A one-pot, three-step synthesis of α-aminophosphonic acids

Article abstract of DOI:10.1055/s-0033-1341064

A total of 20 α-aminophosphonic acids are synthesized in 73-89% yields via a one-pot, three-step procedure involving chlorotrimethylsilane- promoted condensation of carbonyl compounds and primary amines yielding azomethine intermediates, subsequent reaction with tris(trimethylsilyl) phosphite to give the corresponding trimethylsilylphosphonic esters and finally, mild cleavage with methanol-water. The wide scope and simple set-up and work-up procedures of the reported method allow the synthesis of a diverse set of α-aminophosphonic acids possessing two different functional groups. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1341064

PAPER
▌2079
paper
A One-Pot, Three-Step Synthesis of α-Aminophosphonic Acids
Synthesis of α-Aminophosphonic Acids
Sergey V. Ryabukhin,*a,b Dmitriy M. Panov,b Alexander N. Shivanyuk,a Andrey S. Plaskon,b
Evgeniy N. Zarudnitskiy,c Oleg Lukind
a
The Institute of High Technologies, Kyiv National Taras Shevchenko University, 4 Glushkov str., Building 5, Kyiv 03187, Ukraine
Fax +38(050)6424763; E-mail: s.v.ryabukhin@gmail.com
b
Department of Chemistry, Kyiv National Taras Shevchenko University, 64 Volodymyrska str., Kyiv 01601, Ukraine
c
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanska str., Kyiv 02094, Ukraine
d
Curplyx DRS, JSC Macrochem 7th Floor, KOMOD Business Center, 4 Lunacharski str., Kyiv 02002, Ukraine
Received: 05.02.2014; Accepted after revision: 06.03.2014
A few synthetic methodologies have been developed to
vary the nature of the R1 and R2 groups in order to influ-
ence the biological activity of the α-aminophosphonic
acids. For example, N-substituted α-aminomethanephos-
Abstract: A total of 20 α-aminophosphonic acids are synthesized
in 73–89% yields via a one-pot, three-step procedure involving
chlorotrimethylsilane-promoted condensation of carbonyl com-
pounds and primary amines yielding azomethine intermediates,
subsequent reaction with tris(trimethylsilyl) phosphite to give the phonic acids were synthesized in one step through a
Mannich-type reaction of a primary amine (R1NH2),
corresponding trimethylsilylphosphonic esters and finally, mild
cleavage with methanol–water. The wide scope and simple set-up
and work-up procedures of the reported method allow the synthesis
Both the R1 and R2 groups can be varied via a two-step ap-
of a diverse set of α-aminophosphonic acids possessing two differ-
ent functional groups.
formaldehyde (CH2O) and phosphonic acid (H3PO3).8
proach comprising the synthesis and hydrolysis of α-ami-
nophosphonates A (Scheme 1). Compounds A were
Key words: α-aminophosphonic acids, aldehydes, amines, chlo-
prepared through either a one-pot Kabachnik–Fields
rotrimethylsilane, tris(trimethylsilyl) phosphite, one-pot synthesis
reaction9 of carbonyl compounds, primary amines, and a
dialkyl phosphonate [(AlkO)2P(O)H] (Scheme 1), or via
hydrophosphonylation of azomethines with a dialkyl
α-Aminophosphonic acids 1 (Scheme 1) are analogues of
phosphonate.10 A mild Lewis acid catalyzed hydrophos-
α-amino acids in which the carboxylic group is replaced
phonylation of azomethines afforded α-aminophospho-
with a dihydroxyphosphoryl functionality.1 α-Amino-
nates in high yields.11 Dialkyl α-aminophosphonates of
phosphonic acids possess a wide spectrum of biological
type A were prepared in 85–98% yields through a one-pot
chlorotrimethylsilane-promoted reaction of aldehydes
activity.2 For example, oligopeptides incorporating an α-
aminophosphonic acid group are excellent inhibitors of
with primary amines, followed by a lithium perchlorate
proteolytic enzymes.3 Additionally, many derivatives of
(LiClO4) activated reaction with a trialkyl phosphite
α-aminophosphonic acids have been shown to possess an-
[P(OAlk)3].12 Compounds A were also converted into α-
tibacterial,4 antiviral5 and antifungal6 activities. Some α-
aminophosphonic acids, such as glyphosate, glufosinate
and bilanafos are environmentally friendly commercial
aminophosphonic acids through an acid-catalyzed
hydrolysis13 or, in the case of dibenzylphosphonates, by
catalytic hydrogenation.14 The reaction of α-aminophos-
herbicides.7 In connection with the important applications
phonates with bromotrimethylsilane (Me3SiBr)15 or iodo-
of the title structures, a range of synthetic pathways to α-
aminophosphonic acids has been developed. Previously
reported synthetic routes to α-aminophosphonic acids are
summarized in Scheme 1.
trimethylsilane (Me3SiI)16 resulted in the corresponding
trimethylsilyl esters, which were then hydrolyzed with
methanol–water. To avoid the transesterification step, tri-
methylsilylphosphonates were obtained directly through
an Abramov-type reaction of tris(trimethylsilyl) phos-
phite [(Me3SiO)3P] with various electrophilic reagents.
