1-(N-Acylamino)alkyltriarylphosphonium salts with weakened cα-P+ bond strength?synthetic applications

Article abstract of DOI:10.3390/molecules23102453

The α-amidoalkylating properties of 1-(N-acylamino)alkyltriarylphosphonium salts with weakened C_α-P⁺ bond strength are discussed and examined. It is demonstrated that such type of phosphonium salts reacts smoothly with a diverse array of carbon- and heteroatom-based nucleophiles, including 1-morpholinocyclohexene, 1,3-dicarbonyl compounds, benzotriazole sodium salt, p-toluenesulfinate sodium salt, benzylamine, triarylphosphines, and other P-nucleophiles. Reactions are conducted at room temperature, in a short time (5–15 min) and mostly without catalysts. Simple work-up procedures result in good or very good yields of products. The structures of known compounds were established by spectroscopic methods and all new compounds have been fully characterized using ¹H-, ¹³C-, ³¹P-NMR, IR spectroscopy, and high-resolution mass spectrometry. Mechanistic aspects of described transformations are also performed and discussed. It was demonstrated that unique properties make 1-(N-acylamino)alkyl-triarylphosphonium salts with weakened C_α-P⁺ bond strength interesting building blocks with great potential, especially in α-amidoalkylation reactions.

Full text of DOI:10.3390/molecules23102453

molecules
Article
1-(N-Acylamino)alkyltriarylphosphonium
Salts with Weakened Cα-P+ Bond
Strength—Synthetic Applications
Jakub Adamek 1,2,
Karol Erfurt 3
*
, Anna We˛grzyk 1,2, Justyna Kon´czewicz 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@polsl.pl (A.W.);
j.konczewicz@gmail.com (J.K.); 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
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 31 August 2018; Accepted: 23 September 2018; Published: 25 September 2018
Abstract: The α-amidoalkylating properties of 1-(N-acylamino)alkyltriarylphosphonium salts with
weakened Cα-P+ bond strength are discussed and examined. It is demonstrated that such type
of phosphonium salts reacts smoothly with a diverse array of carbon- and heteroatom-based
nucleophiles, including 1-morpholinocyclohexene, 1,3-dicarbonyl compounds, benzotriazole sodium
salt, p-toluenesulfinate sodium salt, benzylamine, triarylphosphines, and other P-nucleophiles.
Reactions are conducted at room temperature, in a short time (5–15 min) and mostly without
catalysts. Simple work-up procedures result in good or very good yields of products. The structures
of known compounds were established by spectroscopic methods and all new compounds have
1
been fully characterized using H-, 13C-, 31P-NMR, IR spectroscopy, and high-resolution mass
spectrometry. Mechanistic aspects of described transformations are also performed and discussed.
It was demonstrated that unique properties make 1-(N-acylamino)alkyl-triarylphosphonium salts
with weakened Cα-P+ bond strength interesting building blocks with great potential, especially in
α-amidoalkylation reactions.
Keywords: organophosphorus chemistry; phosphonium salts;
N-acyliminium cation; N-acylimine
α-amidoalkylating agents;
1. Introduction
Specific structural features of 1-(N-acylamino)alkylphosphonium salts make them very interesting
reagents. The presence of a positively charged nucleofugal phosphonium moiety in the close
surroundings of the N-acyl group determines its unique chemical properties such as high reactivity
in
α-amidoalkylations [1–10]. This type of reactions has enjoyed unflagging interest for years
as a synthetic method with great potential, especially valuable for C-C and C-heteroatom bond
formation [1,11–37].
In general, the reactivity of
of N-acyliminium cation or N-acylimine
this reaction. Of course, the reactivity of N-acyliminium cation
nucleophile is also significant [ ]. To produce the proper -amidoalkylating agents, for instance
N-acyliminium cation or N-acylimine from the most popular precursors such as -amido sulfones
(Z = SO2Ar), N-(1-benzotriazolil)alkylamides (Z = Bt), and N-(1-alkoxyalkyl)amides (Z = OR), it is
α
-amidoalkylating agents
from its precursor and the equilibrium constant of
or N-acylimine toward a
1 depends on the efficiency of the generation
2
3
2
3
1–
3
α
2
3
α
Molecules 2018, 23, 2453; doi:10.3390/molecules23102453
www.mdpi.com/journal/molecules

Molecules 2018, 23, 2453
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necessary to use catalysts, mainly Lewis acids (route
a
, Scheme 1 (I)) [18
–
25
,
29
–
37]. In contrast,
1-(N-acylamino)alkyltriphenylphosphonium salts 1
(Z = Ph3P+ X−) do not require the use of acidic
catalysts because of the permanent positive charge on the phosphonium group. However, the relatively
high stability of Cα-P+ bond forces the use of a base catalyst (e.g., Hünig’s base, DBU, TBD; route
Scheme 1 (I)) and sometimes microwave radiation [1,4–10].
b,
Recently, we have proven that the use of 1-(N-acylamino)alkyltriarylphosphonium salts
from the EWG-substituted triarylphosphines facilitates the cleavage of Cα-P+ bond and thereby the
generation of N-acyliminium cation (Scheme 1 (II)) [ ]. This phenomenon significantly increases
the reactivity of 1-(N-acylamino)alkyltriarylphosphonium salts with weakened Cα-P+ bond strength
and allows us to conduct -amidoalkylation without the need for any catalyst. In this work, we
demonstrate that the abovementioned phosphonium salts react smoothly with various nucleophiles
4 derived
2,3
α
4
in a short time under mild conditions and create new carbon-carbon or carbon-heteroatom bonds with
good or very good yields (Scheme 1 (III)).
Scheme 1. α-Amidoalkylation reactions—various synthetic routes.
2. Results and Discussion
In this section, we focus our studies on the reactivity of phosphonium salts
4 with weakened
Cα-P+ bond strength in
α
-amidoalkylation of various types of carbon- and heteronucleophiles, as
shown in Scheme 2. 1-Morpholinocyclohexene and 1,3-dicarbonyl compounds, such as dimethyl
malonate, diethyl malonate, and ethyl acetoacetate, are used as carbon nucleophiles. In the case
of heteronucleophiles, the reaction toward benzotriazole sodium salt, p-toluenesulfinate sodium

Molecules 2018, 23, 2453
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salt, benzylamine, triarylphosphines, trimethyl phosphite, dimethyl phenylphosphonite, and methyl
diphenylphosphinite is examined.
The synthesis of 1-(N-acylamino)alkyltriarylphosphonium salts
performed according to our previously described procedure, for which the electrochemical
decarboxylative -methoxylation of N-acyl- -amino acids and substitution of the methoxy group by
4 from α-amino acids was
α
α
triarylphosphonium moiety are crucial steps (see Scheme 2) [2,9].
Scheme 2. 1-(N-Acylamino)alkyltriarylphosphonium salts with weakened Cα-P+ bond strength
4—preparation and synthetic application.
2.1. 1-(N-Acylamino)alkyltriarylphosphonium Salts with Weakened Cα-P+ Bond Strength in the Selected
Reaction of C-C Bond Formation
One of the crucial issues of organic synthesis is the formation of new C-C bonds. The possibility
of an effective extension of the carbon skeleton is important in many fields, especially in medicinal
chemistry, agrochemical synthesis, or in the synthesis of natural products.
Several years ago, we had proved that 1-(N-acylamino)alkyltriphenylphosphonium salts
4
(Ar = Ph) reacted quite easily with 1,3-dicarbonyl compounds in the presence of a base such as
DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), or TBD (1,5,7-triaza-
◦
bicyclo[4.4.0]dec-5-ene) under microwave irradiation at 60 C. However, the use of organic bases (DBU,
DBN, TBD) complicates the course of α-amidoalkylation reaction due to the formation of amidinium
and guanidinium salts [10]. To avoid this, in the current work, we used lithium diisopropylamide
(LDA) as a base to produce enolate anions from the corresponding 1,3-dicarbonyl compounds. In our
protocol,
of enolate anions generated using LDA was introduced into the THF solution of the phosphonium salt
. The reaction was performed for 15 min, and the use of microwave irradiation was not necessary.
α-amidoalkylation was conducted under argon, in THF, at room temperature. A THF solution
4
In addition, it was found that the most favorable molar ratio of phosphonium salt
compound: LDA was 1:8:1 (compare experiments 1 and 2, Table 1).
4: 1,3-dicarbonyl
Under the abovementioned conditions, phosphonium salts with weakened Cα-P+ bond
strength
4
react with 1,3-dicarbonyl compounds, including diethyl and dimethyl malonate and
with good yields, regardless of whether
ethyl acetoacetate, to give the corresponding products
6
tris(4-trifluoromethylphenyl)- or tris(3-chlorophenyl)phosphonium salts were used as substrates.
Only in the case of phosphonium salts with the benzyloxy carbamate protective group, the yields were
significantly lower and did not exceed 30% (entry 8, Table 1).

