-catalyzed 7. B-catalyzed phospha-Michael phospha-Michael addition addition of dimethyl of dimethyl phosphite phosphite (1b) with (1b 2-benzylidenemalononitrile) with 2-benzyli- (3). denemalononitrile (3). In summary, in the B-catalyzed phospha-Michael addition of phosphite reagents (1a c. B-catalyzedor phospha-Michael1b) with 2-benzylidenemalononitrile-type addition of dimethyl phosphite substrates(1b) with 2-benzylidenemalono- (3 or 4), no signiﬁcant difference nitrile (3) was recorded for the methyl or the isopropyl substituents of the phosphite as reported for the A-catalyzed reactions above. However, the B-catalyzed reaction of the unsubstituted compound 3 showed a better reaction time than the CH3 substituted compound 4. The outcomes from the B-catalyzed reactions are comparable to those of the A-catalyzed reactions, which could still be explained by the electronic effect of the electron releasing property of the CH3 group. Molecules 2021, 26, 1159 10 of 14

Table 9. Recycling results of B-catalyzed phospha-Michael addition of dimethyl phosphite (1b) with 2-benzylidenemalononitrile (3).

Cycle No. Time(h) Temp. (◦C) Yield (%) a TON 1 1 80 90 (88) b 18 2 1 80 87 18.4 3 1 80 90 (87) 18 4 1 90 90 18 5 1 90 85 (84) 17 6 1 90 85 17 7 1.5 90 90 18 8 3 90 83 16.6 Reaction conditions: T = 80–90 ◦C, cat. B (5 mol%), 1b (0.14 mL, 1.5 mmol), 3 (115 mg, 0.75 mmol), solvent free reaction. a Measured by GC/MS; b isolated yield in parenthesis.

2.2.3. Kinetic Study of B-Catalyzed Phospha-Michael Addition of Diisopropyl Phosphite (1a) with Benzylidenemalononitrile (3) The B-catalyzed phospha-Michael addition reaction of diisopropyl phosphite (1a) with benzylidenemalononitrile (3) showed an increase in product concentration to 49 % in the initial 10 min. Then, 100 % of reactant 3 was converted to a product after 1 h, as shown in Figure S3 in the supplementary material. The integrated rate law derived from the concentration of reactant 3 vs. time showed ln[reactant 3] = −kt + ln[reactant 3]o plot with 2 a rate constant k = 0.055 and R = 0.95, where ln[reactant 3]o = 1.154, as shown in Figure S4 in the supplementary material. This kinetically monitored reaction showed the turnover frequency (TOF) to be 19.2 h−1 at 1 h. When comparing the reaction rate of catalyst B with that of catalyst A, both of the reactions were pseudo ﬁrst order reactions with catalyst A, which had a higher rate constant (k = 0.057) than that (k = 0.055) of catalyst B. The presence of an electron withdrawing ﬂuorous chain on the pyridyl nitrogen had an electronic effect on the activity of the catalyst. Thus, catalyst B showed a slight decrease in reaction rate when compared to catalyst A.

3. Experimental 3.1. General Procedure General Procedures HP 6890 GC containing a 30 m 0.250 mm HP-1 capillary column with a 0.25 mm stationary phase ﬁlm thickness was used to censor the reaction. The same GC instrument with a 5973 series mass selective detector was used to Acquire GC/MS data. The ﬂow rate was 1 mL/min and splitless. Infra-red spectra were obtained on a Perkin Elmer RX I FT-IR Spectrometer. NMR spectra were recorded on Bruker AM 500 and Joel AM 200 using 5 mm sample tubes. The CDCl3, deuterated DMF and deuterated 1 13 ® DMSO were the references for both H and C NMR spectra, and Freon 11 (CFCl3) was the reference for 19F NMR spectra.

3.2. Starting Materials The employed chemicals, reagents and solvents were commercially available and used as received. Diisopropyl phosphite, dimethyl phosphite, triethyl phosphite, 2- benzylidenemalononitrile, 2-(4-methylbenzylidene)malononitrile (note: the local chemical vendors in Taiwan could only supply us with these substrates, which include three phosphites and two malononitriles.), DMAP, saccharin, C11F23CH2OH and 30% CH3ONa/ CH3OH were purchased from either Aldrich or SynQuest.

