Synthesis of alkyl hydrogen (1-aminoalkyl)phosphonates

Article abstract of DOI:10.1016/j.mencom.2011.03.017

Addition of hypophosphorous acid to aldoximes affords (1-aminoalkyl) phosphinic acids which on treatment with bromine in alkanols are transformed into alkyl hydrogen (1-aminoalkyl)phosphonates.

Full text of DOI:10.1016/j.mencom.2011.03.017

Mendeleev
Communications
Mendeleev Commun., 2011, 21, 106–107
Synthesis of alkyl hydrogen (1-aminoalkyl)phosphonates
Radii M. Khomutov,* Elena N. Khurs and Tatyana I. Osipova
V. A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russian
Federation. Fax: +7 499 135 1405; e-mail: khomutov@genome.eimb.relarn.ru
DOI: 10.1016/j.mencom.2011.03.017
Addition of hypophosphorous acid to aldoximes affords (1-aminoalkyl)phosphinic acids which on treatment with bromine in alkanols
are transformed into alkyl hydrogen (1-aminoalkyl)phosphonates.
Alkyl hydrogen (1-aminoalkyl)phosphonates 1 are important
organophosphorus analogues of amino acids and can inhibit enzymes
of amino acid metabolism. Usually they are prepared from the
corresponding phosphonic acids by their conversion into chlorides
tion product were not observed in the case of O-alkylaldoxime.
These observations suggested that the addition of H PO at the
3
2
C=N bond is preceded by the reduction of the N–O bond. It is
known that O-dialkylphosphite esters of ketoxime and ethyl ester
of acetohydroxamic acid can undergo a phosphite-phosphate re-
arrangement by a radical mechanism to give N-phosphorylated
1
or activated esters, or by using dicyclohexylcarbodiimide (DCC).
Reported synthesis of alkyl hydrogen phosphonates from phos-
phinic acids in case of amino derivatives 2 involves amino group
protection, esterification with DCC, oxidation with sodium per-
iodate and removal of protection.2
1
0,11
imines.
This mechanism of N–O bond reduction followed
by H PO addition to the imine double bond is likely to occur in
3
2
the formation of acids 2. We have found the conditions providing
Here we report a convenient method for the preparation of
to control the reaction between oximes and H PO . Phosphinic
3
2
(
1-aminoalkyl)phosphinic acids 2 from oximes, their monoesteri-
fication as well as synthesis of a dipeptide phosphorus analogues
, 4 (Scheme 1, cf. refs. 2–4).
analogues of alanine 2a, valine 2b and leucine 2c were obtained
in yields of about 50% upon regulated addition of oximes to
†
3
H PO and HCl solutions to heated lower alcohols.
3
2
In our one-step procedure for the preparation of monoesters,
R
NOH
the amino group protection, activation and esterification of the
phosphorus acid moiety were achieved by the action of bromine
on solutions of hydrochlorides of amino phosphinic acids 2 in
H3PO2
‡
appropriate alcohols. Here, (1-aminoalkyl)phosphonic acid bromide
O
i, Br /AlkOH
ii, AlkOH/Py
O
2
H
OAlk
OH
is initially formed, whose alcoholysis in the presence of pyridine as
R
P
R
P
OH
8
an HBr scavenger results in monoesters 1. Previously, oxidation of
NH2
NH2
†
A solution of acetaldoxime (29.5 g, 0.5 mol) in MeOH (40 ml) was added
2
2
2
a R = Me
b R = Pri
1a R = Alk = Me
1b R = Me, Alk = Et
