Application of bis(trimethylsilyl) phosphonite in the efficient preparation of new heterocyclic -aminomethyl- H -phosphinic acids

Article abstract of DOI:10.1055/s-0030-1258387

A simple, reproducible, and efficient preparation of new heterocyclic -aminomethyl-H-phosphinic acids is reported. The synthetic protocol is based on the application of bis(trimethylsilyl) phosphonite, as an efficient phosphorous nucleophile, in the reaction with the corresponding heterocyclic imines. Subsequent methanolysis of the addition intermediates leads to the expected heterocyclic -aminomethyl-H-phosphinic acids in fair to good yields. Additionally, acidic hydrolysis of benzhydrylamino derivatives allows the efficient preparation of free -aminomethyl-H-phosphinic acids in good yields and high purity after simple crystallization. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258387

PAPER
437
Application of Bis(trimethylsilyl) Phosphonite in the Efficient Preparation of
New Heterocyclic a-Aminomethyl-H-phosphinic Acids
Heterocyclic
a-
o
A
minomethy
m
l-
H
-phosphinic
A
ci
a
ds sz K. Olszewski,* Bogdan Boduszek
Department of Chemistry, Wroclaw University of Technology, Wybrzeze St. Wyspianskiego 27, 50-370 Wroclaw, Poland
Fax +48(71)3284064; E-mail: tomasz.olszewski@pwr.wroc.pl
Received 21 September 2010; revised 29 November 2010
ylsilyl) phosphonite as a nucleophile in the reaction with
Abstract: A simple, reproducible, and efficient preparation of new
imines.6 Additionally, recent examples of the asymmetric
heterocyclic a-aminomethyl-H-phosphinic acids is reported. The
synthesis of a-aminoalkyl-H-phosphinic acids include the
synthetic protocol is based on the application of bis(trimethylsilyl)
phosphonite, as an efficient phosphorous nucleophile, in the reac-
use of ethyl (1,1-diethoxyethyl){[(diphenylmethyl-
tion with the corresponding heterocyclic imines. Subsequent meth- ene)amino]methyl}phosphinate,7 addition of ethyl
anolysis of the addition intermediates leads to the expected
heterocyclic a-aminomethyl-H-phosphinic acids in fair to good
diethoxymethyl-H-phosphinate to N-(tert-butylsulfi-
nyl)ketimines,8 as well as enzymatic preparation9
yields. Additionally, acidic hydrolysis of benzhydrylamino deriva-
(Scheme 1).
tives allows the efficient preparation of free a-aminomethyl-H-
In spite of the existence of several different techniques for
the synthesis of aliphatic and aromatic amino H-phos-
phinic acids (Scheme 1) surprisingly literature data con-
cerning the preparation of heterocyclic derivatives is
scarce. It is well known that small and simple heteroaro-
matics often have complex biological properties and be-
long to one of the most important classes of compounds in
medicinal chemistry.10 Especially amines containing five-
membered heteroaryl groups such as furans, thiophenes,
thiazoles, and pyrazoles are widely found in both natural
products and drugs.11 Therefore, the union of a heteroaro-
matic fragment with a phosphorus-containing moiety
could result in valuable chemical and biological proper-
ties of such heteroaromatic phosphonates and their deriv-
atives, and their usefulness as, for example, enzyme
inhibitors or chelating agents for heavy metal ions.1,12,13
However, the main difficulty in the synthesis of heterocy-
clic a-amino-H-phosphinic acids is, most probably, the
inapplicability of regular synthetic protocols due to the
possibility of decomposition of some heterocyclic moi-
eties and the occurrence of side reactions e.g. oxidation of
phosphinic acids in good yields and high purity after simple crystal-
lization.