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Table 1. Conditions and yields for α-amidoalkylation of 1,3-dicarbonyl compounds by 1-(N-acylamino)
alkyltriarylphosphonium salts 4.
Phosphonium Salt 4
Entry
1,3-Dicarbonyl Compound, 5
Yield, %
6
Molar Ratio of 4:5:LDA
R1
R2
Ar
1
2
3
4
5
6
7
8
a
t-Bu
t-Bu
t-Bu
t-Bu
Bn
Bn
Bn
BnO
Me
Me
Me
m-C6H4Cl
m-C6H4Cl
p-C6H4CF3
m-C6H4Cl
m-C6H4Cl
m-C6H4Cl
m-C6H4Cl
m-C6H4Cl
diethyl malonate
diethyl malonate
diethyl malonate
ethyl acetoacetate
ethyl acetoacetate
dimethyl malonate
diethyl malonate
ethyl acetoacetate
b
1:2:1
1:8:1
1:8:1
1:8:1
1:8:1
1:8:1
1:8:1
1:8:1
6a
6a
6a
6b
6c
6d
6e
6f
40
65
67
Me
62 a
83 b
63
i-Bu
i-Bu
i-Bu
Bn
52
30 c
A mixture of diastereoisomers in a molar ratio of 1.4:1. A mixture of diastereoisomers in a molar ratio of 1.25:1.
Attempts to isolate an analytically pure sample failed.
c
α
-Amidoalkylation of carbon nucleophiles was successfully extended to enamines. Based on the
recently described protocol [ ], we have demonstrated that 1-(N-acylamino)alkyltriarylphosphonium
salts
with weakened Cα-P+ bond strength react with 1-morpholinocyclohexene in Stork-type
enamination to give the expected products with good yields. We have proved that this reaction can
8
4
8
be conducted in acetonitrile, at room temperature and without using any base catalysts. The optimized
reaction time was 60 min, and the molar ratio of phosphonium salt to 1-morpholinocyclohexene
was 1:2. We were able to separate the major diastereoisomer from the mixture using column
chromatography and crystallization technique. Furthermore, the use of phosphonium salts with
the benzyloxy carbamate protective group resulted in the decrease in reaction efficiency, as already
observed for reactions with 1,3-dicarbonyl compounds (see Table 2).
Table 2. Conditions and yields for
alkyltriarylphosphonium salts 4.
α-amidoalkylation of 1-morpholinocyclohexene by 1-(N-acylamino)
Phosphonium Salt 4
R2
Entry
R1
Yield, %
8
Ar
1
2
3
4
5
t-Bu
Bn
BnO
BnO
BnO
Me
i-Bu
i-Bu
m-C6H4Cl
m-C6H4Cl
m-C6H4Cl
m-C6H4Cl
p-C6H4CF3
8a
8b
8c
8d
8e
63 a
62 b
40 c
33 d
31 c
Bn
CH2Ot-Bu
a
c
b
A mixture of diastereoisomers in a molar ratio of 3.5:1. A mixture of diastereoisomers in a molar ratio of 3.2:1.
d
Only one diastereoisomer was detected and isolated. A mixture of diastereoisomers in a molar ratio of 13.4:1.

Molecules 2018, 23, 2453
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2.2. 1-(N-Acylamino)alkyltriarylphosphonium Salts with Weakened Cα-P+ Bond Strength in
α-Amidoalkylation of Selected Heteronucleophiles
Applications of 1-(N-acylamino)alkyltriphenylphosphonium salts
-amidoalkylation of heteronucleophiles have been reported many times in the literature [5–8,
4
(Ar = Ph) in the
10].
α
Usually in these types of reactions, it was necessary to use base catalysts, elevated temperature,
and microwave irradiation. The effect of the use of 1-(N-acylamino)alkyltriarylphosphonium salts
with weakened Cα-P+ bond strength
4 (R = m-C6H4Cl, p-C6H4CF3) on α-amidoalkylation has not
been investigated so far. Therefore, we selected several heteronucleophiles such as benzotriazole
sodium salt, p-toluenesulfinate sodium salt, benzylamine, and triphenylphosphine, and examined
their
α
-amidoalkylation by phosphonium salts with weakened Cα-P+ bond strength. As it was
expected, reactions of salts with a modified structure of the phosphonium group occurred much
faster and under mild conditions. In none of the described examples was it necessary to use a base
catalyst. The reaction time was only 5–15 min.
α-Amidoalkylation of benzotriazole sodium salt
and sodium p-toluenesulfinate (entries 1–3, Table 3) was conducted at room temperature in CHCl3.
Similar conditions were used for reaction with benzylamine (entries 4 and 5, Table 3). The obtained
aminal derivatives 10d and 10e exhibited limited stability. Therefore, the use of excess amount of the
nucleophile was required to make the alkaline environment safe for aminals.
Table 3. Conditions and yields for
alkyltriarylphosphonium salts 4.
α
-amidoalkylation of selected heteronucleophiles by 1-(N-acylamino)
−
NuH
Nu Na+/
Phosphonium Salt 4
Temp.,
Time,
Min.
Molar
Ratio of 4:9
Entry
Yield, %
10
◦
C
R1
R2
Ar
−
1
2
3
4
5
t-Bu
BnO
t-Bu
t-Bu
Bn
Me
Bn
Me
Me
i-Bu
p-C6H4CF3
m-C6H4Cl
p-C6H4CF3
m-C6H4Cl
p-C6H4CF3
Bt Na+
20
20
15
15
15
5
1:1
1:1
1:1
1:4
1:4
10a
10b
10c
10d
10e
99
70
88
91
55
−
Bt Na+
TolSO2 Na+ 20
Bn-NH2
Bn-NH2
−
20
20
5
1-(N-Acylamino)alkyltriarylphosphonium salts
For example, 1-(N-pivaloylamino)ethyltris(4-trifluoromethylphenyl)phosphonium tetrafluoroborate
4a is completely transformed into 1-(N-pivaloylamino)ethyltriphenylphosphonium
4
react also with triarylphosphines.
(
)
tetrafluoroborate (4b) during the reaction with triphenylphosphine. On the other hand, using
tris(3-chlorophenyl)- phosphine as the nucleophile, we obtain a reaction mixture in which both
1-(N-pivaloylamino)ethyltris(4-trifluoromethylphenyl)phosphonium tetrafluoroborate (4a) and
1-(N-pivaloylamino)ethyltris(3-chlorophenyl)phosphonium tetrafluoroborate (4c) are present in a
molar ratio of 1:3. A mixture of the same composition can also be obtained by the reaction of salt
4c with tris(4-trifluoromethylphenyl)phosphine. These observations may suggest the existence of
some equilibrium, as described by the equations in Scheme 3. The equilibrium of the reaction is
shifted toward more stable and less reactive phosphonium salts, which is evident for the reaction with
triphenylphosphine (equation a, Scheme 3).

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Scheme 3. 1-(N-Acylamino)alkyltriarylphosphonium salts with weakened Cα-P+ bond strength
4—reactions with triarylphosphines.
The results described above have encouraged us to extend the range of P-nucleophiles by trimethyl
phosphite, dimethyl phenylphosphonite, and methyl diphenylphosphinite. It was expected that
reactions with these types of phosphorus nucleophiles may occur quickly at room temperature in
a non-catalytic environment, as for earlier tested nucleophiles. Surprisingly, the first experiments
have shown that reactions are much slower. The analysis of reaction kinetics allowed us to explain
these observations. In 2013, we proposed a plausible reaction mechanism wherein the N-acyliminium
cation or N-acylimine, both generated from the 1-(N-acylamino)alkyltriphenylphosphonium salt
Ar = Ph), reacts with phosphorus nucleophile to form alkoxyphosphonium salt 13—the characteristic
intermediate of the Michaelis–Arbuzov reaction. The final step of the reaction is the dealkylation of
the alkoxyphosphonium salt 13 and may occur directly with triphenylphosphine (see Scheme 4) [ ].
4
(
7
Although we have not yet been able to isolate or even observe the formation of postulated intermediate
product, we assume that 1-(N-acylamino)alkyltriarylphosphonium salts with weakened Cα-P+ bond
strength react with phosphorus nucleophiles in an analogous manner. To prove this, we performed
the reaction of 1-(N-pivaloylamino)ethyltris(3-chlorophenyl)phosphonium tetrafluoroborate (4c) with
trimethyl phosphite. The reaction progress was monitored using NMR spectroscopy. In the reaction
mixture, besides substrates, two products were also detected. Changes in their concentration as
a function of time were measured, as shown in Figure 1. The concentration of the first product
quickly reaches its maximum and then rapidly decreases, while the concentration of the second
one at the beginning of the reaction is low and then increases. The induction period, which
is characteristic for the formation of the final product in the consecutive-type reaction, is very
clearly visible. Detailed NMR (1H- and 31P-NMR) and HR-MS analysis confirmed that the first,
fast-growing product was 1-(N-acylamino)alkyltrimethoxyphosphonium tetrafluoroborate (13a) —the
postulated intermediate of the Michaelis–Arbuzov reaction. As a result of its demethylation, dimethyl
1-(N-pivaloylamino)ethanephosphonate (12a) is formed with a much slower reaction. It seems that the
second step determines the overall rate of the process.
Scheme 4. α-Amidoalkylation of P-nucleophiles by 1-(N-acylamino)alkyltriarylphosphonium salts
4—a plausible mechanism.

