Synthesis and cleavage of pyridone-4 aminophosphonic acids

Article abstract of DOI:10.1080/10426500307846

Some new pyridone aminophosphonic acids were synthesized from pyridone aldimines and tris(trimethylsilyl)phosphite. It was found that the obtained aminophosphonic acids 2 were cleaved in mineral acid solutions to form the corresponding amines 3 and phosphoric acid. Preliminary kinetic measurements were performed.

Full text of DOI:10.1080/10426500307846

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Synthesis and Cleavage of Pyridone-4 Aminophosphonic
Acids
Bogdan Boduszek a , Anna Koreňova b , Michal Uher b & Daniel Végh b
a Wroclaw University of Technology , Wroclaw, Poland
b Slovak Technical University , Bratislava, Slovak Republic
Published online: 27 Oct 2010.
To cite this article: Bogdan Boduszek , Anna Koreňova , Michal Uher & Daniel Végh (2003) Synthesis and Cleavage of
Pyridone-4 Aminophosphonic Acids, Phosphorus, Sulfur, and Silicon and the Related Elements, 178:5, 1047-1053, DOI:
10.1080/10426500307846
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Phosphorus, Sulfur and Silicon, 2003, Vol. 178:1047–1053
C
Copyright 2003 Taylor & Francis
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DOI: 10.1080/10426500390208884
SYNTHESIS AND CLEAVAGE OF PYRIDONE-4
AMINOPHOSPHONIC ACIDS
Bogdan Boduszek,a Anna Korenˇova,b Michal Uher,b
and Daniel Ve´ghb
Wroclaw University of Technology, Wroclaw, Poland;a and
Slovak Technical University, Bratislava, Slovak Republicb
(Received October 15, 2002; in final form October 29, 2002)
Some new pyridone aminophosphonic acids were synthesized from pyri-
done aldimines and tris(trimethylsilyl)phosphite. It was found that the
obtained aminophosphonic acids 2 were cleaved in mineral acid solu-
tions to form the corresponding amines 3 and phosphoric acid. Prelim-
inary kinetic measurements were performed.
Keywords: 1-(N-benzyl)-2-formyl-5-benzyloxy-pyridone-4; bromotri-
methylsilane; cleavage reaction; pyridone derivatives of aminomethyl-
phosphonic acid
Working on the chemistry of heterocyclic aminophosphonate deriva-
tives, we found that certain pyridine,1,2 chromone,3 and coumarin3
derivatives of aminomethylphosphonic acid undergo a cleavage in
strong mineral acid solutions to form heterocyclic secondary amines
and phosphoric acid.1–3 In order to define the scope of these cleavages,
we looked at other aminophosphonate heterocyclic systems that could
demonstrate a similar behavior in acidic conditions. In our search for
such compounds, our attention was drawn to pyridone-4 aminophos-
phonate derivatives, which should yield a similar cleavage. In order
to verify such an hypothesis, we have synthesized some new pyridone-
4 aminophosphonic derivatives, namely the [1-(N-benzyl)-5-benzyloxy-
pyridone-4-yl-2]-methyl(amino)phosphonic acids (2a–c), and we carried
out suitable reactions in acidic solutions.
This work was supported by the Faculty of Chemistry, Wroclaw University of Tech-
nology, and by the Ministry of Education of the Slovak Republic.
Address correspondence to Bogdan Boduszek, Institute of Organic Chemistry, Bio-
chemistry and Biotechnology, Wroclaw University of Technology, 50-370 Wroclaw, Poland.
E-mail: boduszek@kchf.ch.pwr.wroc.pl
1047

1048
B. Boduszek et al.
RESULTS AND DISCUSSION
Synthesis of pyridone aminophosphonic acids was limited by access to
the appropriate aldehydes, which were considered as key starting ma-
terials in the synthesis of such compounds. The pyridone-4 aminophos-
phonic acids 2a–c were obtained in a typical way,4 in the following
sequence of reactions (Scheme 1): A key aldehyde 1 the 1-(N-benzyl)-
2-formyl-5-benzyloxy-pyridone-45 was reacted with primary amines to
obtain the corresponding imines. The imines then were treated with a
mixture of trimethyl phosphite and bromotrimethylsilane, what caused
in situ formation of tris(trimethylsilyl)phosphite,4 which instantly re-
acted with the imines, giving silylated phosphonate intermediates.
Treatment of the intermediates with methanol, caused a removal of
the silylated groups and the formation of the final aminophosphonic
acids 2a–c (Scheme 1).
SCHEME 1
The obtained compounds were tested for prospective cleavage of
a C P bond in acidic conditions. Indeed, pyridone-4 aminophospho-
nic acids 2a–c undergo such a cleavage during heating with mineral
acid solutions (H2SO4, HCl), as it was observed in the case of 2- and
4-pyridylmethyl phosphonate derivatives, reported earlier.1,2 Likewise,
as in the previous case, products of the cleavage were amines, in this
case the pyridone-4 benzylamines 3 and phosphoric acid (Scheme 2).
The N-benzhydryl derivative 2a, besides the cleavage, underwent
SCHEME 2