Key words: heterocycles, phosphorus, aldehydes, imines, hydroly-
sis
a-Aminoalkyl-H-phosphinic acids, as isosters of the natu-
ral a-aminoalkylcarboxylic acids, and short peptides in-
corporating this unit (i.e., phosphinic acid peptides)
represent a very convenient mimic of a substrate in the
transition state of hydrolytic enzymes and, therefore, they
are considered as excellent enzyme inhibitors.1 The effi-
cient synthesis of functionalized phosphinic peptides,
however, is not a trivial issue and usually depends on the
ready availability of simple a-aminoalkyl-H-phosphinic
acids, as building blocks.2
Classical protocols leading to a-aminoalkyl-H-phosphinic
acids rely on: (a) thermal addition of hypophosphorous
acid (H3PO2) to N-protected imines3 and oximes;4 (b) ad-
dition of the hypophosphorous acid salts of secondary
amines to aldehydes;3a,5 or (c) application of bis(trimeth-
R2
R2
R2
N
ref. 3, 4
ref. 6
OSiMe3
OSiMe3
HN
R1
N
+
H3PO2
+
OH
H
H
P
R1
R1
P
R2 = alkyl, aryl, OH
O
chiral methods
ref. 7
ref. 8
O
S
O
P
OEt
OEt
Ph
Ph
ref. 3a, 5
O
OEt
OEt
N
∗
t-Bu
N
∗
H
P
OEt
+
R3
R1
OEt
H2PO2 H3N-R2
+
R2 = chiral or achiral group
R1CHO
R3 = H, Bn
Scheme 1 Classical protocols leading to a-aminoalkyl-H-phosphinic acids
SYNTHESIS 2011, No. 3, pp 0437–0442
x
x
.
x
x
.2
0
1
1
Advanced online publication: 28.12.2010
DOI: 10.1055/s-0030-1258387; Art ID: T18810SS
© Georg Thieme Verlag Stuttgart · New York

438
T. Olszewski, B. Boduszek
PAPER
the P–H bond or cleavage of the C–P bond.14 Therefore,
in connection with our continued interest in the prepara-
tion of heterocyclic phosphonates we decided to embark
on a program to examine the synthesis of heterocyclic a-
amino-H-phosphinic acids. Herein, we wish to disclose
the results of this study.
Table 1 Synthesized Heterocyclic a-Aminoalkyl-H-phosphinic
Acids 4a–o
Imine
2a
R1
R2
Product Yielda (%)
pyridin-3-yl
pyridin-3-yl
pyridin-3-yl
pyrrol-2-yl
Pr
4a
4b
4c
4d
4e
4f
75
80
68
70
77
65
60
62
57
74
80
62
78
82
65
2b
Bn
Our interest toward the preparation of heterocyclic amino
H-phosphinic acids brought us to investigate first the re-
action of hypophosphorous acid (H3PO2) with heterocy-
clic imines3 and next the reaction of hypophosphorous
acid salts of secondary amines with heterocyclic alde-
hydes.5 In spite of many attempts, however, those proto-
cols generally did not work in our hands, giving either
very impure products with poor yields or no products at 2g
all. Our difficulty with the aforementioned methods led us
to think about milder reaction conditions that would not
require the use of hypophosphorous acid. As a conse-
quence, we turned our attention toward the application of
bis(trimethylsilyl) phosphonite (1),6 and to our satisfac-
tion the desired heterocyclic a-aminomethyl-H-phosphin-
ic acids 4a–o were efficiently prepared by addition of this
reagent to the appropriate heterocyclic imines 2a–o. The
bis(trimethylsilyl) phosphonite (1) was easily generated
in situ by heating at 120 °C with an equimolar mixture of
ammonium hypophosphite and hexamethyldisilazane.6
Nucleophilic addition of 1 to imines 2a–o with R1 as var-
ious five- and six-membered heteroaromatics and R2 as an
aromatic or aliphatic group proceeded easily at room tem-
perature for 12 hours (Scheme 2). The thus formed silylat-
ed phosphinic intermediates 3 were then treated with
methanol, as a desilylating agent, to produce the desired
heterocyclic a-aminomethyl-H-phosphinic acids 4a–o de-
rivatives [pyridin-3-yl, pyrrol-2-yl, imidazol-4(5)-yl, fu-
ran-2-yl, and thiophen-2-yl] in good yields (57–82%)
(Table 1). All compounds were isolated as crystalline sol-
ids after simple crystallization from methanol.
2c
CHPh2
Pr
2d
2e
pyrrol-2-yl
Bn
2f
pyrrol-2-yl
CHPh2
Pr
imidazol-4(5)-yl
imidazol-4(5)-yl
imidazol-4(5)-yl
furan-2-yl
4g
4h
4i
2h
Bn
2i
CHPh2
Pr
2j
4j
2k
2l
furan-2-yl
Bn
4k
4l
furan-2-yl
CHPh2
Pr
2m
2n
2o
thiophen-2-yl
thiophen-2-yl
thiophen-2-yl
4m
4n
4o
Bn
CHPh2
a Isolated yield after crystallization.