Molecules 2018, 23, 2453
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Figure 1. Concentration of the substrate 4c, intermediate 13a, and product 12a as a function of time for
the reaction of 1-(N-pivaloylamino)ethyltris(3-chlorophenyl)phosphonium tetrafluoroborate (4c) with
◦
trimethyl phosphite at 26 C.
A plausible mechanism that explains the described kinetic facts is shown in Scheme 4 and
is consistent with the mechanism proposed earlier in 2013. The only difference is that the
generation of N-acyliminium cation from 1-(N-acylamino)alkyltriphenylphosphonium salt
4 (Ar = Ph)
is more difficult. On the other hand, the highnucleophilicity of triphenylphosphine facilitates
dealkylation, which makes the first step crucial for the course of the entire reaction. In the case of
1-(N-acylamino)alkyltriarylphosphonium salts with weakened Cα-P+ bond strength
4
(R = m-C6H4Cl,
p-C6H4CF3), the first step is easier, which facilitates the formation of alkoxyphosphonium salts 13
.
However, due to the lower nucleophilicity of phosphines with electron-withdrawing substituents
[P(m-C6H4Cl)3, P(p-C6H4CF3)3], the rate of dealkylation drops. To overcome this drawback, we
decided to add to the reaction mixture the substoichiometric amounts of methyltriphenylphosphonium
iodide as the dealkylating agent (molar ratio of 1:0.25). This protocol allowed us to obtain
a series of phosphorus analogs of
α
-amino acids 12 (N-acyl-
α-aminoalkanephosphonates 12a–c,
N-acyl- -aminoalkanephosphinate (12d) and N-acyl-
α
α
-aminoalkylphosphine oxide (12e)) with good
or very good yields. Usually, reactions occur efficiently at room temperature. Only in the reaction with
◦
dimethyl phenylphosphonite, it was necessary to raise the temperature to 60 C. At room temperature,
the reaction is very slow even after the addition of methyltriphenylphosphonium iodide (see Table 4).
Finally, we tried to isolate and fully characterize the intermediate of the Michaelis–Arbuzov reaction
13. To this end, we conducted the reaction of 1-(N-pivaloylamino)ethyltris(3-chlorophenyl)phosphonium
tetrafluoroborate (4c) with trimethyl phosphite. Unfortunately, the expected 1-(N-pivaloylamino)
ethyltrimethoxyphosphonium tetrafluoroborate (13a, Scheme 4) was too reactive and attempts
to isolate the analytically pure sample failed. To increase the stability of the intermediate
13, we used triethyl phosphite as the phosphorus nucleophile. This allowed us to isolate
1-(N-pivaloylamino)ethyltriethoxyphosphonium tetrafluoroborate (13b) and determine its basic
physicochemical properties.

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Table 4. Conditions and yields for
α-amidoalkylation of P-nucleophiles by 1-(N-acylamino)
alkyltriarylphosphonium salts 4.
Phosphonium Salt 4
P-Nu 11
R3
Temp., Time,
Molar Ratio
of 4:11
Yield,
%
Entry
12
◦
C
h
R1
R2
Ar
R
R4
1
2
3
4
5
6
a
t-Bu
t-Bu
Bn
BnO
t-Bu
BnO
Me
Me
i-Bu
m-C6H4Cl Me
m-C6H4Cl Me
m-C6H4Cl Me
OMe
OMe
OMe
OMe
Ph
OMe
OMe
OMe
OMe
OMe
Ph
20
20
20
20
60
20
3
3
3
3
2
3
1:1.5
12a
12a
12b
12c
12d
12e
47
85
77
61
69
83
1:1.5 a
1:1.5 a
1:1.5 a
1:1.5 a
1:1.5 a
CH2Ot-Bu p-C6H4CF3 Me
Me
i-Bu
m-C6H4Cl Me
p-C6H4CF3 Me
Ph
Substoichiometric amounts of methyltriphenylphosphonium iodide as a dealkylating agent (molar ratio of 1:0.25)
was used.
3. Experimental Section
3.1. General Information
Melting points were determined in capillaries and were uncorrected. IR spectra were measured on
1
an FT-IR spectrophotometer (ATR method). H- and 13C-NMR were recorded at operating frequencies
of 400 and 100 MHz, respectively, using TMS as the resonance shift standard. 31P-NMR spectra were
recorded at an operating frequency of 161.9 MHz without the resonance shift standard, with respect
to H3PO4 as zero ppm. All chemical shifts (δ) are reported in ppm and coupling constants (J) in Hz.
High-resolution mass spectrometry (HR-MS) analyses were performed on a Xevo G2 Q-TOF mass
spectrometer (Waters, Milford, MA, USA) equipped with an ESI source operating in the positive
ion mode. The accurate mass and composition of molecular ion adducts were calculated using the
MassLynx software incorporated within the instrument.
1H, 13C, and 31P NMR spectra of all new compounds
6, 8, 10, 12, 13 as well as the summary table in
which we compare conditions and yields for reactions of 1-(N-acylamino)alkyltriphenylphosphonium
salts (former studies) and 1-(N-acylamino)alkyltriarylphosphonium salts (the current work) with
selected nucleophiles, are placed in the Supplementary data.
3.2. Syntheses
3.2.1. Substrate Synthesis
Electrochemical decarboxylative α-methoxylation of N-acyl-α-amino acids [2,9]
The electrolysis was conducted in an undivided glass electrolyzer (85 cm3) equipped with a
thermostatic jacket, a magnetic stirrer, a concentrically arranged, cylindrical Pt mesh anode (47 cm2)
and cathode (44 cm2). To the thus prepared electrolyzer, N-acyl-
α
-amino acid (3.0 mmol), SiO2-Pip
-methoxylation
(200 mg), and methanol (30 cm3) were added. The electrochemical decarboxylative
α
was executed while stirring, at a constant current of 0.15 A, at 10 ◦C until a 3.75 F/mol charge had
passed. Then, SiO2-Pip was filtered off, and methanol was evaporated under reduced pressure to
obtain N-(1-methoxyalkyl)amide, which was used in the next reaction without further purification.
Transformation of N-(1-methoxyalkyl)amides to 1-(N-acylamino)alkyltriarylphosphonium salts 4 [2,10]
To a solution of triarylphosphine (1 mmol) in DCM (2 mL), a tetr◦afluoroboric acid diethyl
ether complex (HBF4 Et2O, 136 µl, 161.9 mg, 1 mmol) was added at 0 C. The reaction mixture
·
was stirred for 2 h at room temperature. Thereafter, N-(1-methoxyalkyl)amide (1 mmol) was added
and stirring was continued for 15 min. Evaporation of the solvent yielded the crude 1-(N-acylamino)
alkyltriarylphosphonium salt 4, which was used in the next reaction without further purification.

