A Simple Synthesis of Pyridine Aminophosphinic Acids and Pyridine Aminophosphine Oxides. The Unusual Cleavage of Pyridylmethyl-(N-benzylamino)-phenylphosphinic Acids and Phosphine Oxides in Acidic Solutions

Article abstract of DOI:10.1081/SCC-120026350

Pyridine aminophosphinic acids were synthesized in reaction, of N-(benzyl)-pyridylmethylimines with ethyl phenylphosphinate, in the presence of bromotrimethylsilane. Pyridine aminophosphine oxides were obtained in excellent yields by treatment of the corresponding imines with diphenylphosphine oxide. Among these compounds, the 2-pyridyl and 4-pyridyl derivatives were subject to a simple cleavage in aqueous mineral acid solutions. Products of the cleavages were N-(pyridylmethyl)benzylamines and phenylphosphonic (or diphenylphosphinic) acid, respectively.

Full text of DOI:10.1081/SCC-120026350

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A Simple Synthesis of Pyridine Aminophosphinic
Acids and Pyridine Aminophosphine Oxides. The
Unusual Cleavage of Pyridylmethyl-( N -benzylamino)-
phenylphosphinic Acids and Phosphine Oxides in Acidic
Solutions
Bogdan Boduszek a
a Institute of Organic Chemistry, Biochemistry and Biotechnology, Wroclaw University of
Technology, Wroclaw, Poland
Version of record first published: 16 Aug 2006.
To cite this article: Bogdan Boduszek (2003): A Simple Synthesis of Pyridine Aminophosphinic Acids and Pyridine
Aminophosphine Oxides. The Unusual Cleavage of Pyridylmethyl-( N -benzylamino)-phenylphosphinic Acids and Phosphine
Oxides in Acidic Solutions, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 33:23, 4087-4094
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 23, pp. 4087–4094, 2003
A Simple Synthesis of Pyridine Aminophosphinic
Acids and Pyridine Aminophosphine Oxides.
The Unusual Cleavage of Pyridylmethyl-
(N-benzylamino)-phenylphosphinic Acids and
Phosphine Oxides in Acidic Solutions
*
Bogdan Boduszek
Institute of Organic Chemistry, Biochemistry and
Biotechnology, Wroclaw University of Technology,
Wroclaw, Poland
ABSTRACT
Pyridine aminophosphinic acids were synthesized in reaction of
N-(benzyl)-pyridylmethylimines with ethyl phenylphosphinate, in the
presence of bromotrimethylsilane. Pyridine aminophosphine oxides
were obtained in excellent yields by treatment of the corresponding
imines with diphenylphosphine oxide. Among these compounds, the
*Correspondence: Bogdan Boduszek, Institute of Organic Chemistry,
Biochemistry and Biotechnology, Wroclaw University of Technology, 50-370
Wroclaw, Poland; E-mail: boduszek@kchf.ch.pwr.wroc.pl.
4087
DOI: 10.1081/SCC-120026350
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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4088
Boduszek
2-pyridyl and 4-pyridyl derivatives were subject to a simple cleavage
in aqueous mineral acid solutions. Products of the cleavages were
N-(pyridylmethyl)benzylamines and phenylphosphonic (or diphenyl-
phosphinic) acid, respectively.
Aminophosphonic acids are an important class of compounds,
because of their useful application in organic chemistry and biology.[1]
Various pyridine derivatives of the aminophosphonic acids show prop-
erties that make them attractive in many areas; e.g., as chelating
agents,[2] herbicides,[3a] fungicides,[3b] and neuroactive substances.[3c]
Synthesis and reactions of pyridine aminophosphonic acids and esters
were described in a few articles,[4a–d] but the corresponding pyridine
aminophosphinic acids and aminophosphine oxides were not yet
reported.
Some pyridine aminophosphonic acids[4c] are succumbed to a
cleavage in the presence of strong mineral acids.[4a] For example,
heating of the 2-pyridylmethyl(N-alkylamino)phosphonic acids or
esters, in aqueous sulphuric acid solutions causes a splitting of these
phosphonic acids and formation of the secondary pyridyl-benzyl amines
and phosphoric acid.[4b] The mechanism of such cleavage was given and
discussed.[4d]
In search of other compounds showing a prospective behavior in
acidic conditions, we elaborated a synthetic route leading to some new
pyridine aminophosphinic acids and phosphine oxides.
For synthetic work, we exploited some commercially available
phosphinic esters and phosphines, which were known as good nucleophiles
in reactions with imines.[5] In this case, the ethyl phenylphosphinate
and diphenylphosphine oxide were proved to be effective nucleophilic
reagents, suitable for addition to a C¼N double bond of imines.
Thus, when pyridylmethyl(N-benzyl)imines 1 were mixed in situ
with ethyl phenylphosphinate (or diphenylphosphine oxide) in an inert
solvent, the pyridine amino(phenyl)phosphinates 2 (or the pyridine
amino(diphenyl)phosphine oxides 4) were formed in high yields (Sch. 1).
Such hydrophosphinylation reaction proceeded easily and cleanly, at
room temperature.
Formed pyridyl amino(phenyl)phosphinates 2 were not isolated, but
converted to the aminophosphinic acids 3 by means of bromotrimethyl-
silane (used as dealkylating agent),[6] which was added to a reaction
mixture (Sch. 1). Use of bromotrimethylsilane was allowed to obtain
aminophosphinic acids 3 in a one-pot procedure,[7] without a need of a
hydrolysis of the formed phosphonic esters, in the first stage.