For example, the reaction of tris(trimethylsilyl) phosphite
with carbonyl compounds followed by mild hydrolysis af-
forded α-hydroxyphosphonic acids,17 whereas treatment
of acid chlorides or anhydrides with two molar equiva-
lents of tris(trimethylsilyl) phosphite gave the corre-
sponding hydroxymethylene bisphosphonic acids.18
Trimethylsilyl esters of α-aminophosphonic acids were
also synthesized through the reactions of tris(trimethylsi-
lyl) phosphite with aminoacetals19 and azomethines.20
R1
R1
P
R1
P
H2N
+
HN
R2
HN
R2
O
O
O
P(OX)3
HO
OH
XO
OX
R2
1
A
B
Scheme 1 A basic retrosynthetic analysis of α-aminophosphonic acids
However, the procedures mentioned above cannot be used
for the parallel synthesis of α-aminophosphonic acids on
account of either a narrow scope, or technical complica-
tions with the two-step procedures, such as the isolation
SYNTHESIS 2014, 46, 2079–2084
Advanced online publication: 11.04.2014
DOI: 10.1055/s-0033-1341064; Art ID: SS-2014-Z0091-OP
© Georg Thieme Verlag Stuttgart · New York
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0
3
9
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7
8
8
1
1
4
3
7
-
2
1
0
X

2080
S. V. Ryabukhin et al.
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and purification of intermediates. In this contribution, we spectively. Consequently, the optimization studies re-
describe a one-pot, three-step synthesis of α-aminophos- vealed that a 1:1:3 ratio of reactants (2a:3a:Me3SiCl) in
phonic acids. The process involves: (1) the chlorotrimeth- acetonitrile at room temperature were the best conditions
ylsilane-promoted generation of azomethines from for the synthesis of compound 4a. Our subsequent at-
various aldehydes and amines, (2) reaction with tris(tri- tempts at cleavage of the ethyl groups of 4a in the same
methylsilyl) phosphite to give trimethylsilylphosphonate reaction pot, by the action of bromotrimethylsilane and
intermediates, and (3) mild hydrolysis to afford the target varying the reaction temperature were unsuccessful. On
α-aminophosphonic acids.
the basis of the obtained results and those reported in the
literature (see the introductory section), we reasoned that
the use of tris(trimethylsilyl) phosphite instead of triethyl
phosphite should not influence the yield of the corre-
sponding trimethylsilyl analogue of 4a (Scheme 2). At the
same time, trimethylsilylphosphonates are known to hy-
drolyze smoothly, thereby simplifying the preparation of
the α-aminophosphonic acids in the same reaction pot.
We previously reported a chlorotrimethylsilane-promoted
combinatorial synthesis of azomethines from various
amines and carbonyl compounds.21 In this connection, our
attention was drawn by the aforementioned high-yielding,
one-pot preparation of dialkyl α-aminophosphonates via
the chlorotrimethylsilane/lithium perchlorate mediated
reaction of aldehydes, primary amines, and a trialkyl
phosphite.12 The large excess of lithium perchlorate used
in the reported procedure to facilitate the addition of the
trialkyl phosphite to the azomethine intermediate compli-
cated the isolation and purification steps. This fact makes
the procedure, to a large degree, impractical from the
combinatorial synthesis standpoint. In an attempt to opti-
mize the one-pot preparation of α-aminophosphonates, we
carried out a series of model experiments in which, as
shown in Scheme 2, aniline (2a) was reacted with an equi-
molar amount of benzaldehyde (3a) in the presence of dif-
ferent quantities of chlorotrimethylsilane and lithium
perchlorate in acetonitrile. After sonication of the solution
containing 2a, 3a, chlorotrimethylsilane and lithium per-
chlorate at room temperature for two hours, triethyl phos-
phite [P(OEt)3] was added and the mixture was sonicated
for another two hours. The formation of product 4a was
monitored by 31P NMR spectroscopy of the reaction mix-
ture.
Ph
HN
NH2
i, ii
O
O
O
+
Ph
P
solvent
O
Me3Si
SiMe3
2a
3a
5
iii
Ph
HN
O
Ph
P
HO
OH
1aa
87%
Scheme 3 Preparation of aminophosphonic acid 1aa. Reagents and
conditions: (i) Me3SiCl, r.t.; (ii) P(OSiMe3)3, r.t.; (iii) MeOH–H2O.
The one-pot, three-step synthesis of α-aminophosphonic
acids was optimized using the reaction of aniline (2a) and
benzaldehyde (3a) (Scheme 3) as a model system, by
varying the solvent and the quantity of chlorotrimethylsi-
lane. In a series of experiments similar to those carried out
with the use of triethyl phosphite (see Scheme 2), it was
found that addition of tris(trimethylsilyl) phosphite to the
azomethine intermediate proceeded smoothly in the pres-
ence of three equivalents of chlorotrimethylsilane (with
respect to 2a or 3a) in acetonitrile, 1,4-dioxane or THF to
Ph
HN
NH2
i, ii
O
O
+
Ph
P
MeCN
EtO
4a
38–98%
OEt
2a
3a
Scheme 2 Preparation of diethyl α-aminophosphonate 4a. Reagents
and conditions: (i) Me3SiCl, LiClO4, r.t.; (ii) P(OEt)3, r.t. See text for give α-aminophosphonate 5 (Scheme 3). Compound 5
details.
was hydrolyzed in situ by simply triturating with metha-
nol–water. It was found that the use of a 1:1:3:1 ratio of
reactants [2a:3a:Me3SiCl:P(OSiMe3)3] in anhydrous ace-
tonitrile gave the highest yield of 1aa (optimized condi-
tions). It is noteworthy that the simultaneous addition of
2a, 3a, chlorotrimethylsilane and tris(trimethylsilyl)
phosphite under the optimized conditions, followed by
triturating the reaction mixture with methanol–water gave
an inseparable mixture of 1aa (70%) and the correspond-
ing α-hydroxyphosphonic acid (30%). It was proved in a
separate experiment [by the reaction of 3a with
P(OSiMe3)3 in the presence of Me3SiCl)] that the latter
compound stemmed from a chlorotrimethylsilane-mediat-
ed addition of tris(trimethylsilyl) phosphite to aldehyde
3a. Therefore, it is important to ensure complete conver-
sion of 2a and 3a into the azomethine intermediate prior
to the addition of tris(trimethylsilyl) phosphite. The opti-
The first experiment in which 2a, 3a, chlorotrimethylsi-
lane and lithium perchlorate were mixed in a molar ratio
of 1:1:1:10 showed a moderate conversion of 38%. Inter-
estingly, the exclusion of lithium perchlorate in a second
experiment, while leaving all the other reagents and con-
ditions unchanged, led to the formation of nearly the same
amount of 4a (42%). This observation seemed to indicate
that chlorotrimethylsilane not only promoted the forma-
tion of the azomethine intermediate, but also the addition
of triethyl phosphite to the latter. Therefore, it was envis-
aged that addition of a larger amount of chlorotrimethyl-
silane would lead to an increase in the conversion. Indeed,
the use of two and three equivalents of chlorotrimethylsi-
lane (with respect to 2a or 3a) afforded compound 4a in
high (81%) and nearly quantitative (98%) conversions, re-
Synthesis 2014, 46, 2079–2084
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of α-Aminophosphonic Acids
2081
mization studies showed that a reaction time of two hours
was sufficient for complete generation of the azomethine.