Molecules 2018, 23, 2453
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3.2.2. Reactivity of 1-(N-acylamino)alkyltriarylphosphonium Salts 4 toward Carbon Nucleophiles
Reaction of 1-(N-acylamino)alkyltriarylphosphonium salts 4 with C-H acids—general procedure
A solution of a nucleophile (1.6 mmol), THF (0.5 mmol), and base LDA (2.0 M solution in THF,
0.1 cm3) was stirred under argon atmosphere. After a few minutes, this mixture was relegated to a
solution of 1-(N-acylamino)alkyltriarylphosphonium salt (0.2 mmol) in THF (0.5 cm3) under argon
atmosphere. The resulting reaction mixture was stirred for 15 min at room temperature, and then it
was evaporated under reduced pressure. The product was separated using column chromatography
[toluene/AcOEt 5:1 v/v].
1
Diethyl 1-(pivaloylamino)etylpropanedioate (6a) [10]. Colorless oil (38.5 mg, 67% yield). H-NMR (CDCl3)
δ
6.80 (d, J = 7.5 Hz, 1H, NH), 4.74–4.62 (m, 1H, CαH), 4.29–4.21 (m, 2H, OCH2), 4.21–4.12 (m, 2H,
OCH2), 3.57 (d, J = 3.4 Hz, 1H, CH), 1.32–1.25 (m, 9H, CH3 and 2 OCH2C 3), 1.17 (s, 9H, t-Bu) ppm;
13C-NMR (CDCl3)
177.6 (NHC = O), 168.7 (C = O), 167.7 (C = O), 61.7 (OCH2), 61.5 (OCH2), 55.6
(CαH), 44.2 (CH), 38.6 ( (CH3)3), 27.4 (C( H3)3), 19.0 (CH3), 14.0 (OCH2 H3) ppm; IR (ATR) 2977,
1731, 1647, 1510, 1175 cm−1
×
H
δ
C
C
C
.
Ethyl 2-acetyl-3-(pivaloylamino)butanoate (6b). A mixture of two disatereoisomers in a molar ratio of
1
1.4:1 (31.9 mg, 62% yield). H-NMR (CDCl3)
δ
6.92 (d, J = 8.0 Hz, 1H, NH)a, 6.41 (d, J = 7.8 Hz, 1H,
NH)a, 4.85–4.74 (m, 1H, CαH)a, 4.68–4.57 (m, 1H, CαH)a, 4.33–4.10 (m, 2H, OCH2)b, 3.72 (d, J = 4.9 Hz
1H, CH)a, 3.65 (d, J = 3.6 Hz, 1H, CH)a, 2.26 (s, 3H, CH3CO)a, 2.25 (s, 3H, CH3CO)a, 1.35–1.20 (m,
6H, CH3 and OCH2CH3)b, 1.16 (s, 9H, t-Bu)a, 1.15 (s, 9H, t-Bu)a ppm; 13C-NMR (CDCl3) 203.4a
(CH3
= O), 202.1a (CH3 = O), 178.0a (NHC = O), 177.7a (NHC = O), 169.5a (C = O), 168.2a (C = O),
63.4a (CαH), 62.2a (CαH), 61.6a (OCH2), 61.4a (OCH2), 44.3a (CH), 43.4a (CH), 38.6a ( (CH3)3), 38.6a
,
δ
C
C
C
(
C
(CH3)3), 30.4a (
C C C C
H3CO), 29.0a ( H3CO), 27.4a (C( H3)3), 27.3a (C( H3)3), 19.7a (CH3), 18.7a (CH3),
14.1a (OCH2 H3), 14.1a (OCH2
C
C
H3) ppm; IR (ATR) 3318, 2971, 1730, 1635, 1534, 1301, 1190 cm−1
HRMS (TOF-ESI) calcd for C13H24NO4 [M + H]+ 258.1705, found 258.1701. Separate signals from
both diastereoisomers. b Overlapping signals of both diastereoisomers.
.
a
Ethyl 2-acetyl-5-methyl-3-(phenylacetylamino)hexanoate (6c). A mixture of two disatereoisomers in a molar
1
ratio of 1.25:1 (55.4 mg, 83% yield). H-NMR (CDCl3)
δ
7.39–7.19 (m, 5H, Ph)a, 6.43 (d, J = 9.7 Hz, 1H,
NH)b, 6.02 (d, J = 9.5 Hz, 1H, NH)b, 4.77–4.68 (m, 1H, CαH)b, 4.63–4.54 (m, 1H, CαH)b, 4.21–4.07 (m,
2H, OCH2)a, 3.64 (d, J = 4.9 Hz, 1H, CH)b, 3.60 (d, J = 3.7 Hz, 1H, CH)b, 3.51 (s, 2H, PhCH2)a, 2.23 (s,
3H, CH3CO)b, 2.19 (s, 3H, CH3CO)b, 1.56–1.37 (m, 2H, CH2)a, 1.28–1.14 (m, 4H, CH and OCH2CH3)a,
0.95–0.80 (m, 6H, 2
×
CH3)a ppm; 13C-NMR (CDCl3) 203.2b (CH3 = O), 202.2b (CH3 = O), 170.6b
δ C C
(NHC = O), 170.4b (NHC = O), 169.1b (C = O), 168.1b (C = O), aromatic carbons: 134.7b, 134.6b,
129.3b, 129.3b, 128.9b, 128.8b, 127.2b, 127.2b, 62.4b (CαH), 61.8b (CαH), 61.6b (OCH2), 61.3b (OCH2),
47.1b (Ph
C
H2), 46.2b (Ph
C
H2), 43.9b (CH), 43.8b (CH), 42.7b (CH2), 41.9b (CH2), 30.3b (
C
H3CO), 29.1b
(C CH3),
H3CO), 25.1b (CH), 25.1b (CH), 23.1b(CH3), 22.7b (CH3), 22.1b (CH3), 21.7b (CH3), 14.0b (OCH2
14.0b (OCH2 H3) ppm; IR (ATR) 3275, 2956, 1740, 1648, 1496, 1260, 1144 cm−1. HRMS (TOF-ESI) calcd
C
for C19H28NO4 [M + H]+ 334.2018, found 334.2009. a Overlapping signals of both diastereoisomers.
b
Separate signals from both diastereoisomers.
Dimethyl 3-methyl-1-(phenylacetylamino)butylpropanedioate (6d). Colorless crystals (42.3 mg, 63% yield),
mp 78–80 ◦C. 1H-NMR (CDCl3)
δ 7.41–7.18 (m, 5H, Ph), 6.25 (d, J = 9.6 Hz, 1H, NH), 4.68–4.59 (m,
1H, CαH), 3.69 (s, 3H, OCH3), 3.62 (s, 3H, OCH3), 3.55 (d, J = 3.9 Hz, 1H, CH), 3.52 (s, 2H, PhCH2),
1.54–1.39 (m, 2H, CH2), 1.28–1.19 (m, 1H, CH), 0.90 (d, J = 6.5 Hz, 3H, CH3), 0.86 (d, J = 6.6 Hz, 3H,
CH3) ppm; 13C-NMR (CDCl3)
δ 170.3 (NHC = O), 168.6 (C = O), 168.0 (C = O), aromatic carbons: 134.8,
129.3, 128.8, 127.1, 54.6 (CαH), 52.6 (OCH3), 52.3 (OCH3), 46.8 (PhCH2), 43.9 (CH), 42.1 (CH2), 25.0
(CH), 22.9 (CH3), 21.9 (CH3) ppm; IR (ATR) 3283, 2954, 1736, 1648, 1454, 1263 cm−1. HRMS (TOF-ESI)
calcd for C18H26NO5 [M + H]+ 336.1811, found 336.1805.

