Novel method for the synthesis of α-amino-α- hydroxyalkylphosphinic acids and bis(α-aminoalkyl)phosphinic acids: Nuclephilic addition of α-hydroxy-H-phosphinic acids to diimines

Article abstract of DOI:10.1055/s-0032-1316706

We report here a novel and simple method for the synthesis of α-amino-α-hydroxyalkylphosphinic acids in good yields in two simple steps without any protection-deprotection steps. We have developed an efficient method for the synthesis of α-amino-α-hydroxyalkylphosphinic acids via the reaction of easily available α-hydroxyalkylphosphinic acids with diimines. Treatment of α-hydroxyalkylphosphinic acids with diimines in the presence of trimethylsilyl chloride (TMSCl) gives α-amino-α- hydroxyalkylphosphinic acids in good yields. The reaction gave a mixture of two diastereomeric forms of α-amino-α-hydroxyalkylphosphinic acids. The difference in solubility in organic solvents allowed us to readily separate the diastereoisomers. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316706

LETTER
▌1965
lNettoervel Method for the Synthesis of α-Amino-α′-hydroxyalkylphosphinic Acids
and Bis(α-aminoalkyl)phosphinic Acids: Nuclephilic Addition of α-Hydroxy-
H-phosphinic Acids to Diimines
Nuclephilic Addition of α-Hydroxy-H-phosphinic Acids to Diimines
Babak Kaboudin,*a Hamideh Haghighat,a Saied Alaie,a Tsutomu Yokomatsub
a
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Zanjan 45137 66731, Iran
Fax +98(241)4214949; E-mail: kaboudin@iasbs.ac.ir
b
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horonouchi, Hachioji, Tokyo 192-0392, Japan
Received: 16.04.2012; Accepted after revision: 15.06.2012
1-hydroxy phosphinic acid derivatives, relatively few pa-
Abstract: We report here a novel and simple method for the synthe-
pers have reported on the chemistry of α-amino-α′-hy-
sis of α-amino-α′-hydroxyalkylphosphinic acids in good yields in
droxyphosphinates or α,α′-diaminophophinates.9 There is
two simple steps without any protection–deprotection steps. We
have developed an efficient method for the synthesis of α-amino-α′-
currently only one available method, described by Drag
hydroxyalkylphosphinic acids via the reaction of easily available α- and Oleksyzyn in 2005,10 for the synthesis of α-amino-α′-
hydroxyalkylphosphinic acids with diimines. Treatment of α-
hydroxyalkylphosphinic acids with diimines in the presence of
hydroxyphosphinates starting from α-aminoalkylphos-
phinic acids. However, this method involves a several-
trimethylsilyl chloride (TMSCl) gives α-amino-α′-hydroxyalkyl-
step process, requiring drastic reaction conditions, anaer-
phosphinic acids in good yields. The reaction gave a mixture of two
obic and anhydrous conditions for some steps, long reac-
diastereomeric forms of α-amino-α′-hydroxyalkylphosphinic acids.
The difference in solubility in organic solvents allowed us to readily
separate the diastereoisomers.
tion times, several protection–deprotection steps, and
gives low overall yields and side products.
Key words: phosphinic acids, hydroxyalkylphosphinic acid, ami-
no-α′-hydroxyalkylphosphinic acid, diimines, bis(α-aminoal-
kyl)phosphinic acid
Diimines are good precursors for the synthesis of numer-
ous organic compounds, especially heterocyclic com-
pounds.11 These readily accessible precursors can be
produced by the reaction of aromatic aldehydes with
aqueous ammonia.12 Recently, we have reported the reac-
tion of diimines with hypophosphorus acid for the prepa-
ration of N,N-bis(phosphinomethyl)amines, as a new
class of 1-aminophosphinic acids.13 As part of our efforts
to introduce novel methods for the synthesis of organo-
phosphorus compounds,14 herein we report a new and
simple method for the synthesis of α-amino-α′-hydroxy-
phosphinic acids. We have found that the reaction of aro-
matic aldehydes with ammonia solution followed by
reaction with α-hydroxyphosphinic acids, prepared ac-
cording to well-established procedures, in the presence of
TMSCl gives α-amino-α′-hydroxyphosphinates in good
yields.