As shown in Scheme 4, the optimum reaction conditions
were applied to primary amines 2a–m (Figure 1) and car-
bonyl compounds 3a–j (Figure 2) to afford 20 α-amino-
phosphonic acids 1 in 73–89% yields. Compounds 1
normally precipitated from the reaction mixtures at room
temperature. They were purified by filtering and washing
with methanol. When precipitates did not form, the reac-
tion mixtures were reduced in volume through partial
evaporation of the solvent and crude compounds 1 were
triturated with methanol, filtered, and washed with cold
methanol. These simple work-up procedures afforded
compounds 1 in >95% purity according to the NMR and
LC–MS analyses.
F
MeO
O
O
O
O
3a
3b
3c
3d
H
N
O
O
O
O
S
OH
3e
3f
3g
O2N
O
O
O
S
3h
3i
3j
Figure 2 The selection of carbonyl compounds used for the synthe-
sis of α-aminophosphonic acids 1
R1
HN
ingly, seven out of the 20 phosphonic acids reported here
have been prepared before by other methods, and the re-
ported melting regions for these compounds were often
quite different to those obtained here (see the Supporting
Information for details). The differences found in the re-
ported and observed melting regions might be due to the
different isolation procedures.
i, ii, iii
O
NH2
R2
O
R1
2a–m
R2
P
+
MeCN
HO
OH
3a–j
1
73–89%
Scheme 4 Preparation of aminophosphonic acids 1 using the opti-
mized conditions: (i) Me3SiCl, r.t., sonication, 2 h; (ii) P(OSiMe3)3,
r.t., sonication, 2 h; (iii) MeOH–H2O work-up.
In conclusion, the described one-pot, three-step synthetic
procedure was validated by preparing 20 structurally di-
verse α-aminophosphonic acids. The main benefits of the
described method are easily available reagents, ambient
conditions for all three reaction steps, and simple reaction
work-up and product purification. These advantages indi-
cate that the method should be easily adaptable for the
parallel synthesis of sizable collections of α-aminophos-
phonic acids.
NH2
NH2
NH2
NH2
2a
2c
2d
2b
Me2N
NH2
NH2
NH2
NH2
2e
2f
2g
2h
Me
N
S
Solvents were purified according to standard procedures. Starting
materials were purchased from Acros, Merck or Fluka. Analytical
TLC was performed using Polychrom SI F254 plates. Column chro-
matography was performed using Kieselgel Merck 60 (230–400
mesh) silica gel as the stationary phase. A VWR USC 500 T ultra-
sonic bath was used for sonication. Melting points were measured
on a Buchi melting point apparatus and are uncorrected. NMR spec-
tra were recorded on a Bruker 170 Avance 500 spectrometer (500
MHz for 1H and NOE, 125 MHz for 13C and 202 MHz for 31P), and
NH2
NH2
Me2N
NH2
Cl
2i
2j
2k
F
N
N
NH2
1
NH2
a Varian Unity Plus 400 spectrometer (400.4 MHz for H), using
2l
2m
TMS as the internal standard. Mass spectra were recorded on an
Agilent 1100 LCMSD SL instrument (CI) and Agilent 5890 Series
II 5972 GC–MS instrument (EI). Elemental analyses were carried
out on a Vario MICRO Cube (Elementar) Elemental Micro-Analyzer.
Figure 1 The selection of amines used for the synthesis of α-amino-
phosphonic acids 1
α-Aminophosphonic Acids 1; General Procedure
The structures and compositions of compounds 1 were
confirmed by 1H, 13C and 31P NMR spectroscopy, LC–MS
and elemental analysis. The 1H NMR spectra of α-amino-
phosphonic acids 1 derived from aldehydes contained sig-
nals for the R1 and R2 groups and a pronounced doublet
(2JH,P = 15–25 Hz) at 4.1–5.3 ppm for the methine proton
at the α-position relative to the phosphonate group. The 1H
NMR (DMSO-d6) signals of the protons due to the NH
and OH groups of compounds 1 were difficult to observe,
presumably on account of their mutual exchange. Interest-
Me3SiCl (0.432 g, 4 mmol) was added dropwise to a solution of
amine 2 (1 mmol) and carbonyl compound 3 (1 mmol) in anhydrous
MeCN (1.5–2 mL), and the resulting mixture was sonicated for 2 h
at r.t. P(OSiMe3)3 (0.328 g, 1.1 mmol) was added dropwise and the
mixture was sonicated for another 2 h at r.t. The mixture was diluted
with MeOH (5 mL) and H2O (0.1 mL, 5 mmol). Dilution normally
caused precipitation of the product. The precipitated product was
filtered and washed with MeOH (1 mL). In cases where no precipi-
tation occurred, the mixture was further sonicated for 2 h and then
left to stand for 24 h at 0 °C. Alternatively, the solvents were re-
moved under reduced pressure and the residue was triturated with
cold MeOH (2 mL) and filtered.
© Georg Thieme Verlag Stuttgart · New York
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2082
S. V. Ryabukhin et al.
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[Phenyl(phenylamino)methyl]phosphonic Acid (1aa)
31P NMR (202 MHz, CF3COOD): δ = 14.4.