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Pyridine Aminophosphinic Acids
4089
O
OEt
PhP
H
O
P
1. Me3SiBr
2. MeOH
O
OEt
Ph
OH
Ph
CH
NH
CH
NH
P
CHCl3 , rt
N
N
CH2Ph
CH2Ph
CH NCH2Ph
N
2a-c
3a-c
1a-c
O
O
Ph
Ph
Ph2P
H
CH
NH
P
CHCl3 , rt
N
CH2Ph
4a-c
a
b
c
: 2-pyridyl, : 3-pyridyl, : 4-pyridyl
Scheme 1. Synthesis of pyridine aminophosphinic acids and pyridine phosphine
oxides.
As a result of this procedure, was an effective preparation of the
desired pyridine aminophosphinic acids 3 and phosphine oxides 4, in
high yields and purity.
The aim of this work was to demonstrate that, despite of the reported
pyridine aminophosphonic acids,[4a–d] other pyridine phosphorus
compounds (as for example, these ones presented here), are also
susceptible for a cleavage. Indeed, pyridine aminophosphinic acids 3a,c
and phosphine oxides 4a,c proved to be exceptionally easily cleaved in
aqueous mineral acid solutions, at ambient temperature. Thus, the
2-pyridylmethyl(N-benzylamino)phenylphosphinic acid (3a) in aq. 10%
H2SO4 (or HCl) was split to form the N-(2-pyridylmethyl)-benzylamine
(5a) and phenylphosphonic acid (6) (Sch. 2).
Cleavage of the 3a proceeded in a few hours at 20ꢀC and it therefore
could be monitored by means of 31P NMR and 1H spectroscopy, in
deuterated solvents. Likewise, the 4-pyridylmethyl(N-benzylamino)-
phenylphosphinic acid (3c) was cleaved in aq. 10% H2SO4, however,
rate of the cleavage was considerably slower. A complete decomposition
of the 3c at 20ꢀC required about 70 h, as it was estimated from the NMR
spectra.
A detailed inspection of these cleavages revealed, that pyridyl
benzylamines (5a,c) and phenylphosphonic acid (6) (Sch. 2) were only
products in these processes.

