Comparative studies on the amidoalkylating properties of N-(1-methoxyalkyl)amides and 1-(N-acylamino)alkyltriphenylphosphonium salts in the michaelis-arbuzov-like reaction: A new one-pot transformation of N-(1-methoxyalkyl)amides into phosphonic or phosphinic analogs of N-Acyl-α-amino acids

Article abstract of DOI:10.1080/10426507.2012.729237

It was demonstrated that N-(1-methoxyalkyl)amides do not react with trimethyl phosphite under neutral or basic conditions. The treatment of N-(1-methoxyalkyl)amides with trialkyl phosphites or dialkyl phosphonites, triphenylphosphonium tetrafluoroborate, and Huenig's base caused immediate formation of the corresponding 1-(N-acylamino)-alkyltriphenylphosphonium tetrafluoroborates, followed by the slow Michaelis-Arbuzov-like reaction of phosphonium salt with phosphites or phosphonites to α-(N-acylamino)- alkanephosphonic or α-(N-acylamino)alkanephosphinic acid esters, respectively. A plausible mechanism of the considered transformations, assuming an equilibrium between N-(1-alkoxyalkyl)amide, triphenylphosphonium tetrafluoroborate, 1-(N-acylamino)alkyltriphenyl-phosphonium salt, N-acylimine, and N-acyliminium salts, is discussed.

Full text of DOI:10.1080/10426507.2012.729237

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Phosphorus, Sulfur, and Silicon and the
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Comparative Studies on the
Amidoalkylating Properties of N-
(1-Methoxyalkyl)Amides and 1-(N-
Acylamino)Alkyltriphenylphosphonium
Salts in the Michaelis–Arbuzov-Like
Reaction: A New One-Pot Transformation
of N-(1-Methoxyalkyl)Amides into
Phosphonic or Phosphinic Analogs of N-
Acyl-α-Amino Acids
Jakub Adamek a , Agnieszka Październiok-Holewa a , Katarzyna
Zielińska a & Roman Mazurkiewicz a
a Department of Organic Chemistry, Biochemistry and
Biotechnology , Silesian University of Technology , Gliwice , Poland
Accepted author version posted online: 05 Oct 2012.Published
online: 05 Jul 2013.
To cite this article: Jakub Adamek , Agnieszka Październiok-Holewa , Katarzyna Zielińska &
Roman Mazurkiewicz (2013) Comparative Studies on the Amidoalkylating Properties of N-(1-
Methoxyalkyl)Amides and 1-(N-Acylamino)Alkyltriphenylphosphonium Salts in the Michaelis–Arbuzov-
Like Reaction: A New One-Pot Transformation of N-(1-Methoxyalkyl)Amides into Phosphonic or
Phosphinic Analogs of N-Acyl-α-Amino Acids, Phosphorus, Sulfur, and Silicon and the Related
Elements, 188:7, 967-980, DOI: 10.1080/10426507.2012.729237
To link to this article: http://dx.doi.org/10.1080/10426507.2012.729237
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Phosphorus, Sulfur, and Silicon, 188:967–980, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.729237
COMPARATIVE STUDIES ON THE AMIDOALKYLATING
PROPERTIES OF N-(1-METHOXYALKYL)AMIDES AND
1-(N-ACYLAMINO)ALKYLTRIPHENYLPHOSPHONIUM
SALTS IN THE MICHAELIS–ARBUZOV-LIKE REACTION:
A NEW ONE-POT TRANSFORMATION OF
N-(1-METHOXYALKYL)AMIDES INTO PHOSPHONIC OR
PHOSPHINIC ANALOGS OF N-ACYL-α-AMINO ACIDS
Jakub Adamek, Agnieszka Paz´dzierniok-Holewa,
Katarzyna Zielin´ska, and Roman Mazurkiewicz
Department of Organic Chemistry, Biochemistry and Biotechnology,
Silesian University of Technology, Gliwice, Poland
GRAPHICAL ABSTRACT
Abstract It was demonstrated that N-(1-methoxyalkyl)amides do not react with trimethyl
phosphite under neutral or basic conditions. The treatment of N-(1-methoxyalkyl)amides
with trialkyl phosphites or dialkyl phosphonites, triphenylphosphonium tetrafluoroborate,
and Hu¨nig’s base caused immediate formation of the corresponding 1-(N-acylamino)-
alkyltriphenylphosphonium tetrafluoroborates, followed by the slow Michaelis–Arbuzov-like
reaction of phosphonium salt with phosphites or phosphonites to α-(N-acylamino)-
alkanephosphonic or α-(N-acylamino)alkanephosphinic acid esters, respectively. A plausible
mechanism of the considered transformations, assuming an equilibrium between N-(1-
alkoxyalkyl)amide, triphenylphosphonium tetrafluoroborate, 1-(N-acylamino)alkyltriphenyl-
phosphonium salt, N-acylimine, and N-acyliminium salts, is discussed.
Keywords Amidoalkylating agents; 1-(N-acylamino)alkyltriphenylphosphonium salts; N-
(1-methoxyalkyl)amides; Michaelis–Arbuzov-like reaction; phosphorus analogs of N-acyl-
α-amino acids
Received 12 August 2012; accepted 7 September 2012.
The financial help of the Ministry of Science and Higher Education of Poland (Grant No. N N204 165636)
is gratefully acknowledged.
Address correspondence to Jakub Adamek, Department of Organic Chemistry, Biochemistry and Biotechnol-
ogy, Silesian University of Technology, Krzywoustego 4, 44-100 Gliwice, Poland. E-mail: jakub.adamek@polsl.pl
967

