Synthesis of dimethylphosphinyl-substituted α-amino(aryl) methylphosphonic acids and their esters

Article abstract of DOI:10.1515/znb-2008-1009

Dimethylphosphinylmethylamine (1) and its aldimines 2 were used for the preparation of dimethyl and diethyl α-amino(aryl)methylphosphonates 3a -1 via imine hydrophosphonylation and Kabachnik-Fields reaction. Their acid hydrolysis gave rise to the correspo

Full text of DOI:10.1515/znb-2008-1009

Synthesis of Dimethylphosphinyl-substituted
α-Amino(aryl)methylphosphonic Acids and Their Esters
Yulian Zagraniarskya, Bojidarka Ivanovaa, Karamfil Nikolova, Sabi Varbanovb,
and Tsvetanka Cholakovaa
a University of Sofia, Faculty of Chemistry, 1, J. Bourchier av., 1164 Sofia, Bulgaria
b Institute of Organic Chemistry with a Centre of Phytochemistry, Bulgarian Academy of Sciences,
1113 Sofia, Bulgaria
Reprint requests to Assoc. Prof. Dr. T. Cholakova. E-mail: tcholakova@chem.uni-sofia.bg
Z. Naturforsch. 2008, 63b, 1192 – 1198; received June 24, 2008
Dimethylphosphinylmethylamine (1) and its aldimines 2 were used for the preparation of
dimethyl and diethyl α-amino(aryl)methylphosphonates 3a – l via imine hydrophosphonylation and
Kabachnik-Fields reaction. Their acid hydrolysis gave rise to the corresponding α-aminophosphonic
acids 4a – e. Compounds 3 and 4 have two different phosphorus-containing groups – phosphonyl and
dimethylphosphinyl – and might have interesting biological activity.
Key words: Dimethylphosphinyl-substituted Phosphonates and α-Aminophosphonic Acids,
Kabachnik-Fields Reaction, Imine Hydrophosphonylation
Introduction
The present work is a continuation of our pre-
vious investigations concerning imines of dimethyl-
phosphinylmethylamine as precursors for the prepa-
ration of new organophosphorus compounds, contain-
ing a dimethylphosphinyl group, with potential biolog-
ical activity [6, 7]. These imines have been obtained
only recently [8], and their potential as polyfunctional
reagents is not fully revealed. We wish to report now
the synthesis of some new α-aminophosphonates and
their hydrolysis to the corresponding α-aminophos-
phonic acids. The combination of an α-aminophos-
phonic and a phosphine oxide moiety could result in a
series of compounds with potential herbicide and plant
growth regulating activities.
Studies on aminophosphonic acids started in the
early 1950s, and since then considerable efforts have
been devoted to the synthesis and investigation of bio-
logical activity of α-aminophosphonic acids, largely
because of their structural analogy with α-amino-
carboxylic acids [1a – c]. Several α-aminophosphon-
ic acid derivatives such as the herbicide Glyphosate
(Roundup) and the antibacterial Alafosfalin are widely
used commercially.
Results and Discussion
The standard synthesis of α-aminophosphonates in-
For the preparation of the desired α-aminophos-
volves thermal addition of dialkylphosphites to imines, phonates we chose the Kabachnik-Fields reaction and
which themselves may be generated in situ from the its parent imine hydrophosphonylation, in order to
amine and the corresponding aldehyde. These ther- compare them and find better reaction conditions
mal reactions are particularly useful for the large (Scheme 1).
scale preparation of simple α-aminophosphonates.
Phosphonates 3a – h were obtained (as we reported
Various modifications have been introduced in recent earlier [6] for 3a – c and 3f – h) in good yields and pu-
years with the aim of avoiding solvents and provid- rity (Table 1) by addition of dimethyl or diethyl phos-
ing mild reaction conditions, especially using Lewis phite to the C=N bond of the aldimines 2a – e (Method
(Mg(ClO4)2, SnCl4) and Brønsted (CF3COOH, HBF4, A). ◦The reaction mixtures were heated in toluene at
◦
H3PO4, p-TsOH) acids as catalysts [2 – 5].
80 C (70 C for 3e) for 8 h. The crude phospho-
c
0932–0776 / 08 / 1000–1192 $ 06.00 ꢀ 2008 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
Unauthenticated
Download Date | 11/18/19 3:59 AM

Y. Zagraniarsky et al. · Dimethylphosphinyl-substituted α-Amino(aryl)methylphosphonic Acids
1193
Ar
R
Ar
R
3a
3b
3c
3d
3e
C6H5
CH3
CH3
CH3
CH3
CH3
3f
3g
3h
3i
C6H5
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
Method A: 80 ◦C, 8 h, toluene
Method B1: 80 ◦C, 8 h, toluene
Method B2: r. t., 24 h, TFA (25 mol %)
C6H4-Cl-4
C6H4-OCH3-4
C6H4-CH3-4
C6H4-NO2-4
C6H4-Cl-4
C6H4-OCH3-4
C6H4-CH3-4
C6H4-NO2-4
3j
Scheme 1.