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Diethyl 3-methyl-1-(phenylacetylamino)butylpropanedioate (6e). Colorless crystals (37.8 mg, 52% yield), mp
93.5–95.5 ◦C. 1H-NMR (CDCl3)
7.42–7.19 (m, 5H, Ph), 6.30 (d, J = 9.6 Hz, 1H, NH), 4.68–4.60 (m, 1H,
CαH), 4.30–4.00 (m, 4H, 2 OCH2), 3.52 (s, 2H, PhCH2), 3.52 (d, J = 2.8 Hz, 1H, CH), 1.57–1.37 (m, 2H,
CH2), 1.36–1.06 (m, 7H, CH and 2 OCH2C 3), 0.90 (d, J = 6.5 Hz, 3H, CH3), 0.86 (d, J = 6.6 Hz, 3H,
CH3) ppm; 13C-NMR (CDCl3)
170.2 (NHC = O), 168.3 (C = O), 167.7 (C = O), aromatic carbons: 134.9,
129.3, 128.8, 127.1, 61.7 (OCH2), 61.4 (OCH2), 54.9 (CαH), 46.8 (Ph H2), 43.9 (CH), 42.2 (CH2), 25.0
(CH), 22.9 (CH3), 22.0 (CH3), 14.0 (OCH2 H3), 13.9 (OCH2 H3) ppm; IR (ATR) 3362, 2964, 1745, 1656,
1533, 1345, 1144 cm−1. HRMS (TOF-ESI) calcd for C20H30NO5 [M + H]+ 364.2124, found 364.2122.
δ
×
×
H
δ
C
C
C
Reaction of 1-(N-acylamino)alkyltriarylphosphonium salts with 1-morpholinocyclohexene—
general procedure
To a solution of 1-(N-acylamino)alkyltriarylphosphonium salt
4
4
(0.25 mmol) in MeCN (1 cm3),
1-morpholinocyclohexene (84.1 µL, 83.7 mg, 0.5 mmol) was added. After 1 h of stirring at room
temperature, an aqueous solution of citric acid (20%) (1.125 cm3) was added. Stirring was continued
for 45 min, and then a saturated solution of KHCO3 was added. Thereafter, the mixture was extracted
with DCM (5
×
3 cm3), and the organic layer was combined and dried over MgSO4. Then, the
solvent was evaporated under reduced pressure and the crude product was purified using column
chromatography [toluene/EtOAc 2:1 v/v (8a), 5:1 (8b, 8c, 8e) or 10:1 v/v (8d)].
N-[1-(2-oxocyclohexyl)ethyl]pivalamide (8a). A mixture of two disatereoisomers in a molar ratio of
3.5:1 (35.5 mg, 63% yield). The major diastereoisomers was isolated using column chromatography
[toluene/EtOAc 2:1] and crystallization from toluene. Colorless crystals, mp 124–126 ◦C. 1H-NMR
(CDCl3)
2H, CH2), 2.11–2.01 (m, 2H, CH2), 1.91–1.83 (m, 1H, C
J = 7.0 Hz, 3H, CH3), 1.17 (s, 9H, t-Bu) ppm; 13C-NMR (CDCl3)
(CαH), 45.6 (CH), 43.1 (CH2), 38.7 (
δ
6.51 (d, J = 8.1 Hz, 1H, NH), 4.19–4.10 (m, 1H, CαH), 2.56–2.48 (m, 1H, CH), 2.39–2.30 (m,
H), 1.74–1.57 (m, 3H, CH and CH2), 1.22 (d,
214.2 (C = O), 178.0 (NHC = O), 55.4
H3)3), 24.8 (CH2), 20.0
H
H
δ
C
(CH3)3), 32.7 (CH2), 28.4 (CH2), 27.6 (C(C
(CH3) ppm; IR (ATR) 3339, 2961, 2869, 1706, 1627, 1526, 1305, 1209, 1117 cm−1. HRMS (TOF-ESI) calcd
for C13H24NO2 [M + H]+ 226.1807, found 226.1800.
N-[1-(2-oxocyclohexyl)-3-methylbutyl]phenylacetamide (8b). A mixture of two disatereoisomers in a
molar ratio of 3.2:1 (46.7 mg, 62% yield). The major diastereoisomers was isolated using column
chromatography [toluene/EtOAc 5:1] and crystallization from toluene. Colorless crystals, mp
◦
1
115.5–117.5 C. H-NMR (CDCl3)
(m, 1H, CαH), 3.51 (s, 2H, PhC 2), 2.49–2.40 (m, 1H, CH), 2.31–2.18 (m, 2H, CH2), 2.07–1.96 (m, 2H,
CH2), 1.86–1.75 (m, 1H, CH), 1.65–1.37 (m, 5H, CH and 2 CH2), 1.21–1.09 (m, 1H, CH), 0.86 (d,
J = 6.5 Hz, 3H, CH3), 0.83 (d, J = 6.6 Hz, 3H, CH3) ppm; 13C-NMR (CDCl3)
213.5 (C = O), 170.7
(NHC = O), aromatic carbons: 135.3, 129.1, 128.8, 127.1, 54.8 (CαH), 48.7 (Ph H2), 44.2 (CH), 43.1
δ 7.42–7.09 (m, 5H, Ph), 6.13 (d, J = 9.7 Hz, 1H, NH), 4.10–3.99
H
×
δ
C
(CH2), 43.1 (CH2), 32.6 (CH2), 28.3 (CH2), 25.2 (CH), 25.0 (CH2), 23.1 (CH3), 22.0 (CH3) ppm; IR (ATR)
3273, 2954, 2865, 1702, 1633, 1552, 1455, 1315, 1138 cm−1. HRMS (TOF-ESI) calcd for C19H28NO2
[M + H]+ 302.2120, found 302.2115.
Benzyl N-[1-(2-oxocyclohexyl)-3-methylbutyl]carbamate (8c). Only one disatereoisomer was detected
1
and isolated. Colorless oil (31.7 mg, 40% yield). H-NMR (CDCl3)
J = 10.1 Hz, 1H, NH), 5.09 (d, J = 12.5 Hz, 1H, PhC
δ
7.42–7.27 (m, 5H, Ph), 5.42 (d,
HO), 5.06 (d, J = 12.4 Hz, 1H, PhCH O), 3.83–3.69
(m, 1H, CαH), 2.54–2.44 (m, 1H, CH), 2.38–2.23 (m, 2H, CH2), 2.15–1.99 (m, 2H, CH2), 1.93–1.82 (m, 1H,
H), 1.74–1.55 (m, 5H, CH and 2 CH2), 1.28–1.16 (m, 1H, CH), 0.91 (d, J = 6.4 Hz, 3H, CH3), 0.89
(d, J = 6.5 Hz, 3H, CH3) ppm; 13C-NMR (CDCl3)
213.1 (C = O), 156.5 (NHC = O), aromatic carbons:
136.8, 128.4, 127.9, 127.9, 66.5 (Ph H2O), 54.7 (CαH), 50.8 (CH), 43.4 (CH2), 43.2 (CH2), 32.3 (CH2), 28.1
H
H
C
H
H
×
δ
C
(CH2), 25.1 (CH2), 25.1 (CH), 23.2 (CH3), 21.9 (CH3) ppm; IR (ATR) 3439, 3333, 2952, 2866, 1699, 1499,
1213, 1052 cm−1. HRMS (TOF-ESI) calcd for C19H28NO3 [M + H]+ 318.2069, found 318.2061.