968
J. ADAMEK ET AL.
INTRODUCTION
α-Aminoalkanephosphonic acids 2 and α-aminoalkanephosphinic acids 3, as struc-
tural analogues and mimetics of α-amino acids, display a broad spectrum of biological
activity and, therefore, have been the subject of significant current interest.1–3 One of the
most general and widely used methods for the synthesis of these compounds consists
in the amidoalkylation of trialkyl phosphites or dialkyl phosphonites, respectively, in a
Michaelis–Arbuzov-like reaction (Scheme 1).4
Scheme 1
Numerous α-amidoalkylating reagents of a general structure 1 have been used in
those reactions, where X represents some nucleofugal leaving group, usually OH, OR, Cl,
Br, NHCOR, SO2Ar, or 1-benzotriazolyl (Scheme 1).4–13
The limitations and disadvantages of most of the above-mentioned amidoalkylating
agents were reviewed by Katritzky et al.4,14–17 Many of them (X = OR, Cl, Br) are relatively
unstable compounds that cannot be stored for a prolonged period of time and thus have
to be prepared in situ. Preparation of some of these amidoalkylating agents (X = Cl,
Br) is relatively difficult or labor-consuming. Most of them (X = OH, NHCOR, or 1-
benzotriazolyl), including the most frequently used α-alkoxy derivatives (X = OR), require
activation with Lewis acids, which are often quite expensive (e.g., ZrCl4, VCl3, CeCl3, or
InCl3).4,13–17 Application of Lewis acid has also been shown to diminish the activity of a
reacting nucleophile and also necessitates a labor-consuming aqueous work-up procedure,
which usually destroys the catalyst.
N-(1-Alkoxyalkyl)amides 5 represent an especially interesting class of amidoalkylat-
ing agents, as they can be obtained directly from easily accessible N-acyl-α-amino acids 4 by
electrochemical decarboxylative α-alkoxylation (usually α-methoxylation), well known as
the Hofer–Moest reaction (Scheme 2; transformation 4 to 5).18–30 N-(1-Alkoxyalkyl)amides
Scheme 2

COMPARATIVE STUDIES ON THE AMIDOALKYLATING PROPERTIES
969
5 can also be obtained by electrochemical oxidation of N-alkylamides, lactams, and N-
alkylcarbamates in methanol.23,31,32 Recently, we described an effective and convenient
procedure for the Hofer–Moest decarboxylative α-methoxylation of a variety of N-acyl-α-
amino acids in the presence of silica gel-supported piperidine as a base.33 The possibility
of employing a large variety of natural α-amino acids (both proteinogenic and unproteino-
genic) in this synthesis, as well as a nearly infinite array of unnatural α-amino acids both
provide potential access to a wide variety of structurally diverse N-(1-alkoxyalkyl)amides,
which significantly broadens the scope of possible synthetic application of their amidoalky-
lating properties.
N-(1-Alkoxyalkyl)amides are also promising intermediates for a relatively straight-
forward two-stage transformation of N-acyl-α-amino acids into their phosphonic or phos-
phinic analogs. In 1981, Shono et al. reported the Michaelis–Arbuzov-like reaction of
N-(1-methoxyalkyl)amides with trialkyl or triphenyl phosphites in the presence of Lewis
acids (TiCl4, ZnCl2, SnCl4, or BF3·OEt2) to the corresponding α-aminoalkylphosphonic
acid derivatives.9 About 10 years later Seebach and Gerber described the decarboxylative
α-methoxylation of the C-terminal amino acid of dipeptides followed by the reaction of
α-methoxy derivatives with trialkyl or triaryl phosphites in the presence of TiCl4 to the
corresponding phosphonodipeptide derivatives, which were usually obtained in moderate
to good yields based on the dipeptide.34,35
Recently, we reported on a very simple and efficient transformation of N-(1-
methoxyalkyl)amides5tothehithertounknown1-(N-acylamino)alkyltriphenylphosphonium
salts 6 (Scheme 2).33,36,37 We also demonstrated that the phosphonium salts 6 display strong
amidoalkylating properties when activated with organic bases. They react smoothly with
oxygen, nitrogen, sulphur, and carbon nucleophiles in the presence of (i-Pr)2EtN (Hu¨nig’s
base) or DBU to give α-amidoalkylation products 7.36 Moreover, α-amidoalkylation of tri-
alkyl phosphites or dialkyl phosphonites with 1-(N-acylamino)alkyltriphenylphosphonium
salts, followed by a Michaelis–Arbuzov-like rearrangement, enabled us to perform an
effective three-stage transformation of N-acyl-α-amino acids 4 to their phosphonic or
phosphinic analogs 2 or 3, respectively (Scheme 2).
In the present paper, we report our comparative and mechanistic study on the
amidoalkylation properties of N-(1-methoxyalkyl)amides 5 and 1-(N-acylamino)alkyl-
triphenylphosphonium salts 6 in the Michaelis–Arbuzov-like reaction with trialkyl phos-
phites, as well as investigations on the mechanism of the transformation of N-(1-
methoxyalkyl)amides 5 to phosphonium salts 6. These investigations have allowed us
to simplify the above-mentioned three-stage transformation of N-acylamino acids 4 into
their phosphorus analogues 2 or 3 to a simple two-stage method which does not use Lewis
acids.
RESULTS AND DISCUSSION
Themechanismof theMichaelis–Arbuzov-likereactionof N-(1-methoxyalkyl)amides
5 and 1-(N-acylamino)alkyltriphenylphosphonium salts 6 was studied based mainly on
the reaction of N-(1-methoxyethyl)pivaloamide 5a and the corresponding 1-(N-
pivaloylamino)ethyltriphenylphosphonium tetrafluoroborate 6a with trialkyl phosphites.
◦
The reaction of phosphonium salt 6a with trimethyl phosphite in CD2Cl2 at 20 C
was very slow; after 157 min the reaction mixture contained only about 13% of the expected
aminophosphonic acid derivative 2, apart from the starting reagents (Table 1, entry 1).