Table 1. Yields of dimethylphosphinyl-substituted α-amino-
(aryl)methylphosphonates 3a – j, prepared by different meth-
ods (see Scheme 1).
Yield (%)a
Method A Method B1 Method B2
Ar
R
3a C6H5
CH3
CH3
72 (53)b
98 (88)b
87 (77)b
94 (84)
64 (54)
–
–
–
–
–
–
–
–
3b C6H4-Cl-4
3c C6H4-OCH3-4 CH3
3d C6H4-CH3-4 CH3
3e C6H4-NO2-4 CH3
Next, the CF3COOH-promoted three-component
–
63 (61)
–
80 (69)
–
67 (63)
86 (78)
synthesis of α-aminophosphonates 3 starting from
aldehydes, amine 1 and dialkylphosphites under
solvent-free conditions (Method B2) was examined,
and the results are shown in Table 1. The reaction was
carried out at r. t. for 24 h, and the aminophospho-
nates 3e, g, i, j were obtained in yields comparable
with those received by two previous methods (A and
B1) and also in high purity (1H NMR). Method B2 is
solvent-free, avoids prolonged heating of the reaction
mixture and is more convenient although it requires
long reaction times. Acetophenone did not react under
the same reaction conditions, but cyclohexanone gave
the desired product 3k in good yield (64 %) and high
purity.
3f C6H5
CH2CH3 89 (75)b
CH2CH3 96 (70)b
93 (69)b
84 (57)b
70 (53)b
91 (88)
52 (50)
3g C6H4-Cl-4
3h C6H4-OCH3-4 CH2CH3 89 (69)b
3i C6H4-CH3-4 CH2CH3
–
–
3j C6H4-NO2-4 CH2CH3
a
Yields of the crude reaction product; yields after purification are
given in parentheses; b these results have been published in our pre-
vious publication [6].
nates 3 are pure enough to be used without further pu-
rification (except for the standard work-up by which
the starting compounds are removed by extraction of
the acidified water solution with CH2Cl2). They are
low melting crystals or oils that tend to crystallize
over time.
The α-aminophosphonate 3l, containing an amino
group in the aromatic ring, could not be prepared by
the Kabachnik-Fields reaction, that is why we obtained
it with good yield (76%) and purity by reduction of the
ester 3j (Scheme 2).
At the outset, we performed the Kabachnik-Fields
reaction applying its classical thermal conditions
(Method B1) by mixing all three components (amine 1,
dialkylphosphite and aromatic aldehyde) in tolue◦ne
◦
and heating the reaction mixture at 80 C (70 C
for 3j) for 8 h. Aminophosphonates 3f – j were ob-
The hydrolysis of the phosphonates 3 was car-
tained also in high yields (70– 93 %) and purity. No ried out with 12 M hydrochloric acid under reflux
traces of side products like hydroxyphosphonates or (Scheme 3). After evaporation of volatiles and treat-
trialkylphosphates were observed in the reaction mix- ment with propylene oxide we obtained the crude α-
tures by 31P NMR spectroscopy.
aminophosphonic acids 4a – e with excellent purity
Unauthenticated
Download Date | 11/18/19 3:59 AM

1194
Y. Zagraniarsky et al. · Dimethylphosphinyl-substituted α-Amino(aryl)methylphosphonic Acids
Scheme 2.
1320 cm−1, common to all the IR spectra, corresponds
to the δas(CH3) vibration of the phosphine oxide frag-
ment [6 – 8]. The compounds studied are further char-
acterized by in-plane modes of the aromatic systems at
about 1600 and 1500 cm−1 and by out-of-plane modes
in the range 690– 900 cm−1 typical for mono- and p-
disubstituted benzene derivatives.
The 1H NMR spectra of the new phosphonates 3d, e,
i – l are similar to those observed for the previously re-
ported compounds [6] and are in accordance with their
structure.
Ar
Yield (%)a
1
The H NMR spectra of the α-aminophosphonic
acids 4 also confirm their structure. The resonance
signals for the (CH3)2PO groups appear as doublets
4a C6H5
98 (45)
63 (23)
4b C6H4-Cl-4
a
4c
C6H4-OCH3-4 85 (28)
Yields of the crude reac-
2
for six protons with JPH = −13.7 to −13.9 Hz, ex-
4d C6H4-CH3-4
4e C6H4-NO2-4
59 (45)
85 (59)
tion product; yields after pu-
rification in parentheses.
cept for 4e which gives two doublets for three pro-
tons each with close chemical shifts (δ = 1.71 and
1.72 ppm, 2JPH = −13.8 and −13.5 Hz). The protons
of the methylene groups form an ABX system with the
phosphine oxide phosphorus atom (X part). The ex-
act signs and values of the chemical shifts and J con-
Scheme 3.