3.3. Preparation of Catalyst A DMAP (0.5 g, 4.09 mmol) and saccharin (0.74 g, 4.09 mmol) were transferred to a 250 mL round bottomed ﬂask. An amount of 100 mL of anhydrous THF was added to the mixture and reﬂuxed at 60 ◦C overnight. The initial stage the reaction mixture appeared to be a white turbid solution. The reaction mixture turned transparent by the end of the Molecules 2021, 26, 1159 11 of 14

reaction. THF was removed by applying the vacuum to obtain the white solid precipitate of DMAP·HSac adduct with 95% yield (see Scheme1).

Analytical Data of Catalyst A Catalyst A has been prepared by Lu’s group [28] before as a recyclable acylation catalyst. Thus, the FT-IR and NMR spectra of catalyst A were used to identify the compound (see FT-IR spectrum in Section 5.1 and Figure S5 in SM).

3.4. Preparation of Catalyst B

RfCH2OH (11.0 mmol) and CH3ONa (30% in methanol) (10.0 mmol) were charged ◦ into a N2 filled two neck round-bottomed flask, then stirred continuously at 65 C for 4 h before methanol was vacuum pumped to facilitate the reaction conversion to the fluorinated alkoxide product. The fine powdered fluorinated alkoxide (10.0 mmol) was then dissolved in dry THF (30 mL), and (BrCH2)-py·HBr (10 mmol) was added. The mixture was allowed to reflux for 4 h, and the completeness of the reaction was checked by sampling the reaction mixtures and analyzing the aliquots with GC/MS. Finally, the pure product was isolated by using CH2Cl2/H2O extraction to find a white solid material with 78 % yield (see Scheme5)[42–45].

Analytical Data of Catalyst B (4-23F-py) 1 ◦ H-NMR (500 MHz, DMSO-d6, at 80 C): δ (ppm) 8.55 (d, J = 6 Hz, 2H, H2, H5), 19 7.30 (d, J = 6 Hz, 2H, H3, H6) 4.74 (s, 2H, py-CH2), 4.23 (t, J = 15 Hz, 2H, CH2CF2), F ◦ 3 NMR (470.5 MHz, d-DMSO, at 80 C) δ −80.9 (t, JFF = 7.52, 3F, -CF3), −119.3 (2F), −121.2 (12F), −122.2 (2F), −122.8 (2F), −125.6 (2F); 13C NMR (113 MHz, d-DMSO, at 80 ◦C) δ 72.5 −1 (py-CH2), 68.2 (CH2CF2), 122.5, 147.0, 150.5, (py, 5 Cs), 105.0~116.0 (C11F23). FT-IR (cm ): + + v (py, m) 1603.8, 1468.1; v (CF2 stretch, s) 1200.6, 1146.3. MS (M ; m/z =): 691 (M ), 122 (C7H8NO), 108 (C6H6NO), 92(C6H6N) (see FT-IR spectrum in Section 5.2 and Figure S6 in SM).

3.5. Procedures in Catalytic Phospha-Michael Addition Reaction The reactants 2-benzylidenemalononitrile substrate (115 mg, 1 equivalent), phosphite reagent (2 equivalent) and the catalyst (A or B, (0.05 equivalent)) were added together, and the reaction was carried out without solvent for all the catalysts (see Schemes2,3,6 and7). Then, the reaction mixture was set to react at 80–100 ◦C for the given period of time before GC/MS analysis was performed to conﬁrm the completion of the reaction.

3.6. Procedures in Catalytic Recovery of DMAP·HSac (A) In a typical run, 2-benzylidenemalononitrile substrate (115 mg, 0.75 mmol) and phosphite reagent (1.5 mmol) were added into a 10 mL reaction tube containing a magnetic stirrer bar, then the DMAP·HSac (A) (5 mol%) was added to the reaction tube. The reaction was carried out under solvent free conditions. Then, the reaction mixture was set to react at ◦ 80–100 C under N2 gas for the given period of time. After the completion of the reaction, the product mixtures were cooled down to room temperature (25 ◦C), and then 5 mL of non-polar solvent (e.g., diethyl ether) was added to the reaction mixture. The reaction tube was centrifuged to separate the catalyst and reaction mixture. After the catalyst was recovered by decantation and washed three times by the same solvent, it was then dried under vacuum, and the same amounts of reactants were used to carry out the next cycle of reaction. Once the catalytic recovery was complete, GC/MS analysis was performed, the pure product was isolated by using CH2Cl2/H2O extraction and the CH2Cl2 layer was pumped under reduced pressure to obtain the pure product. The product was ﬁnally analyzed by using 1H NMR spectroscopy. Molecules 2021, 26, 1159 12 of 14