Synthesis and Cleavage of Pyridone-4 Aminophosphonic Acids
1049
furthermore the reaction of removal of the benzhydryl group in these
acidic conditions, giving the pyridone amine 3a0, with an unsubstituted
amino group (Scheme 2).
The formed heterocyclic amines (3a0–c) were isolated from the re-
action mixture by alkalization and extraction, then characterized by
spectroscopy methods.
The mechanism of the cleavage of 2a–c seems to be similar, as that
one which was proposed for the cleavage of related pyridyl aminophos-
phonic acids.2 Likewise, as in the previous cases,2,3 a driving force caus-
ing the cleavage is an electrophilic attack of the hydronium ion (H3O+)
on the protonated aminophosphonate 2 (Scheme 3), and in consequence,
the leaving of a phosphonate group as a protonated metaphosphate
(+PO3H2). The formed metaphosphate is a very reactive species and
reacts immediately with water to produce H3PO4 and to regenerate a
proton (Scheme 3).
SCHEME 3
Additional evidence for the proposed mechanism came from some
kinetic data obtained from these cleavages. Kinetic data are given in
Table I.
TABLE I Kinetics for Acid-Catalyzed Cleavage of 2b,c in aq. H2SO4/D2SO4
at 95 0.5 C
Conc. of Compd.
Conc. of Acid
1
1
a
1
Compound
mol
L
Acid
mol
L
105
k
s
kH/kD
obs
2b
0.037
0.038
0.038
0.038
0.015
0.015
0.015
0.022
H2SO4
H2SO4
H2SO4
D2SO4
H2SO4
H2SO4
H2SO4
D2SO4
0.5
1.44 0.07
2.50 0.12
2.87 0.15
2.06 0.10
1.53 0.08
2.62 0.13
2.20 0.11
1.88 0.09
1.0
2.0
1.0
0.5
1.0
2.0
1.0
1.21
1.39
2c
aRates reproducible to 5%.

1050
B. Boduszek et al.
Kinetics were measured only for acids 2b,c, because the N-
benzhydryl derivative (2a) decomposed in the applied conditions, which
might give up inaccurate kinetic results for 2a. Because the cleavages
can be monitored easily by means of 31P NMR, we calculated pseudo-
first-order constants (kobs), on the basis of the concentrations of un-
reacted aminophosphonic acids and formed phosphoric acid. A depen-
dence of the kobs on the concentration of the H+ was found. Results (see
Table I) show that kobs depends on the [H+]. Hence, the cleavage is an
acid-catalyzed reaction and the protons play a crucial role in the cleav-
age. For D2SO4 solutions rates were slower markedly in comparison
with H2SO4 solutions, at the same concentrations. Observed kinetic iso-
tope effects (for 2b; kH/kD = 1.21, and for 2c; kH/kD = 1.39) were rather
small, but existence of the kH/kD > 1, indicated that protons were in-
volved in the rate-determining step.2
The 31P NMR spectra of the phosphonic acids 2a–c in aqueous
solutions of sulphuric acid showed two phosphorus signals for each
individual compound. NMR spectra of 2a–c in DMSO showed only one
signal for phosphorus. Occurrence of two close signals, after adding of
sulphuric acid to the sample, gives evidence that there are two proto-
nated species formed from the pyridone aminophosphonic acids 2a–c
under influence of a strong mineral acid. As seen from the pyridone
structure (Scheme 4), there are two possible sites able for protonation
in the pyridone ring.
SCHEME 4
Protonation of oxygen in the pyridone ring gives form A, but pro-
tonation of the heterocyclic nitrogen may give form B (Scheme 4).