(1H NMR, 31P{ H} NMR) in 59 – 98 % yield. For the
purpose of their structure analysis they were purified
by recrystallization from methanol or water/acetone
with high losses.
Structure and purity of all new compounds 3d, e, i –
l and 4a–e were confirmed by IR and 1H and 31P NMR
spectral data and elemental analyses.
1
2
stants (2JHH = −15.1 to −15.3 Hz and JPH = −7.0
to −7.5 Hz) were obtained through calculations. The
signals of the methine protons in the phosphonic moi-
2
ety -CH(Ar)–PO3H2 are doublets with JPH = −15.6
The solid state IR spectra of compounds 4 are to −16.4 Hz.
1
The 31P{ H} NMR spectra of the α-aminophos-
characterized by multiple absorption maxima in the
+
range 3000 – 2200 cm−1 typical for a NH2 and as-
phonic acids 4a, b, d, e exhibit two resonance signals:
at δ = 47.88 – 48.56 ppm typical for tertiary phosphine
oxides [6 – 8] and at δ = 8.75 – 9.80 ppm characteristic
for α-aminophosphonic acids [11].
sociated OH-group. The intense absorptions at 3450
and 3550 cm−1 are assigned to ν(NH) and ν(OH)
stretching vibrations and are usually observed for non-
hydrogen bonded groups. A low frequency shifting
of ν(P=O) (phosphonate) by about 70 cm−1 from
the typical 1257– 1250 cm−1 region [9, 10] to 1190–
1170 cm−1, is probably due to intermolecular hydro-
gen bonding (P=O···H–O–P). The ν(P=O) stretching
mode of the phosphine oxide group in all acids 4 ap-
pears between 1170 and 1140 cm−1, as for the imines
2 [8], where there is no possibility of hydrogen bond-
ing. This value indicates the absence of inter- or in-
tramolecular interactions with participation of the dis-
All dimethylphosphinyl substituted α-aminophos-
phonates 3 and α-aminophosphonic acids 4 are un-
der investigation for their potential herbicide and plant
growth regulating activity.
Experimental Section
Starting materials
The imines 2 were prepared according to the litera-
ture procedure [8]. Dimethyl and diethyl phosphite (purum,
cussed structural fragments. The strong absorption at Fluka) were purified by distillation prior to use.
Unauthenticated
Download Date | 11/18/19 3:59 AM

Y. Zagraniarsky et al. · Dimethylphosphinyl-substituted α-Amino(aryl)methylphosphonic Acids
1195
Characterization of the compounds
20 : 1) gave 3d as a colorless oil. Yield: 84 %. – IR (CHCl3):
ν = 3330 (NH), 1600 (Ph), 1460 (Ph), 1290 (CH3–P),
1230 (P=O), 1160 (P=O), 1050, 1030 (PO−C) cm−1. –
1H NMR (250.13 MHz, [D6]DMSO): δ = 1.33 (d, 3H,
Melting points (uncorrected): micro hot-stage apparatus
Boetius PHMK 05. The IR spectra were recorded with a
Bomem-Michelson 100 FTIR spectrometer with resolution
2 cm−1 and 150 scans, using the solid state KBr pellet tech-
nique for acids 4 and CHCl3 as a solvent (0.05 mm KBr
cell) for phosphonates 3. 1H NMR spectra were recorded
on an Avance DRX 250 (250.13 MHz) spectrometer, with
2
2
CH3P, JPH = −12.9 Hz), 1.38 (d, 3H, CH3P, JPH
=
4
−12.9 Hz), 2.30 (d, 3H, CH3–C6H4, JHH = 1.6 Hz),
2.57 – 2.68 (m, 2H, CH2P; after D2O exchange 2.60, dd,
2
2
1H, JHH = −14.3 Hz, JPH= −7.9 Hz and 2.67, dd, 1H,
2JHH = −14.3 Hz, JPH = −8.5 Hz), 3.46 (d, 3H, CH3O,
2
[D6]DMSO for 3 and D2O for 4 as solvents. 31P{ H} NMR
1
3JPH = 10.6 Hz), 3.69 (d, 3H, CH3O, JPH = 10.5 Hz),
3
spectra: Bruker Avance 400 (161.92 MHz). Chemical shifts
are measured relative to TMS as internal (1H) or 85 %
2
3
4.26 (dd, 1H, CHAr, JPH = −21.0 Hz, JHH = 9.0 Hz;
2
after D2O exchange 4.22, d, JPH = −21.0 Hz), 7.17 (d,
1
H3PO4 (31P{ H}) as external standard. Column chromatog-
2H, Har.
,
3JHH = 7.8 Hz), 7.28 (dd, 2H, Har.
,
3JHH
=
raphy purifications were carried out on Merck silica gel 60
(0.04 – 0.063 mm) with CH2Cl2/CH3OH (20 : 1) as eluent.