phorus. Also, lack of the possibility of tautomerization of
the formed three-coordinated, silylated phosphorus ester
into less nucleophilic four-coordinated phosphonate-like
ester additionally secures the nucleophilic character of the
applied reagent. As a consequence, all reactions proceed-
ed at room temperature and the presence of undesired side
products arising from oxidation of the P–H bond and/or
cleavage of the C–P bond were not detected.14
R2
N
It is important to mention, that a twofold excess of bis(tri-
methylsilyl) phosphonite (1) over the heterocyclic imines
2 was found to be the best combination to avoid formation
of the undesired dialkylated phosphinic acids (resulting
from the undesired condensation of imines 2 with silylat-
ed phosphinic intermediates 3). Larger excess of the phos-
phonite 1 (up to 10-fold excess was tested) was found to
be impractical because of the presence of large amount of
unreacted hypophosphorous acid that impeded the isola-
tion and purification of the desired acids 4.
O
R2
OSiMe3
OSiMe3
Me3Si
R1
R1
(Me3Si)2NH
2
N
P
H
P
H
H
Δ
OSiMe3
H
CH2Cl2
r.t., 12 h
P
O
NH4
1
O
3
MeOH
(57–82%)
R2
HN
As it was mentioned earlier, simple a-aminoalkyl-H-
phosphinic acids with free amino groups are often used as
building blocks in the synthesis of more complex struc-
tures, for example, phosphinic pseudopeptides, with inter-
esting biological activity.2 Therefore, we also explored
the possibility to prepare free heterocyclic a-aminometh-
yl-H-phosphinic acids in order to increase their synthetic
value and application in, for example, peptide synthesis.
First we examined the direct hydrolysis of silylated inter-
mediates 3 using 1 M hydrochloric acid in methanol, how-
ever, the final acids 6 were obtained in poor yields only
OH
R1
P
H
4
O
Scheme 2 Synthesis of heterocyclic a-aminoalkyl-H-phosphinic
acids 4
The presence of a bulky trimethylsilyl group in bis(tri-
methylsilyl) phosphonite (1) increases the power of such
a nucleophile due to formation of a stable, three-coordi-
nated phosphorus moiety with a free electron pair at phos-
Synthesis 2011, No. 3, 437–442 © Thieme Stuttgart · New York

PAPER
Heterocyclic a-Aminomethyl-H-phosphinic Acid
439
OSiMe3
H
P
OSiMe3
Me3Si
R1
CHPh2
CHPh2
OH
CHPh2
N
MeOH
HN
R1
N
1
OSiMe3
P
R1
P
CH2Cl2
r. t., 12 h
H
H
2
O
4
O
3
1 M aq HCl
O
NH3
NH2⋅HCl
O
OH
R1
P
R1
P
MeOH
(65–70%)
H
H
O
O
6
5
Scheme 3 Synthesis of free a-aminoalkyl-H-phosphinic acids 6
and only the most representative frequencies are reported. Reported
melting points are uncorrected. All reagents were used as received
from the commercial supplier. All solvents for extractions and reac-
tions were technical grade and were dried before use using standard
techniques.
(<20%). Additionally, isolation of the products 6 using
this one-pot protocol was tedious and required repeated
crystallizations in order to obtain analytically pure sam-
ples. Later on, we discovered that the desired acids 6 de-
rivatives of pyridin-3-yl, imidazol-4(5)-yl, and thiophen-
2-yl can be conveniently prepared, as depicted in
Scheme 3, by the addition of bis(trimethylsilyl) phospho-
nite (1) to heterocyclic N-benzhydrylimines 2, isolation of
the (benzhydrylamino)methyl-H-phosphinic acids 4 and
subsequent removal of the benzhydryl group under acidic
conditions.15 The desired acids 6 were isolated as neutral
zwitterionic salts after treatment of the intermediates 5
with propylene oxide as an HCl scavenger. It is important
Heterocyclic a-Aminomethyl-H-phosphinic Acids 4a–o; Gener-
al Procedure
Neat secondary aromatic or aliphatic amine (5.0 mmol) was inject-
ed at r.t. into a soln of the heterocyclic aldehyde (5.0 mmol) in
CH2Cl2 (30 mL) and the reaction was stirred overnight. After this
time, anhyd MgSO4 was added and the mixture was stirred for an
additional 0.5 h. After removal of the drying agent the mixture was
concentrated affording crude imines 2 that were used directly in the
next step. In a 100-mL round-bottom flask fitted with condenser
to mention that no ion-exchange chromatography was re- were mixed ammonium hypophosphite (0.83 g, 10.0 mmol) and
hexamethyldisilazane (2.1 mL, 10.0 mmol) and the reaction vessel
was heated at 120 °C for 2 h producing in situ bis(trimethylsilyl)
quired and the free a-aminoalkyl-H-phosphinic acids 6
were obtained in fair to good yields (65–70%) as white
phosphonite (1, 10.0 mmol). The mixture was cooled to r.t. and then
solids after simple crystallization (Scheme 3, Table 2).
