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

Article abstract of DOI:10.3390/molecules26041159

Phospha-Michael addition, which is the addition reaction of a phosphorus-based nucleophile to an acceptor-substituted unsaturated bond, certainly represents one of the most versatile and powerful tools for the formation of P-C bonds, since many different

Full text of DOI:10.3390/molecules26041159

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;
eskedartessema18@gmail.com (E.T.); vijayanathe123@gmail.com (V.E.); st121321@gmail.com (J.-H.Z.);
ka-longabc@gmail.com (K.L.C.)
Department of Pediatrics, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University,
Taoyuan 333, Taiwan
Department of Medical Biotechnology and Laboratory Sciences, College of Medicine, Chang Gung University,
Taoyuan 333, Taiwan; crshen@mail.cgu.edu.tw
Department of Ophthalmology, Linkou Medical Center, Chang Gung Memorial Hospital,
Taoyuan 333, Taiwan
2
3
4
5
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
6
7
Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221-0172, USA
Development Center for Smart Textile, National Taipei University of Technology, Taipei 106, Taiwan
Correspondence: chioufan2008@gmail.com (C.-F.C.); peng.zhang@uc.edu (P.Z.);
normanlu@mail.ntut.edu.tw (N.L.)
ꢀꢁꢂꢃꢄꢅꢆ
Citation: Tessema, E.; Elakkat, V.;
Chiu, C.-F.; Zheng, J.-H.; Chan, K.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-
ophile to an acceptor-substituted unsaturated bond, certainly represents one of the most versatile and
powerful tools for the formation of P-C bonds, since many different electrophiles and P nucleophiles
can be combined with each other. This offers the possibility to access many diversely functionalized
products. In this work, two kinds of basic pyridine-based organo-catalysts were used to efficiently
catalyze phospha-Michael addition reactions, the 4-N,N-dimethylaminopyridinium saccharinate
4-N,N-Dimethylaminopyridinium
Saccharinate Salt or a Fluorous
Long-Chained Pyridine: Two Types
of Reusable Base Catalysts. Molecules
2021, 26, 1159. https://doi.org/
10.3390/molecules26041159
(DMAP
·
Hsac) salt and a fluorous long-chained pyridine (4-Rf-CH2OCH2-py, where Rf = C11F23).
These catalysts have been synthesized and characterized by Lu’s group. The phospha-Michael addi-
Academic Editor: Alessandra Puglisi
tion of diisopropyl, dimethyl or triethyl phosphites to
those catalysts showed very good reactivity with high yield at 80–100 C in 1–4.5 h with high catalytic
recovery and reusability. With regard to significant catalytic recovery, sometimes more than eight
α
,
β
-unsaturated malonates in the presence of
◦
Received: 5 February 2021
Accepted: 19 February 2021
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
used to efficiently recover the catalyst for eight cycles in all the reactions. Thus, the easy separation of
the catalysts from the products revealed the outstanding efficacy of our systems. To our knowledge,
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
these are good examples of the application of recoverable organo-catalysts to the DMAP Hsac adduct
·
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;
adduct; thermomorphic; phosphite
Copyright:
© 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
1. Introduction
The chemistry of phosphonates has inspired an increasing interest following their
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
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their preparation is an important goal in organic synthesis [
1–4
]. To date, intensive studies
have been reported in their synthetic application in biomedical fields, such as peptide
mimicking [ ], enzyme inhibition [ ], metabolic inquiries [ ], pharmacological activity
study [ ] and biological activities [ ]. These transformations, however, require the use of
5
6
7
8
9
a base catalyst to promote tautomeric equilibria of H-phosphonates in favor of a reactive
form of phosphites [10].
Among the main methods of the synthesis of phosphonates through C-P bond for-
mation is the addition of phosphite nucleophile across the carbon–carbon double bond,
which is called the phospha-Michael reaction [11
,12]. This reaction has been catalyzed
by metal oxides [13], acids [14], bases [15 16], radical initiator [17
,
,
18] transition metal
catalysts [19], tetramethylguanidine [20], microwave [21], HClO4.-SiO2 [22], nano-sized
ZnO [23], sodium stearate [24], and so on. Although phospha-Michael addition could
proceed by these catalyzed methods, many of these reagents cannot be reused, and in
many instances, long reaction time; drastic reaction conditions; and sometimes, according
to the nature of the catalyst, tedious work-up is needed. Therefore, the development of a
new method to overcome these shortcomings still remains an ongoing challenge for the
synthesis of these significant scaffolds. Recently, some recoverable catalyst systems have
also been reported to be active, such as magnetically recyclable heterogeneous organic
base [25] and 3-aminopropylated silica gel [26].
Reported here, the 4-N,N-dimethylaminopyridinium saccharinate (DMAP Hsac) salt
·
was used as a catalyst in the current work. This salt was synthesized by the reversible
acid-base reaction of the basic 4-N,N-dimethylaminopyridine (DMAP) with the acidic
saccharine (Hsac). During the equilibrium, there is always a very small amount of free
DMAP present in the solution (see Equation 1), and this free DMAP can homogeneously
and effectively catalyze the phospha-Michael addition reactions [27]. Additionally, this
salt of 4-N,N-dimethylaminopyridinium saccharinate (DMAP Hsac), which is an ionic
·
compound, is usually insoluble in most non-polar solvents. It can be easily precipitated
out to achieve the phase separation by adding the non-polar solvents. (e.g., ether, hexane
etc.) [27
,
28]. This special solubility property of DMAP Hsac makes the adduct act as a
·
good catalytic bridge between heterogeneous and homogeneous catalysis, as the addition
of non-polar solvent makes the catalyst precipitate out. Likewise, in the 2nd part of this
research, the fluorous long-chained pyridine (4-Rf-CH2OCH2-py where Rf = C11F23), as a
base catalyst, works under thermomorphic conditions with a feature of homogeneously
catalyzing phospha-Michael addition at a high temperature in a neat reaction where the
reactants serve as the solvent, forming heterogeneous precipitation at a lower temperature.
The thermomorphic method is an alternative way to use the different solubility of fluorous
long-chained compounds between high and low temperature in the common organic
compounds [29–35]. In this method, a fluorous chain-containing pyridine-based catalyst
could be soluble at high temperatures during the catalytic reactions, but insoluble at room
temperature for the recovery of catalysts via a simple liquid–solid separation [36–38].
(1)
In this work, two kinds of basic pyridine-based organo-catalysts, which are the
DMAP Hsac adduct and a fluorous long-chained pyridine (py), were used to efficiently
·
catalyze phospha-Michael addition reactions. To our knowledge, these are two good
examples of recoverable phospha-Michael addition reaction catalyzed by organo-bases,
which are DMAP Hsac adduct in neat condition and a fluorous long-chained py under
·
thermomorphic mode. Taking into consideration their good catalytic efficiency and good
heterogenous separation, these two catalysts could be regarded as very good alternatives
to most homogeneous catalysts.

