Michaelis-Arbuzov-type reaction of 1-imidoalkyltriarylphosphonium salts with selected phosphorus nucleophiles

Article abstract of DOI:10.3390/molecules24183405

In this study, Michaelis-Arbuzov-type reaction of 1-imidoalkyltriarylphosphonium salts with phosphites, phosphonites, and phosphinites was used in the synthesis of a wide range of phosphorus analogs of α-amino acids such as 1-imidoalkylphosphonates, 1-imidoalkylphosphinates, and 1-imidoalkylphosphine oxides. Large differences were observed in the reactivity of substrates depending on their structure, especially on the type of phosphonium moiety and N-protecting group. The conditions under which the expected products can be obtained in good to excellent yields have been developed. Mechanistic aspects of the transformation have been provided.

Full text of DOI:10.3390/molecules24183405

molecules
Article
Michaelis-Arbuzov-Type Reaction of
1-Imidoalkyltriarylphosphonium Salts with Selected
Phosphorus Nucleophiles
Jakub Adamek 1,2,
Karol Erfurt 3
*
, Anna We˛grzyk-Schlieter 1,2, Klaudia Stec´ 1,2, Krzysztof Walczak 1 and
1
Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology,
Silesian University of Technology, B. Krzywoustego 4, 44-100 Gliwice, Poland;
anna.wegrzyk-schlieter@polsl.pl (A.W.-S.); stec-k@o2.pl (K.S.); krzysztof.walczak@polsl.pl (K.W.)
Biotechnology Center of Silesian University of Technology, B. Krzywoustego 8, 44-100 Gliwice, Poland
Department of Chemical Organic Technology and Petrochemistry, Silesian University of Technology,
B. Krzywoustego 4, 44-100 Gliwice, Poland; karol.erfurt@polsl.pl
2
3
*
Correspondence: jakub.adamek@polsl.pl; Tel.: +48-032-237-1080; Fax: +48-032-237-2094
Academic Editor: Erika Bálint
Received: 9 September 2019; Accepted: 16 September 2019; Published: 19 September 2019
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: In this study, Michaelis-Arbuzov-type reaction of 1-imidoalkyltriarylphosphonium salts
with phosphites, phosphonites, and phosphinites was used in the synthesis of a wide range of
phosphorus analogs of α-amino acids such as 1-imidoalkylphosphonates, 1-imidoalkylphosphinates,
and 1-imidoalkylphosphine oxides. Large differences were observed in the reactivity of substrates
depending on their structure, especially on the type of phosphonium moiety and N-protecting group.
The conditions under which the expected products can be obtained in good to excellent yields have
been developed. Mechanistic aspects of the transformation have been provided.
Keywords: organophosphorus chemistry; phosphonium salts; phosphonates; phosphinates;
phosphine oxides
1. Introduction
The chemistry of phosphorus analogs of
decades [ 10]. The replacement of flat carboxylic moiety with either the phosphonyl, phosphinyl,
or phosphinoyl group in the structure of -amino acids enables them to have extremely valuable
α-amino acids has enjoyed unflagging interest for
1
–
α
biological properties. These compounds are strong bioregulators and are used in agrochemicals as
growth regulators, fungicides, and insecticides; they show antiviral, antibacterial, and anticancer
properties [1–3,6,9,11–13].
1-Imidoalkylphosphonates, 1-imidoalkylphosphinates, and 1-imidoalkylphosphine oxides can
be classified as a specific group of phosphorus analogs of
blocks in the synthesis of many bioactive compounds such as phosphopeptides and statins (which
act as enzyme inhibitors) [14 15], oligonucleotides [16], cytotoxic agents (e.g., cryptophycin 52) [17],
α-amino acids. They are used as building
,
and herbicides and plant growth regulators (2,4,5-imidazolidinetriones) [18]. Moreover, they are
used in the synthesis of macrocyclic ligands, which are useful in medical diagnostics for obtaining
luminescent probes and contrast agents in magnetic resonance imaging (MRI) [19,20]. This type of
phosphorus analogs of α-amino acids exhibits also antibacterial and antifungal properties [21].
Thesynthesisof1-imidoalkylphosphonates, 1-imidoalkylphosphinates, and1-imidoalkylphosphine
oxides described in the literature are mainly based on the Michaelis-Arbuzov- or Michaelis-Becker-type
reaction of the corresponding halides with phosphorus nucleophiles, and in most cases, they are related
Molecules 2019, 24, 3405; doi:10.3390/molecules24183405
www.mdpi.com/journal/molecules

Molecules 2019, 24, 3405
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to the simplest derivatives (
1
, R1 = H; I and II, Scheme 1) [15
,
19,
22
–
29]. Other known methods are rather
labor consuming and require more sophisticated substrates such as 1-hydroxyalkylphosphonates [30
]
or silyl compounds [31] (Scheme 1, I, path D and E), which limits the structural diversity of the products
obtained. Scheme 1 presents a fused summary of the various approaches discussed above.