MS (APSI): m/z = 228 [M – 1]+.
Yield: 0.23 g (87%); colorless crystals; mp 115–117 °C.
1H NMR (500 MHz, DMSO-d6): δ = 4.67 (d, 2JP,H = 24.2 Hz, 1 H),
6.52 (t, 3JH,H = 7.3 Hz, 1 H), 6.68 (d, 3JH,H = 7.8 Hz, 2 H), 7.02 (t,
3JH,H = 7.8 Hz, 2 H), 7.20 (t, 3JH,H = 7.3 Hz, 1 H), 7.28 (t, 3JH,H = 7.3
Hz, 2 H), 7.47 (d, 3JH,H = 7.8 Hz, 2 H).
13C NMR (125 MHz, DMSO-d6): δ = 56.7 (d, 1JC,P = 142 Hz), 114.1,
117.3, 127.2, 128.2, 128.7 (d, 3JC,P = 5 Hz), 129.1, 138.7, 147.6 (d,
2JC,P = 14 Hz).
Anal. Calcd for C10H16NO3P: C, 52.40; H, 7.04; N, 6.11. Found: C,
52.32; H, 6.89; N, 6.27.
[(Butylamino)(phenyl)methyl]phosphonic Acid (1fa)
Yield: 0.17 g (73%); colorless crystals; mp 231–233 °C.
1H NMR (500 MHz, DMSO-d6): δ = 0.76 (t, 3JH,H = 7.3 Hz, 3 H),
1.10–1.24 (m, 2 H), 1.53–1.67 (m, 2 H), 2.74–2.79 (m, 1 H), 2.87–
2
31P NMR (202 MHz, DMSO-d6): δ = 18.6.
MS (APSI): m/z = 262 [M – 1]+.
2.95 (m, 1 H), 4.46 (d, JP,H = 16.9 Hz, 1 H), 7.34–7.38 (m, 3 H),
7.52 (d, 3JH,H = 7.2 Hz, 2 H).
13C NMR (125 MHz, DMSO-d6): δ = 12.9, 19.4, 27.1, 47.0 (d,
Anal. Calcd for C13H14NO3P: C, 59.32; H, 5.36; N, 5.32. Found: C,
59.47; H, 5.27; N, 5.42.
3JC,P = 5 Hz), 59.6 (d, 1JC,P = 144 Hz), 128.7, 129.0, 129.7 (d, 2JC,P
=
5 Hz), 131.5 (d, 3JC,P = 4 Hz).
[Phenyl(p-tolylamino)methyl]phosphonic Acid (1ba)
31P NMR (202 MHz, DMSO-d6): δ = 12.0.
MS (APSI): m/z = 242 [M – 1]+.
Yield: 0.22 g (85%); colorless crystals; mp 139–141 °C.
1H NMR (500 MHz, DMSO-d6): δ = 2.10 (s, 3 H), 4.63 (d, 2JP,H
=
Anal. Calcd for C11H18NO3P: C, 54.32; H, 7.46; N, 5.76. Found: C,
54.18; H, 7.55; N, 5.88.
24.5 Hz, 1 H), 6.58 (d, 3JH,H = 8.1 Hz, 2 H), 6.82 (d, 3JH,H = 8.1 Hz,
2 H), 7.19 (t, 3JH,H = 7.1 Hz, 1 H), 7.27 (t, 3JH,H = 7.1 Hz, 2 H), 7.45
(d, 3JH,H = 7.1 Hz, 2 H).
[(Cyclohexylamino)(phenyl)methyl]phosphonic Acid (1ga)
Yield: 0.20 g (78%); colorless crystals; mp 192–194 °C.
13C NMR (125 MHz, DMSO-d6): δ = 20.5, 56.9 (d, 1JC,P = 145 Hz),
3
1H NMR (500 MHz, DMSO-d6): δ = 0.90–1.11 (m, 3 H), 1.21–1.39
(m, 2 H), 1.48–1.58 (m, 1 H), 1.63–1.69 (m, 2 H), 1.95–2.08 (m, 1
H), 2.89–2.97 (m, 1 H), 4.51 (d, 2JP,H = 17.1 Hz, 2 H), 7.40 (s, 3 H),
7.55 (s, 2 H).
13C NMR (125 MHz, DMSO-d6): δ = 23.6, 23.7, 27.4, 30.1 (d,
3JC,P = 4 Hz), 57.4 (d, 1JC,P = 145 Hz), 126.6, 128.5 (d, 2JC,P = 6 Hz),
129.7, 130.7.
114.2, 125.8, 127.1, 128.2, 128.6 (d, JC,P = 5 Hz), 129.6, 138.8,
145.3 (d, 2JC,P = 14 Hz).
31P NMR (202 MHz, DMSO-d6): δ = 18.9.
MS (APSI): m/z = 276 [M – 1]+.
Anal. Calcd for C14H16NO3P: C, 60.65; H, 5.82; N, 5.05. Found: C,
60.52; H, 5.69; N, 5.12.
[(Benzylamino)(Phenyl)methyl]phosphonic Acid (1ca)
31P NMR (202 MHz, DMSO-d6): δ = 12.1.
MS (APSI): m/z = 268 [M – 1]+.
Yield: 0.21 g (78%); colorless crystals; mp 238–240 °C.
1H NMR (500 MHz, DMSO-d6): δ = 4.09 (d, 2JH,H = 13.4 Hz, 1 H),
4.15 (d, 2JH,H = 13.4 Hz, 1 H), 4.27 (d, 2JP,H = 17.0 Hz, 1 H), 7.30–
7.35 (m, 8 H), 7.45 (d, 3JH,H = 6.3 Hz, 2 H).
Anal. Calcd for C13H20NO3P: C, 57.99; H, 7.49; N, 5.20. Found: C,
57.82; H, 7.35; N, 5.28.