970

COMPARATIVE STUDIES ON THE AMIDOALKYLATING PROPERTIES
971
The addition of a substoichiometric amount of Hu¨nig’s base (0.1 mol per 1 mol
of phosphonium salt) significantly speeded up the reaction. After 146 min, the reaction
mixture contained 67% of the expected product, 32% of the starting phosphonium salt,
43% of trimethyl phosphite, 10% of triphenylphosphine, and 63% of methyltriphenylphos-
phonium tetrafluoroborate, whereas after 65 h a 97% yield of the product was achieved
(entries 2 and 3). It seems to be clear that the catalytic effect of Hu¨nig’s base in the in-
vestigated Michaelis–Arbuzov-like reaction consists in deprotonation of the nitrogen atom
of phosphonium salt, which initiates the cleavage of the C–P bond, elimination of triph-
enylphosphine and the formation of N-acylimine 8 in equilibrium with N-acyliminium salt
8 · HBF4 as the active amidoalkylating agents (Scheme 3). The reaction of N-acylimine or
N-acyliminium salt with trimethyl phosphite gives trialkoxyphosphonium salt 9, which is
a characteristic intermediate of the Michaelis–Arbuzov reaction. The final step of the ordi-
nary Michaelis–Arbuzov reaction consists in dealkylation of the trialkoxyphosphonium salt
with a halogen counterion. It is evident that, in the discussed experiments, trialkoxyphos-
phonium tetrafluoroborate is dealkylated directly by triphenylphosphine with the formation
of methyltriphenylphosphonium tetrafluoroborate and the expected aminophosphonic acid
derivative 2.
Scheme 3
The approach of the bulky triphenylphosphine molecule to the α-atom of the alkoxy
group in an SN2 reaction can be hindered by steric reasons. To avoid this problem, the
addition of substoichiometric amounts of iodide anion in the form of methyltriphenyl-
phosphonium iodide as dealkylating agent was tested. A comparison of the results of
experiments 2 and 4 led to the conclusion that in the case of phosphonium salts with a rel-
atively small methyl group at the α-position, the addition of methyltriphenylphosphonium
iodide did not markedly accelerate the reaction. This means that, in such a case, triph-
enylphosphine can effectively dealkylate the trialkoxyphosphonium salt even in the case of
phosphonium salts 6 with a bulky acyl group or a reaction with triethyl phosphite (entries 6
and 7). On the other hand, in the case of more sterically hindered phosphonium salts with
a bulky substituent at the α-position, for example, derived from Cbz–Phe–OH 6c (entry
8), the Michaelis–Arbuzov reaction without the addition of methyltriphenylphosphonium
iodide was slow. After 160 min the conversion of the phosphonium salt into the correspond-
ing aminophosphonic acid derivative reached only 10% at 20 ◦C. The same phosphonium
salt 6c in the presence of methyltriphenylphosphonium iodide, used in a molar ratio of

972
J. ADAMEK ET AL.
1:0.25, was converted into the expected product in 49% after 152 min, whereas after 18 h
the reaction mixture contained 64% of the product and 1.06 mol of methyltriphenylphos-
phonium salt per 1 mol of the starting phosphonium salt 6c (entries 9-10). This proves
that methyl iodide, formed in the demethylation reaction, reacts with triphenylphosphine to
methyltriphenylphosphonium iodide, and thus restores the iodide anion which, therefore,
can be considered as a real nucleophilic catalyst of the considered reaction (Scheme 3,
R3 = Me).
As was expected, the corresponding N-(1-methoxyethyl)pivaloamide 5a did not re-
act directly with trimethyl phosphite. The reaction also did not take place in the pres-
ence of Hu¨nig’s base or methyltriphenylphosphonium iodide (entries 11–13). Therefore,
a direct reaction of the N-(1-methoxyethyl)pivaloamide with trimethylphosphite in the
Michaelis–Arbuzov reaction under neutral or basic conditions is not possible.
Attempting to find the conditions for a “one-pot” reaction of N-(1-methoxyalkyl)-
amides 5 with trialkyl phosphites, we studied their transformation to 1-(N-acylamino)alkyl-
triphenylphosphonium salts 6 in detail.
Our first developed method for displacement of the methoxy groups of N-(1-
methoxyalkyl)amides with the triphenylphosphonium group consisted in heating of a ho-
mogeneous mixture of the amide with triphenylphosphonium tetrafluoroborate at 45–70 ◦C
under reduced pressure (0.1–0.2 mm Hg) for 2 h.33 Our recent investigations revealed, how-
ever, that high or even quantitative yields of this transformation could be achieved simply
by dissolution of N-(1-methoxyalkyl)amide and triphenylphosphonium tetrafluoroborate
in CD2Cl2 at room temperature for 5 to 15 min and by evaporation of the solvent.33 The
reaction was so fast that it was not possible to monitor the reaction progress in the range of
low or medium conversions by 1H NMR spectroscopy.33
Developing these studies, we found that the addition of an equimolar amount of
Hu¨nig’s base to a mixture of 1-(N-pivaloylamino)ethyltriphenylphosphonium tetrafluoro-
borate 6a and methanol in CD2Cl2, obtained in situ from N-(1-methoxyethyl)pivaloamide
5a and triphenylphosphonium tetrafluoroborate, initiated unexpectedly a slow reverse reac-
tion. After 60 min, the reaction mixture contained 23% of the methoxy derivative 5a, 57%
of the phosphonium salt 6a, and 22% of the enamide 10a, whereas after 80 h, the mixture
contained about 60% of the N-(1-methoxyethyl)pivaloamide 5a, 35% of enamide 10a, and
a trace amount of the phosphonium salts 6a. We obtained almost the same result by starting
from a solution of equimolar amounts of 1-(N-pivaloylamino)ethyltriphenylphosphonium
tetrafluoroborate 6a, methanol and Hu¨nig’s base in CD2Cl2: after 60 min the reaction mix-
ture contained 18% of the methoxy derivative 5a, 57% of the phosphonium salt 6a and
18% of the enamide 10a. When only 0.1 mol of Hu¨nig’s base per 1 mol of phosphonium
salt 6a and 1 mol of methanol were used, the reverse reaction stopped at about 10% of
conversion to N-(1-methoxyethyl)pivaloamide 5a. These results prove that the investigated
displacement of the methoxy group of N-(1-methoxyalkyl)amides with triphenylphosphine
is a reversible reaction.
The nature of the driving force of the discussed reverse displacement of the phos-
phonium group with methanol (Scheme 4, reaction “b”) can be explained by taking into
account that the summing up of the first two equations in Scheme 4 gives the third equation.
This means that the relations between the free energies of these reactions are as follows:
ꢁGa + ꢁGb = ꢁGc, and consequently ꢁGb = ꢁGc – ꢁGa. The free energy of the third
reaction is evidently negative; the reaction of Hu¨nig’s base with triphenylphosphonium
tetrafluoroborate in CD2Cl2 immediately gave a mixture of free triphenylphosphine and
Hu¨nig’s base salt. This analysis indicates that the negative value of free energy of reaction