Scheme 1. 1-Imidoalkylphosphonates, 1-imidoalkylphosphinates, and 1-imidoalkylphosphine
oxides—various synthetic routes.
In 2017, we described a three-step protocol for the synthesis of 1-imidoalkyltriarylphosphonium
salts from
α
-amino acids and demonstrated their reactivity as imidoalkylating agents on the example
33]. In this study, we present the results of our research on
of reaction with aromatic compounds [32
,
the synthetic utility of 1-imidoalkyltriarylphosphonium salts in the Michaelis-Arbuzov-type reaction
with phosphorus nucleophiles (III, Scheme 1).
2. Results and Discussion
The reactivity of 1-imidoalkylphosphonium salts toward phosphorus nucleophiles was
investigated based on the reaction of 1-(phthalimido)ethyltris(4-trifluoromethylphenyl)phosphonium
salt 2a with trimethyl phosphite (Scheme 2).

Molecules 2019, 24, 3405
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O
N
O
O
BF4
O
P(OMe)3
-MeBF4

N
N
N
-P(p-C6H4CF3)3
P(p-C6H4CF3)3 BF4
2a
P(OMe)2
O
O
O
O
O
3a
1a
Scheme 2.
Reaction of 1-(phthalimido)ethyltris(4-trifluoromethylphenyl)phosphonium
tetrafluoroborate 2a with trimethyl phosphite.
We assumed that in the first stage of the reaction, it is necessary to cleave the Cα–P+ bond
and form a corresponding carbenium cation 3a (Scheme 2). Our previous research has shown that
depending on the type of 1-imidoalkylphosphonium salt, the cations can be efficiently generated
at a high temperature, which is appropriate for that of salt. The appropriate temperature for
tris(4-trifluoromethylphenyl)phosphonium salts was about 90–100 ◦C [32]. Therefore, we decided
to conduct the first experiments at 100 ◦C. Indeed, it was confirmed that the reaction proceeds at an
acceptable rate at this temperature (reaction time was 2 h; the minimum temperature at which any
visible progress of the reaction observed was equal to 80 ◦C).
Then, we investigated the effect of molar ratio of substrates and the type of solvent on the reaction
yield (entries 1–5, Table 1). It should be noted that one of the Michaelis-Arbuzov reaction stages is
dealkylation of the alkoxyphosphonium salt
we used methyltriphenylphosphonium iodide as the catalyst (iodide anions are a good dealkylating
agent) [34
36]. The progress of the reaction was monitored based on 1H-NMR spectroscopy. The highest
yields were obtained by conducting the reaction in chloroform at a molar ratio of reagents equal
to 1:10:0.25 (salt :P-nucleophile:catalyst). We also proved that the addition of the catalyst was not
4 (see Scheme 3) [34,35]. To facilitate the course of this step,
–
2
necessary, but it improved the yields (compare entries 6 and 7, Table 1). In turn, the change in the
polarity of the solvent did not give any positive effects on the reaction (compare entries 3–5, Table 1).
O
O
O
R1
BF4
R1
R1
PAr3 or I
N
N
N
A
A
A
A
PR2R3OR
P(R2R3OR) BF4
PR2R3
-PAr3R BF4
or RI
O
O
O
O
O
O
R1
4
1

N
A
-PAr3
PAr3 BF4
-H
O R4
N
O
2
R1
BF4
R5
N
A
O
O
5
3
Scheme 3.
α-Amidoalkylation of P-nucleophiles by 1-imidoalkyltriarylphosphonium salts 2—a
plausible mechanism.
Next, we determined the scope of applicability of the developed method. To this end, we
modified the structure of 1-imidoalkylphosphonium salt (phosphonium moiety, N-protecting group,
and substituent R1 at the α-position) and changed the type of phosphorus nucleophile.
Modifications in the phosphonium moiety (the introduction of electron-withdrawing groups)
and changes of the N-protecting group had the greatest influence on the course of the examined
reaction. The highest yields were obtained for 1-(N-phthalimido)alkylphosphonium salt derivatives
of tris(3-chlorophenyl)phosphine and tris(4-trifluorophenyl)phosphine. Based on our results,
1-(N-succinimido)alkylphosphonium salts showed significantly less reactivity. To increase the yield,
we had to raise the temperature and increase the concentration of phosphorus nucleophile (entry 18,
Table 1). The reaction of triphenylphosphonium salt 2c also required higher temperature, but in this
case, the yield was still poor (entry 9, Table 1).