Synthesis and Cleavage of Pyridone-4 Aminophosphonic Acids
1051
Pyridones are weak bases and protonation of heterocyclic nitrogen
(or oxygen) occurs in the presence of strong acids.7 In this case (the
formula 2a–c), there are two nitrogen atoms able to be protonated.
Amino groups are considerably stronger bases than heterocyclic nitro-
gen (or oxygen) atoms and therefore they are protonated, first, to make
additionally difficult the further protonation of the molecule. However,
the entire protonation of the 2a–c might be achieved in the presence
of very strong acids. Such an appearance of two forms A and B is very
characteristic for sulphuric acid solutions of the 2a–c. The forms A are
situated at higher fields and have lower values of 31P NMR shifts (the
difference is about 0.25 ppm). It seems that the forms A are responsible
for the cleavage of aminophosphonic acids 2a–c.3 31P NMR spectra of
the 2a–c showed that a 31P signal attributed to A disappeared quickly
when the sample was heated, leaving an unchanged B signal. However,
further heating of the sample causes gradual disappearance of a signal
attributed to B, and an enlarged a signal for a product (H3PO4). One can
say that cleavage of the 2a–c is the result of the tautomeric change of B
to A, the form that is responsible for cleavage of the molecule. Obtained
kinetic data (see Table I) reflects tautomeric equilibrium between these
forms at cleavage conditions.
EXPERIMENTAL SECTION
NMR spectra were recorded on a Bruker Avance TM DRX 300 MHz
1
in DMSO-d6, D2O and in CDCl3, using 300.13 MHz for H NMR, and
121.51 MHz for 31P NMR spectra. Melting points were measured on
a Digital Melting Point Apparatus Electrothermal 9200. Elemental
analyses were done in the Laboratory of Instrumental Analysis in the
Institute.
1-(N-Benzyl)-2-formyl-5-benzyloxy-pyridone-4 (1) was obtained by
oxidation of the 1-(N-Benzyl)-2-hydroxymethyl-5-benzyloxy-pyridone-4
with SeO2, according to a typical procedure described in.5 White pow-
der, m.p. 73–75 C; 1H NMR(CDCl3): 9.54 (s, 1H, CH O), 7.33–6.90 (m,
10H, 2x Ph), 7.09 (s, 1H, 6-py), 6.99 (s, 1H, 3-py), 5.42 (s, 2H, PhCH2O),
5.21 (s, 2H, PhCH2-N).
Procedure for Preparation of the Pyridone
Aminophosphonic Acids 2a–c
The procedure for the preparation of aminophosphonic acids was
followed:4,6 1-(N-Benzyl)-2-formyl-5-benzyloxy-pyridone-4 (1) (0.64 g,
2.0 mmol) was dissolved in methylene chloride (25 mL) and the

1052
B. Boduszek et al.
appropriate amine was added (2.1 mmol). The mixture was left for
3 days, then anh. sodium sulfate was added, filtered, and to the fil-
trate, trimethyl phosphite was added (0.3 g, 2.4 mmol), followed by
bromotrimethylsilane (1.5 g, 9.8 mmol). The mixture was left for 24 h
and evaporated to dryness. A residue remained, which was dissolved
in methanol (5 mL) and refrigerated. Next day the solvent was evap-
orated and the residue was treated with acetone (10 mL), followed by
diethyl ether (10 mL) and refrigerated. The separated product was col-
lected by filtration and crystallized from acetone to give the pyridone
aminophosphonic acids 2a–c, as white, amorphous solids.
[1-(N-Benzyl)-5-benzyloxy-pyridone-4-yl-2]-methyl(N-benzhydryl-
amino)phosphonic acid (2a): Yield 63%, m.p. 162–164 C, 1H
NMR(DMSO), , ppm: 8.69 (s, 1H, py-6), 7.74 (s, 1H, py-3), 7.45–
6.80 (m., 20H, Ph’s), 5.74 and 5.47 (dd, 2H, PhCH2O, J = 16.2 Hz), 5.25
(s, 2H, PhCH2N), 4.50 (s, 1H, CHPh2), 4.20 (d, 1H, CH-P, J = 20.4 Hz).
31P NMR, , ppm: 14.32(s). Elemental Anal. for 2a: Calc. N 4.94, P
5.47; Found: N 4.78, P 5.52.
[1-(N-Benzyl)-5-benzyloxy-pyridone-4-yl-2]-methyl(N-benzylamino)-
phosphonic acid (2b): Yield 48%, m.p. 171–173 C, 1H NMR(DMSO), ,
ppm: 8.39 (s, 1H, py-6), 7.75 (s, 1H, py-3), 7.37–7.00 (m., 15H, Ph’s),
5.54 (dd, 2H, PhCH2O), 5.12 (s, 2H, PhCH2N), 4.22 (s, 1H, CH-P, J =
17.5 Hz), 3.71 and 3.46 (dd, 2H, PhCH2NH, J = 13.2 Hz). 31P NMR, ,
ppm: 8.57(s). Elemental Anal. for 2b: Calc. N 5.71, P 6.32; Found: N
5.61, P 6.38.
[1-(N-Benzyl)-5-benzyloxy-pyridone-4-yl-2]-methyl(N-butylamino)-
phosphonic acid (2c): Yield 84%, m.p. 204–205 C, 1H NMR(DMSO),
, ppm: 8.73 (s, 1H, py-6), 7.97 (s, 1H, py-3), 7.4–7.2 (m., 10H, Ph’s),
5.71 (dd, 2H, PhCH2O), 5.18 (dd, 2H, PhCH2N), 4.46 (d, 1H, CH-P, J =
15.1 Hz), 2.71 (m., 2H, NHCH2), 1.37–1.12 (m., 4H, CH2CH2), 0.73 (t,
3H, CH3, J = 7.1 Hz). 31P NMR, , ppm: 3.86(s). Elemental Anal. for
2c: Calc. N 6.14, P 6.79; Found: N 6.05, P 6.82.
Cleavage of the 2a–c and Isolation of the Amines 3a’–c
A sample of aminophosphonic acid (2a–c) (0.5 mmol) was mixed with
20% aq. HCl (10 mL) and the mixture was refluxed for 12 h. Then solu-
tion was evaporated to dryness and the residue was made alkaline by
treatment with an excess of 5% aq. sodium bicarbonate solution. The
oily product that separated was extracted three times with chloroform
(3 25 mL); the extract was dried (anh. Na2SO4), filtered, and evap-
orated to give the amines 3a0–c, as orange-yellow solids. Amine 3a0:
yield: 52%, m.p. 88–92 C, 1H NMR(CDCl3): 7.30–6.95 (m, 12H, arom.),
5.14 (bs, 2H, OCH2),3.79 (bs, 2H, CH2N), 2.60 (bs, 2H),