COMPARATIVE STUDIES ON THE AMIDOALKYLATING PROPERTIES
973
Scheme 4
“b” (ꢁGb < 0), which is necessary for the spontaneous course of this reaction, is achieved,
because the free energy of reaction “c” is more negative than the free energy of reaction
“a” (ꢁGc < ꢁGa). Therefore, a high negative value of free energy of the formation of
the Hu¨nig’s base salt in reaction “c” must be responsible for a negative value of ꢁGb and,
consequently, is the driving force of the reverse displacement of the phosphonium group
with methanol in the presence of Hu¨nig’s base.
Assuming that the equilibrium between N-(1-alkoxyalkyl)amides 5 and 1-
(N-acylamino)alkyltriphenylphosphonium salts 6 is achieved via N-acylimines 8 or
N-acyliminium salts 8 · HBF4 (Scheme 5), we tried to find favorable conditions for
a direct Michaelis–Arbuzov-like reaction of N-(1-methoxyethyl)pivaloamide 5a with
trimethylphosphite in the presence of triphenylphosphonium tetrafluoroborate and Hu¨nig’s
base. As was expected, N-(1-methoxyethyl)pivaloamide 5a was immediately transformed
to the corresponding phosphoni◦um salt 6a at the molar ratio of the reagents of 1:1.5:1.0:0.1,
respectively, in CD2Cl2 at 20 C in a yield of about 99%. However, after 182 min, the
Scheme 5

974
J. ADAMEK ET AL.
reaction mixture contained 18% of the expected α-aminoethanephosphonic acid derivative
2a, and after about 80 h, the reaction system approached equilibrium with a yield of
2a at a level of 80% (Table 1, entries 14–15). The final reaction mixture also contained
the starting N-(1-methoxyethyl)amide 5a (11%), phosphonium salt 6a (10%), methanol
(63%), triphenylphosphine (11%), methyltriphenylphosphonium tetrafluoroborate (82%),
starting trimethylphosphite (28%), and, unexpectedly, dimethylphosphite (10%). Very
similar results were obtained in a reaction of amide 5a with triethylphosphite (entries
16–17).
A plausible mechanism of the considered transformations, assuming an equilibrium
between N-(1-alkoxyalkyl)amide 5, triphenylphosphonium tetrafluoroborate, 1-(N-acyl-
amino)alkyltriphenylphosphonium salt 6, N-acylimine 8, and N-acyliminium salts 8 · HBF4,
is shown in Scheme 5.
It seems that the mechanism of transforming N-(1-methoxyalkyl)amides 5 to triph-
enylphosphonium tetrafluoroborates 6 consists in the protonation of the methoxy group,
followed by the elimination of methanol with formation of the acyliminium salt 8 · HBF4
in equilibrium with the acylimine 8. The α-amidoalkylation of trimethylphosphite with 8
· HBF4 or 8 finally gave the expected Michaelis–Arbuzov reaction product 2 or 3, as was
discussed above.
The final yield of the Michaelis–Arbuzov-like reaction of amide 5a with
trimethylphosphite (entry 15) was fairly good (80%); however, the reaction was relatively
slow. Adding 0.25 mol of methyltriphenylphosphonium iodide per 1 mol of amide 5a
to the reaction mixture distinctly speeded up the reaction (entry 18); however, the final
reaction yield was worse (46%, entry 19) due to the intensive demethylation of trimethyl
phosphite with triphenylphosphonium tetrafluoroborate to dimethyl phosphite, which
was evidently catalyzed by methyltriphenylphosphonium iodide (Scheme 5). Raising the
◦
reaction temperature to 60 C speeded up the reaction; however, the reaction yield did
not exceed 50% (entry 20). Finally, we demonstrated that using triethyl phosphite instead
of trimethyl phosphite significantly decreased the amount of the undesired phosphite’s
dealkylation and allowed to obtain a good final reaction yield (entry 21).
The aforementioned observations enabled us to elaborate an effective one-pot pro-
cedure for the synthesis of α-(N-acylamino)alkanephosphonic or α-(N-acylamino)alkane-
phosphinic acid esters directly from N-(1-methoxyalkyl)amides 5 and trialkyl phosphites or
dialkyl phosphonites, respectively, without the use of Lewis acids. For N-(1-methoxyethyl)-
amides 5a,b with a small methyl group at the α-position (Table 1, entries 22–25) heating
of these reagents in CH2Cl2 in the presence of triphenylphosphoniu◦m tetrafluoroborate
and Hu¨nig’s base in a molar ratio of 1:1.5:1:0.1, respectively, at 60 C for 2 h, without
the use of methyltriphenylphosphonium iodide, gave the expected products in good yields.
For amides 5c–e with a bulky alkyl or aryl substituent at the α-position (entries 26–28)
the use of methyltriphenylphosphonium iodide as the catalyst of the Michaelis–Arbuzov
reaction was necessary. In consequence, in these cases triethylphosphite or diethylphos-
phonite must be used to avoid dealkylation of the phosphorus nucleophile. A simple work-
up procedure of the reaction mixtures, using no water, is a special advantage of this
method.
CONCLUSIONS
TheMichaelis–Arbuzov-likereactionof 1-(N-acylamino)alkyltriphenylphosphonium
tetrafluoroborates 6 with trimethyl phosphite to α-(N-acylamino)alkanephosphonic acid