the flask was placed in an ice bath. Anhyd CH2Cl2 (15.0 mL) was
gradually injected followed by addition of a soln of the heterocyclic
Table 2 Synthesized Free Heterocyclic a-Aminoalkyl-H-phosphin-
imine 2 (5 mmol) in anhyd CH2Cl2 (10.0 mL). Stirring was contin-
ic Acids 6a–c
ued at r.t. for 12 h and then the mixture was concentrated under re-
duced pressure. The oily residue was placed in an ice bath, cold
4
R1
Product
6a
Yielda (%)
MeOH (10 mL) was slowly injected and the resulting soln was
placed in the freezer for crystallization. The precipitated heterocy-
clic a-aminomethyl-H-phosphinic acids 4a–o were collected by fil-
tration, washed with cold Et2O and dried under high vacuum.
4c
4i
4o
pyridin-3-yl
imidazol-4(5)-yl
thiophen-2-yl
70
65
67
6b
6c
(Propylamino)(pyridin-3-yl)methyl-H-phosphinic Acid (4a)
White solid; yield: 800 mg (75%); mp 201–203 °C.
IR (neat): 2330 (P–H), 1156 (P=O), 1010 cm–1 (P–O).
a Isolated yield after crystallization.
1H NMR (D2O): d = 8.50 (d, J = 4.8 Hz, 1 H, 4-PyH), 8.43 (s, 1 H,
2-PyH), 7.88 (d, J = 7.5 Hz, 1 H, 6-PyH), 7.84–6.04 (d, J = 550 Hz,
1 H, P–H), 7.45 (dd, J = 8.0 Hz, J = 5.0 Hz, 1 H, 5-PyH), 4.25 (d,
J = 12.0 Hz, 1 H, CHP), 2.87–2.71 (m, 2 H, CH2), 1.52–1.41 (m, 2
H, CH2), 0.67 (t, J = 7.0 Hz, 3 H, CH3).
13C NMR (D2O): d = 148.7, 148.1, 138.9, 127.0, 125.3, 60.1 (d,
JC-P = 69 Hz), 49.1, 19.1, 10.2.
In conclusion, we reported here an efficient and simple
synthesis of new heterocyclic a-amino-H-phosphinic
acids by addition of bis(trimethylsilyl) phosphonite to het-
erocyclic imines. Additionally, acidic hydrolysis of ben-
zhydrylamino derivatives leads to free a-aminomethyl-H-
phosphinic acids, useful building blocks in the synthesis
of, for example, phosphinic pseudopeptides, in good
yields after simple crystallization.
31P NMR (D2O): d = 15.5 (s).
HRMS: m/z [M + H]+ calcd for C9H16N2O2P: 215.0871; found:
215.0875.
1H (300 MHz), 13C (75 MHz), and 31P (120 MHz) NMR spectra
were recorded on a Bruker Avance TM DRX (300 MHz) spectrom-
(Benzylamino)(pyridin-3-yl)methyl-H-phosphinic Acid (4b)14a
White solid; yield: 1.0 g (80%); mp 215–216 °C.
IR (neat): 2335 (P–H), 1150 (P=O), 1040 cm–1 (P–O).
1
eter; referenced to initial TMS (d = 0.0 ppm) for H NMR and
CDCl3 (d = 77.0 ppm) for 13C NMR. IR spectra were taken as neat
Synthesis 2011, No. 3, 437–442 © Thieme Stuttgart · New York

440
T. Olszewski, B. Boduszek
PAPER
1H NMR (D2O): d = 8.52 (d, J = 5.0 Hz, 1 H, 4-PyH), 8.40 (s, 1 H,
2-PyH), 7.93 (d, J = 7.5 Hz, 1 H, 6-PyH), 7.92–6.08 (d, J = 555 Hz,
1 H, P–H), 7.56 (dd, J = 8.0 Hz, J = 5.0 Hz, 1 H, 5-PyH), 7.32–7.20
(m, 5 H, Ph), 4.28 (d, J = 12.9 Hz, 1 H, CHP), 4.11 (s, 2 H, CH2Ph).