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2. Results and Discussion
2.1. Recoverable DMAP·HSac-Catalyzed Phospha-Michael Addition Reaction
2.1.1. Synthesis of DMAP·HSac (Catalyst A)
The preparation of DMAP HSac (A) followed Lu’s literature procedure [28]. The
·
reaction of DMAP with saccharin, as shown in Scheme 1, in tetrahydrofuran (THF) solvent
at 60 ◦C, took place for 2 h in a nitrogen atmosphere to yield a white solid product of the
adduct (A).
Scheme 1. Synthesis of the DMAP·HSac adduct (A).
2.1.2. Recoverable DMAP·HSac-Catalyzed Phospha-Michael Addition Reaction
The DMAP
addition reactions, where
phite compounds [1a (R= isopropyl); 1b (R= methyl)] and tris(organo)phosphite compound
(R = ethyl)] with 2-benzylidinemelanonitrile-type substrates [ (X = H); (X = CH3)] as
indicated in Schemes 2 and 3.
·
HSac adduct A was then examined for the following neat phospha-Michel
A
catalyzed addition of alkyl (R group) substituted diorganophos-
[2
3
4
Scheme 2. The DMAP HSac (A)-catalyzed phospha-Michael addition of diisopropyl phosphite (1a) with benzyliden
·
emalononitrile-type substrates [3 (X = H); 4 (X = CH3)].
Scheme 3. A-catalyzed phospha-Michael addition of dimethyl phosphite (1b) with 2-benzylidenemalononitrile-type
substrates [3 (X = H); 4 (X = CH3)].
a.
A-catalyzed phospha-Michael addition of diisopropyl phosphite (1a) and benzylidenemalonon-
itrile (3)
As shown in Scheme 2, the DMAP
reaction of diisopropyl phosphite (1a) with 2-benzylidenemalononitrile (
·
HSac (
A
)-catalyzed phospha-Michael addition
) was selected
as a catalyst using a solvent free
3
to demonstrate the feasibility of recycling usage with
A
◦
method, at 80 C mainly for 1 h. In this time, the reaction was successfully carried out
to afford the product in quantitative conversions, as shown in Scheme 2 and Table 1.