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Benzyl N-[1-(2-oxocyclohexyl)-2-phenylethyl]carbamate (8d). A mixture of two disatereoisomers in a
molar ratio of 13.4:1 (29.0 mg, 33% yield). The major diastereoisomers was isolated using column
◦
chromatography [toluene/EtOAc 10:1]. Colorless crystals, mp 99–101 C. 1H-NMR (CDCl3)
δ 7.42–7.06
(m, 10H, 2
1H, PhCH
×
Ph), 5.65 (d, J = 10.0 Hz, 1H, NH), 5.07 (d, J = 12.3 Hz, 1H, PhC
O), 3.95–3.87 (m, 1H, CαH), 2.99 (dd, J1 = 13.5, J2 = 7.3 Hz, 1H, PhC
H
HO), 5.00 (d, J = 12.4 Hz
H), 2.92 (dd, J1 = 13.5
,
,
H
H
J2 = 8.5 Hz, 1H, PhCH
(m, 2H, CH2), 1.87–1.78 (m, 1H, CH), 1.77–1.51 (m, 3H, CH and CH2) ppm; 13C-NMR (CDCl3)
(C = O), 156.4 (NHC = O), aromatic carbons: 138.6, 136.7, 129.1, 128.5, 128.4, 127.9, 127.8, 126.4, 66.4
H
), 2.51–2.41 (m, 1H, CH), 2.40–2.31 (m, 1H, CH), 2.29–2.17 (m, 1H, CH), 2.09–1.92
δ
213.5
(PhCH2O), 54.2 (CαH), 51.9 (CH), 43.2 (CH2), 40.3 (PhCH2), 32.6 (CH2), 28.1 (CH2), 25.0 (CH2) ppm; IR
(ATR) 3308, 2929, 1721, 1697, 1541, 1341, 1242, 1094, 1051 cm−1. HRMS (TOF-ESI) calcd for C22H26NO3
[M + H]+ 352.1913, found 352.1913.
Benzyl N-[1-(2-oxocyclohexyl)-2-tert-butoxyethyl]carbamate (8e). Only one disatereoisomer was detected
1
and isolated. Colorless oil (26.9 mg, 31% yield). H-NMR (CDCl3)
δ
7.38–7.28 (m, 5H, Ph), 5.57 (d,
O), 3.89–3.79
(m, 1H, CαH), 3.44 (d, J = 7.1 Hz, 2H, CH2Ot-Bu), 2.90–2.82 (m, 1H, CH), 2.38–2.27 (m, 2H, CH2),
2.09–2.00 (m, 2H, CH2), 1.92–1.85 (m, 1H, C H), 1.78–1.64 (m, 3H, CH and CH2), 1.12 (s, 9H, t-Bu)
ppm; 13C-NMR (CDCl3)
213.8 (C = O), 156.4 (NHC = O), aromatic carbons: 136.6, 128.5, 128.0, 73.1
(O (CH3)3), 66.6 (Ph H2O), 62.1 ( H2Ot-Bu), 52.5 (CαH), 50.0 (CH), 42.8 (CH2), 31.9 (CH2), 28.1
(CH2), 27.5 (OC(
J = 9.7 Hz, 1H, NH), 5.11 (d, J = 12.3 Hz, 1H, PhCHHO), 5.06 (d, J = 12.3 Hz, 1H, PhCHH
H
H
δ
C
C
C
C
H3)3), 24.9 (CH2) ppm; IR (ATR) 3432, 2972, 2935, 2867, 1701, 1499, 1363, 1195,
1057 cm−1. HRMS (TOF-ESI) calcd for C20H30NO4 [M + H]+ 348.2175, found 348.2173.
3.2.3. Reactivity of 1-(N-Acylamino)alkyltriarylphosphonium Salts 4 toward Heteronucleophiles
Reaction of 1-(N-acylamino)alkyltriarylphosphonium salts
general procedure
4
with benzotriazole sodium salt—
To a solution of 1-(N-acylamino)alkyltriarylphosphonium salt
4
(0.5 mmol) in CHCl3 (1 cm3),
benzotriazole sodium salt (0.5 mmol) was added. The reaction mixture was stirred at room temperature
for 15 min. Thereafter, it was filtered through a fluted filter and the filtrate was evaporated under
reduced pressure. The residue was crystallized from toluene.
◦
N-[1-(Benzotriazol-1-yl)ethyl]pivalamide (10a) [
1H-NMR (CDCl3)
7.41–7.35 (m, 1H, aromatic), 6.88 (dq, J1 = 9.1, J2 = 6.7 Hz, 1H, CαH), 6.63 (d, J = 8.8 Hz, 1H, NH), 2.04
(d, J = 6.7 Hz, 3H, CH3), 1.15 (s, 9H, t-Bu) ppm; 13C-NMR (100 MHz, CDCl3)
178.2 (C = O), aromatic
carbons: 145.5, 132.4, 127.7, 124.4, 119.5, 110.4, 58.7 (CαH), 38.7 ( (CH3)3), 27.2 (C( H3)3), 20.7 (CH3)
ppm; IR (ATR) 3346, 2969, 1668, 1512, 1193, 1152, 1065 cm−1
6]. Colorless crystals (121.9 mg, 99% yield), mp 142–144 C.
δ
8.06–8.02 (m, 1H, aromatic), 7.85–7.79 (m, 1H, aromatic), 7.54–7.48 (m, 1H, aromatic),
δ
C
C
.
Benzyl N-[1-(benzotriazol-1-yl)-2-phenylethyl]carbamate (10b) [ ]. Colorless crystals (130.4 mg, 70% yield),
6
◦
1
mp 117.5–119.5 C. H-NMR (CDCl3)
δ
8.00 (d, J = 8.4 Hz, 1H, aromatic), 7.54 (d, J = 7.5 Hz, 1H,
aromatic), 7.42–7.35 (m, 1H, aromatic), 7.33–7.27 (m, 4H, aromatic), 7.27–7.20 (m, 2H, aromatic),
7.19–7.12 (m, 3H, aromatic), 7.11–7.04 (m, 2H, aromatic), 6.71–6.58 (m, 1H, CαH), 6.02 (d, J = 8.9 Hz,
1H, NH), 5.10 (d, J = 12.4 Hz, 1H, PhC
PhC H), 3.63 (dd, J1 = 13.8, J2 = 6.6 Hz, 1H, PhCH
carbons: 145.5, 136.0, 134.7, 131.9, 129.1, 128.7, 128.5, 128.4, 128.1, 127.7, 127.3, 124.1, 119.7, 109.7, 67.5
(Ph H2O), 65.8 (CαH), 41.1 (PH H2) ppm; IR (ATR) 3177, 3008, 1712, 1548, 1280, 1261, 1244, 1195,
1046, 1022 cm−1
H
HO), 4.97 (d, J = 12.2 Hz, 1H, PhCH
H
O), 3.80–3.68 (m, 1H,
H
H
) ppm; 13C-NMR (CDCl3)
δ 160.3 (C = O), aromatic
C
C
.
Reaction of 1-(N-pivaloylamino)ethyltris(4-trifluoromethylphenyl)phosphonium tetrafluoroborate 4a with
sodium p-toluenesulfinate
To a solution of 1-(N-pivaloylamino)ethyltris(4-trifluoromethylphenyl)phosphonium tetrafluoroborate
4a (340.7 mg, 0.5 mmol) in CHCl3 (1 cm3), sodium p-toluenesulfinate (89.1 mg, 0.5 mmol) was added.

Molecules 2018, 23, 2453
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The reaction mixture was stirred at room temperature for 15 min. Thereafter, it was filtered through
a fluted filter and the filtrate was evaporated under reduced pressure. The residue was crystallized
from toluene.
N-[1-(p-Toluenesulfonyl)ethyl]pivalamide (10c) [
5
]. Colorless crystals (124.7 mg, 88% yield), mp
7.77 (d, J = 8.3 Hz, 2H, aromatic), 7.33 (d, J = 7.9 Hz, 2H, aromatic), 5.98
(d, J = 10.2 Hz, 1H, NH), 5.41 (dq, J1 = 10.2, J2 = 7.0 Hz, 1H, CαH), 2.42 (s, 3H, CH3), 1.62 (d, J = 7.0 Hz
3H, CH3), 1.01 (s, 9H, t-Bu) ppm; 13C-NMR (CDCl3)
176.9 (C = O), aromatic carbons: 145.1, 133.5,
129.6, 129.1, 64.3 (CαH), 38.7 ( (CH3)3), 27.2 (C( H3)3), 21.6 (CH3), 13.2 (CH3) ppm; IR (ATR) 3372,
2973, 1677, 1516, 1308, 1287, 1135, 1083, 1016, 724 cm−1
◦
143–145 C. 1H-NMR (CDCl3)
δ
,
δ
C
C
.
Reaction of 1-(N-acylamino)alkyltriarylphosphonium salts 4 with benzylamine—general procedure
To a stirred solution of 1-(N-acylamino)alkyltriarylphosphonium salt (0.25 mmol) in DCM
(1 cm3), benzylamine (109.4
l, 110 mg, 1 mmol) was added dropwise. Stirring was continued for
4
µ
5 min at room temperature. Thereafter, the mixture was evaporated under reduced pressure and dried.
The residue was purified using column chromatography [DCM/MeOH/Et3N, 5:1:0.2 v/v/v].
◦
N-[1-(Benzylamino)ethyl]pivalamide (10d). Yellow crystals (53.3 mg, 91% yield), mp 56.5–58.5 C.
1H-NMR (CDCl3)
δ
7.35–7.29 (m, 4H, aromatic), 7.26–7.21 (m, 1H, aromatic), 5.67 (d, J = 6.7 Hz,
1H, NH), 4.90 (qd, J1 = 6.2, J2 = 1.6 Hz, 1H, CαH), 3.77 (s, 2H, PhCH2), 1.92 (br s, 1H, NH), 1.32 (d,
J = 6.2 Hz, 3H, CH3), 1.17 (s, 9H, t-Bu) ppm; 13C-NMR (CDCl3)
178.1 (C = O), aromatic carbons:
(CH3)3), 27.4 (C( H3)3), 21.6 ppm (CH3); IR
(ATR) 3328, 2971, 1622, 1527, 1475, 1144, 1097 cm−1. HRMS (TOF-ESI) calcd for C14H23N2O [M + H]+
235.1810, found 235.1802.
δ
140.1, 128.4, 127.9, 126.9, 60.9 (CαH), 49.8 (Ph
C
H2), 38.6 (
C
C
N-[1-(Benzylamino)-3-methylbutyl]phenylacetamide (10e). Colorless crystals (42.7 mg, 55% yield), mp
93–95 ◦C. 1H-NMR (CDCl3)
1H, CαH), 3.68 (s, 2H, PhCH2NH), 3.54 (s, 2H, PhCH2), 1.66 (br s, 1H, NH), 1.64–1.53 (m, 1H, CH),
1.45–1.28 (m, 2H, CH2), 0.87 (d, J = 6.6 Hz, 3H, CH3), 0.84 (d, J = 6.6 Hz, 3H, CH3) ppm; 13C-NMR
δ
7.59–6.96 (m, 10H, 2
×
Ph), 5.33 (d, J = 8.3 Hz, 1H, NH), 4.82–4.75 (m,
(CDCl3)
δ 170.9 (C = O), aromatic carbons: 140.3, 135.0, 129.3, 129.0, 128.4, 128.0, 127.3, 126.9, 63.3
(CαH), 49.6 (Ph
C
H2), 44.5 (PhCH2), 44.1 (CH2), 24.9 (CH), 22.6 (CH3), 22.5 (CH3) ppm; IR (ATR) 3306,
2962, 2946, 1632, 1518, 1144, 1009 cm−1. HRMS (TOF-ESI) calcd for C20H27N2O [M + H]+ 311.2123,
found 311.2121.
Reaction of 1-(N-pivaloylamino)ethyltris(4-trifluoromethylphenyl)phosphonium tetrafluoroborate 4a
with triphenylphosphine
To
a
solution of 1-(N-pivaloylamino)ethyltris(4-trifluromethylphenyl)phosphonium
tetrafluoroborate 4a (102.2 mg, 0.15 mmol) in DCM (1 cm3), triphenylphosphine (39.3 mg,
0.15 mmol) was added. The homogeneous mixture was allowed to react at room temperature for 5 min,
and 1-(N-pivaloylamino)ethyltriphenylphosphonium tetrafluoroborate (4b) [9] was precipitated with
Et2O, separated by decantation, and dried under reduced pressure.
1-(N-Pivaloylamino)ethyltriphenylphosphonium tetrafluoroborate (4b). Colorless crystals
◦
1
(70.2 mg, 98% yield), mp 160.5–162.5 C. H-NMR (CDCl3)
5.82–5.73 (m, 1H, CαH), 1.72 (dd, J1 = 17.8, J2 = 7.4 Hz, 3H, CH3), 0.91 (s, 9H, t-Bu) ppm; 13C-NMR
(CDCl3) 179.7 (d, J = 2.3 Hz, C = O), aromatic carbons: 134.8 (d, J = 3.0 Hz), 134.5 (d, J = 9.2 Hz), 130.0
(d, J = 12.3 Hz), 118.4 (d, J = 82.5 Hz), 45.0 (d, J = 53.4 Hz, CαH), 38.5 ( (CH3)3), 26.8 (C( H3)3), 17.4
(d, J = 4.6 Hz, CH3) ppm; 31P NMR (161.9 MHz, CDCl3)
29.2 ppm; IR (ATR) 3373, 1684, 1516, 1447,
1136, 1040 cm−1
δ
7.89–7.64 (m, 16H, 3
×
Ph and NH),
δ
C
C
δ
.