Molecules 2019, 24, 3405
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Table 1. Synthesis of 1-imidoalkylphosphonates, 1-imidoalkylphosphinates, and 1-imidoalkylphosphine
oxides—conditions and yields.
O
O
R1
R1
PR2R3OR
N
N
A
A
PAr3 BF4
PR2R3
O
O
O
2
1
PN a
Molar Ratio of
2:PN:Catalyst
Time,
h
Yield,
%
Entry
2
A
R1
Ar
Solvent
T, ◦
C
1
(PR2R3OR)
36 b
70 b
85 b
50 b
51 b
76 c
52 c
70 c
22 c,d
95 c
90 c
86 c
99 c
91 c
94 c
83 c
nr e
65 c
59 c,f
37 c,g
94 c,h
47 c
35 c
88 c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2a
2a
2e
2e
2f
o-C6H4
o-C6H4
o-C6H4
o-C6H4
o-C6H4
o-C6H4
o-C6H4
o-C6H4
o-C6H4
o-C6H4
o-C6H4
o-C6H4
o-C6H4
o-C6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
p-C6H4CF3
p-C6H4CF3
p-C6H4CF3
p-C6H4CF3
p-C6H4CF3
p-C6H4CF3
p-C6H4CF3
m-C6H4Cl
Ph
m-C6H4Cl
p-C6H4CF3
p-C6H4CF3
p-C6H4CF3
p-C6H4CF3
m-C6H4Cl
m-C6H4Cl
p-C6H4CF3
p-C6H4CF3
p-C6H4CF3
p-C6H4CF3
p-C6H4CF3
p-C6H4CF3
p-C6H4CF3
p-C6H4CF3
P(OMe)3
P(OMe)3
P(OMe)3
P(OMe)3
P(OMe)3
P(OMe)3
P(OMe)3
P(OMe)3
P(OMe)3
P(OMe)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
P(OEt)3
CHCl3
CHCl3
CHCl3
CH3CN
C6H5Cl
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH3CN
CH3CN
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
1:1.5:0.25
1:5:0.25
1:10:0.25
1:10:0.25
1:10:0.25
1:10:0.25
1:10:-
1:10:0.25
1:10:0.25
1:10:0.25
1:10:0.25
1:10:-
1:10:0.25
1:10:-
1:10:0.25
1:10:-
1:10:0.25
1:30:0.25
1:10:0.25
1:10:-
1:10:0.25
1:10:0.25
1:10:-
100
2
2
2
2
2
2
2
2
0.5
2
2
2
0.5
0.5
2
2
2
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1c
1d
1d
1e
1e
1f
100
100
100
100
100
100
120
150
170
100
100
80
Me
Me
Ph
Ph
80
o-C6H4 i-Bu
o-C6H4 i-Bu
120
120
180
150
100
100
80
100
100
80
2f
2g
2h
2a
2a
2e
2a
2a
2e
(CH2)2
(CH2)2
o-C6H4
o-C6H4
o-C6H4
o-C6H4
o-C6H4
o-C6H4
H
Me
Me
Me
Ph
Me
Me
Ph
1g
1h
1h
1i
1j
1j
PhP(OMe)2
PhP(OMe)2
PhP(OMe)2
Ph2P(OMe)
Ph2P(OMe)
Ph2P(OMe)
0.5
0.5
0.5
0.5
0.5
0.5
1:10:0.25
1k
a
b
d
PN-phosphorus nucleophile. Yield estimated by 1H-NMR. c Isolated yields. N-Vinylphthalimide was also
e
f
obtained as a side product in 59% yield. No reaction. A mixture of diastereoisomers (1ha
of 1:0.95. Attempts to separate diastereoisomers failed. A mixture of diastereoisomers (1ha
of 1:0.9. Attempts to separate diastereoisomers failed. A mixture of diastereoisomers (1ia
+
1hb) in a molar ratio
1hb) in a molar ratio
g
+
h
+ 1ib) in a molar ratio of
1:0.9. Attempts to separate diastereoisomers success.
Changes of substituents in the
Only in the case of phosphonium salts 2d and 2e (no possibility of the side
α
-position did not significantly affect reaction conditions or yields.
-elimination reaction),
β
higher yields of the expected products were noticed, which was particularly apparent in the preparation
of 1-imidoalkylphosphinates and 1-imidoalkylphosphine oxides (entries 21 and 24, Table 1).