Molecules 2021, 26, 1159
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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
and proceeded to the next cycle. The products were quantified with GC/MS analysis by
comparison to internal standard (anisole). As shown in Table 1, -catalyzed phospha-
Michael addition of 1a with could give rise to good yield and recycling results for a total
of eight times without using any solvent.
A was dried under vacuum
A
3
Table 1. Recycling results of
with benzylidenemalononitrile (3) at 80 C.
A
-catalyzed phospha-Michael addition of diisopropyl phosphite (1a
)
◦
◦
Cycle No.
Time (h)
Temp. ( C)
Yield (%) a
TON
99 (97) b
99
99 (96)
99
99 (95)
98
99
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1.5
1.5
80
80
80
80
80
80
80
80
19.8
19.8
19.8
19.8
19.8
19.6
19.8
19.8
99
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. Measured by GC/MS; b isolated yield in parenthesis.
a
The phospha-Michel addition reaction of 1a with
3
showed high yield and good
◦
recycling result for eight cycles by usin◦g 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 Table 2). 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
with benzylidenemalononitrile (3) at 100 C.
A
-catalyzed◦phospha-Michael addition of diisopropyl phosphite (1a
)
◦
Cycle No.
Time (h)
Temp. ( C)
Yield (%) a
TON
100 (98) b
100
99 (97)
100
99 (98)
100
100
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
99
100
99
100
100
100
99
100
100
100
100
100
100
100
100
99
100
100
100
100
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. Measured by GC/MS; b isolated yield in parenthesis.
a

Molecules 2021, 26, 1159
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b.
A
-catalyzed phospha-Michael addition of diisopropyl phosphite (1a) with 2-(4-methylben-
zylidene)malononitrile (4)
The catalyst -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 reduced the rate of the reaction, leading to increased reaction
time (Table 3) compared to the unsubstituted one (3, X = H).
A
(
4
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
99 (99) b
97
99 (96)
99
96 (95)
96
95
1
2
3
4
5
6
7
8
2.5
2.5
3
3
3
3
3
3.5
80
80
80
80
80
80
80
80
19.8
19.4
19.8
19.8
19.2
19.2
19
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. Measured by GC/MS; b isolated yield in parenthesis.
a
c.
A-catalyzed phospha-Michel addition of dimethyl phosphite (1b) and 2-benzylidenemalo-
nonitrile (3)
Table 4 shows the result of the reactivity and recycling of the
Michael addition reaction of dimethyl phosphite (1b) with 2-benzylidenemalononitrile (
A
-catalyzed phospha-
).
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 sub-
strate (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.
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
100 (96) b
99
99 (95)
97
99 (94)
95
96
1
2
3
4
5
6
7
8
1
1
1
1
1
1.5
1.5
2
80
80
80
80
80
80
80
80
20
19.8
19.8
19.4
19.8
19
19.2
19.6
98
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. Measured by GC/MS; b isolated yield in parenthesis.
a
d.
A-catalyzed phospha-Michael addition of dimethyl phosphite (1b) and 2-(4-methylbenzylidene)
malononitrile (4)
In Table 5, 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
(Table 5) compared to the unsubstituted substrate (3, X = H).