with stirring over 1 h under N to a boiling solution of 95% H PO (70 g,
2
3
2
i
1 mol) in 125 ml of 3% HCl in MeOH. The mixture was refluxed for 4 h,
kept for 12 h at 20°C and evaporated in vacuo at <45°C; the residue was
c R = Pr CH2
Z-Ala-OSu or
Z-Leu-OSu
HBr/AcOH
dissolved in a minimum amount of water, neutralized with 25% NH OH
4
with stirring and cooling, and chromatographed on a Dowex 50x8 resin
NH2
NH2
+
(
H form, elution with 0.5 n NH OH). Ninhydrin positive fractions were
H
N
H
4
i, Br2 /AlkOH
ii, AlkOH/Py
Me
OH
N
Me
OH
evaporated in vacuo; the residue was dried in vacuo over P O and KOH
2 5
R'
R'
6
to give 30 g (55%) of acid 2a. A TLC-homogeneous product was obtained
by chromatography on a Dowex 50x8 resin (H form, elution with 15%
aqueous Pr OH), followed by evaporation of the appropriate fractions
O
P
O
P
+
O
O
H
OAlk
i
3
4
4
a R' = Alk = Me
b R' = Pr CH2, Alk = Et
in vacuo and drying of the residue in vacuo over P4O10 and KOH. Ascending
i
TLC was performed on Silufol UV2 plates (Kavalier, Czechoslovakia),
54
i
Scheme 1
system: Pr OH–25% NH4OH–H2O, 7:1:2 (A); the compounds were detected
by colour reactions with ninhydrin and ammonium molybdate. Known acids
6
6
2
b, yield 53%, and 2c, yield 49%, were obtained by a similar manner.
Acids of type 2 are usually accessed through addition of
‡
A solution of Br (650 mg, 4.06 mmol) in CHCl (1 ml) was added at
2
3
5
,6
7
H PO or bis(trimethylsilyl)phosphonite to N-substituted imines.
3
2
4°C with stirring to a solution of acid 2a (436 mg, 4 mmol) in 5 ml of dry
MeOH containing 1 equiv. of HCl. After discoloration, the mixture was
gradually added at 4°C with stirring to dry MeOH (10 ml) containing
pyridine (1.2 g, 14 mmol). The mixture was kept for 12 h at 20°C and
The use of benzhydryl protection was reported in a three-stage
preparation of phosphinic analogues of protein amino acids.
Recently we have invented one-step synthesis of acids 2 by a
reaction of oximes with anhydrous H PO2 that involved the
addition of this acid to the C=N bond and reduction of the N–O
bond. This approach is further investigated in the present study.
The possible intermediate, [1-(N-hydroxyamino)ethyl]phosphinic
acid, on the pathway to acid 2a was independently obtained by
reduction of acetophosphinic acid oxime. However, this com-
pound was not converted to acid 2 on treatment with H PO .
8
9
evaporated in vacuo; the residue was dissolved in H O (3 ml) and the
2
3
+
product was isolated on a Dowex 50x8 resin (H form, elution with 15%
i
aqueous Pr OH). The fractions containing monoester 1a according to TLC
(system A) were evaporated in vacuo; the residue was dried in vacuo over
P4O10 and KOH to give 450 mg (80%) of monoester 1a, mp 232–234°C
1
(
decomp.), R 0.53 (A). H NMR (400 MHz, D O) d: 1.34 (dd, 3H,
f
2
3
3
3
2
JHH 7.3 Hz, J 14.9 Hz), 3.34 (dq, 1H, J 7.3 Hz, J 12.5 Hz),
HP
HH
HP
3
31
3
2
3.53 (d, 3H, J 10.4 Hz). P NMR (162 MHz, D O) d: 17.7 (dqq, 1P,
HP
3
2
3
10.4 Hz, 2JPH 12.5 Hz).
2,PH
Similarly, reduction of the N–O bond and formation of an addi-
J1,PH 14.9 Hz, J
©
2011 Mendeleev Communications. All rights reserved.
– 106 –