13C NMR (D2O): d = 148.0, 147.6, 139.3, 130.9, 130.1, 129.7,
129.3, 127.9, 125.4, 59.9 (d, JC-P = 71 Hz), 51.1.
31P NMR (D2O): d = 16.8 (s).
HRMS: m/z [M + H]+ calcd for C13H16N2O2P: 263.0871; found:
13C NMR (D2O): d = 129.9, 129.5, 129.2, 129.0, 128.8, 128.3,
128.0, 126.7, 124.0, 122.0, 114.5, 112.5, 61.0, 58.9 (d, JC-P = 80
Hz).
31P NMR (D2O): d = 17.1 (s).
HRMS: m/z [M + H]+ calcd for C18H20N2O2P: 327.1184; found:
327.1187.
[Imidazol-4(5)-yl](propylamino)methyl-H-phosphinic Acid
(4g)
White solid; yield: 600 mg (60%); mp 200–202 °C.
263.0872.
(Benzhydrylamino)(pyridin-3-yl)methyl-H-phosphinic Acid
IR (neat): 2347 (P–H), 1160 (P=O), 1050 cm–1 (P–O).
(4c)
1H NMR (D2O): d = 7.95–6.12 (d, J = 548 Hz, 1 H, P–H), 7.66 (s, 1
H), 7.19 (s, 1 H), 4.14 (d, J = 15.3 Hz, 1 H, CHP), 2.80–2.75 (m, 2
H, CH2), 1.52–1.45 (m, 2 H, CH2), 0.75 (t, J = 6.0 Hz, 3 H, CH3).
White solid; yield: 1.1 g (68%); mp 229–232 °C.
IR (neat): 2341 (P–H), 1160 (P=O), 1050 cm–1 (P–O).
1H NMR (D2O): d = 8.52 (d, J = 5.0 Hz, 1 H, 4-PyH), 8.41 (s, 1 H,
2-PyH), 7.90 (d, J = 7.5 Hz, 1 H, 6-PyH), 7.89–6.08 (d, J = 550 Hz,
1 H, P–H), 7.56 (dd, J = 7.8 Hz, J = 5.0 Hz, 1 H, 5-PyH), 7.35–7.15
(m, 10 H, Ph), 4.98 (s, 1 H, CHPh2), 4.12 (d, J = 10.0 Hz, 1 H,
CHP).
13C NMR (D2O): d = 148.5, 147.8, 139.4, 131.0, 130.6, 129.7,
129.5, 129.2, 129.3, 128.7, 128.0, 127.9, 126.5, 60.1, 57.9 (d,
JC-P = 70 Hz).
13C NMR (D2O): d = 137.2, 128.1, 118.7, 56.4 (d, JC-P = 89 Hz),
48.4, 19.2, 10.3.
31P NMR (D2O): d = 17.3 (s).
HRMS: m/z [M]+ calcd for C7H14N3O2P: 203.0824; found:
203.0825.
(Benzylamino)[imidazol-4(5)-yl]methyl-H-phosphinic Acid
(4h)
White solid; yield: 775 mg (62%); mp 210–211 °C.
31P NMR (D2O): d = 21.8 (s).
HRMS: m/z [M + H]+ calcd for C19H20N2O2P: 339.1184; found:
IR (neat): 2351 (P–H), 1165 (P=O), 1030 cm–1 (P–O).
339.1180.
1H NMR (D2O): d = 8.00–6.15 (d, J = 557 Hz, 1 H, P–H), 7.60 (s, 1
H), 7.32–7.18 (m, 6 H), 4.15 (d, J = 15.0 Hz, 1 H, CHP), 4.00 (s, 2
H, CH2Ph).
13C NMR (D2O): d = 137.5, 131.0, 130.5, 130.2, 130.0, 129.8,
118.5, 56.0 (d, JC-P = 80.0 Hz), 52.0.
31P NMR (D2O): d = 17.5 (s).
HRMS: m/z [M]+ calcd for C11H14N3O2P: 251.0824; found:
(Propylamino)(pyrrol-2-yl)methyl-H-phosphinic Acid (4d)
White solid: yield: 700 mg (70%); mp 145–147 °C.
IR (neat): 2338 (P–H), 1165 (P=O), 1050 cm–1 (P–O).
1H NMR (D2O): d = 8.06–6.36 (d, J = 535 Hz, 1 H, P–H), 6.94 (s, 1
H), 6.25 (s, 1 H), 6.23 (dd, J = 4.0 Hz, J = 5.0 Hz, 1 H), 4.32 (d,
J = 11.0 Hz, 1 H, CHP), 2.94–2.76 (m, 2 H, CH2), 1.69–1.51 (m, 2
H, CH2), 0.87 (t, J = 7.0 Hz, 3 H, CH3).