Molecules 2021, 26, 1159
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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
3
4
5
6
7
8
2
2
2
2
2
2
2
4
80
80
80
80
80
80
100
100
100
100 (96) b
100 (96)
100 (97)
100
20
20
20
20
20
20
20
18
100
100
90
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. Measured by GC/MS; b isolated yield in parenthesis.
a
e.
A-catalyzed phospha-Michael addition of triethyl phosphite (2) and 2-benzylidenemalon-
onitrile (3)
As shown in Table 6, the
(2) with 2-benzylidenemalononitrile (3
A
-catalyzed phospha-Michael addition of triethyl phosphite
) 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.
slightly diminished after each step to the 8th cycle. In
A
Scheme 4, the different kind of phosphite (
substituted product.
2) used in this reaction is seen to yield an alkyl
Table 6. Recycling results of
benzylidenemalononitrile (3).
A-catalyzed phospha-Michael addition of triethyl phosphite (2) 2-
◦
Cycle No.
Time (h)
Temp. ( C)
Yield (%) a
TON
100 (96) b
100
100 (97)
100
100 (97)
100
100
1
2
3
4
5
6
7
8
1
1
1
1
2
2
2
4
80
80
80
80
80
100
100
100
20
20
20
20
20
20
20
15
75
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. Measured by GC/MS; b isolated yield in parenthesis.
a
Scheme 4. A-catalyzed phospha-Michael addition of triethyl phosphite (
malononitrile (3).
2) with 2-benzylidene
In summary, in the
A-catalyzed phospha-Michel addition of phosphite reagents (1a,
1b or ) with 2-benzylidenemalononitrile-type substrates (
2
3
or ), the methyl, ethyl and
4
isopropyl substituents of the phosphite did not show a significant difference in their yields
and reaction times. However, after several recycles, the triethyl substituted phosphite
did not maintain its reaction speed as the previous cycles (see Table 6). Additionally,
for the phosphorus-acceptor saturated bond containing 2-benzylidenemalononitrile-type

Molecules 2021, 26, 1159
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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
2-benzylidenemalononitrile-type substrates (
tion mechanism [39 40], demonestrating the base assisted P-H bond cleavage and adding
the H and P-containing moiety into the two sides of the double bond (see Figure S1
in SM). However, the -catalyzed similar reaction of tris(organo)phosphite ( ) with 2-
benzylidenemalononitrile ( ) followed a different mechanism through the O-C bond cleav-
A
-catalyzed reactions of diorganophosphite compounds (1a or 1b) with
3
or ), the reactions followed the cited reac-
4
,
A
2
3
age of one -OC2H5 group to add the phosphonate group [P(O)(O C2H5)2] and the ethyl
groups into the two sides of the double bond (Scheme 4).
2.1.3. Kinetic Study of A-Catalyzed Phospha-Michael Addition Reaction of Diisopropyl
Phosphite (1a) with Benzylidenemalononitrile (3)
The phospha-Michael addition of diisopropyl phosphite (1a) with benzylidenemalonon-
itrile (
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
vs. time showed the ln[reactant ] = kt + ln[reactant ]o plot with a rate constant k = 0.057
and R2 = 0.97, where [reactant
]o = 3 M and ln[reactant ]o = 1.074, as shown in Figure S2
3
) was also studied kinetically at 80 ◦C (see Figure 1). The reaction showed a drastic
3
3
3
−
3
3
(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 catalyst (see in Figure 1). Likewise, Sobani and her coworkers reported the reaction of
diethyl phosphite with 2-benzylidenemalononitrile ( ) in the absence of the catalyst to give
A or by using saccharine as
3
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 coworkers
reported that the reaction of diethyl phosphite with the electron withdrawing group substi-
tuted 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.
100
80
Catalyst A
Without a catalyst
Saccharin
60
40
20
0
0
10
20
30
40
50
60
70
80
90
Time (min)
Figure 1. Kinetic study of phospha-Michael addition of diisopropyl phosphite (1a) with benzylidene-
malononitrile ( ) with and without a catalyst . (Note: saccharin as a catalyst was also tested, but it
showed no catalytic effect.)
3
A