3.7. Procedures in Catalytic Recovery of Rf-py Catalyst (B)

For the Rf-py catalyst, 2-benzylidenemalononitrile substrate (115 mg, 0.75 mmol) and phosphite reagent (1.5 mmol) were added into a 10 mL reaction tube containing a magnetic stirrer bar, then catalyst B (5 mol%) was added. The reaction was carried out under solvent free conditions. The excess phosphite in the reaction acted as solvent. The catalyst showed thermomorphic properties at 80 ◦C. The reaction mixture was set to react at 80–100 ◦C under N2 gas for the given period of time. After the completion of reaction, the product mixtures were cooled down to room temperature (25 ◦C) to let the catalyst getting precipitated at the bottom of the reaction tube. After centrifugation, the supernatant solution containing the reaction mixture was removed carefully by using a syringe. The precipitated catalyst B was washed three times by the same solvent (e.g., ether) and dried under vacuum. After GC/MS analysis was complete, the product was isolated using CH2Cl2/H2O extraction and analyzed by using 1H NMR spectroscopy and the GC/MS method.

4. Conclusions Developing a recoverable catalyst with a better activity, easier separation and effective recycling with a better yield is the goal of scientists. Reported here, this work showed effective catalysis by using pyridine-based organo-catalyst bases, the DMAP·Hsac adduct and a fluorous long-chained pyridine. In the A-catalyzed phospha-Michael addition of phosphite reagents with 2-benzylidenemalononitrile-type substrates, the methyl, ethyl and the isopropyl substituents of the phosphite did not show a significant difference in their yields and reaction times. However, after several cycles, the triethyl substituted phosphite did not maintain its reaction speed. Additionally, for the unsaturated malonates substrates, the unsubstituted compound showed a shorter reaction time than the CH3 substituted compound. Here, the electron releasing CH3 group was found to retard the speed of the reaction. Generally, it was found that the DMAP·Hsac (A) catalyst system showed a relatively better catalytic activity than its fluorous long-chained pyridine (B) counterpart. This could result from the effect of the strong electron-withdrawing property of the fluorous chain on the pyridyl nitrogen, so pyridyl nitrogen basicity was reduced. In these catalyzed reactions, solubility differences and thermomorphic properties were effectively used to recover the DMAP·Hsac adduct in Section 2.1 and a fluorous long- chained pyridine in Section 2.2, respectively. The product yield was also found to be high in every reaction run; sometimes, it even reached 100%. In summary, these catalyst systems were proven to be successful with a very high yield and are very effectively recycled, sometimes up to 16 times (as shown in Table2), almost without a loss of activity. Both of the recoverable py-based systems reported here are supposed to also work effectively for any kind of recoverable phospha-Michael addition and most recyclable base-catalyzed reactions in general—e.g., recyclable base-catalyzed aldol condensation and recyclable base-catalyzed racemization. Therefore, we believe that these two types of organo-catalysts with heterogenous separation may also eliminate the involvement of metal-based catalyst systems in these kinds of catalytic reactions in the near future.

Supplementary Materials: The following are available online: kinetic studies, GC/MS data of reactants and products and 1H NMR spectra of products. Author Contributions: N.L., C.-F.C., C.-R.S. and P.Z. performed the conceptualization and had the research idea; E.T., V.E., J.-H.Z. and K.L.C. performed syntheses and characterization of the palladium complexes, and conducted the catalytic studies. N.L., P.Z. and C.-F.C. analyzed the obtained data and wrote the manuscript. All authors have read and agreed to the published version of the manuscript. Funding: We gratefully acknowledge the Ministry of Science and Technology in Taiwan (MOST 109-2113-M-027-003) and university joint grants: NTUT-CGMH-109-07. Data Availability Statement: The data presented in this study are available in the article. Acknowledgments: We thank Huan-Cheng Change for collaboration in the early phase of this project. Conﬂicts of Interest: The authors declare no conﬂict of interest. Molecules 2021, 26, 1159 13 of 14

Sample Availability: Catalyst A and some of the ﬂuorous compounds are available from the authors.

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