COMPARATIVE STUDIES ON THE AMIDOALKYLATING PROPERTIES
975
esters needed the presence of a basic catalyst (Hu¨nig’s base). The trimethoxyphos-
phonium salt, which is a characteristic intermediate of the Michaelis–Arbuzov
reaction, can be demethylated directly by triphenylphosphine to give the expected
α-aminoalkanephosphonic acid derivatives. For more sterically hindered phosphonium
salts 6, demethylation of the trimethoxyphosphonium salt could be speeded up by
iodide anion as a nucleophilic catalyst introduced with a methyltriphenylphosphonium
iodide. It was demonstrated that a direct reaction of the N-(1-methoxyalkyl)amides with
trimethyl phosphite to α-(N-acylamino)alkanephosphonic acid esters under neutral or
basic conditions is not possible. Dissolution of N-(1-methoxyalkyl)amide and triph-
enylphosphonium tetrafluoroborate in CD2Cl2 at room temperature caused the immediate
formation of 1-(N-acylamino)alkyltriphenylphosphonium tetrafluoroborates in high
yields. The addition of an equimolar amount of Hu¨nig’s base to this reaction mixture
initiated a slow reverse reaction. These observations made it possible to elaborate the
effective one-pot procedure for the synthesis of α-(N-acylamino)alkanephosphonic 2 or
α-(N-acylamino)alkanephosphinic acid esters 3 directly from N-(1-methoxyalkyl)amides
5 and trialkyl phosphites or dialkyl phosphonites, respectively, without the use of Lewis
acids. The developed method, in connection with the previously elaborated effective
procedure for the electrochemical decarboxylative α-methoxylation of N-acyl-α-amino
acids to N-(1-methoxyalkyl)amides,33 establishes a new, effective, two-stage method
for the transformation of N-acyl-α-amino acids into their phosphonic or phosphinic
analogs. The plausible mechanism of the considered transformations, assuming an
equilibrium between N-(1-alkoxyalkyl)amide 5, triphenylphosphonium tetrafluoroborate,
1-(N-acylamino)alkyltriphenylphosphonium salt 6, N-acylimine 8, and N-acyliminium
salts, was discussed.
EXPERIMENTAL
General Methods
Melting points were determined in capillary tubes with the Stiriling SMP 3 apparatus
and are uncorrected. IR spectra were measured with a Nicolett 6700 FTIR spectropho-
1
tometer (ATR method). H and 13C NMR spectra were recorded with a Varian UNITY
INOVA-300 spectrometer at operating frequencies of 300 and 75.5 MHz, respectively, or
with an Agilent NMR Magnet 400 MHz spectrometer at operating frequencies of 400 and
100.5 MHz, respectively, using TMS as the resonance shift standard. 31P NMR spectra were
recorded with a Varian-600 spectrometer operating at 242.8 MHz, using 80% orthophos-
phoric acid as the resonance shift standard. All chemical shifts (δ) are reported in ppm, and
coupling constants (J) in Hz.
Transformation of N-(1-Methoxyalkyl)amides 5 or 1-(N-Acylamino)alkyl-
triphenylphosphonium Salts 6 to α-(N-Acylamino)alkanephosphonates 2 (1H
NMR Experiments). Reactions were carried out in NMR tubes. To a solution of N-
(1-methoxyalkyl)amide 5 (0.314 mmol) or 1-(N-acylamino)alkyltriphenylphosphonium
tetrafluoroborate 6 (0.314 mmol) in CD2Cl2 (0.65 mL) trialkyl phosphite (0.471 mmol),
triphenylphosphonium tetrafluoroborate, Hu¨nig’s base and methyltriphenylphosphonium
iodide were added in the molar ratio shown in Table 1. The progress of the reaction was
monitored by 1H NMR spectroscopy.