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2.2. Recoverable Fluorous Long-Chained Pyridine-Catalyzed Phospha-Michael Addition Reaction
2.2.1. Synthesis of RfCH2OCH2-py (Catalyst B)
The synthesis of RfCH2OCH2-py (catalyst
B) proceeds through two steps, as re-
ported in the literature [41]. The initial step starts from the deprotonation of readily
available fluorinated alcohols. Thus, Rf-CH2OH, where Rf = C11F23, was treated with
30% CH3ONa/CH3OH to give the corresponding alkoxides whose nucleophilic attack
on 4-(BrCH2)-py HBr gave rise to the synthesis of fluorous long-chained pyridine B, [4-
·
(RfCH2OCH2)-py)] (see Scheme 5).
Scheme 5. Synthesis of RfCH2OCH2-py catalyst B.
2.2.2. Recoverable Fluorous Rf-py-Catalyzed Phospha-Michael Addition
a.
B-catalyzed phospha-Michael addition of diisopropyl phosphite (1a) with 2-benzylidenemalono-
nitrile (3).
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 with as a catalyst using a solvent free method, at 80 C for 1 h. At the end of
B
each cycle, the product mixtures were cooled to room temperature, resulting in catalyst
precipitation due to their thermomorphic behavior where the solubility of the catalyst
increased dramatically with the increasing temperature [36
the catalyst was recovered by decantation. The recovered catalyst
,
38]. Finally, after centrifugation,
was dried under
B
vacuum and proceeded to the next cycle. The products were quantified with GC/MS
analysis through comparison to the internal standard (e.g., anisole). As shown in Table 7,
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.
Scheme 6. The
B
-catalyzed phospha-Michael addition of diisopropyl phosphite (1a) with 2-benzylidenemalononitrile-type
substrates [3 (X = H), or 4 (X = CH3)].
b.
B
-catalyzed phospha-Michael addition diisopropyl phosphite (1a) with 2-(4-methylbenzylidene)
malononitrile (4)
The -catalyzed phospha-Michael addition of diisopropyl phosphite (1a) with 2-(4-
methylbenzylidene)malononitrile ( ) was successfully carried out under thermomorphic
B
4
conditions at 5 mol% catalyst loading as shown in Scheme 6 above (Table 8). However,
an elongated reaction time was observed compared to the reaction using unsubstituted
2-benzylidenemalononitrile (
3). It followed the same trend compared to the similar A-
catalyzed reaction mentioned above (see Table 3).

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) with
Table 7. Recycling results of
2-benzylidenemalononitrile (3) at 80 C.
B
-catalyzed phospha-Michael addition of diisopropyl phosphite (
1
◦
◦
Cycle No.
Time (h)
Temp. ( C)
Yield (%) a
TON
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
80
80
80
80
80
80
80
80
100
100
100
100
99
98
98
20
20
20
20
19.8
19.6
19.6
19.2
96
Reaction conditions: T = 80 ◦C, cat.
B
(5 mol%), 1a (0.25 mL, 1.5 mmol), 3 (115 mg, 0.75 mmol), solvent free
a
reaction. Measured by GC/MS.
Table 8. Recycling results of
B-catalyzed phospha-Michael addition of diisopropyl phosphite (1a)
with 2-(4-methylbenzylidene)malononitrile (4).
◦
Cycle No.
Time (h)
Temp. ( C)
Yield (%) a
TON
98 (98) b
98
98 (96)
97
97 (95)
96
94
1
2
3
4
5
6
7
8
4.5
4.5
4.5
4.5
4.5
4.5
4.5
4.5
80
80
80
80
80
80
80
80
19.6
19.6
19.6
19.4
19.4
19.2
18.8
18.8
94
Reaction conditions: T = 80 ◦C, cat.
B
, 4-23F-py, (5 mol%), 1a (0.23 mL, 1.37 mmol),
4
(115 mg, 0.68 mmol), solvent
free reaction. Measured by GC/MS; b isolated yield in parenthesis.
a
c.
B-catalyzed phospha-Michael addition of dimethyl phosphite (1b) with 2-benzylidenemalono-
nitrile (3)
The -catalyzed phospha-Michael addition of dimethyl phosphite (1b) with 2-benzylid-
B
enemalononitrile ( ) (see Scheme 7) was also found to be effective with good recoveries, as
3
shown in Table 9. The reaction time recorded for this reaction is almost the same as the
time for A-catalyzed similar reaction.
Scheme 7. B-catalyzed phospha-Michael addition of dimethyl phosphite (1b) with 2-benzylidenemalononitrile (3).
In summary, in the
or 1b) with 2-benzylidenemalononitrile-type substrates (
was recorded for the methyl or the isopropyl substituents of the phosphite as reported for
the -catalyzed reactions above. However, the -catalyzed reaction of the unsubstituted
compound showed a better reaction time than the CH3 substituted compound 4. The
outcomes from the -catalyzed reactions are comparable to those of the -catalyzed
B-catalyzed phospha-Michael addition of phosphite reagents (1a
3
or ), no significant difference
4
A
B
3
B
A
reactions, which could still be explained by the electronic effect of the electron releasing
property of the CH3 group.