In the end, we proved that the described protocol could be used not only in reactions with
phosphites but also with other phosphorus nucleophiles such as phosphonites and phosphinites
(entries 19–24, Table 1). The expected products—1-imidoalkylphosphinates and 1-imidoalkylphosphine
oxides—were obtained with satisfactory to excellent yield.
Based on our previous research [32–36] and above-described facts, we proposed a plausible
mechanism of the Michaelis-Arbuzov-type reaction of 1-imidoalkylphosphonium salts with phosphorus
nucleophiles (Scheme 3). It seems that the first stage is crucial for the course of the entire reaction.
In the case of 1-imidoalkylphosphonium salts with weakened Cα–P+ bond strength (Ar = m-C6H4Cl,
p-C6H4CF3), the generation of imidocarbenium cation
lower (80–120 ◦C) than that of 1-imidoalkyltriphenylphosphonium salt (Ar = Ph, 150 ◦C). Moreover,
the high temperature promoted side reactions—the formation of enimides by -elimination. All these
3 was easier and the reaction temperature was
5
β
factors affect the efficiency of the synthesis. Yields were much higher when 1-imidoalkylphosphonium
salts with weakened Cα–P+ bond strength were used as substrates (see Table 1).
In the second stage, the alkoxyphosphonium salt
4 was formed as a result of nucleophilic
attack by phosphorus (PR2R3OR, Scheme 3). Dealkylation of this intermediate led to the expected
products: 1-imidoalkylphosphonates, 1-imidoalkylphosphinates, and 1-imidoalkylphosphine oxides.

Molecules 2019, 24, 3405
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The addition of catalyst facilitated this stage and improved the yield of the reaction. However, at the
elevated temperature, phosphines generated in the first step could also act as the dealkylating agent.
We think it explains the possibility of conducting the reaction without a catalyst (but with lower yields).
3. Experimental Section
3.1. General Information
Melting points were determined in capillaries and were uncorrected. Next, 1H- and 13C-NMR
spectra were recorded at operating frequencies of 400 and 100 MHz, respectively, using tetramethylsilane
(TMS) as the resonance shift standard. 31P-NMR spectra were recorded at operating frequencies of
161.9 MHz without the resonance shift standard, with respect to H3PO4 as 0 ppm. All chemical shifts
(δ) are reported in ppm and coupling constants (J) in Hz. IR-spectra were measured on an FT-IR
spectrophotometer (attenuated total reflectance method; ATR). High-resolution mass spectrometry
(HR-MS) analyses were performed on a Waters Xevo G2 Q-TOF mass spectrometer equipped with
an electrospray ionization (ESI) source operating in the positive ion mode. The accurate mass and
composition of the molecular ion adducts were calculated using the MassLynx software incorporated
within the instrument.
3.2. Synthesis
3.2.1. Substrate Synthesis
The synthesis of 1-imidoalkyltriarylphosphonium salts
2 from α-amino acids was performed
according to our previously described three-step procedure [32].
3.2.2. General Procedure for the Reaction of 1-Imidoalkyltriarylphosphonium Salts 2 with
Phosphorus Nucleophiles
To a suspension of 1-imidoalkyltriarylphosphonium salt
2 (0.25 mmol, 1.0 equiv.) in CHCl3
(2 cm3) placed in a glass vial sealed with a screw-cap a phosphorus nucleophile (2.5 mmol, 10 equiv.)
and, in the case of a catalytic reaction, methyltriphenylphosphonium iodide (25.3 mg, 0.0625 mmol,
0.25 equiv.) was added. The reaction was carried out under conditions given in Table 1. Then,
the solvent was evaporated to dryness under reduced pressure and the product was isolated by
column chromatography using 50 cm3 of hexane and then ethyl acetate as the eluent. If necessary,
purification can be repeated using acetonitrile or toluene:ethyl acetate (5:1, v/v) as the eluent (this is
particularly useful during the separation of diastereoisomers 1h and 1i). The crystalline compounds
were recrystallized from toluene.
Dimethyl 1-(N-Phthalimido)ethylphosphonate (1a) [37]. White crystals (53.8 mg, 76% yield), m.p.