13C NMR (125 MHz, DMSO-d6): δ = 50.3 (d, 3JC,P = 5 Hz), 57.7 (d,
1JC,P = 147 Hz), 128.6, 128.7, 129.1 (d, 3JC,P = 2 Hz), 129.3, 129.8,
129.9, 130.8, 131.1 (d, 2JC,P = 5 Hz).
31P NMR (202 MHz, DMSO-d6): δ = 11.5.
MS (APSI): m/z = 276 [M – 1]+.
({[2-(Dimethylamino)ethyl]amino}[phenyl]methyl)phosphonic
Acid (1ha)
Yield: 0.21 g (82%); colorless crystals; mp 162–163 °C.
1H NMR (500 MHz, DMSO-d6): δ = 2.48 (s, 6 H), 2.67–2.81 (m, 1
H), 2.84–2.96 (m, 1 H), 3.06–3.16 (m, 2 H), 4.08 (d, 2JP,H = 18.1 Hz,
1 H), 7.25–7.37 (m, 1 H), 7.53–7.62 (m, 2 H).
13C NMR (125 MHz, DMSO-d6): δ = 42.9, 44.5, 55.5 (d, 3JC,P = 4
Anal. Calcd for C14H16NO3P: C, 60.65; H, 5.82; N, 5.05. Found: C,
60.55; H, 5.70; N, 5.16.
Hz), 61.5 (d, 1JC,P = 137 Hz), 127.4, 128.3, 129.5, 137.5 (d, 2JC,P
=
5 Hz).
[(Phenethylamino)(phenyl)methyl]phosphonic Acid (1da)
Yield: 0.22 g (75%); colorless crystals; mp 263–265 °C.
31P NMR (202 MHz, DMSO-d6): δ = 11.7.
MS (APSI): m/z = 257 [M – 1]+.
1H NMR (500 MHz, DMSO-d6): δ = 2.89–3.00 (m, 2 H), 3.00–3.10
(m, 1 H), 3.14–3.22 (m, 1 H), 4.51 (d, 2JP,H = 17.0 Hz, 1 H), 7.05 (d,
3JH,H = 7.3 Hz, 2 H), 7.12 (t, 3JH,H = 7.3 Hz, 1 H), 7.15–7.21 (m, 2
H), 7.31–7.38 (m, 3 H), 7.52 (d, 3JH,H = 6.8 Hz, 2 H).
Anal. Calcd for C11H19N2O3P: C, 51.16; H, 7.42; N, 10.85. Found:
C, 51.03; H, 7.38; N, 11.01.
13C NMR (125 MHz, DMSO-d6): δ = 31.5, 48.4, 59.2 (d, 1JC,P = 144
Hz), 126.9, 128.6, 128.7, 128.8, 129.1, 129.7 (d, 2JC,P = 6 Hz), 131.3
(d, 3JC,P = 5 Hz), 137.2.
31P NMR (202 MHz, DMSO-d6): δ = 11.9.
MS (APSI): m/z = 290 [M – 1]+.
({[3-(Dimethylamino)propyl]amino}[phenyl]methyl)phosphon-
ic Acid (1ia)
Yield: 0.23 g (82%); colorless crystals; mp 156–158 °C.
1H NMR (500 MHz, DMSO-d6): δ = 2.12–2.22 (m, 2 H), 2.68 (s, 6
H), 2.83–2.90 (m, 1 H), 3.01–3.21 (m, 3 H), 4.51 (d, 2JP,H = 16.5 Hz,
1 H), 7.37–7.47 (m, 3 H), 7.58–7.67 (m, 2 H).
13C NMR (125 MHz, DMSO-d6): δ = 20.8, 42.3, 44.4, 53.9, 60.2,
(d, 1JC,P = 138 Hz), 128.8, 128.9, 130.0 (d, 3JC,P = 5 Hz), 132.8 (d,
2JC,P = 4 Hz).
31P NMR (202 MHz, DMSO-d6): δ = 10.8.
MS (APSI): m/z = 271 [M – 1]+.
Anal. Calcd for C15H18NO3P: C, 61.85; H, 6.23; N, 4.81. Found: C,
61.64; H, 6.10; N, 4.84.
[(Isopropylamino)(phenyl)methyl]phosphonic Acid (1ea)
Yield: 0.18 g (79%); colorless crystals; mp 241–243 °C.
1H NMR (500 MHz, CF3COOD): δ = 1.56 (t, 3JH,H = 7.6 Hz, 6 H),
3.50–3.74 (m, 1 H), 5.02 (d, 2JP,H = 14.7 Hz, 1 H), 7.63 (s, 5 H).
Anal. Calcd for C12H21N2O3P: C, 52.93; H, 7.77; N, 10.29. Found:
C, 52.80; H, 7.72; N, 10.34.
13C NMR (125 MHz, CF3COOD): δ = 17.6, 19.6, 48.8 (d, 3JC,P = 4
Hz), 59.2 (d, 1JC,P = 145 Hz), 126.8, 128.4, 129.7, 130.6.
Synthesis 2014, 46, 2079–2084
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Synthesis of α-Aminophosphonic Acids
2083
3
[({2-[Methyl(phenyl)amino]ethyl}amino)(phenyl)methyl]phos-
phonic Acid (1ja)
2 H), 6.98–7.06 (m, 3 H), 7.18 (t, JH,H = 7.5 Hz, 1 H), 7.25 (d,
3JH,H = 7.5 Hz, 1 H), 7.29 (s, 1 H).
Yield: 0.28 g (89%); colorless crystals; mp 222–224 °C.
13C NMR (125 MHz, DMSO-d6): δ = 21.6, 56.5 (d, 1JC,P = 149 Hz),
113.7, 116.9, 125.8 (d, 3JC,P = 5 Hz), 127.9 (d, 3JC,P = 3 Hz), 128.1,
129.1, 129.2, 137.1, 138.9 (d, 3JC,P = 2 Hz), 148.1 (d, 2JC,P = 14 Hz).