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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
90 (88) b
87
90 (87)
90
85 (84)
85
90
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1.5
3
80
80
80
90
90
90
90
90
18
18.4
18
18
17
17
18
16.6
83
3
Reaction conditions: T = 80–90 ◦C, cat.
B
(5 mol%), 1b (0.14 mL, 1.5 mmol),
(115 mg, 0.75 mmol), solvent free
reaction. Measured by GC/MS; b isolated yield in parenthesis.
a
2.2.3. Kinetic Study of B-Catalyzed Phospha-Michael Addition of Diisopropyl Phosphite
(1a) with Benzylidenemalononitrile (3)
The
with benzylidenemalononitrile (
the initial 10 min. Then, 100 % of reactant
in Figure S3 in the supplementary material. The integrated rate law derived from the
concentration of reactant vs. time showed ln[reactant ] = kt + ln[reactant ]o plot with
a rate constant k = 0.055 and R2 = 0.95, where ln[reactant
]o = 1.154, as shown in Figure S4
B
-catalyzed phospha-Michael addition reaction of diisopropyl phosphite (1a
) showed an increase in product concentration to 49 % in
was converted to a product after 1 h, as shown
)
3
3
3
3
−
3
3
in the supplementary mater−ia1l. This kinetically monitored reaction showed the turnover
frequency (TOF) to be 19.2 h 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
which had a higher rate constant (k = 0.057) than that (k = 0.055) of catalyst . The presence
of an electron withdrawing fluorous chain on the pyridyl nitrogen had an electronic effect
A,
B
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
DMSO were the references for both 1H and 13C 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 phos-
phites 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
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reaction. THF was removed by applying the vacuum to obtain the white solid precipitate
of DMAP·HSac adduct with 95% yield (see Scheme 1).
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 Scheme 5) [42–45].
Analytical Data of Catalyst B (4-23F-py)
1H-NMR (500 MHz, DMSO-d6, at 80 C):
δ (ppm) 8.55 (d, J = 6 Hz, 2H, H2, H5),
◦
7.30 (d, J = 6 Hz, 2H, H3, H6) 4.74 (s, 2H, py-CH2), 4.23 (t, J = 15 Hz, 2H, CH2CF2), 19F
NMR (470.5 MHz, d-DMSO, at 80 ◦C) δ −80.9 (t, 3JFF = 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
(py-CH2), 68.2 (CH2CF2), 122.5, 147.0, 150.5, (py, 5 Cs), 105.0~116.0 (C11F23). FT-IR (cm−1):
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 Schemes 2, 3, 6 and 7).
◦
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 phos-
phite 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
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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 -catalyzed phospha-Michael addition of
A
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
showed a relatively better catalytic activity than its fluorous long-chained pyridine (
·
Hsac (A) catalyst system
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 Table 2), 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
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Sample Availability: Catalyst
A
and some of the fluorous compounds are available from the authors.
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