TLC: Merck silica gel 60 F254 on aluminum sheets, layer
thickness 0.2 mm, mobile phase: CH2Cl2 : CH3OH=15 : 1.
8.2 Hz, JHH = 2.1 Hz). – 31P{ H} NMR (161.92 MHz,
CDCl3): δ = 25.89 (P(O)(OCH3)2), 44.17 (P(O)(CH3)2). –
C13H23NO4P2 (319.27): calcd. C 48.90, H 7.26, N 4.39;
found C 48.59, H 7.51, N 4.40.
4
1
General procedure for the preparation of
α-aminophosphonates 3
Dimethyl [(dimethylphosphinylmethyl)amino]-
(4-nitrophenyl)methylphosphonate (3e)
Method A: The imine 2 (2 mmol) was dissolved in toluene
(5 mL, 15 mL for 2e), and dimethyl or diethyl phosphite
(0.23 mL or 0.32 mL, respectiv◦ely, 2.5◦mmol) was added.
The mixture was heated at 80 C (70 C for 3e) for 8 h,
and after that the solvent was removed in a vacuum. The
residue was dissolved in water (10 mL), and 2 M HCl (2 mL)
was added. The solution was washed with diethyl ether
(3 × 20 mL), and the aqueous layer was made alkaline with
solid Na2CO3 and then extracted with CH2Cl2 (3×20 mL).
The organic layer was washed with water (2×20 mL), dried
and evaporated. The crude products 3a – h (1H NMR, TLC:
one spot) were used in the next step without purification. For
the purpose of their structure analysis they were purified by
recrystallization from cyclohexane/ethyl acetate (3a, f – h) or
column chromatography (3b – e).
Method B1: A mixture of amine 1 (0.22 g, 2 mmol), di-
ethyl phosphite (0.40 mL, 3 mmol) and the corresponding
aldehyde (2 mmol) in dry toluene (5 mL) was heated at 80 ◦C
(70 ◦C for 3j) for 8 h. The solvent was removed in a vacuum,
and the residue was worked up as described in Method A.
Method B2: A mixture of amine 1 (0.22 g, 2 mmol),
dimethyl or diethyl phosphite (0.28 mL or 0.40 mL, re-
spectively, 3 mmol), the corresponding carbonyl compound
(2 mmol) and trifluoroacetic acid (0.04 mL, 0.5 mmol) was
stirred at r. t. for 24 h (48 h for 3k). The solvent was removed
in a vacuum, and the residue was worked up as described in
Method A. The crude phosphonates 3e, g, i – k were purified
by column chromatography for the purpose of their spectro-
scopic analysis.
Yield of crude α-aminophosphonate: 64 % (Method A)
and 63 % (Method B2). Column chromatography (dichloro-
methane/methanol = 20 : 1) gave 3e as a yellowish oil. Yield:
54 % and 61 %, respectively. – IR (CHCl3): ν = 3330 (NH),
1600 (Ph), 1510 (NO2), 1340 (NO2), 1300 (P–CH3), 1240
(P=O), 1160 (P=O), 1050, 1030 (PO–C) cm−1. – 1H NMR
(250.13 MHz, [D6]DMSO): δ = 1.34 (d, 3H, CH3P, 2JPH
=
2
−13.0 Hz), 1.41 (d, 3H, CH3P, JPH = −13.1 Hz), 2.57 –
2.77 (m, 2H, CH2P; after D2O exchange 2.65, dd, 1H,
2JHH = −14.3 Hz, 2JPH = −8.6 Hz and 2.73, dd, 1H, 2JHH
=
2
−14.3 Hz, JPH = −7.0 Hz), 2.92 – 3.07 (m, 1H, NH; dis-
3
appears after D2O exchange), 3.54 (d, 3H, CH3O, JPH
=
3
10.6 Hz), 3.72 (d, 3H, CH33O, JPH = 10.6 Hz), 4.63 (dd,
2
1H, CHAr, JPH = −22.3, JHH = 9.2 Hz; after D2O ex-
change 4.56, d, 2JPH = −22.5 Hz), 7.70 (dd, 2H, Har., 3JHH
=
8.8 Hz, 4JHH = 2.1 Hz), 8.25 (d, 2H, Har., 3JHH = 8.5 Hz). –
C12H20N2O6P2 (350.25): calcd. C 41.15, H 5.76, N 8.00;
found C 41.39, H 5.58, N 7.87.