976
J. ADAMEK ET AL.
Interaction of N-(1-Methoxyethyl)pivaloamide 5a With Triphenylphos-
phonium Tetrafluoroborate and Hu¨ nig’s Base (1H NMR Experiment). The re-
action was carried out in NMR tube. Triphenylphosphonium tetrafluoroborate (109.9 mg,
0.314 mmol) was added to a solution of N-(1-methoxyethyl)pivaloamide 5a (50.0 mg,
0.314 mmol) in CD2Cl2 (0.65 mL). After 10 min. Hu¨nig’s base (0.055 mL, 40.6 mg,
1
0.314 mmol) was added. The progress of the reaction was monitored by H NMR spec-
troscopy before and after adding Hu¨nig’s base.
Interaction of 1-(N-Pivaloylamino)ethyltriphenylphosphonium Tetraflu-
oroborate 6a With Methanol and Hu¨ nig’s Base (1H NMR Experiment). The
reaction was carried out in NMR tube. Hu¨nig’s base (0.055 mL, 40.6 mg, 0.314 mmol) was
added to a solution of 1-(N-pivaloylamino)ethyltriphenylphosphonium tetrafluoroborate
6a (149.9 mg, 0.314 mmol) and methanol (0.013 mL, 10.0 mg, 0.314 mmol) in CD2Cl2
(0.65 mL). The progress of the reaction was monitored by 1H NMR spectroscopy.
One-Pot Procedure For the Synthesis of α-(N-Acylamino)alkanephospho-
nates 2 or α-(N-Acylamino)alkanephosphinates 3 From N-(1-Methoxyalkyl)-
amides 5. The reactions were carried out in a glass vial sealed with a screw-cap. Triph-
enylphosphonium tetrafluoroborate (164.9 mg, 0.471 mmol), trialkyl phosphite, diethyl
phenylphosphonite or diethyl ethylphosphonite (0.707 mmol), Hu¨nig’s base (6.1 mg,
0.047 mmol), and methyltriphenylphosphonium iodide (47.7 mg, 0.118 mmol) (only in
experiments 26–28) were added to a solution of N-(1-methoxyalkyl)amide 5 (0.471 mmol)
in dichloromethane (1.0 mL). The homogeneous solution was heated at 60 ◦C for 2 h. The
solvent was evaporated under reduced pressure, the residue was extracted with toluene (3 ×
1 mL) at 50 ◦C and the toluene was evaporated. The crude product was purified by column
chromatography (silica gel, CH2Cl2/MeOH, 20:1 v/v or 40:1 v/v).
Dimethyl 1-(N-Pivaloylamino)ethanephosphonate (2a)
◦
Colorless crystals, m.p.: 128–129 C, 98.3 mg, 88%. IR (ATR), ν (cm−1): 3273,
1
1652, 1527, 1223, 1204, 1057, 1027, 1007. H NMR (300 MHz, CDCl3): δ = 6.16 (d, J
= 9.0 Hz, 1H, NH), 4.58 (ddq, J1 = 15.6 Hz, J2 = 9.3 Hz, J3 = 7.5 Hz, 1H, CH), 3.77
(d, J = 10.5 Hz, 3H, OCH3), 3.76 (d, J = 10.5 Hz, 3H, OCH3), 1.39 (dd, J1 = 17.0 Hz,
J2 = 7.4 Hz, 3H, CH3), 1.22 (s, 9H, t-Bu). 13C NMR (75.5 MHz, CDCl3): δ = 177.6 (d, J
= 5.0 Hz, C O), 53.0 (d, J = 6.8 Hz, OCH3), 52.7 (d, J = 6.8 Hz, OCH3), 40.1 (d, J =
156.7 Hz, CH), 38.5 (s, C(CH3)3), 27.2 (s, C(CH3)3), 15.4 (s, CH3). 31P NMR (242.8 MHz,
CDCl3): δ = 29.1, identical by comparisons with literature data.38
Diethyl 1-(N-Pivaloylamino)ethanephosphonate (2b)
NMR experiment: 1H NMR (300 MHz, CDCl3): δ = 5.93 (d, J = 8.7 Hz, 1H, NH),
4.60–4.43 (m, 1H, CH), 4.20–4.05 (m, 4H, OCH2CH3), 1.39–1.32 (m, 9H, OCH2CH3,
CH3), 1.21 (s, 9H, t-Bu). 13C NMR (75.5 MHz, CDCl3): δ = 177.4 (d, J = 5.4 Hz, C O),
62.3 (d, J = 7.0 Hz, OCH2CH3), 62.2 (d, J = 6.4 Hz, OCH2CH3), 40.4 (d, J = 156.3 Hz,
CH), 38.5 (C(CH3)3), 27.2 (C(CH3)3), 16.3 (d, J = 6.0 Hz, OCH2CH3), 16.2 (d, J = 6.0 Hz,
OCH2CH3), 15.5 (CH3); identical by comparison with literature data.39