251.0824.
13C NMR (D2O): d = 123.7, 121.0, 113.1, 111.5, 58.6 (d, JC-P = 90
(Benzhydrylamino)[imidazol-4(5)-yl]methyl-H-phosphinic
Acid (4i)
White solid; yield: 912 mg (57%); mp 224–226 °C.
Hz), 50.7, 21.6, 12.8.
31P NMR (D2O): d = 16.8 (s).
HRMS: m/z [M + H]+ calcd for C8H16N2O2P: 203.0871; found:
IR (neat): 2340 (P–H), 1160 (P=O), 1050 cm–1 (P–O).
203.0870.
1H NMR (D2O): d = 8.0–6.14 (d, J = 557 Hz, 1 H, P–H), 7.62 (s, 1
H), 7.36–7.20 (m, 11 H), 4.95 (s, 1 H, CHPh2), 4.14 (d, J = 14.5 Hz,
1 H, CHP).
13C NMR (D2O): d = 138.5, 130.5, 130.0, 129.9, 129.7, 129.5,
129.0, 128.7, 128.2, 114.0, 117.9, 62.15, 56.6 (d, JC-P = 82.0 Hz).
31P NMR (D2O): d = 18.1 (s).
HRMS: m/z [M + H]+ calcd for C17H19N3O2P: 328.1134; found:
(Benzylamino)(pyrrol-2-yl)methyl-H-phosphinic Acid (4e)
White solid: yield: 947 mg (77%); mp 156–157 °C.
IR (neat): 2330 (P–H), 1160 (P=O), 1050 cm–1 (P–O).
1H NMR (D2O): d = 8.06–6.42 (d, J = 520 Hz, 1 H, P–H), 7.44–7.35
(m, 5 H, Ph), 6.98 (s, 1 H), 6.31 (s, 1 H), 6.23 (dd, J = 4.0 Hz, J = 5.0
Hz, 1 H), 4.35 (d, J = 13.0 Hz, 1 H, CHP), 4.13 (s, 2 H, CH2Ph).
13C NMR (D2O): d = 129.1, 129.0, 127.5, 126.4, 123.5, 120.9,
112.1, 111.0, 57.6 (d, JC-P = 87 Hz), 51.7.
328.1136.
(Furan-2-yl)(propylamino)methyl-H-phosphinic Acid (4j)
White solid; yield: 740 mg (74%); mp 176–178 °C.
31P NMR (D2O): d = 16.9 (s).
HRMS: m/z [M + H]+ calcd for C12H16N2O2P: 251.0871; found:
IR (neat): 2345 (P–H), 1165 (P=O), 1040 cm–1 (P–O).
251.0869.
1H NMR (D2O): d = 8.01–6.15 (d, J = 566 Hz, 1 H, P–H), 7.49 (s, 1
H), 6.55 (s, 1 H), 6.40 (s, 1 H), 4.34 (d, J = 15.0 Hz, 1 H, CHP),
2.84–2.74 (m, 2 H, CH2), 1.57–1.45 (m, 2 H, CH2), 0.75 (t, J = 6.5
Hz, 3 H, CH3).
13C NMR (D2O): d = 145.3, 142.7, 113.8, 111.3, 56.0 (d, JC-P = 86
Hz), 48.5, 19.1, 10.2.
31P NMR (D2O): d = 13.6 (s).
HRMS: m/z [M]+ calcd for C8H14NO3P: 203.0711; found: 203.0712.
(Benzhydrylamino)(pyrrol-2-yl)methyl-H-phosphinic Acid (4f)
White solid; yield: 1.0 g (65%); mp 160–162 °C.
IR (neat): 2345 (P–H), 1175 (P=O), 1040 cm–1 (P–O).
1H NMR (D2O): d = 8.0–6.36 (d, J = 530 Hz, 1 H, P–H), 7.30–7.10
(m, 10 H, Ph), 6.95 (s, 1 H), 6.30 (s, 1 H), 6.25 (dd, J = 4.7 Hz,
J = 5.0 Hz, 1 H), 4.95 (s, 1 H, CHPh2), 4.10 (d, J = 12.0 Hz, 1 H,
CHP).