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Reaction of 1-(N-acylamino)alkyltriarylphosphonium salts 4 with triarylphosphines—NMR scale
To a solution of 1-(N-acylamino)alkyltriarylphosphonium salt (0.025 mmol) in CDCl3 (0.65 cm3),
the corresponding triarylphosphine (0.025 mmol) was added. Reactions were conducted in NMR tubes
at 26 ◦C, and their course was monitored using NMR spectroscopy.
Reaction of 1-(N-acylamino)alkyltriarylphosphonium salts
Michaelis–Arbuzov type reaction—general procedure
4 with phosphorus nucleophiles in
To a stirred solution of 1-(N-acylamino)alkyltriarylphosphonium salt
4 (0.25 mmol) and
methyltriphenylphosphonium iodide (25.3 mg, 0.0625 mmol) in DCM (2 cm3), phosphorus nucleophile
(0.375 mmol) was added, and the mixture was stirred for 3 h at room temperature (12a–c and 12e)
or for 2 h at 60 ◦C (12d). The mixture was evaporated under reduced pressure and the residue was
◦
extracted with toluene (3
×
1 cm3) at 50 C. The solvent was evaporated under reduced pressure, and
the product was isolated using column chromatography [DCM/MeOH 20:1 v/v].
Dimethyl 1-(N-pivaloylamino)ethanephosphonate (12a) [ ]. Colorless crystals (50.4 mg, 85% yield), mp
5.96 (d, J = 8.1 Hz, 1H, NH), 4.65–4.49 (m, 1H, CαH), 3.78 (d,
J = 4.4 Hz, 3H, OCH3), 3.75 (d, J = 4.3 Hz, 3H, OCH3), 1.38 (dd, J1 = 16.8, J2 = 7.4 Hz, 3H, CH3), 1.21
(s, 9H, t-Bu) ppm; 13C-NMR (CDCl3)
177.6 (d, J = 5.1 Hz, C = O), 53.1 (d, J = 7.0 Hz, OCH3), 52.9
(d, J = 6.5 Hz, OCH3), 40.1 (d, J = 156.4 Hz, CαH), 38.6 ( (CH3)3), 27.3 (C( H3)3), 15.5 (CH3) ppm;
31P-NMR (CDCl3) δ 28.5 ppm; IR (ATR) 3281, 2956, 1659, 1529, 1224, 1205, 1057, 1026, 1007 cm−1
7
◦
1
125.5–127.5 C. H-NMR (CDCl3)
δ
δ
C
C
.
Dimethyl 1-(N-phen◦ylcetylamino)-3-methylbutanephosphonate (12b) [
4]. Colorless crystals (60.3 mg, 77%
δ 7.39–7.23 (m, 5H, Ph), 5.72 (d, J = 9.9 Hz, 1H, NH), 4.62–4.48
yield), mp 117–119 C. 1H-NMR (CDCl3)
(m, 1H, CαH), 3.73 (d, J = 10.6 Hz, 3H, OCH3), 3.63 (d, J = 10.6 Hz, 3H, OCH3), 3.60 (s, 2H, PhCH2),
1.61–1.44 (m, 3H, CH2 and CH), 0.88 (d, J = 5.9 Hz, 6H, 2 170.5
CH3) ppm; 13C-NMR (CDCl3)
(d, J = 4.3 Hz, C = O), aromatic carbons: 134.6, 129.2, 128.9, 127.4, 53.1 (d, J = 7.2 Hz, OCH3), 53.0 (d,
J = 6.6 Hz, OCH3), 43.7 (Ph H2), 43.2 (d, J = 155.5 Hz, CαH), 38.1 (d, J = 1.8 Hz, CH2), 24.5 (d, J = 13.4
Hz, CH), 23.2 (CH3), 21.1 (CH3) ppm; 31P-NMR (CDCl3)
27.6 ppm; IR (ATR) 3243, 2959, 1673, 1540,
1217, 1027, 836, 742 cm−1
×
δ
C
δ
.
Dimethyl 1-(N-benzyloxycarbonylamino)-2-tert-butoxyethanephosphonate (12c) [
mg, 61% yield), mp 59.5–61.5 ◦C. 1H-NMR (CDCl3)
7.41–7.28 (m, 5H, Ph), 5.29 (d, J = 8.8 Hz, 1H,
NH), 5.13 (s, 2H, PhCH2O), 4.33–4.19 (m, 1H, CαH), 3.76 (d, J = 10.6 Hz, 3H, OCH3), 3.75 (d, J = 10.3
4]. Colorless crystals (54.8
δ
Hz, 3H, OCH3), 3.61 (dd, J1 = 9.4, J2 = 3.8 Hz, 1H, C
CH
Ot-Bu), 1.18 (s, 9H, t-Bu) ppm; 13C-NMR (CDCl3)
128.2, 128.1, 73.7 (O (CH3)3), 67.2 (Ph H2O), 60.6 (
J = 5.8 Hz, OCH3), 48.3 (d, J = 156.0 Hz, CαH), 27.3 (OC(
IR (ATR) 3293, 2974, 1699, 1532, 1278, 1235, 1039, 1023, 756, 697 cm−1
H
δ
HOt-Bu), 3.54 (dd, J1 = 9.4, J2 = 3.8 Hz, 1H,
155.7 (C = O), aromatic carbons: 136.2, 128.5,
H
C
C
CH2Ot-Bu), 53.3 (d, J = 6.0 Hz, OCH3), 52.6 (d,
C
H3)3) ppm; 31P-NMR (CDCl3)
δ
26.1 ppm;
.
Methyl p◦henyl(1-pivaloylaminoethyl)phosphinate (12d). Colorless crystals (48.9 mg, 69% yield), mp
1
131–133 C. H-NMR (CDCl3)
δ
7.84–7.75 (m, 2H, aromatic), 7.59–7.43 (m, 3H, aromatic), 5.76 (d,
J = 9.6 Hz, 1H, NH), 4.79–4.67 (m, 1H, CαH), 3.67 (d, J = 10.8 Hz, 3H, OCH3), 1.45 (dd, J1 = 14.6,
J2 = 7.3 Hz, 3H, CH3), 0.92 (s, 9H, t-Bu) ppm; 13C-NMR (CDCl3)
177.3 (d, J = 4.7 Hz, C = O), aromatic
carbons: 132.8 (d, J = 2.8 Hz), 132.4 (d, J = 9.4 Hz), 128.5 (d, J = 12.5 Hz), 127.5 (d, J = 124.2 Hz), 51.8
(d, J = 7.1 Hz, OCH3), 42.3 (d, J = 115.5 Hz, CαH), 38.5 ( (CH3)3), 27.1 (C( H3)3), 14.4 (CH3) ppm;
δ
C
C
31P-NMR (CDCl3)
δ
42.9 ppm. IR (ATR) 3264, 2954, 1660, 1531, 1198, 1139, 1027, 799 cm−1; HRMS
(TOF-ESI) calcd for C14H23NO3P [M + H]+ 284.1416, found 284.1405.
Diphenyl 1-(N-benzyloxycarbonylamino)-3-methylbutylphosphine oxide (12e) [
8
]. Colorless crystals (87.5 mg,
Ph), 5.40 (d, J = 10.6 Hz,
HO), 4.89 (d, J = 12.5 Hz, 1H, PhCH O), 4.83–4.72 (m, 1H,
CαH), 1.83–1.66 (m, 2H, CH2), 1.36–1.21 (m, 1H, CH), 0.90 (d, J = 6.5 Hz, 3H, CH3), 0.86 (d, J = 6.6 Hz
3H, CH3) ppm; 13C-NMR (CDCl3)
156.1 (d, J = 4.5 Hz, C = O), aromatic carbons: 136.4, 132.0 (d,
83% yield), mp 173.5–175.5 ◦C. 1H-NMR (CDCl3)
δ
7.87–7.09 (m, 15H, 3
×
1H, NH), 5.02 (d, J = 12.5 Hz, 1H, PhC
H
H
,
δ