Diethyl [(dimethylphosphinylmethyl)amino]-
(4-methylphenyl)methylphosphonate (3i)
Yield of crude α-aminophosphonate: 91 % (Method B1)
and 67 % (Method B2). Column chromatography (dichloro-
methane/methanol = 20 : 1) gave 3i as a colorless oil. Yield:
88 % and 63 %, respectively. – IR (CHCl3): ν = 3330
(NH), 1600 (Ph), 1290 (CH3−P), 1230 (P=O), 1160 (P=O),
1050, 1020 (PO–C), 960, 930 (OC–C) cm−1. – 1H NMR
(250.13 MHz, [D6]DMSO): δ = 1.05 (t, 3H, CH3CH2,
Dimethyl [(dimethylphosphinylmethyl)amino]-
(4-methylphenyl)methylphosphonate (3d)
3JHH = 7.1 Hz), 1.22 (t, 3H, CH3CH2, JHH = 7.1 Hz),
3
2
1.33 (d, 3H, CH3P, JPH = −13.0 Hz), 1.37 (d, 3H, CH3P,
Yield of crude α-aminophosphonate: 94 % (Method 2JPH = −13.0 Hz), 2.29 (s, 3H, CH3-Ar), 2.55 – 2.70 (m,
A). Column chromatography (dichloromethane/methanol = 3H, NH and CH2P; after D2O exchange 2.61, dd, 1H,
Unauthenticated
Download Date | 11/18/19 3:59 AM

1196
Y. Zagraniarsky et al. · Dimethylphosphinyl-substituted α-Amino(aryl)methylphosphonic Acids
2
2JHH = −14.3 Hz, JPH = −8.5 Hz and 2.68, dd, 1H, Diethyl (4-aminophenyl)[(dimethylphosphinylmethyl)-
2
2JHH = −14.3 Hz, JPH = −7.4 Hz), 3.69 – 3.91 (m, 2H, amino]methylphosphonate (3l)
3
POCH2CH3), 4.04 (dq, 2H, POCH2CH3, JPH = 7.8 Hz,
2
Reduction of nitrophosphonate 3j: To 0.20 g (0.51 mmol)
of the ester 3j dissolved in ethanol (4 mL) a solution of
SnCl2 · 2H2O (1.2 g, 5.3 mmol) in 10 M HCl (8 mL) was
added dropwise. The reaction mixture was stirred at r. t.
for 6 h. It was made alkaline with solid Na2CO3 and ex-
tracted with dichloromethane (3×20 mL). The organic layer
was dried and evaporated in a vacuum. Yield of crude
α-aminophosphonate: 76 %. Column chromatography (di-
chloromethane/methanol = 20 : 1) gave 3l as a colorless oil.
Yield: 73 %. – IR (CHCl3): ν = 3470 (NH2), 3390 (NH),
3330, 3200 (NH2), 1615 (NH2), 1605 (Ph), 1290 (P–CH3),
1240 (P=O), 1160 (P=O), 1050, 1030 (PO–C), 965, 940
(OC–C) cm−1. – 1H NMR (250.13 MHz, [D6]DMSO):
3JHH = 7.1 Hz), 4.19 (dd, 1H, CHAr, JPH = −20.7 Hz,
2
3JHH = 8.6 Hz, after D2O exchange 4.13, d, JPH
=
−20.9 Hz), 7.17 (d, 2H, Har.
,
3JHH = 7.9 Hz), 7.28 (dd,
2H, Har., JHH = 8.1 Hz, JHH = 1.8 Hz). – C15H27NO4P2
(347.33): calcd. C 51.87, H 7.84, N 4.03; found C 51.60,
H 7.95, N 3.74.
3
4
Diethyl [(dimethylphosphinylmethyl)amino]
(4-nitrophenyl)methylphosphonate (3j)
Yield of crude α-aminophosphonate: 52 % (Method
B1) and 86 % (Method B2). Column chromatography
(dichloromethane/methanol = 20 : 1) gave 3j as a yellowish
oil. Yield: 50 % and 78 %, respectively. – IR (CHCl3): ν =
3330 (NH), 1600 (Ph), 1500 (NO2), 1340 (NO2), 1300 (P–
CH3), 1240 (P=O), 1160 (P=O), 1050, 1020 (PO–C), 975,
930 (OC–C) cm−1. – 1H NMR (250.13 MHz, [D6]DMSO):
3
δ = 1.03 (t, 3H, CH3CH2, JHH = 7.1 Hz), 1.20 (t, 3H,
3
2
CH3CH2, JHH = 7.1 Hz), 1.34 (d, 3H, CH3P, JPH
=
2
−13.1 Hz), 1.37 (d, 3H, CH3P, JPH = −13.1 Hz), 2.27 –
2.44 (m, 1H, NH, disappears after D2O exchange), 2.54 –
2.75 (m, 2H, CH2P; after D2O exchange 2.59, dd, 1H,
3
δ = 1.09 (t, 3H, CH3CH2, JHH = 7.1 Hz), 1.23 (t, 3H,
2JHH = −14.4 Hz, JPH = −8.2 Hz and 2.69, dd, 1H,
2
3
2
CH3CH2, JHH = 7.1 Hz), 1.34 (d, 3H, CH3P, JPH
=
2JHH = −14.4 Hz, JPH = −7.2 Hz), 3.52 – 3.92 (m, 2H,
2
2
−13.1 Hz), 1.40 (d, 3H, CH3P, JPH = −13.1 Hz), 2.60 –
2
3
POCH2CH3), 3.90 (dd, 1H, CHAr, JPH = −19.9, JHH
=
2.74 (m, 2H, CH2P; after D2O exchange 2.65, dd, 1H,
3
11.3 Hz), 4.01 (dq, 2H, POCH2CH3, JPH = 7.5 Hz,
2JHH = −14.3 Hz, JPH = −8.4 Hz and 2.71, dd, 1H,
2
3JHH = 7.1 Hz), 5.03 (bs, 2H, NH2), 6.53 (d, 2H, Har.