75.0–77.0 ◦C. 1H-NMR (400 MHz, CD3CN)
δ
7.71–7.80 (m, 4H, Phth), 4.59 (dq, J1 = 18.7 Hz, J2 = 7.6 Hz,
1H, CαH), 3.69 (d, J = 10.7 Hz, 3H, OCH3), 3.63 (d, J = 10.7 Hz, 3H, OCH3), 1.57 (dd, J1 = 16.3 Hz,
J2 = 7.6 Hz, 3H, CH3) ppm; 13C-NMR (100 MHz, CD3CN)
168.4 (C=O), aromatic carbons: 135.6,
132.7, 124.2, 54.1 (d, J = 6.5 Hz, OCH3), 53.8 (d, J = 6.8 Hz, OCH3), 43.2 (d, J = 158.0 Hz, CαH), 13.5
δ
(CH3) ppm; 31P-NMR (161.9 MHz, CD3CN)
δ 25.1 ppm; IR (ATR) 2960, 1709, 1380, 1280, 1253, 1021,
906, 877, 832, 806, 712, 681 cm−1 (Supplementary Materials).
Dimethyl N-◦Phthalimidomethylphosphonate (1b) [24]. White crystals (63.9 mg, 95% yield), m.p.
1
145.5–147.5 C. H-NMR (400 MHz, CD3CN)
δ 7.84–7.89 (m, 2H, Phth), 7.80–7.84 (m, 2H, Phth),
4.06 (d, J = 11.2 Hz, 2H, CH2), 3.75 (d, J = 10.9 Hz, 6H, 2
168.2 (C=O), aromatic carbons: 135.6, 132.8, 124.3, 54.0 (d, J = 6.1 Hz, OCH3), 33.2 (d, J = 157.6 Hz,
CH2) ppm; 31P-NMR (161.9 MHz, CD3CN)
22.1 ppm; IR (ATR) 2974, 1715, 1403, 1238, 1060, 1014, 903,
845, 715, 701 cm−1
×
OCH3) ppm; 13C-NMR (100 MHz, CD3CN)
δ
δ
.

Molecules 2019, 24, 3405
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1
Diethyl 1-(N-Phthalimido)ethylphosphonate (1c) [30]. Resin (70.0 mg, 90% yield). H-NMR (400 MHz,
CD3CN) 7.75–7.88 (m, 4H, Phth), 4.61 (dq, J1 = 18.5 Hz, J2 = 7.6 Hz, 1H, CαH), 4.00–4.20 (m, 4H,
OCH2CH3), 1.66 (dd, J1 = 16.1 Hz, J2 = 7.6 Hz, 3H, CH3), 1.28 (td, J1 = 7.1 Hz, J2 = 0.5 Hz, 3H,
OCH2CH3), 1.23 (td, J1 = 7.0 Hz, J2 = 0.5 Hz, 3H, OCH2CH3) ppm; 13C-NMR (100 MHz, CD3CN)
168.4 (d, J = 1.8 Hz, C=O), aromatic carbons: 135.5, 132.7, 124.1, 63.7 (d, J = 6.5 Hz, O H2CH3), 63.4 (d,
J = 6.5 Hz, O H2CH3), 43.9 (d, J = 158.0 Hz, CαH), 16.8 (d, J = 5.7 Hz, OCH2CH3), 13.4 (CH3) ppm;
31P-NMR (161.9 MHz, CD3CN) δ 22.6 ppm; IR (ATR) 2989, 1716, 1383, 1010, 906, 879, 719 cm−1
δ
2
×
δ
C
C
.
Diethyl Phenyl(N-phthalimido)methylphosphonate (1d) [38]. White crystals (92.4 mg, 99% yield), m.p.
102.5–104.5 ◦C. 1H-NMR (400 MHz, CD3CN) δ 7.77–7.90 (m, 4H, Ph), 7.56–7.66 (m, 2H, Ph), 7.28–7.41
(m, 3H, Ph), 5.70 (d, J = 24.6 Hz, 1H, CαH), 4.00–4.19 (m, 4H, 2
3H, OCH2CH3), 1.20 (t, J = 7.0 Hz, 3H, OCH2CH3) ppm; 13C-NMR (100 MHz, CD3CN)
J = 3.3 Hz, C=O), aromatic carbons: 135.7, 134.7, 132.5, 130.3, 129.5, 129.3, 124.4, 64.3 (d, J = 6.6 Hz,
H2CH3), 63.6 (d, J = 6.9 Hz, O H2CH3), 52.3 (d, J = 156.9 Hz, CαH), 16.7 (d, J = 5.3 Hz, OCH2CH3),
16.6 (d, J = 5.3 Hz, OCH2
H3) ppm; 31P-NMR (161.9 MHz, CD3CN)
1383, 1359, 1254, 1053, 1026, 1014, 969, 890, 802, 728, 719, 697 cm−1
×
OCH2CH3), 1.21 (t, J = 7.1 Hz,
δ
168.4 (d,
O
C
C
C
δ
18.4 ppm; IR (ATR) 2988, 1712,
.