31P NMR (202 MHz, DMSO-d6): δ = 19.0.
MS (APSI): m/z = 276 [M – 1]+.
1H NMR (500 MHz, CF3COOD): δ = 3.48 (s, 3 H), 3.47–3.57 (m, 2
H), 4.26–4.38 (m, 2 H), 4.86 (d, 2JP,H = 17.2 Hz, 1 H), 7.45–7.62 (m,
7 H), 7.62–7.67 (m, 3 H).
13C NMR (125 MHz, CF3COOD): δ = 42.5, 46.8, 54.8, 62.2 (d,
1JC,P = 143 Hz), 119.9, 125.9, 128.4 (d, 3JC,P = 6 Hz), 129.8, 131.1,
131.3, 131.9, 138.1 (d, 2JC,P = 9 Hz).
31P NMR (202 MHz, CF3COOD): δ = 12.5, 12.6.
MS (APSI): m/z = 319 [M – 1]+.
Anal. Calcd for C14H16NO3P: C, 60.65; H, 5.82; N, 5.05. Found: C,
60.57; H, 5.70; N, 5.18.
[(Phenylamino)(thien-3-yl)methyl]phosphonic Acid (1ae)
Yield: 0.24 g (88%); colorless crystals; mp 132–133 °C.
Anal. Calcd for C16H21N2O3P: C, 59.99; H, 6.61; N, 8.75. Found: C,
59.87; H, 6.54; N, 8.80.
1H NMR (500 MHz, DMSO-d6): δ = 4.82 (d, 2JP,H = 23.5 Hz, 1 H),
6.56 (t, 3JH,H = 7.2 Hz, 1 H), 6.74 (d, 3JH,H = 7.6 Hz, 2 H), 7.02 (t,
3JH,H = 7.6 Hz, 2 H), 7.16–7.22 (m, 1 H), 7.38–7.42 (m, 2 H).
13C NMR (125 MHz, DMSO-d6): δ = 52.7 (d, 1JC,P = 147 Hz), 114.0,
117.5, 123.1 (d, 3JC,P = 8 Hz), 125.5, 128.7 (d, 3JC,P = 4 Hz), 129.2,
139.6, 147.6 (d, 2JC,P = 13 Hz).
31P NMR (202 MHz, DMSO-d6): δ = 18.4.
MS (APSI): m/z = 268 [M – 1]+.
[({2-[(4-Chlorophenyl)thio]ethyl}amino)(phenyl)methyl]phos-
phonic Acid (1ka)
Yield: 0.30 g (82%); colorless crystals; mp 258–260 °C.
1H NMR (500 MHz, CF3COOD): δ = 3.23–3.32 (m, 3 H), 3.41–3.51
(m, 1 H), 4.86 (d, 2JP,H = 17.8 Hz, 1 H), 7.18–7.30 (m, 4 H), 7.38–
7.48 (m, 4 H), 7.48–7.62 (m, 1 H).
1
13C NMR (125 MHz, CF3COOD): δ = 29.8, 46.2, 61.1 (d, JC,P
=
144 Hz), 126.3, 128.3 (d, 3JC,P = 5 Hz), 129.4, 129.5, 129.7, 130.7,
Anal. Calcd for C11H12NO3PS: C, 49.07; H, 4.49; N, 5.20. Found:
C, 48.95; H, 4.44; N, 5.31.
132.1, 134.8.
31P NMR (202 MHz, CF3COOD): δ = 13.5.
MS (APSI): m/z = 356 [M – 1]+.
[(2-Hydroxyphenyl)(phenylamino)methyl]phosphonic Acid
(1af)
Yield: 0.20 g (75%); colorless crystals; mp 131–134 °C.
Anal. Calcd for C15H17ClNO3PS: C, 50.35; H, 4.79; N, 3.91. Found:
C, 50.22; H, 4.71; N, 4.04.
1H NMR (500 MHz, DMSO-d6): δ = 5.01 (d, 2JP,H = 24.3 Hz, 1 H),
6.51 (t, 3JH,H = 7.3 Hz, 1 H), 6.68 (d, 3JH,H = 8.2 Hz, 2 H), 6.72 (t,
3JH,H = 7.3 Hz, 1 H), 6.89 (d, 3JH,H = 7.3 Hz, 1 H), 6.96–7.05 (m, 3
H), 7.36 (d, 3JH,H = 7.3 Hz, 1 H).
[(4-Fluorophenyl)(phenylamino)methyl]phosphonic Acid (1ab)
Yield: 0.24 g (84%); colorless crystals; mp 187–189 °C.
1H NMR (500 MHz, DMSO-d6): δ = 4.70 (d, 2JP,H = 24.4 Hz, 1 H),
6.53 (t, 3JH,H = 7.1 Hz, 1 H), 6.67 (d, 3JH,H = 8.0 Hz, 2 H), 7.01 (t,
3JH,H,F = 8.0 Hz, 2 H), 7.11 (t, 3JH,H,F = 8.0 Hz, 2 H), 7.45–7.55 (m,
2 H).
13C NMR (125 MHz, DMSO-d6): δ = 49.2 (d, 1JC,P = 150 Hz), 113.4,
115.8, 116.9, 119.4, 125.5, 128.1 (d, 3JC,P = 6 Hz), 128.9 (d, 3JC,P
=
4 Hz), 129.1, 148.8 (d, 2JC,P = 15 Hz), 155.7 (d, 3JC,P = 6 Hz).
31P NMR (202 MHz, DMSO-d6): δ = 20.4.
MS (APSI): m/z = 278 [M – 1]+.
13C NMR (125 MHz, DMSO-d6): δ = 55.7 (d, 1JC,P = 146 Hz), 113.8,
2
115.0 (d, JC,F = 22 Hz), 117.1, 129.2, 130.5 (m), 135.1, 147.8 (d,
2JC,P = 14 Hz), 161.2 (d, 1JC,F = 243 Hz).