,
2JHH = −14.3 Hz, JPH = −7.3 Hz), 2.84 – 2.98 (m, 1H,
2
3JHH = 8.2 Hz), 7.02 (dd, 2H, Har.
,
3JHH = 8.5 Hz,
NH; disappears after D2O exchange), 3.79 – 3.98 (m, 2H,
4JHH = 2.0 Hz). – 31P{ H} NMR (161.92 MHz, CDCl3):
δ = 24.03 (P(O)(OCH2CH3)2), 43.65 (P(O)(CH3)2). –
C14H26N2O4P2 · H2O (348.32): calcd. C 48.28, H 7.52,
N 8.04; found C 48.61, H 7.82, N 7.85.
1
3
POCH2CH3), 4.07 (dq, 2H, POCH2CH3, JPH = 8.0 Hz,
3JHH = 7.1 Hz), 4.55 (dd, 1H, CHAr, JPH = −22.0,
2
3JHH = 8.4 Hz, after D2O exchange 4.49, d, JPH = −22.1
2
4
Hz), 7.69 (dd, 2H, Har.
,
3JHH = 8.9 Hz, JHH = 2.1 Hz),
1
8.25 (d, 2H, Har.
,
3JHH = 8.4 Hz). – 31P{ H} NMR
General procedure for the preparation of
α-aminophosphonic acids 4a – e
(161.92 MHz, CDCl3): δ = 24.69 (P(O)(OCH2CH3)2),
43.02 (P(O)(CH3)2). – C14H24N2O6P2 · H2O (396.31):
calcd. C 42.43, H 6.61, N 7.07; found C 42.26, H 6.38,
N 6.85.
The crude phosphonates 3a – e (without purification) were
heated under reflux with 12 M hydrochloric acid (2 mL) for
2 h. The volatiles of the reaction mixture were evaporated at
reduced pressure to leave the corresponding α-aminophos-
phonic acid hydrochloride. It was repeatedly taken up in ace-
tone (3 – 4 mL) and evaporated. Then the residue was dis-
solved in a small amount of methanol (1 – 1.5 mL) and ace-
tone (4 – 5 mL), and an excess of propylene oxide (2 mL)
was added. After stirring for 5 – 10 min a white precipi-
tate of α-aminophosphonic acid 4 was formed. It was fil-
tered off and washed with cold acetone. The α-aminophos-
phonic acids 4 were recrystallized from the corresponding
solvent.
Diethyl 1-[(dimethylphosphinylmethyl)amino]-
cyclohexylphosphonate (3k)
Yield of crude α-aminophosphonate: 64 % (Method
B2). Column chromatography (dichloromethane/methanol =
20 : 1) gave 3k as a colorless oil. Yield: 61 %. – IR
(CHCl3): ν = 3650 – 2800 (OH, H2O and NH), 1670 (H2O),
1290 (P−CH3), 1220 (P=O), 1140 (P=O), 1060, 1020
(PO–C), 940 (OC–C) cm−1. – 1H NMR (250.13 MHz,
3
[D6]DMSO): δ = 1.23 (t, 6H, CH3CH2, JHH = 7.0 Hz),
1.37 – 1.46 (m, 2H, cyclohexyl), 1.41 (d, 6H, CH3P, 2JPH
=
−13.1 Hz), 1.48 – 1.62 (m, 6H, cyclohexyl), 1.65 – 1.75
[(Dimethylphosphinylmethyl)amino](phenyl)-
methylphosphonic acid (4a)
(m, 2H, cyclohexyl), 2.88 – 2.96 (m, 2H, CH2P), 4.02 (dq,
3
3
4H, POCH2CH3, JPH = 8.1 Hz, JHH = 7.0 Hz). –
C13H29NO4P2 · H2O (343.34): calcd. C 45.48, H 9.10,
N 4.08; found C 45.66, H 9.11, N 4.09.
Yield of crude α-aminophosphonic acid 4a: 98 %. Re-
crystallization from methanol gave 4a as colorless crystals.
Unauthenticated
Download Date | 11/18/19 3:59 AM

Y. Zagraniarsky et al. · Dimethylphosphinyl-substituted α-Amino(aryl)methylphosphonic Acids
1197
Yield: 45 %. M. p. 215 – 217 ◦C. – IR (KBr): ν = 2600 – 2000 (307.220): calcd. C 43.00, H 6.23, N 4.56; found C 42.80,
(OH), 1610 (Ph), 1498 (Ph), 1320 (CH3), 1170 (P=O), 1140 H 5.95, N 4.33.