1
Diethyl 3-Methyl-1-(N-phthalimido)butylphosphonate (1e). Resin (83.0 mg, 94% yield). H-NMR (400 MHz,
CD3CN)
4.03–4.17 (m, 4H, 2xOC
1.27 (td, J1 = 7.1 Hz, J2 = 0.5 Hz, 3H, OCH2CH3), 1.23 (td, J1 = 7.0 Hz, J2 = 0.5 Hz, 3H, OCH2CH3),
0.91 (d, J = 6.7 Hz, 3H, CH3), 0.88 (d, J = 6.5 Hz, 3H, CH3) ppm; 13C-NMR (100 MHz, CD3CN)
168.7
(d, J = 1.4 Hz, C=O), aromatic carbons: 135.6, 132.5, 124.2, 63.6 (d, J = 6.5 Hz, O H2CH3), 63.3 (d,
J = 6.6 Hz, H2CH3), 46.8 (d, J = 156.2 Hz, CαH), 35.9 (d, J = 1.2 Hz, CH2), 25.7 (d, J = 12.3 Hz, CH),
23.2 (OCH2
δ
7.80–7.87 (m, 4H, Phth), 4.58 (ddd, J1 = 19.6 Hz, J2 = 11.9 Hz, J3 = 4.3 Hz, 1H, CαH),
H
2CH3), 2.39–2.49 (m, 1H, CH), 1.60–1.69 (m, 1H, CH), 1.48–1.55 (m, 1H, CH),
δ
C
O
C
C
H3), 21.2 (OCH2C δ
H3), 16.8 (CH3), 16.7 (CH3) ppm; 31P-NMR (161.9 MHz, CD3CN)
22.3 ppm; IR (ATR) 2959, 1713, 1379, 1249, 1051, 1017, 963, 717 cm−1; HRMS (ESI-TOF) calculated for
C17H25NO5P [M + H]+ 354.1470 found 354.1469.
1
Diethyl 1-(N-Succinimido)ethylphosphonate (1g). Resin (42.8 mg, 65% yield). H-NMR (400 MHz, CD3CN)
δ
4.57 (dq, J1 = 19.1 Hz, J2 = 7.5 Hz, 1H, CαH), 4.04–4.30 (m, 4H, 2xOCH2CH3), 2.73 (s, 4H, 2xCH2),
1.57 (dd, J1 = 16.0 Hz, J2 = 7.5 Hz, 3H, CH3), 1.35 (t, J = 6.6 Hz, 3H, OCH2CH3), 1.33 (t, J = 6.8 Hz, 3H,
OCH2CH3) ppm; 13C-NMR (100 MHz, CD3CN)
176.4 (C=O), 63.4 (d, J = 6.4 Hz, O H2CH3), 62.4 (d,
J = 6.6 Hz, O H2CH3), 43.6 (d, J = 158.2 Hz, CαH), 28.2 (CH2), 16.5 (OCH2CH3), 16.5 (OCH2 H3), 13.0
δ
C
C
C
(CH3) ppm; 31P-NMR (161.9 MHz, CD3CN)
δ 22.4 ppm; IR (ATR) 2984, 1702, 1387, 1238, 1195, 1051,
1017, 960, 797 cm−1; HRMS (ESI-TOF) calculated for C10H19NO5P [M + H]+ 264.1001 found 264.1001.
Methyl phenyl [1-(N-Phthalimido)ethyl]phosphinate (1ha + 1hb). A mixture of two diastereoisomers, resin
1
(48.6 mg, 59% yield). H-NMR (400 MHz, CD3CN)
δ
7.78–7.81 (m, 2H, Ph)a, 7.58–7.77 (m, 4H, Ph)a,
7.37–7.56 (m, 3H, Ph)a, 4.68–4.80 (m, 1H, CαH)a, 3.68 (d, J = 10.8 Hz, 3H, OCH3)b, 3.66 (d, J = 10.7 Hz,
3H, OCH3)b, 1.69 (dd, J1 = 14.5 Hz, J2 = 7.6 Hz, 1H, CH3)b, 1.60 (dd, J1 = 15.5 Hz, J2 = 7.6 Hz, 2H,
CH3)b ppm; 13C-NMR (100 MHz, CD3CN)
δ 168.4 (d, J = 1.2 Hz, C=O), 168.2 (d, J = 1.1 Hz, C=O),
aromatic carbons: 135.5, 135.4, 133.8 (d, J = 2.7 Hz), 133.8 (d, J = 2.8 Hz), 133.6 (d, J = 9.9 Hz), 133.1 (d,
J = 9.9 Hz), 132.7, 132.5, 130.2 (d, J = 18.3 Hz), 129.6, 129.5, 129.0 (d, J = 18.3 Hz), 124.0, 123.9, 52.5 (d,
J = 6.5 Hz, OCH3), 52.4 (d, J = 6.1 Hz, OCH3), 46.8 (d, J = 109.0 Hz, CαH), 46.7 (d, J = 108.0 Hz, CαH),
13.1 (d, J = 2.7 Hz, CH3), 12.6 (d, J = 1.3 Hz, CH3) ppm; 31P-NMR (161.9 MHz, CD3CN)
δ 39.3, 39.0 ppm;
IR (ATR) 2947, 1711, 1378, 1226, 1120, 1023, 992, 879, 791, 718, 697 cm−1; HRMS (ESI-TOF) calculated
a
for C17H17NO4P [M + H]+ 330.0895 found 330.0898. Overlapping signals of both diastereoisomers.