Synthesis 2011, No. 3, 437–442 © Thieme Stuttgart · New York

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Heterocyclic a-Aminomethyl-H-phosphinic Acid
441
(Benzylamino)(furan-2-yl)methyl-H-phosphinic Acid (4k)
White solid; yield: 1.0 g (80%); mp 185–186 °C.
IR (neat): 2345 (P–H), 1160 (P=O), 1060 cm–1 (P–O).
1H NMR (D2O): d = 8.0–6.14 (d, J = 557 Hz, 1 H, P–H), 7.52 (s, 1
H), 7.32–7.25 (m, 5 H), 6.55 (s, 1 H), 6.42 (s, 1 H), 4.35 (d, J = 14.7
Hz, 1 H, CHP), 4.0 (s, 2 H, CH2Ph).
13C NMR (D2O): d = 131.5, 130.7, 130.5, 129.9, 129.7, 129.5,
129.3, 129.1, 129.0, 128.7, 128.2, 127.8, 64.15, 57.6 (d, JC-P = 99.0
Hz).
31P NMR (D2O): d = 26.2 (s).
HRMS: m/z [M + H]+ calcd for C18H19NO2PS: 344.0796; found:
344.0799.
13C NMR (D2O): d = 145.5, 142.7, 130.4, 130.2, 129.9, 129.4,
114.0, 111.5, 55.9 (d, JC-P = 84.0 Hz), 50.5.
31P NMR (D2O): d = 13.7 (s).
HRMS: m/z [M + H]+ calcd for C12H15NO3P: 252.0711; found:
252.0709.
Free Heterocyclic a-Aminomethyl-H-phosphinic Acids 6a–c
In a round-bottom flask equipped with condenser was placed (benz-
hydrylamino)methyl-H-phosphinic acid 4c,i,o (2.0 mmol). 1 M Aq
HCl (20.0 mL) was added and the mixture was stirred at reflux for
2 h. The mixture was cooled and then extracted with toluene (3 × 10
mL). The organic layer was discarded and the aqueous layer was
concentrated under reduced pressure.16 The crude was dissolved in
MeOH (15 mL), propylene oxide was added (10 mL), and the pre-
cipitated products, free a-aminomethyl-H-phosphinic acids 6a–c
were collected by filtration and dried under high vacuum.
(Benzhydrylamino)(furan-2-yl)methyl-H-phosphinic Acid (4l)
White solid; yield: 992 mg (62%); mp 193–195 °C.
IR (neat): 2345 (P–H), 1160 (P=O), 1050 cm–1 (P–O).
1H NMR (D2O): d = 8.0–6.14 (d, J = 557 Hz, 1 H, P–H), 7.52 (s, 1
H), 7.43–7.00 (m, 10 H), 6.60 (s, 1 H), 6.45 (s, 1 H), 4.90 (s, 1 H,
CHPh2), 4.30 (d, J = 14.0 Hz, 1 H, CHP).
(Amino)(pyridin-3-yl)methyl-H-phosphinic Acid (6a)6c
White solid; yield: 240 mg (70%); mp 165–167 °C.
13C NMR (D2O): d = 145.50, 140.2, 130.2, 129.9, 129.8, 129.5,
129.0, 128.9, 128.5, 128.0, 114.0, 111.0, 63.15, 55.6 (d, JC-P = 80.0
Hz).
31P NMR (D2O): d = 14.6 (s).
HRMS: m/z [M + H]+ calcd for C18H19NO3P: 328.1024; found:
328.1024.
IR (neat): 2330 (P–H), 1156 (P=O), 950 cm–1 (P–O).
1H NMR (D2O): d = 8.70 (d, J = 5.0 Hz, 1 H, 4-PyH), 8.67 (s, 1 H,
2-PyH), 8.57 (d, J = 7.0 Hz, 1 H, 6-PyH), 7.80–6.10 (d, J = 510 Hz,
1 H, P–H), 7.90 (dd, J = 8.0 Hz, J = 5.0 Hz, 1 H, 5-PyH), 5.0 (d,
J = 10.0 Hz, 1 H, CHP).
13C NMR (D2O): d = 149.5, 148.7, 139.0, 127.5, 125.7, 61.0 (d,
JC-P = 70 Hz).
(Propylamino)(thiophen-2-yl)methyl-H-phosphinic Acid (4m)
White solid; yield: 858 mg (78%); mp 179–181 °C.
IR (neat): 2355 (P–H), 1172 (P=O), 1050 cm–1 (P–O).