(P=O), 710 (Ph) cm−1. – 1H NMR (250.13 MHz, D2O):
δ = 1.70 (d, 6H, (CH3)2P, 2JPH = −13.7 Hz), 3.47 (dd, 1H,
[(Dimethylphosphinylmethyl)amino](4-methylphenyl)-
methylphosphonic acid (4d)
2
2
CH2, JHH = −15.2, JPH = −7.3 Hz), 3.60 (dd, 1H, CH2,
2JHH = −15.2, 2JPH = −7.5 Hz), 4.59 (d, 1H, CHPh, 2JPH
=
Yield of crude α-aminophosphonic acid 4d: 59 %. Re-
crystallization from water/acetone◦gave 4d as colorless crys-
tals. Yield: 45 %. M. p. 196 – 198 C. – IR (KBr): ν = 3560
(OH), 3446 (NH), 2800 – 2200 (hydrogen bonded OH), 1598
(Ph), 1568 (Ph), 1500 (Ph), 1360 (CH3), 1190 (P=O), 1170
(P=O), 886 (Ph) cm−1. – 1H NMR (250.13 MHz, D2O):
1
−15.6 Hz), 7.49 – 7.55 (m, 5Har.). – 31P{ H} NMR (D2O):
δ = 9.80 (PO3H2), 48.42 (CH3P=O). – C10H17NO4P2
(277.194): calcd. C 43.33, H 6.18, N 5.05; found C 43.05,
H 5.86, N 5.39.
(4-Chlorophenyl)[(dimethylphosphinylmethyl)-
amino]methylphosphonic acid (4b)
2
δ = 1.69 (d, 6H, (CH3)2P, JPH = −13.7 Hz), 2.37 (s,
2
2
3H, CH3Ar), 3.45 (dd, 1H, CH2, JHH = −15.3, JPH
=
=
2
2
−7.4 Hz), 3.58 (dd, 1H, CH2, JHH = −15.3, JPH
Yield of crude α-aminophosphonic acid 4b: 63 %. Re-
crystallization from methanol gave 4b as colorless crystals.
Yield: 23 %. M. p. 127 – 130 ◦C. – IR (KBr): ν = 3200 –
2400 (OH), 1620 (Ph), 1556 (Ph), 1494 (Ph), 1350 (CH3),
2
−7.5 Hz), 4.50 (d, 1H, CHAr, JPH = −15.6 Hz), 7.34 (d,
2H, Har., 3JHH = 8.3 Hz), 7.42 (dd, 2H, Har., 3JHH = 8.3 Hz,
4JHH = 1.5 Hz). – 31P{ H} NMR (D2O): δ = 9.43 (PO3H2),
1
47.88 (CH3P=O). – C11H19NO4P2 · H2O (309.235): calcd.
1182 (P=O), 1166 (P=O), 856 (Ph) cm−1. – 1H NMR
C 42.72, H 6.84, N 4.53; found C 42.40, H 6.64, N 4.61.
2
(250.13 MHz, D2O): δ = 1.71 (d, 6H, (CH3)2P, JPH
=
=
=
2
2
−13.7 Hz), 3.49 (dd, 1H, CH2, JHH = −15.2, JPH
[(Dimethylphosphinylmethyl)amino](4-nitrophenyl)-
methylphosphonic acid (4e)
2
2
−7.3 Hz), 3.62 (dd, 1H, CH2, JHH = −15.2, JPH
2
−7.5 Hz), 4.55 (d, 1H, CHAr, JPH = −15.7 Hz), 7.48 –
7.54 (m, 4Har.). – 31P{ H} NMR (D2O): δ = 9.54 (PO3H2),
1
Yield of crude α-aminophosphonic acid 4e: 85 %. Re-
crystallization from water gave 4e as yellowish crystals.
Yield: 59 %. M. p. 222 – 224 ◦C. – IR (KBr): ν = 3000 –
2200 (OH), 1600 (Ph), 1575 (Ph), 1510 (Ph), 1550 (NO2),
1350 (NO2), 1337 (CH3), 1174 (P=O), 1140 (P=O) cm−1. –
48.56 (CH3P=O). – C10H16ClNO4P2 · H2O (329.654):
calcd. C 36.43, H 5.50, N 4.25; found C 36.57, H 5.37,
N 4.52.