Phosphorus–carbon bond formation is an active and im-
portant research area for the preparation of organophos-
phorus compounds such as phosphinates.1 Phosphinic
peptides and pseudopepides are an important class of
compounds that exhibit a variety of interesting and useful
properties in biological activities.2 The structure of the
phosphinic functional group mimics the transition state of
peptide hydrolysis, and the symmetric nature of phosphin-
ic acid derivatives is expected to benefit in their binding
to the homodimer of HIV-protease having C2-axis sym-
metry.3 α-Functionalized phosphinic acid derivatives
have attracted a great deal of attention due to their useful-
ness both in medicinal and material chemistry.4 Among
the α-functional phosphinic acids, α-hydroxyphosphinic
acids, and α-aminophosphinic are interesting classes of
compounds possessing broad biological activities.5 Some
α-hydroxyphosphinic acids are useful intermediates for
preparing α-hydroxyphosphinyl peptides showing good
inhibitory activity against renin.6 α-Aminoalkylphosphin-
ic derivatives have potential biological properties such as
antibacterial, herbicidal, and fungicidal activity.7 Further-
more, the conjunction of two functionalities in the same
molecule such as α-amino-α′-hydroxyphosphinates or
α,α′-diaminophophinates affords powerful inhibitors of
HIV-1 protease and human aminopeptidase N (CD13).8 In
contrast to the widely studied synthesis of 1-amino or
α-Hydroxy-H-phosphinic acids 1 were obtained in multi-
gram quantities (48–81% isolated yield, Scheme 1) from
the reaction of aldehydes and hypophosphorus acid in re-
fluxing ethanol for 48 hours, according to a literature pro-
cedure.15
O
P
O
EtOH
OH
R
RCHO
+
H
P
H
reflux, 48 h
48–81%
H
OH
OH
1a R = Ph 52%
1b R = o-ClC6H4 63%
1c R = p-ClC6H4 48%
1d R = α-naphthyl 81%
1e R = C6H13 66%
Scheme 1
SYNLETT 2012, 23, 1965–1969
Advanced online publication: 23.07.2012
DOI: 10.1055/s-0032-1316706; Art ID: ST-2012-D0330-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Diimines 2 were obtained in quantitative yield from the
reaction of aromatic aldehydes with ammonium hydrox-

1966
B. Kaboudin et al.
LETTER
ide solution at reflux for five hours, according to a litera- without any additives in toluene for 24 hours at room tem-
ture procedure (Scheme 2).16
perature gave 3a in 21% isolated yield (Table 1, entry 7).
However, the yield increased to 83% when the reaction
was carried out for four hours at reflux (Table 1, entry 8).
Therefore, when the reaction was carried out for four
hours at reflux in the presence of TMSCl, a diastereomeric
mixture of α-amino(phenyl)methy[α′-hydroxy(phe-
nyl)methyl]phosphinic acid (3a) was obtained in 83%
yield (in a 63:37 ratio of diastereoisomers, Scheme 3).
Ar
reflux, 5 h
N
N
NH4OH
+
ArCHO
Ar
2a Ar = Ph
2b Ar = p-MeC6H4
2c Ar = p-MeOC6H4
2d Ar = p-FC6H4
2e Ar = o-ClC6H4
2f Ar = α-naphthyl
Ar
Ph
O
OH
TMSCl, toluene
4 h, Ar, reflux
Ph
P
N
N
+
H
Scheme 2
OH
1a
Ph
Ph
O
2a
Initially, the reaction of [α-hydroxy(phenyl)methyl]phos-
phinic acid (1a) with 1-phenyl N,N′-bis[(1E)-phenylme-
thylidene]methanediamine (2a) was chosen as the model
reaction, and the experimental data for the screening con-
ditions are listed in Table 1.