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4090
Boduszek
O
P
OH
Ph
CH
NH
O
CH2 NH CH2Ph
H +
OH
Ph
P
+
OH
N
aq. H2SO4 , rt
N
CH2Ph
3a,c
5a,c
6
O
Ph
Ph
CH
NH
P
O
P
CH2 NH CH2Ph
H +
Ph
Ph
OH
+
N
aq. H2SO4 , rt
N
CH2Ph
4a,c
5a,c
7
a
c
: 2-pyridyl, : 4-pyridyl
Scheme 2. Cleavage of pyridine aminophosphinic acids 3 and pyridine
phosphine oxides 4.
Cleavages of the aminophosphinic acids 3 were considerably
accelerated at elevated temperatures. For instance, boiling solutions of
the 3a, or 3c, in aq. 10% H2SO4 were completely cleaved in a few
minutes, giving the corresponding pyridyl benzylamines (5a,c) and
phenylphosphonic acid (6).
The pyridine phosphine oxides 4a,c were also easily cleaved. Thus,
the 2-pyridylmethyl(N-benzylamino)diphenylphosphine oxide (4a) in aq.
10% H2SO4, was cleaved to form the N-(2-pyridylmethyl)benzylamine
(5a) and diphenylphosphinic acid (7), (Sch. 2). Cleavage of the 4a
proceeded in a few hours at room temperature, but this cleavage
might be completed in a few minutes at 90–95ꢀC. Also, the 4-pyridyl-
methyl- (N-benzylamino)diphenylphosphine oxide (4c) was split to form
the amine 5c and diphenylphosphinic acid (7), at the same conditions
(Sch. 2).
Chemistry and character of cleavages of the pyridine amino-
phosphinic acids and phosphine oxides resemble the cleavages of pyridine
aminophosphonic acids, reported a few years ago.[4b,d] It is worthy to
point out, that the pyridine aminophosphinic acids 3 and phosphine
oxides 4 are split much faster than related aminophosphonic acids.[4d]
Estimated rates (calculated from NMR spectra) of cleavage of the 3
and 4 are about 102 times larger, than the rates of cleavage of the
corresponding pyridine aminophosphonic acids.[4d]

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Pyridine Aminophosphinic Acids
4091
¼
Mechanistic aspects of the C P bond splitting, observed on pyridyl
aminophosphinic acids and pyridyl phosphine oxides, are now under a
detailed investigation in our laboratory. According to preliminary results,
the considered cleavages bear an electrophilic character, being a kind of
substitution of a phosphinic group by an electrophile. The stability of
pyridine aminophosphinic acids 3 and aminophosphine oxides 4 in
neutral, or basic solutions might confirm the above assertion. Studies
on chemistry of these compounds and the results will be given in a
separate publication.
EXPERIMENTAL
NMR spectra were taken on a Bruker Avance TM DRX spectrometer
1
in D2O or CDCl3, at 300 MHz for H, and 121.5 MHz for 31P nucleus,
respectively. Melting points were measured on a Electrothermal
9200 apparatus. Elemental analyses were done in the Laboratory of
Instrumental Analysis, in the Institute. All commercially available
reagents were used as received from the Aldrich Company.
A Typical Procedure for Preparation of Pyridine
Aminophosphinic Acids 3
A mixture of 2-. 3-, or 4-pyridinecarboxaldehyde (1.07 g, 10 mmol)
and benzylamine (1.07 g, 10 mmol) in CHCl3 (25 mL) was prepared. The
mixture was left for 24 h, then anh. Na2SO4 added (4–5 g), filtered and the
filtrate (containing the imine 1a–c), was used directly in a next step. To a
stirred solution of the imine, ethyl phenylphosphinate (1.7 g, 10 mmol) was
added followed by bromotrimethylsilane (4.6 g, 30 mmol). After 24 h,
reaction mixture was evaporated and a resulting oily product was
dissolved in methanol (10 mL), diethyl ether added (20 mL) and a mixture
was refrigerated. Phosphinic acid 3 has been separated as a crystalline
solid. The product was collected by filtration, washed with diethyl ether
and dried.
2-Pyridylmethyl(N-benzylamino)phenylphosphinic acid (3a). Yield
81%. M.p.: 185–187ꢀC. 1H NMR (D2O): ꢀ 8.41–8.37 (m, 2H, pyr),
7.85–7.79 (m, 2H, pyr.), 7.41–7.15 (m, 10H, Ph’s), 4.78–4.74 (d, 1H,
J ¼ 11.8 Hz, CH-P), 4.40–4.20 (m, 2H, CH2N). 31P NMR: ꢀ 20.03 (s).
Anal. calcd. for C19H19N2O2P, requires N, 8.28; P, 9.15. Found: N,
8.21; P, 9.11%.