1H NMR (250.13 MHz, D2O): δ = 1.71 (d, 3H, CH3P, 2JPH
=
[(Dimethylphosphinylmethyl)amino](4-methoxyphenyl)-
methylphosphonic acid (4c)
2
−13.8 Hz), 1.72 (d, 3H, CH3P, JPH = −13.5 Hz), 3.49
2
2
(dd, 1H, CH2, JHH = −15.1, JPH = −7.0 Hz), 3.63 (dd,
2
2
Yield of crude α-aminophosphonic acid 4c: 85 %. Recrys-
tallization from methanol gave 4c as colorless crystals. Yield:
28 %. M. p. 143 – 145 ◦C. – IR (KBr): ν = 3200 – 2400 (OH),
1605 (Ph), 1560 (Ph), 1510 (Ph), 1350 (CH3), 1255 (CH3O–
1H, CH2, JHH = −15.1, JPH = −7.1 Hz), 4.65 (d, 1H,
CHAr, 2JPH = −16.4 Hz), 7.50 (dd, 2H, Har., 3JHH = 8.9 Hz,
4JHH = 1.7 Hz), 8.33 (d, 2H, Har., 3JHH = 8.7 Hz). – 31P{ H}
1
NMR (D2O): δ = 8.75 (PO3H2), 48.56 (CH3P=O). –
C10H16N2O6P2 (322.191): calcd. C 37.28, H 5.01, N 8.69;
found C 37.38, H 5.21, N 8.41.
C6H4), 1175 (P=O), 1165 (P=O), 855 (Ph). – 1H NMR
2
(250.13 MHz, D2O): δ = 1.69 (d, 6H, (CH3)2P, JPH
=
=
=
=
2
2
−13.7 Hz), 3.44 (dd, 1H, CH2, JHH = −15.2 Hz, JPH
Acknowledgement
2
2
−7.2 Hz), 3.56 (dd, 1H, CH2, JHH = −15.2 Hz, JPH
−7.6 Hz), 3.86 (s, 3H, CH3OAr), 4.49 (d, 1H, CHAr, 2JPH
We would like to thank the Ministry of Education and Sci-
ence of the Republic of Bulgaria for the kind financial sup-
port.
−15.8 Hz), 7.09 (d, 2H, Har.
,
3JHH = 8.7 Hz), 7.50 (dd,
3
4
2H, Har., JHH = 8.5 Hz, JHH = 1.7 Hz). – C11H19NO5P2
[1] a) P. Mastalerz, P. Kafarski, in Aminophosphonic
and Aminophosphinic Acids, Chemistry and Biolog-
ical Activity, (Eds.: V. P. Kukhar, H. R. Hudson),
John Wiley, Chichester-Toronto, 2000, chapter 1,
pp. 1 – 32; b) J. Oleksyzsyn, in Aminophosphonic
and Aminophosphinic Acids, Chemistry and Biolog-
ical Activity, (Eds.: V. P. Kukhar, H. R. Hudson),
John Wiley, Chichester-Toronto, 2000, chapter 15,
pp. 537 – 558; c) H. R. Hudson, in Aminophospho-
nic and Aminophosphinic Acids, Chemistry and Bio-
logical Activity, (Eds.: V. P. Kukhar, H. R. Hudson),
John Wiley, Chichester-Toronto, 2000, chapter 13,
pp. 443 – 474.
[2] S. Laschat, H. Kunz, Synthesis 1992, 90 – 95.
[3] S. Bhagat, A. Chakraborti, J. Org. Chem. 2007, 72,
1263 – 1270.
[4] J. Wu, W. Sun, H.-G. Xia, X. Sun, Org. Biomol. Chem.
2006, 4, 1663 – 1666.
[5] T. Akiyama, M. Sanada, K. Fuchibe, Synlett 2003,
1463 – 1464.
Unauthenticated
Download Date | 11/18/19 3:59 AM

1198
Y. Zagraniarsky et al. · Dimethylphosphinyl-substituted α-Amino(aryl)methylphosphonic Acids
[6] T. Cholakova, Y. Zagraniarsky, G. Ha¨gele, T. Tosheva,
[9] C. Hubert, B. Oussaid, G. Etemad-Moghadam,
M. Koenig, B. Garriguea, Synthesis 1994, 51 – 55.
[10] L. Cottier, G. Descotes, G. Gonera, G. Grabowski,
J. Lewkowski, R. Skowronski, Phosphorus, Sulfur and
Silicon 1996, 118, 181 – 188.
[11] D. Green, U. Gruss, G. Ha¨gele, H. R. Hudson, L. Lind-
blom, M. Pianka, Phosphorus, Sulfur and Silicon 1996,
113, 179 – 207.
B. Ivanova, R. Scopelliti, S. Varbanov, Z. Naturforsch.
2005, 60b, 215 – 220.
[7] T. Cholakova, Y. Zagraniarsky, S. Simova, S. Varbanov,
A. Dobrev, Phosphorus, Sulfur and Silicon 2005, 180,
1721 – 1728.
[8] S. Varbanov, A. Georgieva, G. Ha¨gele, H. Keck,
V. Lachkova, Phosphorus, Sulfur and Silicon 2000,
159, 109 – 121.
Unauthenticated
Download Date | 11/18/19 3:59 AM