OH
OH
P
O
P
OH
NH2
anti stereoisomer 3a
OH
NH2
OH
OH
O
Table 1 Synthesis of 3a from the Reaction of 1a with 2a under Var-
ious Conditions
O
P
P
OH NH2
Ph
OH NH2
syn stereoisomers 3a
O
OH
O
OH
Ph
P
Ph
P
Ph
N
N
+
H
Scheme 3
OH
1a
OH NH2
Ph
Ph
3a
2a
The 31P NMR spectrum of this mixture exhibited two
peaks at δ = 32.90 and 33.37 ppm due to the diastereoiso-
mers. The 1H NMR spectrum exhibited two doublets at δ
= 4.02 and 4.08 ppm indicative of N–HC–P coupling. Be-
cause of the presence of two stereogenic carbons bonded
to the phosphorus atom and due to the prototropic transfer
of the acidic proton between the phosphoryl (P=O) and
acidic (P–OH) sites, these compounds theoretically exist
as four diastereomeric forms: two syn compounds and two
anti compounds as shown in Scheme 4. When the mixture
of diastereoisomers 3a was washing with a solvent mix-
ture of ethanol–water (9:1) and dried in air at room tem-
perature a single diastereoisomer was obtained. As we
were unable to obtain an X-ray crystal of the two diaste-
reoisomers of 3a, their unambiguous stereochemical as-
signments have not been determined.
Entry Reagent
solvent
T
(°C)
Time Yield
(h)
(%)a
1
2
3
4
5
6
7
8
–
EtOH
r.t.
24
24
24
24
24
12
24
3
–
–
–
–
EtOH
reflux
r.t.
HMDS
HMDS
toluene
toluene
toluene
toluene
toluene
toluene
b
reflux
r.t.
–
b
TMSCl–Et3N
TMSCl–Et3N
TMSCl
–
b
reflux
r.t.
–
21
83
TMSCl
reflux
a Isolated yield of product 3a.
b Unknown mixture.
This process was successfully applied to other α-hydroxy-
H-phosphinic acids 1 and dimines 2 as summarized in Ta-
ble 2. As shown in Table 2, the reaction of α-hydroxy-H-
phosphinic acids 1a–e with dimines 2a–f, in the presence
of TMSCl, afforded a mixture of diastereoisomers of α-
amino-α′-hydroxyphosphinates 3a–m in good yields.
Treatment of 1a with 2a in ethanol at room temperature or
reflux failed after 24 hours to form 3a (Table 1, entries 1
and 2). When the reaction was carried out in the presence
of HMDS17 in dry toluene for 24 hours at reflux, a mixture
of unknown products resulted (Table 1, entry 4). Treat-
ment of 1a with 2a in toluene in the presence of HMDS at
room temperature failed after 24 hours to form 3a (Table
1, entry 3). When the reaction was carried out in the pres-
ence of a mixture of TMSCl and Et3N in dry toluene for
12 hours at reflux or for 24 hours at room temperature,18
it gave a mixture of unknown products (Table 1, entries 5
and 6). Treatment of 1a with 2a in the presence of TMSCl
A plausible mechanism is outlined in Scheme 4 for the
synthesis of α-amino-α′-hydroxyphosphinic acids. On the
basis of literature reports for the activation of phosphinic
acids17–19 and the reactions reported for diimines,20 we be-
lieve that the present process proceeds via the activation
of α-hydroxy-H-phosphinic acid by TMSCl and attack of
activated intermediate 21,224 to the protonated diimine giv-
ing an α-imino-α′-hydroxyphosphinic acid intermediate 5
Synlett 2012, 23, 1965–1969
© Georg Thieme Verlag Stuttgart · New York

LETTER
Nuclephilic Addition of α-Hydroxy-H-phosphinic Acids to Diimines
1967
which undergoes subsequent hydrolysis in the workup to by P–C bond breaking of 3d and followed by nucleophilic
the α-amino-α′-hydroxyphosphinic acid compound attack of activated intermediate 7d to the protonated dii-
(Scheme 4).
mine 2d, affording bis[α-amino(p-methoxyphenyl)]phos-
phinic acid (6d, Scheme 5, o-chlorobenzaldehyde was
detected by TLC). Similar results were obtained when [α-
hydroxy-(α-naphthyl)methyl]phosphinic acid (1d) was
used as a phosphinic acid precursor.