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4092
Boduszek
3-Pyridylmethyl(N-benzylamino)phenylphosphinic acid (3b). Yield
84%. M.p.: 225–227ꢀC. 1H NMR(D2O): ꢀ 8.56 (d, 1 H, J ¼ 5.7 Hz,
pyr-6), 8.29 (s, 1H, pyr-2), 8.18 (d, 1 H, pyr-4), 7.42 (m, 1H,
pyr-5), 7.32–7.10 (m, 10H, Ph’s), 4.59–4.55 (d, 1H, J ¼ 11.1 Hz, CH-P),
4.20 (bs, 2H, CH2N). 31P NMR: ꢀ 21.18 (s). Anal. calcd. for
C19H19N2O2P, requires N, 8.28; P, 9.15. Found: N, 8.19; P,
9.10%.
4-Pyridylmethyl(N-benzylamino)phenylphosphinic acid (3c). Yield
80%. M.p.: 171–173ꢀC. 1H NMR(D2O): ꢀ 8.44 (d, 2H, J ¼ 6.5 Hz,
pyr-2,6), 7.53 (d, 2H, J ¼ 5.7 Hz, pyr-3,5), 7.45–7.12 (m, 10H, Ph’s),
4.69–4.65 (d, 1H, J ¼ 11.2 Hz, CH-P), 4.24 (d, 2H, J ¼ 3.1 Hz, CH2N).
31P NMR: ꢀ 20.52 (s). Anal. calcd. for C19H19N2O2P, requires N, 8.28; P,
9.15. Found: N, 8.17; P, 9.14%.
A typical procedure for preparation of pyridine aminophosphine oxides
4. To a solution of imine 1a c (3 mmol), in CHCl (25 mL), prepared as
2
3
described above, diphenylphosphine oxide (0.61 g, 3 mmol) in CHCl3
(10 mL) was added. A mixture was left for 24 h and evaporated to
dryness. A resulting oily product was dissolved in diethyl ether
(10 mL), then hexane added (10 mL) and refrigerated. Product (4a c)
2
separated as a crystalline solid, which was filtered, washed with hexane
and dried.
2-Pyridylmethyl(N-benzylamino)diphenylphosphine oxide (4a). Yield
88%. M.p.: 102–104ꢀC. 1H NMR(CDCl3): ꢀ 8.41 (d, 1H, J ¼ 3.9 Hz,
pyr-6), 7.77–7.14 (m, 18H, arom), 4.69–4.65 (d, 1H, J ¼ 13.5 Hz,
CH-P), 3.81–3.77 (d, 1H, J ¼ 13.0 Hz, CH2N), 3.56–3.51 (d, 1H,
J ¼ 13.0 Hz, CH2N). 31P NMR:
ꢀ
31.49 (s). Anal. calcd. for
C25H23N2OP, requires C, 75.36; H, 5.82; N, 7.03; P, 7.77. Found: C,
75.11; H, 5.92; N, 6.82; P, 8.01%.
3-Pyridylmethyl(N-benzylamino)diphenylphosphine oxide (4b). Yield
94%. M.p.: 134–6ꢀC. 1H NMR(CDCl3): ꢀ 8.46 (d, 1H, J ¼ 3.9 Hz,
pyr-6), 8.16 (s, 1H, pyr-2), 7.82–7.08 (m, 17 H, arom), 4.41–4.38 (d,
1H, J ¼ 10.2 Hz, CH-P), 3.86–3.82 (d, 1H, J ¼ 13.2 Hz, CH2N),
3.48–3.44 (d, 1H, J ¼ 13.3 Hz, CH2N). 31P NMR: ꢀ 32.80 (s). Anal.
calcd. for C25H23N2OP, requires C, 75.36; H, 5.82; N, 7.03; P, 7.77.
Found: C, 75.23; H, 5.85; N, 6.98; P, 7.72%.
4-Pyridylmethyl(N-benzylamino)diphenylphosphine oxide (4c). Yield
91%. M.p.: 148–149ꢀC. 1H NMR(CDCl3): ꢀ 8.42 (d, 2H, J ¼ 5.5 Hz,
pyr-2,6), 7.76 (m, 2H. py-3,5), 7.49–7.08 (m, 15H, Ph’s), 4.39–4.34 (d,
1H, J ¼ 11.4 Hz, CH-P), 3.86–3.82 (d, 1H, J ¼ 13.3 Hz, CH2N), 3.48–3.44
(d, 1H, J ¼ 13.3 Hz). 31P NMR: ꢀ 32.40 (s). Anal. calcd. for C25H23N2OP,
requires C, 75.36; H, 5.82; N, 7.03; P, 7.77. Found: C, 75.09; H, 5.75; N,
6.91; P, 7.99%.