Mendeleev Commun., 2011, 21, 106–107
(
1-aminoalkyl)phosphinic acids with bromine in water was used to
access the corresponding phosphonic acids. In a similar way, esters
were obtained from the known compounds 3, which were
The products prepared are promising biologically active com-
pounds. Preliminary in vitro experiments with Magnaporthe grisea
(Hebert) Barr fungi, the originator of rice blast, under various
growing conditions on solid media, showed that monoesters 1
and 4 inhibited the pigmentation and growth of mycelium (espe-
4
prepared by acylation of racemic acids 2 with activated esters
of N-protected l-amino acids, followed by deprotection of the
dipeptide analogue. The reaction was accompanied by the forma-
tion of minor amounts of the corresponding phosphonic acids
which were easily separated by ion exchange chromatography.
3,4
–3
cially ester 4b at concentrations <10 mg cm ), whereas the cor-
responding phosphonic acids were inactive.
This study was supported by the Russian Foundation for Basic
Research (grant no. 09-04-01115-A), the Programme for support
of leading scientific schools (project no. NSh-64658.2010.4) and
the International Research Centre (project USDA ARS no. 3745).
The following compounds were obtained by the analogous technique.
1
1
b, yield 73%, mp 235–238°C (decomp.). R 0.51 (A). H NMR (400 MHz,
f
3
3
3
D O) d: 1.17 (t, 3H, J 7.1 Hz), 1.34 (dd, 3H, J 7.3 Hz, J 14.9 Hz),
2
HH
HH
HP
3
2
3
3
.34 (dq, 1H, J 7.3 Hz, J 12.6 Hz), 3.90 (dq, 1H, J 7.3 Hz,
JHP 12.5 Hz). P NMR (162 MHz, D O) d: 16.4 (dtq, 1P, J
HH HP HH
2
31
3
14.9 Hz,
2
1,PH
3J
2
References
7.8 Hz, J 12.6 Hz).
2,PH
PH
4
a, yield 79%, decomp. at 223–226°C. R 0.55 (A); a 1:1 mixture of
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2 D. S. Karanewsky and M. C. Badia, Tetrahedron Lett., 1986, 27, 1751.
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4 E. K. Baylis and W. Pickles, Eur. Pat. Appl. 2,039 (C1.C07F9/48), 1979
(Chem. Abstr., 1980, 92, 181668s).
f
1
two diastereomers. Diastereomer 4'a: H NMR (400 MHz, D O) d: 1.21 (dd,
H, J 7.4 Hz, J 15.2 Hz), 1.43 (d, 3H, J 7.1 Hz), 3.46 (d, 3H,
JHP 10.2 Hz), 3.96 (q, 1H, J 7.1 Hz), 4.06 (dq, 1H, J 7.4 Hz,
JHP 14.0 Hz). P NMR (162 MHz, D O) d: 22.3 (dqq, 1P, J
2
3
3
3
3
HH HP HH
3
3
3
HH
HH
2
31
3
15.2 Hz,
2
1,PH
3J
2
1
10.2 Hz, J 14.0 Hz); diastereomer 4''a: H NMR (400 MHz, D O)
2,PH
PH
2
3
3
3
5 H. Schmidt, Chem. Ber., 1948, 81, 477.
d: 1.21 (dd, 3H, J 7.4 Hz, J 15.2 Hz), 1.41 (d, 3H, J 7.1 Hz), 3.49
d, 3H, J 10.2 Hz), 3.94 (q, 1H, J 7.1 Hz), 4.07 (dq, 1H, J 7.4 Hz,
JHP 14.0 Hz). P NMR (162 MHz, D O) d: 22.2 (dqq, 1P, J
HH
HP
HH
3
3
3
6 B. Kaboudin and N. As-Habei, Tetrahedron Lett., 2003, 44, 4243.
7 E. A. Boyd, W. C. Chan and V. M. Loh Jr., Tetrahedron Lett., 1996, 37,
1647.
(
HP HH HH
2
31
3
15.2 Hz,
2
1,PH
3J
2
10.2 Hz, J 14.0 Hz).
2,PH
PH
8
E. K. Baylis, C. D. Campbell and J. G. Dingwall, J. Chem. Soc., Perkin
Trans. 1, 1984, 2845.
4
b, yield 64%, decomp. at 220–227°C, R 0,68 (A); a 2:1 mixture of
f
1
two diastereomers. Diastereomer 4'b: H NMR (400 MHz, D O) d: 0.84
d, 3H, J 6.3 Hz), 0.86 (d, 3H, J 6.3 Hz), 1.14 (t, 3H, J 7.1 Hz),
.20 (dd, 3H, J 7.3 Hz, J 15.2 Hz), 1.49–1.72 (m, 3H), 3.79 (dd, 1H,
J1,HH 7.1 Hz, J
2
9
R. M. Khomutov and T. I. Osipova, Izv. Akad. Nauk SSSR, Ser. Khim.,
3
3
3
(
HH HH HH
1
978, 1951 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1978, 27, 1722).
3
3
1
HH HP
1
0 Yu. L. Kruglyak, G. A. Leibovskaya, I. I. Sretenskaya, V. V. Sheluchenko
and I. V. Martynov, Zh. Org. Khim., 1968, 38, 943 (in Russian).
11 Yu. L. Kruglyak, M. A. Landau, G. A. Leibovskaya, I. V. Martynov,
L. I. Saltykova and M. A. Sokol’sky, Zh. Org. Khim., 1969, 39, 215 (in
Russian).
3
3
3
3
5.2 Hz), 3.85 (dq, 2H, J 7.1 Hz, J 7.1 Hz), 4.06
HH HP
1,HH
3
2
31
(
1
(
1
dq, 1H, J 7.3 Hz, J 14.7 Hz). P NMR (162 MHz, D O) d: 20.9 (dtq,
HH
HP
2
3
3
2
1
P, J
15.2 Hz, J
7.1 Hz, J 14.7 Hz); diastereomer 4''b: H NMR
1
,PH
2,PH PH
3
3
400 MHz, D O) d: 0.85 (d, 3H, J 6.3 Hz), 0.87 (d, 3H, J 6.3 Hz),
.11 (t, 3H, J 7.1 Hz), 1.22 (dd, 3H, J 7.3 Hz, J 15.2 Hz),
.49–1.72 (m, 3H), 3.80 (dd, 1H, J
2
3
HH
HH
3
3
HH
HH
HP
3
3
1
7.1 Hz, J
5.2 Hz), 3.87 (dq, 2H,
1,HH
1,HH
3
3
3
2
J
7.1 Hz, J 7.1 Hz), 4.04 (dq, 1H, J 7.3 Hz , J 14.7 Hz).
HH
HP
HH
HP
31
3
3
P NMR (162 MHz, D O) d: 20.9 (dtq, 1P, J
15.2 Hz, J
7.1 Hz,
2
1,PH
2,PH
2J 14.7 Hz).
Received: 19th July 2010; Com. 10/3568
PH
–
107 –