31P NMR (202 MHz, DMSO-d6): δ = 16.8.
MS (APSI): m/z = 280 [M – 1]+.
Anal. Calcd for C13H14NO4P: C, 55.92; H, 5.05; N, 5.02. Found: C,
55.87; H, 4.94; N, 5.17.
[(4-Acetamidophenyl)(benzylamino)methyl]phosphonic Acid
(1cg)
Yield: 0.26 g (77%); colorless solid; mp 272–274 °C.
Anal. Calcd for C13H13FNO3P: C, 55.52; H, 4.66; N, 4.98. Found:
C, 55.43; H, 4.50; N, 5.08.
1H NMR (500 MHz, DMSO-d6): δ = 2.05 (s, 3 H), 3.72 (d, 2JH,H
=
[(4-Methoxyphenyl)(phenylamino)methyl]phosphonic Acid
(1ac)
Yield: 0.22 g (77%); colorless crystals; mp 162–163 °C.
11.3 Hz, 1 H), 3.80 (d, 2JH,P = 15.9 Hz, 1 H), 4.13 (d, 2JH,H = 11.3
Hz, 1 H), 7.30–7.45 (m, 7 H), 7.51–7.61 (m, 2 H), 10.18 (br s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 24.2, 49.3, 59.3 (d, 1JC,P = 134
1H NMR (500 MHz, DMSO-d6): δ = 3.71 (s, 3 H), 4.58 (d, 2JP,H
=
3
2
Hz), 119.1, 129.0, 129.1 (d, JC,P = 5 Hz), 130.3 (d, JC,P = 8 Hz),
17.4 Hz, 1 H), 6.51 (t, 3JH,H = 7.8 Hz, 1 H), 6.66 (d, 3JH,H = 7.8 Hz,
2 H), 6.85 (d, 3JH,H = 7.8 Hz, 2 H), 7.00 (t, 3JH,H = 7.8 Hz, 2 H), 7.37
(d, 3JH,H = 7.8 Hz, 2 H).
132.7, 134.6, 139.4, 162.8, 168.9.
31P NMR (202 MHz, DMSO-d6): δ = 9.1.
MS (APSI): m/z = 333 [M – 1]+.
13C NMR (125 MHz, DMSO-d6): δ = 55.5 (d, 1JC,P = 147 Hz), 55.6,
113.7, 116.9, 129.1, 129.7 (d, 3JC,P = 5 Hz), 130.7 (d, 3JC,P = 3 Hz),
148.1 (d, 2JC,P = 15 Hz), 159.2.
Anal. Calcd for C16H19N2O4P: C, 57.48; H, 5.73; N, 8.38. Found: C,
57.57; H, 5.80; N, 8.26.
31P NMR (202 MHz, DMSO-d6): δ = 19.3.
MS (APSI): m/z = 292 [M – 1]+.
{[(4-Fluorobenzyl)amino](4-nitrophenyl)methyl}phosphonic
Acid (1lh)
Yield: 0.27 g (79%); colorless crystals; mp 244–246 °C.
Anal. Calcd for C14H16NO4P: C, 57.34; H, 5.50; N, 4.78. Found: C,
57.17; H, 5.43; N, 4.88.
1H NMR (500 MHz, DMSO-d6): δ = 4.14–4.21 (m, 2 H), 4.51 (d,
2JP,H = 17.1 Hz, 1 H), 7.13 (t, 3JH,H,F = 8.5 Hz, 2 H), 7.50 (t, 3JH,H,F
=
[(Phenylamino)(m-tolyl)methyl]phosphonic Acid (1ad)
Yield: 0.23 g (82%); colorless crystals; mp 130–132 °C.
6.0 Hz, 2 H), 7.79 (d, 3JH,H = 8.2 Hz, 2 H), 8.20 (d, 3JH,H = 8.2 Hz, 2
H).
1H NMR (500 MHz, DMSO-d6): δ = 2.27 (s, 3 H), 4.60 (d, 2JH,P
=
13C NMR (125 MHz, DMSO-d6): δ = 49.7, 58.2 (d, 1JC,P = 134 Hz),
115.7 (d, JC,F = 22 Hz), 123.7, 128.1 (d, JC,F = 3 Hz), 131.1 (d,
15.2 Hz, 1 H), 6.52 (t, 3JH,H = 7.1 Hz, 1 H), 6.57 (d, 3JH,H = 8.1 Hz,
2
3
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2079–2084

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S. V. Ryabukhin et al.
PAPER
3JC,P = 4 Hz), 133.4 (d, 2JC,P = 11 Hz), 140.9, 147.7, 162.4 (d, 1JC,F
55 Hz).
31P NMR (202 MHz, DMSO-d6): δ = 10.2.
MS (APSI): m/z = 339 [M – 1]+.
=
(4) (a) Allen, J. G.; Atherton, F. R.; Hall, M. J.; Hassall, C. H.;
Holmes, S. W.; Lambert, R. W.; Nisbet, L. J.; Ringrose, P.
S. Nature 1978, 272, 56. (b) Pratt, R. F. Science 1989, 246,
917.
(5) Chen, M.-H.; Chen, Z.; Song, B.-A.; Bhadury, P. S.; Yang,
S.; Cai, X.-J.; Hu, D.-Y.; Xue, W.; Zeng, S. J. Agric. Food
Chem. 2009, 57, 1383.
Anal. Calcd for C14H14FN2O5P: C, 49.42; H, 4.15; N, 8.23. Found:
C, 49.49; H, 4.26; N, 8.11.
(6) Maier, L.; Diel, P. J. Phosphorus, Sulfur Silicon Relat. Elem.
1991, 57, 57.
({[(1-Phenyl-1H-pyrazol-4-yl)methyl]amino}(thien-2-yl)meth-
yl)phosphonic Acid (1mi)
(7) Duke, S. O.; Powles, S. B. Pest Manag. Sci. 2008, 64, 319.