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Pyridine Aminophosphinic Acids
4093
Cleavage of Aminophosphinic Acids 3 and
Isolation of the Products 5, 6
A sample of pyridine aminophosphonic acid (3a or 3c) (0.34 g,
1 mmol) was dissolved in 10% aq. H2SO4 (10 mL) and the solution was
kept at room temperature for 12 h (3a) and for 72 h (3c), respectively. The
reaction mixture was then alkalized with sodium carbonate (1.6 g,
15 mmol) and extracted with chloroform (25 mL), and the extract was
evaporated to give the amine, as an oily product (5a or 5c, 0.18 g, ꢁ90%).
The amines 5a,c were characterized as oxalate salts.[4b] Aqueous layer
remained was acidified with aq. 10% H2SO4 (5 mL) and evaporated to
dryness. A residue was treated with absolute ethanol (25 mL), filtered and
the filtrate evaporated to give phenylphosphonic acid 6 (0.15 g), as a
white solid.
Cleavage of the 3 at elevated temperature: a sample of pyridine
aminophosphinic acid (3a or 3c) (0.34 g, 1 mmol) was dissolved in 10%
aq. H2SO4 (10 mL) and refluxed for 15 min. Work-up and isolation of the
products (5,6) was carried out as described above.
Cleavage of Aminophosphine Oxides 4 and
Isolation of the Products 5, 7
A sample of pyridine aminodiphenylphosphine oxide (4a or 4c)
(0.20 g, 0.5 mmol) was dissolved in 10% aq. H2SO4 (3 mL) and solution
was left for 48 h. After several hours, diphenylphosphinic acid (7) began
to separate as a crystalline solid. The crystalline product was (after 48 h)
collected by filtration and dried (0.10 g). The filtrate remained, was
alkalized with sodium carbonate (0.5 g) and extracted with chloroform
(10 mL). Evaporation of the extract gave the crude amines (5a,c) (0.10 g),
which were characterized as oxalate salts.[4b]
A cleavage of aminophosphine oxides (4a,c) at elevated temperature
was done as follows: A sample of the 4a or 4c (0.20 g, 0.5 mmol) was
dissolved in aq. 10% H2SO4 and refluxed for 15 min. Isolation of the
products was carried out as described above.
The products of the cleavages: N-(pyridylmethyl)benzylamines are
known compounds and their physico-chemical data are given in
the Lit.[4b] Likewise, phenylphosphonic acid and diphenylphosphinic
acid are known, commercial compounds and their data are given
elsewhere.

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4094
Boduszek
ACKNOWLEDGMENT
This work was supported by the Faculty of Chemistry, Wroclaw
University of Technology.
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1. Kukhar, V.P.; Hudson, H.R. Aminophosphonic and aminophosphinic
acids; Chemistry and Biological Activity; John Wiley & Sons, Ltd.:
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Chem. 1992, 35, 1345–1358.
4. (a) Boduszek, B. Phosphorus, Sulfur, and Silicon 1996, 113, 209–218;
(b) Boduszek, B. Tetrahedron 1996, 52, 12483–12494; (c)
Boduszek, B. Phosphorus, Sulfur, and Silicon 1997, 122, 27–32; (d)
Boduszek, B.; Latajka, R.; Lesniak, W. Phosphorus, Sulfur, and
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6. Wozniak, L.; Chojnowski, J. Tetrahedron 1989, 45, 2465–2472.
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Received in Poland April 18, 2003