Synthesis and Cleavage of Pyridone-4 Aminophosphonic Acids
1053
1
Amine 3b: yield: 63%, H NMR(CDCl3): 7.45–7.08 (m, 17H, arom.),
5.25 (bs, 2H), 3.79 (bs, 2H), 3.57 (bs, 2H), 3.49 (bs, 2H), m.p. of oxalate
of 3b: 220–223 C (dec.).
1
Amine 3c: yield: 55%, m.p. 117–118 C, H NMR(CDCl3): 7.28–6.98
(m, 10H, arom.), 6.39 (s, 1H, py-3), 5.27 (bs, 2H, OCH2), 3.91 (bs, 2H,
CH2N), 3.51 (bs, 2H, CH2NH), 2.51 (m, 2H, NCH2), 1.35–1.18 (m, 4H,
CH2CH2), 0.81 (t, 3H, CH3).
Procedure for Kinetic Runs
Stock aqueous solutions of sulphuric acid (with the conc. of H2SO4):
c = 0.5, 1.0, and 2.0 mol L 1 and a solution of deuterated sulphuric acid
in D2O with conc. of D2SO4 c = 1.0 mol L 1 were prepared. Samples of
aminophosphonic acid 2b,c (10 0.1 mg) and sulphuric acid solution
(0.5 mL) were mixed together in NMR tubes and thermostated at 95 C
for a specified period of time (3, 6, 9, and 12 h). The NMR tubes were
then cooled and 31P NMR spectra were recorded. The pseudo-first-order
rate constants (kobs) were determined from 31P NMR spectra by plotting
dependence of log(a-x) on time (where the “a-x” represents an actual
concentration of non-reacted aminophosphonic acid). Kinetic runs were
repeated three times. In most cases, a dependence of log(a-x) on time
was obeyed very well.
REFERENCES
[1] B. Boduszek, Tetrahedron, 52, 12483 (1996).
[2] B. Boduszek, R. Latajka, and W. Lesniak, Phosphorus, Sulfur, and Silicon, 165, 53
(2000).
[3] B. Boduszek, R. Latajka, and U. Walkowiak, Polish J. Chem., 75, 63 (2001).
[4] B. Boduszek, Polish J. Chem., 75, 663 (2001).
[5] A. Korenova, F. Povazanec, M. Uher, and M. Hajas, Chem. Papers, 51, 383 (1997).
[6] B. Boduszek and M. Uher, Synth. Commun., 30, 1749 (2000).
[7] J. A. Joule and G. F. Smith, Heterocyclic Chemistry (Van Nostrand Reinhold, London,
1978), chap. 4.