(8) (a) Moedritzer, K.; Irani, R. R. J. Org. Chem. 1966, 31,
1603. (b) Lazar, I.; Sherry, A. D. Synthesis 1995, 453.
(c) Bazakas, K.; Lukes, I. J. Chem. Soc., Dalton Trans.
1995, 1133. (d) Convey, P. V.; Davey, R. J.; Griffin, J. L.;
Whiting, A. Chem. Commun. 1998, 1467.
Yield: 0.29 g (82%); colorless crystals; mp 246–247 °C.
1H NMR (500 MHz, DMSO-d6): δ = 4.43 (d, 2JH,H = 13.7 Hz, 1 H),
4.57 (d, 2JH,H = 13.7 Hz, 1 H), 5.32 (d, 2JP,H = 17.6 Hz, 1 H), 7.14–
7.22 (m, 1 H), 7.43 (br s, 1 H), 7.50–7.74 (m, 6 H), 8.56 (d, 3JH,H
=
8.5 Hz, 2 H).
13C NMR (125 MHz, DMSO-d6): δ = 40.1, 57.1 (d, 1JC,P = 147 Hz),
114.1, 122.5, 126.2 (d, 3JC,P = 5 Hz), 125.1, 129.9, 130.5, 132.2 (d,
2JC,P = 7 Hz), 132.4, 133.5, 136.8, 137.4.
31P NMR (202 MHz, DMSO-d6): δ = 11.6.
MS (APSI): m/z = 348 [M – 1]+.
(9) (a) Kabachnik, M. I.; Medved, T. Ya.; Dyatlova, N. M.;
Arkhipova, O. G.; Rudomino, M. V. Russ. Chem. Rev. (Engl.
Transl.) 1968, 38, 503. (b) Gallardo-Macias, R.; Nakayama,
K. Synthesis 2010, 57.
(10) (a) Alfonsov, V. A. Phosphorus, Sulfur Silicon Relat. Elem.
2008, 183, 2637. (b) Issleib, K.; Ralszuweit, A.; Richter, H.-
J.; Tonk, W. Z. Chem. 1983, 23, 434.
Anal. Calcd for C15H16N3O3PS: C, 51.57; H, 4.62; N, 12.03. Found:
C, 51.73; H, 4.73; N, 11.87.
(11) Firouzabadi, H.; Iranpoor, N.; Sobhani, S. Synthesis 2004,
2692.
[1-(Phenylamino)cyclohexyl]phosphonic Acid (1aj)
(12) Saidi, M. R.; Azizi, N. Synlett 2002, 1347.
(13) (a) Kudzin, Z. H.; Kotynski, A. Synthesis 1980, 1028.
(b) Huber, R.; Knierzinger, A.; Obrecht, J.-P.; Vasella, A.
Helv. Chim. Acta 1985, 68, 1730. (c) Liavielle, G.;
Hautefaye, P.; Schaeffer, C.; Boutin, J. A.; Cudennec, C. A.;
Pierre, A. J. Med. Chem. 1991, 34, 1998.
(14) (a) Bird, J.; Mello, R. C. D.; Harper, G. P.; Hunter, D. J.;
Karran, E. H. J. Med. Chem. 1994, 37, 158. (b) Jacobsen, E.
N.; Joly, G. D. J. Am. Chem. Soc. 2004, 126, 4102.
(15) (a) Maier, L.; Diel, P. J. Phosphorus, Sulfur Silicon Relat.
Elem. 1991, 57, 57. (b) Cherenok, S.; Kalchenko, V.;
Solovyov, A.; Tsymbal, I.; Failla, S.; Consiglio, G. A.;
Finocchiaro, P. Heteroat. Chem. 2001, 12, 58.
(16) Ntai, I.; Bachmann, B. O. Bioorg. Med. Chem. Lett. 2008,
18, 3068.
Yield: 0.19 g (74%); colorless crystals; mp 161–164 °C.
1H NMR (500 MHz, DMSO-d6): δ = 1.16–1.24 (m, 1 H), 1.37–1.52
(m, 5 H), 1.68–1.76 (m, 2 H), 2.12–2.18 (m, 2 H), 6.74 (t, 3JH,H = 7.2
Hz, 1 H), 7.10 (t, 3JH,H = 7.2 Hz, 2 H), 7.16 (d, 3JH,H = 7.2 Hz, 2 H).
13C NMR (125 MHz, DMSO-d6): δ = 20.4 (d, 3JC,P = 4 Hz), 25.4 (d,
1
2JC,P = 8 Hz), 29.6, 57.2 (d, JC,P = 158 Hz), 119.2, 119.5, 128.6,
144.4.
31P NMR (202 MHz, DMSO-d6): δ = 24.9.
MS (APSI): m/z = 254 [M – 1]+.
Anal. Calcd for C12H18NO3P: C, 56.47; H, 7.11; N, 5.49. Found: C,
56.38; H, 7.00; N, 5.62.
(17) (a) Bouchemal, N.; Lecouvey, M.; Mallard, I.; Migianu, E.
Tetrahedron Lett. 2004, 45, 4511. (b) Guliaiko, I. V.;
Kolodiazhnyi, O. I. Phosphorus, Sulfur Silicon Relat. Elem.
2008, 183, 677.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
(18) (a) Migianu-Griffoni, E.; Mbemba, C.; Burgada, R.;
Lecouvey, M.; Lecercle, D.; Taran, F. Tetrahedron 2009, 65,
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C.; Koscielski, L. A.; Oldfield, E. J. Med. Chem. 2006, 49,
5804.
(19) Nifant’ev, E. E.; Popkova, T. N.; Kukhareva, T. S.; Bekker,
A. R. J. Gen. Chem. USSR (Engl. Transl.) 1988, 58, 1550.
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A.; Tolmachev, A. A.; Shivanyuk, A. N. Mol. Diversity
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References
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Synthesis 2014, 46, 2079–2084
© Georg Thieme Verlag Stuttgart · New York