Molecules 2018, 23, 2453
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J = 2.8 Hz), 131.9 (d, J = 2.8 Hz), 131.5, 131.3, 131.1 (d, J = 9.2 Hz), 130.9 (d, J = 9.0 Hz), 128.8 (d,
J = 11.4 Hz), 128.4 (d, J = 11.6 Hz), 128.4, 127.9, 127.6, 66.8 (Ph H2O), 48.1 (d, J = 79.5 Hz, CαH), 37.5
(d, J = 3.5 Hz, CH2), 24.5 (d, J = 11.0 Hz, CH), 23.4 (CH3), 21.0 (CH3) ppm; 31P-NMR (CDCl3)
33.5
ppm; IR (ATR) 3181, 2954, 1702, 1545, 1436, 1263, 1187, 1120 cm−1
C
δ
.
Reaction of 1-(N-pivaloylamino)ethyltris(3-chlorophenyl)phosphonium tetrafluoroborate 4c with trimethyl
phosphite—measurement of changes in concentrations of the substrate 4c, intermediate 13a and product 12a
by NMR
To a solution of 1-(N-pivaloylamino)ethyltris(3-chlorophenyl)phosphonium tetrafluoroborate
4c (29.0 mg, 0.05 mmol) in CDCl3 (0.65 cm3), trimethyl phosphite (8.9
µL, 9.3 mg, 0.075 mmol) was
added. Dimethyldiphenylsilane (5 mg) was used as the internal standard. The reaction mixture was
placed directly into the NMR tube. Changes in the concentrations of substrate 4c, intermediate 13a
and product 12a were monitored using 1H-NMR spectroscopy.
,
Reaction of 1-(N-pivaloylamino)ethyltris(3-chlorophenyl)phosphonium tetrafluoroborate 4c with triethyl
phosphite–synthesis of 1-(N-pivaloylamino)ethyltriethoxyphosphonium tetrafluoroborate 13b
To
a
stirred solution of 1-(N-pivaloylamino)ethyltris(3-chlorophenyl)phosphonium
L, 62.3 mg,
tetrafluoroborate (4c, 145.2 mg, 0.25 mmol) in DCM (1 cm3), triethyl phosphite (64.6
µ
0.375 mmol) was added. Stirring was continued for 30 min at room temperature. Thereafter the
intermediate product 13b was precipitated with Et2O, separated by decantation, and dried under
reduced pressure. In order to obtain the triethoxyphosphonium salt 13 with a higher purity, the
reaction should be carried out under argon atmosphere.
1-(N-Pivaloylamino)ethyltriethoxyphosphonium tetrafluoroborate (13b). Colorless oil (47.6 mg, 50% yield).
1H-NMR (CDCl3)
(m, 6H, 3
OCH2CH3), 1.23 (s, 9H, t-Bu) ppm; 13C-NMR (CDCl3)
(d, J = 148.6 Hz, CαH), 38.5 ( (CH3)3), 27.1 (C( H3)3), 15.9 (d, J = 6.0 Hz, OCH2C
δ
7.53 (t, J = 8.2 Hz, 1H, NH), 4.69 (dq, J1 = 19.7, J2 = 7.0 Hz, 1H, CαH), 4.62–4.46
OCH2), 1.56 (dd, J1 = 20.2, J2 = 7.3 Hz, 3H, CH3), 1.48 (td, J1 = 7.0, J2 = 0.9 Hz, 9H, 3
179.9 (C = O), 70.2 (d, J = 9.1 Hz, OCH2), 42.3
H3), 14.0 (CH3) ppm;
×
×
δ
C
C
31P-NMR (CDCl3)
δ
37.0 ppm; IR (ATR) 3375, 2973, 1664, 1515, 1030 cm−1. HRMS (TOF-ESI) calcd for
C13H29NO4P [M]+ 294.1834, found 294.1829.
4. Conclusions
Modification of the phosphonium group by introducing electron-withdrawing substituents results
in the weakening of the Cα-P+ bond and makes it susceptible to cleavage. This phenomenon is the
cause of the high reactivity of 1-(N-acylamino)alkyltriarylphosphonium salts with weakened Cα-P+
bond strength. As we have demonstrated, these types of phosphonium salts react smoothly, usually at
room temperature with various types of nucleophiles such as 1-morpholinocyclohexene, 1,3-dicarbonyl
compounds, benzotriazole sodium salt, p-toluenesulfinate sodium salt, benzylamine, triarylphosphines,
and other P-nucleophiles. Only in the case of 1,3-dicarbonyl compounds, it was necessary to use
a strong base to generate enolate anions. Reactions with 1-morpholinocyclohexene, benzotriazole
sodium salt, p-toluenesulfinate sodium salt, benzylamine, and triarylphosphines do not require the use
of any catalysts and occur quite fast (5–60 min). Other examined P-nucleophiles also react efficiently
with 1-(N-acylamino)alkyltriarylphosphonium salts. However, the quickly formed intermediate,
in the absence of any dealkylating agent, slowly transforms into a final product. Therefore, to
facilitate the reaction, we used a substoichiometric amount of the dealkylating agent in the form
of methyltriphenylphosphonium iodide.
The use of 1-(N-acylamino)alkyltriarylphosphonium salts with weakened Cα-P+ bond strength
allowed us to discover interesting mechanistic aspects of the examined reactions. Detection,
isolation, and characterization of 1-(N-acylamino)alkyltrialkoxyphosphonium salt 13b—the reactive
intermediate in the Michaelis–Arbuzov type reaction, were particularly important.

Molecules 2018, 23, 2453
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Futher studies on expanding the range of nucleophiles, which can be used in
α
-amidoalkylation by
1-(N-acylamino)alkyltriarylphosphonium salts with weakened Cα-P+ bond strength, are in progress.
Supplementary Materials: The following are available online at http://www.mdpi.com/1420-3049/23/10/2453/
s1, Supporting information includes a summary table (comparison of conditions and yields for reactions of
1-(N-acylamino)alkyltriphenylphosphonium salts (former studies) and 1-(N-acylamino)alkyltriarylphosphonium
salts (the current work) with selected nucleophiles), 1H, 13C, and 31P NMR spectra of all new compounds
6, 8, 10,
12, 13. Supplementary data associated with this article can be found in the online version.
Author Contributions: Conceptualization, J.A.; Formal analysis, J.A., A.W., J.K. and K.E.; Investigation, J.A.,
A.W., J.K. and K.E.; Methodology, J.A. and A.W.; Supervision, J.A. and K.W.; Writing—original draft, J.A.;
Writing—review & editing, J.A. and A.W.
Funding: This research received no external funding.
Acknowledgments: This work received financial support from the National Science Center, Poland (NCN) under
Grant No. 2015/19/D/ST5/00733.
Conflicts of Interest: The authors declare no conflict of interest.
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©
2018 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 (http://creativecommons.org/licenses/by/4.0/).