COMPARATIVE STUDIES ON THE AMIDOALKYLATING PROPERTIES
977
Dimethyl 1-(N-Benzyloxycarbonylamino)ethanephosphonate (2c)
1
Oil, 94.7 mg, 70%. IR (ATR), ν (cm−1): 3243, 1717, 1538, 1231, 1043. H NMR
(300 MHz, CDCl3): δ = 7.37–7.29 (m, 5H, Ph), 5.58 (d, J = 9.6 Hz, 1H, NH), 5.11 (s, 2H,
OCH2), 4.29–4.10 (m, 1H, CH), 3.74 (d, J = 10.2 Hz, 3H, OCH3), 3.71 (d, J = 10.5 Hz,
3H, OCH3), 1.38 (dd, J1 = 16.8 Hz, J2 = 7.5 Hz, 3H, CH3). 13C NMR (75.5 MHz, CDCl3):
δ = 155.6 (d, J = 6.0 Hz, C O); 136.1, 128.3, 128.0, 127.9 – aromatic carbons; 66.9
(CH2), 53.1 (d, J = 7.6 Hz, OCH3), 52.8 (d, J = 6.8 Hz, OCH3), 42.7 (d, J = 158.6 Hz,
CH), 15.6 (CH3). 31P NMR (242.8 MHz, CDCl3): δ = 28.5, identical by comparison with
literature data.40
Dimethyl 1-(N-Benzyloxycarbonylamino)-2-phenylethanephosphonate
(2d)
NMR experiment: IR (ATR), ν (cm−1): 3241, 2954, 1720, 1539, 1262, 1227, 1039.
1H NMR (300 MHz, CDCl3): δ = 7.35-7.17 (m, 10H, Ph), 5.12 (d, J = 10.2 Hz, 1H, NH),
5.00 (s, 2H, OCH2), 4.43 (dddd, J1 = 16.0 Hz, J2 = J3 = 10.1 Hz, J4 = 4.5 Hz, 1H,
CH), 3.74 (d, J = 10.8 Hz, 3H, OCH3), 3.70 (d, J = 10.5 Hz, 3H, OCH3), 3.23 (ddd, J1
= 13.8 Hz, J2 = 9.1 Hz, J3 = 4.7 Hz, 1H, CH2Ph), 2.87 (ddd, J1 = 14.4 Hz, J2 = J3 =
10.1 Hz, 1H, CH2Ph). 13C NMR (75.5 MHz, CDCl3): δ = 155.7 (d, J = 6.0 Hz, C O);
136.4, 136.2, 129.2, 128.4, 128.4, 128.0, 127.8, 126.8 – aromatic carbons; 66.9 (OCH2),
53.2 (d, J = 6.8 Hz, OCH3), 53.0 (d, J = 6.8 Hz, OCH3), 48.2 (d, J = 157.8 Hz, CH), 35.8
(CH2), identical by comparisons with literature data.41
Diethyl 1-(N-Benzyloxycarbonylamino)-2-phenylethanephosphonate (2e)
1
Oil, 140.1 mg, 76%. IR (ATR), ν (cm−1): 3237, 1717, 1538, 1259, 1221, 1024. H
NMR (300 MHz, CDCl3): δ = 7.32–7.17 (m, 10H, Ph), 5.58 (d, J = 10.2 Hz, 1H, NH),
4.98 (s, 2H, OCH2), 4.39 (dddd, J1 = 15.9 Hz, J2 = J3 = 10.5 Hz, J4 = 4.5 Hz, 1H, CH),
4.15–3.97 (m, 4H, OCH2CH3), 3.22 (ddd, J1 = 14.4 Hz, J2 = 8.2 Hz, J3 = 4.5 Hz, 1H,
CH2Ph), 2.89 (ddd, J1 = 14.4 Hz, J2 = J3 = 10.1 Hz, 1H, CH2Ph), 1.27 (t, J = 7.1 Hz, 3H,
OCH2CH3), 1.21 (t, J = 7.2 Hz, 3H, OCH2CH3). 13C NMR (75.5 MHz, CDCl3): δ = 155.7
(d, J = 6.0 Hz, C O); 136.7, 136.5, 136.3, 129.1, 128.2, 127.8, 127.7, 126.5 – aromatic
carbons; 66.6 (OCH2), 62.6 (d, J = 6.8 Hz, OCH2CH3), 62.3 (d, J = 6.8 Hz, OCH2CH3),
48.6 (d, J = 157.0 Hz, CH), 35.7 (CH2), 16.2 (s, OCH2CH3), 16.1 (s, OCH2CH3). 31P
NMR (242.8 MHz, CDCl3): δ = 24.5, identical by comparison with literature data.13
Diethyl 1-(N-Benzyloxycarbonylamino)phenylmethanephosphonate (2f)
◦
Colorless crystals, m.p.: 116-117 C, 144.0 mg, 81%. IR (ATR), ν (cm−1): 3235,
1713, 1547, 1250, 1231, 1025. 1H NMR (300 MHz, CDCl3): 7.47–7.26 (m, 10H, Ph), 6.26
(dd, J1 = 9.6 Hz, J2 = 4.5 Hz, 1H, NH), 5.17 (dd, J1 = 18.3 Hz, J2 = 9.3 Hz, 1H, CH),
5.14 (d, J = 12.3 Hz, 1H, OCH2), 5.04 (d, J = 12.3 Hz, 1H, OCH2), 4.16–3.99 (m, 2H,
OCH2CH3), 3.92–3.67 (m, 2H, OCH2CH3), 1.24 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.07
(t, J = 7.2 Hz, 3H, OCH2CH3). 13C NMR (75.5 MHz, CDCl3): 155.7 (d, J = 8.3 Hz,
C O); 136.1, 135.3, 128.5, 128.5, 128.0, 128.0, 127.9, 127.8 – aromatic carbons; 67.1
(OCH2), 63.2 (d, J = 7.6 Hz, OCH2CH3), 63.0 (d, J = 7.6 Hz, OCH2CH3), 52.5 (d, J =