1H NMR (D2O): d = 7.94–6.11 (d, J = 543 Hz, 1 H, P–H), 7.43 (d,
J = 5.0 Hz, 1 H), 7.13 (s, 1 H), 6.98 (dd, J = 4.0 Hz, J = 5.0 Hz, 1
H), 4.48 (d, J = 13.6 Hz, 1 H, CHP), 2.84–2.75 (m, 2 H, CH2), 1.57–
1.45 (m, 2 H, CH2), 0.74 (t, J = 7.5 Hz, 3 H, CH3).
13C NMR (D2O): d = 133.4, 132.0, 131.5, 130.7, 60.1 (d, JC-P = 87
Hz), 50.9, 21.6, 12.8.
31P NMR (D2O): d = 20.5 (s).
HRMS: m/z [M + H]+ calcd for C6H10N2O2P: 173.0402; found:
173.0407.
(Amino)[imidazol-4(5)-yl]methyl-H-phosphinic Acid (6b)
White solid; yield: 209 mg (65%); mp 205–207 °C.
IR (neat): 2347 (P–H), 1160 (P=O), 1060 cm–1 (P–O).
1H NMR (D2O): d = 7.90–6.07 (d, J = 548 Hz, 1 H, P–H), 7.60 (s, 1
H), 7.17 (s, 1 H), 4.10 (d, J = 14.7 Hz, 1 H, CHP).
13C NMR (D2O): d = 138.5, 128.0, 119.1, 57.4 (d, JC-P = 87 Hz).
31P NMR (D2O): d = 17.1 (s).
HRMS: m/z [M]+ calcd for C4H8N3O2P: 161.0354; found: 161.0355.
31P NMR (D2O): d = 16.6 (s).
HRMS: m/z [M + H]+ calcd for C8H15NO2PS: 220.0483; found:
220.0485.
(Benzylamino)(thiophen-2-yl)methyl-H-phosphinic Acid (4n)
White solid; yield: 1.0 g (82%); mp 187–188 °C.
IR (neat): 2342 (P–H), 1165 (P=O), 1030 cm–1 (P–O).
(Amino)(thiophen-2-yl)methyl-H-phosphinic Acid (6c)
White solid; yield: 237 mg (67%); mp 225–227 °C.
IR (neat): 2355 (P–H), 1172 (P=O), 1040 cm–1 (P–O).
1H NMR (D2O): d = 7.94–6.11 (d, J = 543 Hz, 1 H, P–H), 7.44 (d,
J = 5.0 Hz, 1 H), 7.20 (s, 1 H), 7.1 (dd, J = 4.0 Hz, J = 5.0 Hz, 1 H),
4.50 (d, J = 12.6 Hz, 1 H, CHP).
13C NMR (D2O): d = 138.4, 127.0, 125.5, 124.8, 61.0 (d, JC-P = 85
Hz).
1H NMR (D2O): d = 8.0–6.15 (d, J = 552 Hz, 1 H, P–H), 7.53 (d,
J = 5.0 Hz, 1 H), 7.36–7.09 (m, 7 H), 4.56 (d, J = 13.8 Hz, 1 H,
CHP), 4.12 (s, 2 H, CH2Ph).
13C NMR (D2O): d = 131.0, 130.3, 130.1, 129.8, 129.7, 129.3,
129.1, 128.2, 57.3 (d, JC-P = 85.5 Hz), 50.2.
31P NMR (D2O): d = 16.7 (s).
HRMS: m/z [M + H]+ calcd for C12H15NO2PS: 268.0483; found:
31P NMR (D2O): d = 22.0 (s).
HRMS: m/z [M + H]+ calcd for C5H9NO2PS: 178.0013; found:
268.0487.
178.0016.
(Benzhydrylamino)(thiophen-2-yl)methyl-H-phosphinic Acid
(4o)
Acknowledgment
White solid; yield: 1.1 g (65%); mp 196–197 °C.
IR (neat): 2340 (P–H), 1167 (P=O), 1050 cm–1 (P–O).
1H NMR (D2O): d = 8.0–6.15 (d, J = 555 Hz, 1 H, P–H), 7.49–7.15
(m, 13 H), 4.98 (s, 1 H, CHPh2), 3.90 (d, J = 16.5 Hz, 1 H, CHP).
Financial support from the Faculty of Chemistry, Wroclaw Univer-
sity of Technology is kindly acknowledged.
Synthesis 2011, No. 3, 437–442 © Thieme Stuttgart · New York

442
T. Olszewski, B. Boduszek
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Synthesis 2011, No. 3, 437–442 © Thieme Stuttgart · New York