bSeparate signals of both diastereoisomers.
Methyl Phenyl[phenyl(N-phthalimido)methyl]phosphinate (1i). A mixture of two diastereoisomers (92.0 mg,
94% yield). Diastereoisomers were separated by column chromatography (toluene:ethyl acetate;
5:1, v/v).

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1
Methyl Phenyl[phenyl(N-phthalimido)methyl]phosphinate (1ia, the first diastereoisomer). Resin. H-NMR
(400 MHz, CD3CN)
4H, Ph), 5.83 (d, J = 17.9 Hz, 1H, CαH), 3.63 (d, J = 11.0 Hz, 3H, OCH3) ppm; 13C-NMR (100 MHz,
CD3CN) 168.1 (d, J = 2.6 Hz, C=O), aromatic carbons: 135.6, 134.2, 133.8 (d, J = 2.9 Hz), 133.1
(d, J = 9.9 Hz), 132.2, 131.1, 131.0, 129.5 (d, J = 12.7 Hz), 129.5 (d, J = 0.8 Hz), 129.5, 124.2, 55.1 (d,
δ 7.71–7.75 (m, 4H, Ph), 7.63–7.71 (m, 5H, Ph), 7.44–7.52 (m, 1H, Ph), 7.33–7.43 (m,
δ
J = 107.3 Hz, CαH), 52.6 (d, J = 6.5 Hz, OCH3) ppm; 31P-NMR (161.9 MHz, CD3CN)
δ 36.3 ppm; IR
(ATR) 3059, 1717, 1379, 1070, 1033, 717, 696 cm−1; HRMS (ESI-TOF) calculated for C22H19NO4P [M +
H]+ 392.1052 found 392.1054.
Methyl Phenyl[phenyl(N-phthalimido)methyl]phosphinate (1ib
1H-NMR (400 MHz, CD3CN)
7.80–7.90 (m, 4H, Ph), 7.42–7.55 (m, 5H, Ph), 7.31–7.40 (m, 2H,
Ph), 7.23–7.30 (m, 3H, Ph), 5.87 (d, J = 21.5 Hz, 1H, CαH), 3.63 (d, J = 11.0 Hz, 3H, OCH3) ppm;
13C-NMR (100 MHz, CD3CN)
168.7 (d, J = 2.5 Hz, C=O), aromatic carbons: 135.7, 134.5 (d, J = 2.5 Hz),
, the second diastereoisomer). Resin.
δ
δ
134.0 (d, J = 9.1 Hz), 133.6 (d, J = 2.8 Hz), 132.6, 130.3, 130.2, 129.5 (d, J = 1.6 Hz), 129.3 (d, J = 2.2 Hz),
129.0 (d, J = 13.0 Hz), 124.4, 55.6 (d, J = 104.5 Hz, CαH), 52.5 (d, J = 6.7 Hz, OCH3) ppm; 31P-NMR
(161.9 MHz, CD3CN)
HRMS (ESI-TOF) calculated for C22H19NO4P [M + H]+ 392.1052 found 392.1052.
δ ;
36.7 ppm; IR (ATR) 3060, 1716, 1381, 1236, 1071, 1024, 889, 791, 717, 695 cm−1
Diphenyl 1-(N-Phthalimido)ethylphosphine oxide (1j). White crystals (44.1 mg, 47% yield), m.p.