978
J. ADAMEK ET AL.
155.5 Hz, CH), 16.3 (d, J = 6.0 Hz, OCH2CH3), 16.0 (d, J = 5.3 Hz, OCH2CH3). 31P
NMR (242.8 MHz, CDCl3): δ = 21.9, identical by comparison with literature data.42
Ethyl [1-(N-pivaloylamino)ethyl]phenylphosphinate (3a)
◦
Colorless crystals, m.p.: 120–121 C, 95.2 mg, 68%. IR (ATR), ν (cm−1): 2976,
1648, 1527, 1198, 1120, 1025. 1H NMR (300 MHz, CDCl3): δ = 7.85–7.42 (m, 5H, Pha),
6.06 (d, J = 9.3 Hz, 1H, NHb), 5.80 (d, J = 9.9 Hz, 1H, NHb), 4.80–4.52 (m, 1H, CHa),
b
b
4.20–4.03 (m, 2H, OCH2CH3 ), 4.03–3.80 (m, 2H, OCH2CH3 ), 1.45 (dd, J1 = 14.6 Hz,
b
b
J2 = 7.4 Hz, 3H, CH3 ), 1.21 (dd, J1 = 16.4 Hz, J2 = 7.4 Hz, 3H, CH3 ), 1.31 (t, J =
7.1 Hz, 3H, OCH2CH3 ), 1.30 (t, J = 7.1 Hz, 3H, OCH2CH3 ), 1.20 (s, 9H, t-Bub), 0.91
(s, 9H, t-Bub). 13C NMR (75.5 MHz, CDCl3): δ = 177.7 (d, J = 5.3 Hz, C Ob), 177.3 (d,
J = 5.3 Hz, C Ob); 132.8 (d, J = 2.3 Hz), 132.6 (d, J = 2.3 Hz), 132.3 (d, J = 9.8 Hz),
132.0 (d, J = 9.8 Hz) 132.1, 132.0, 128.7 (d, J = 12.8 Hz), 128.7 (d, J = 12.1 Hz) –
b
b
aromatic carbonsb; 61.4 (d, J = 7.0 Hz, OCH2CH3 ), 61.3 (d, J = 6.9 Hz, OCH2CH3 ),
b
b
43.6 (d, J = 75.5 Hz, CHb), 43.6 (d, J = 81.5 Hz, CHb), 38.8 (C(CH3)3 ), 38.5 (C(CH3)3 ),
b
b
b
b
b
27.4 (C(CH3)3 ), 27.1 (C(CH3)3 ), 16.6 (d, J = 6.0 Hz, OCH2CH3 ), 16.4 (d, J = 6.0 Hz,
OCH2CH3 ), 15.0 (CH3 ), 14.3 (CH3 ). 31P NMR (242.8 MHz, CDCl3): δ = 41.9, 41.7.
HRMS (EI) calcd. for C15H24NO3PNa [M + Na]+: 320.1386, found 320.1400.
aOverlapping signals of two diastereomers. bOne of two signals of two diastereomers.
b
b
b
Ethyl [1-(N-pivaloylamino)ethyl]ethylphosphinate (3b)
Resin, 79.8 mg, 68%. IR (ATR), ν (cm−1): 3289, 2976, 1644, 1529, 1187, 1029. 1H
NMR (400 MHz, CDCl3): δ = 6.18 (d, J = 9.2 Hz, NHb), 5.95 (d, J = 8.8 Hz, 1H, NHb),
4.50–4.38 (m, 1H, CHa), 4.17–4.02 (m, 2H, OCH2CH3 ), 1.77–1.66 (m, 2H, PCH2CH3 ),
a
a
1.38–1.34 (m, 3H, CH3 ), 1.34–1.30 (m, OCH2CH3 ), 1.22 (s, 9H, t-Bub), 1.21 (s, 9H,
a
a
t-Bub), 1.19–1.09 (m, 3H, PCH2CH3 ). 13C NMR (100.5 MHz, CDCl3): δ = 177.9 (d, J =
a
4.0 Hz, C Ob), 177.5 (d. J = 5.0 Hz, C Ob), 61.0 (d, J = 7.0 Hz, OCH2CH3 ), 60.9 (d,
b
J = 7.0 Hz, OCH2CH3 ), 42.0 (d, J = 98.5 Hz, CHb), 41.9 (d, J = 105.5 Hz, CHb), 38.7
b
b
b
b
b
(C(CH3)3 ), 38.6 (C(CH3)3 ), 27.5 (C(CH3)3 ), 27.3 (C(CH3)3 ), 19.4 (d, J = 89.4 Hz,
b
b
b
PCH2CH3 ), 19.2 (d, J = 90.4 Hz, PCH2CH3 ), 16.7 (d, J = 5.0 Hz, OCH2CH3 ), 16.6 (d,
b
b
b
J = 5.0 Hz, OCH2CH3 ), 14.7 (d, J = 1.5 Hz, CH3 ), 13.9 (d, J = 0.5 Hz, CH3 ), 5.7 (d, J =
5.0 Hz, PCH2CH3 ), 5.6 (d, J = 5.0 Hz, PCH2CH3 ). 31P NMR (242.8 MHz, CDCl3): δ =
56.1, 55.9. HRMS (EI) calcd. for C11H24NO3PNa [M + Na]+: 272.1386, found 272.1400.
aOverlapping signals of two diastereomers. bOne of two signals of two diastereomers.
b
b
Ethyl [1-(N-Benzyloxycarbonylamino)-2-tert-butoxyethyl]phenylphos-
phinate (3c)
1
Oil, 132.4 mg, 67%. IR (ATR), ν (cm−1): 3225, 2975, 1716, 1537, 1194, 1024. H
NMR (300 MHz, CDCl3): δ = 7.83–7.28 (m, 10H, Pha), 5.40 (d, J = 10.2 Hz, 1H, NHa),
b
b
5.11 (d, J = 12.0 Hz, 1H, OCH2 ), 5.09 (d, J = 12.0 Hz, 1H, OCH2 ), 5.07 (d, J = 12.6 Hz,
1H, OCH2 ), 5.03 (d, J = 12.0 Hz, 1H, OCH2 ), 4.44–4.36 (m, 1H, CHb), 4.31–4.24 (m,
b
b
1H, CHb), 4.21–3.99 (m, 2H, OCH2CH3 ), 3.71–3.59 (m, 2H, CH2 ), 1.32 (t, J = 7.2 Hz,
a
a
3H, OCH2CH3 ), 1.29 (t, J = 7.2 Hz, 3H, OCH2CH3 ), 1.07 (s, 9H, t-Bub), 1.05 (s, 9H,
t-Bub). 13C NMR (75.5 MHz, CDCl3): δ = 155.8 (C Ob), 155.6 (C Ob); 136.3a, 132.4b
(d, J = 2.3 Hz), 132.3b (d, J = 2.3 Hz), 132.0a, 132.0b (d, J = 10.6 Hz), 131.9b (d, J =
b
b

COMPARATIVE STUDIES ON THE AMIDOALKYLATING PROPERTIES
979
9.8 Hz), 128.4a, 128.4b (d, J = 12.8 Hz), 128.2b (d, J = 11.3 Hz), 128.0a, 127.9a – aromatic
a
a
b
carbons; 73.4 (C(CH3)3 ), 66.9 (CH2 ), 61.4 (d, J = 6.8 Hz, OCH2CH3 ), 60.1 (d, J =
2.3 Hz, OCH2CH3 ), 59.8 (CβH2 ), 51.6 (d, J = 80.8 Hz, CHb), 50.2 (d, J = 82.3 Hz, CHb),
b
a
27.1 (C(CH3)3 ), 16.4 (d, J = 5.3 Hz, OCH2CH3 ), 16.3 (d, J = 5.3 Hz, OCH2CH3 ). 31
P
a
b
b
NMR (242.8 MHz, CDCl3): δ = 40.1, 38.8. HRMS (EI) calcd. for C22H30NO5PNa [M +
Na]+: 442.1754, found 442.1764.
aOverlapping signals of two diastereomers. bOne of two signals of two diastereomers.
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