138.0–140.0 ◦C. 1H-NMR (400 MHz, CD3CN)
7.89–7.99 (m, 2H, Ph), 7.67–7.76 (m, 6H, Ph), 7.54–7.66
(m, 3H, Ph), 7.29–7.44 (m, 3H, Ph), 5.27 (qd, J1 = 7.5 Hz, J2 = 6.5 Hz, 1H, CαH), 1.69 (dd, J1 = 14.0 Hz,
J2 = 7.5 Hz, 3H, CH3) ppm; 13C-NMR (100 MHz, CD3CN)
168.4 (d, J = 1.0 Hz, C=O), aromatic carbons:
δ
δ
135.4, 133.3 (d, J = 2.7 Hz), 133.0 (d, J = 2.8 Hz), 132.9 (d, J = 18.6 Hz), 132.4, 132.4 (d, J = 8.8 Hz),
131.9 (d, J = 21.6 Hz), 131.8 (d, J = 9.2 Hz), 129.9 (d, J = 11.4 Hz), 129.4 (d, J = 11.6 Hz), 123.9, 47.2 (d,
J = 74.7 Hz, CαH), 12.9 (d, J = 1.9 Hz, CH3) ppm; 31P-NMR (161.9 MHz, CD3CN)
δ 28.7 ppm; IR (ATR)
3057, 1710, 1376, 1202, 1116, 1046, 878, 715, 698, 669 cm−1; HRMS (ESI-TOF) calculated for C22H19NO3P
[M + H]+ 376.1103 found 376.1104.
Diphenyl Phenyl(N-phthalimido)methylphosphine oxide (1k). White crystals (96.2 mg, 88% yield), m.p.
233.0–235.0 ◦C. 1H-NMR (400 MHz, CD3CN)
δ
7.82–7.90 (m, 2H, Ph), 7.71–7.79 (m, 2H, Ph), 7.56–7.68
(m, 6H, Ph), 7.32–7.50 (m, 6H, Ph), 7.21–7.30 (m, 3H, Ph), 6.24 (d, J = 12.3 Hz, 1H, CαH) ppm; 13C-NMR
(100 MHz, CD3CN) 167.5 (d, J = 2.2 Hz, C=O), aromatic carbons: 134.2, 133.0, 132.2 (d, J = 2.8 Hz),
δ
132.0 (d, J = 3.2 Hz), 132.0 (d, J = 8.9 Hz), 131.8 (d, J = 7.9 Hz), 131.6 (d, J = 9.3 Hz), 130.9, 130.8, 130.8
(d, J = 9.5 Hz), 128.8 (d, J = 1.7 Hz), 128.8, 128.7 (d, J = 11.8 Hz), 128.4 (d, J = 11.9 Hz), 123.6, 55.4 (d,
J = 71.2 Hz, CαH) ppm; 31P-NMR (161.9 MHz, CD3CN)
δ 22.2 ppm; IR (ATR) 3058, 1717, 1372, 1345,
1321, 1199, 1119, 1101, 1074, 887, 709, 693 cm−1; HRMS (ESI-TOF) calculated for C27H21NO3P [M + H]+
438.1259 found 438.1262.
4. Conclusions
The possibility of the synthetic use of 1-imidoalkyltriarylphosphonium salts in reactions with
phosphorus nucleophiles was investigated. It has been noticed that the structure of the substrates has
a great impact on the course of the studied reaction. Moreover, 1-(N-phthalimido)alkylphosphonium
salts with weakened Cα–P+ bond strength show the highest reactivity and react under milder conditions
in comparison with other 1-imidoalkylpohosphonium salts. The reaction may be conducted with
or without the addition of a catalyst. It has been demonstrated, that not only phosphites but also
phosphonites, and phosphinites can be used as phosphorus nucleophiles. The most favorable reaction
conditions for all examined types of 1-imidoalkylphosphonium salts and P-nucleophiles were proposed.
A plausible reaction mechanism, which explains the currently obtained results, was also presented.
Our research confirmed a universal character of the developed method and its considerable
potential in the synthesis of phosphorus analogs of α-amino acids.
Further studies on expanding the range of nucleophiles (not only P-nucleophiles), which can be
used in a reaction with 1-imidoalkyltriarylphosphonium salts, are in progress.

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Supplementary Materials: Supporting information includes 1H-, 13C-, 31P-NMR and IR spectra of all new
compounds. Supplementary data associated with this article can be found in the online version.
Author Contributions: Conceptualization, J.A.; Formal analysis, J.A., A.W.-S., K.S. and K.E.; Investigation, J.A.,
A.W.-S., K.S. and K.E.; Methodology, J.A. and A.W.-S.; Supervision, J.A. and K.W.; Writing—original draft, J.A.;
Writing—review & editing, J.A. and A.W.-S.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
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2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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(CC BY) license (http://creativecommons.org/licenses/by/4.0/).