Ar
O
OH
O
OH
TMSCl, toluene
4 h, Ar, reflux
R
P
R
P
Ar
N
N
+
H
OH
OH NH2
Ar
Ar
In summary, we report herein a novel and simple method
for the synthesis of α-amino-α′-hydroxyalkylphosphinic
1
2
3
work-up
EtOH
– 2HCl
OTMS
TMSCl
Table 2 Reaction of 1-Hydroxyphosphinic Acids 1 with Diimines 2
Ar
Ar
OTMS
O
O
OH
O
H
R
P
Ar
OH
R
P
TMSCl, toluene
4 h, Ar, reflux
R
P
Ar
– TMSCl
R
P
N
N
N
N
OTMS
+
H
OH
N
– [ArCH=NH]
OH
OH
OH NH2
Ar
Ar
Ar
Ar
1
2
3
Ar
4
5
Entry 1 R
2 Ar
Product 3 Yield of 3 drb
Scheme 4
(%)a
1
2
Ph
Ph
Ph
Ph
3a
3b
3c
83
80
78
71
64
60
73
54
87
54
66
56
44
63:37
67:33
65:35
70:30
58:42
88:12
59:41
75:25
63:37
85:15
76:24
70:30
88:12
Surprisingly, we found that when the reaction of [α-hy-
droxy-(o-chlorophenyl)methyl]phosphinic acid (1b) with
1-(p-methoxyphenyl)-N,N′-bis[(1E)-(p-methoxyphenyl)-
methylidene]methanediamine (2d) was carried out under
reflux for 24 hours in the presence of TMSCl, the reaction
mixture was very complex and only one product was iso-
lated in pure form after workup. The reaction gave a white
solid that was determined to have the molecular formula
C16H21N2O4P by ESI-HRMS {observed [M + 2Na]+ at
m/z = 381.0961} and elemental analysis. This molecular
formula is consistent with bis[α-amino(p-methoxyphe-
nyl)methyl]phosphinic acid. The 31P NMR spectrum of
the product exhibited one peak at δ = 36.14 ppm. The 1H
NMR spectrum of the product exhibited a doublet peak at
δ = 3.08 ppm indicative of HC–P coupling (3JHP = 9.1 Hz).
On the other hand, the 13C NMR of the product exhibited
one doublet peak at δ = 53.0 ppm (α-carbon to phosphorus
atom). As we were unable to obtain an X-ray crystal of the
single diastereoisomer of 6d, its unambiguous stereo-
chemical assignment has not been determined. It is sug-
gested that the intermediate 7d may be generated in situ
p-MeC6H4
p -FC6H4
3
4
o-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
α-naphthyl
α-naphthyl
α-naphthyl
n-C6H13
p-MeOC6H4 3d
5
Ph
3e
3f
6
o-ClC6H4
p-MeC6H4
p-FC6H4
β-naphthyl
Ph
7
3g
3h
3i
8
9
10
11
12
13
3j
p-MeC6H4
p-FC6H4
Ph
3k
3l
3m
a Isolated yields of mixtures of two diastereoisomers.
b Diastereomeric ratio was calculated by 31P NMR spectroscopy.
Ar
O
P
MeO
OMe
OH
TMSCl, toluene
24 h, Ar, reflux
OH
O
N
N
+
P
H
Cl
OH
Ar
Ar
NH2 NH2
1b
6d
2d Ar = p-MeOC6H4-
TMSCl, toluene
4 h, Ar, reflux
2d
OMe
OMe
continued reflux
for 24 h
OH
O
TMSO
P
P
–o-ClC6H4CHO
TMSO
Cl
O
NH2
NH2
H
3d
7d
Scheme 5
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1965–1969

1968
B. Kaboudin et al.
LETTER
Grabowiecka, A.; Kosikowska, P.; Yiotakis, A.; Kafarski,
P.; Berlicki, L. J. Med. Chem. 2008, 51, 5736.
(8) (a) Drag, M.; Grzywa, R.; Oleksyszyn, J. Bioorg. Med.
Chem. Lett. 2007, 17, 1516. (b) Grzywa, R.; Oleksyszyn, J.;
Salvesen, G. S.; Drag, M. Bioorg. Med. Chem. Lett. 2010,
20, 2497.
(9) (a) Dreyer, G. B.; Abdel-Meguid, S. S.; Zhao, B.; Murthy,
K.; Winborne, E.; Choi, J. W.; DesJarlais, R. L.; Minnich,
M. D.; Culp, J. S.; Debouck, C.; Tomaszek, T. A. Jr.; Meek,
T. D. Biochemistry 1993, 32, 7972/. (b) Cristau, H.-J.;
Herve, A.; Virieux, D. Tetrahedron 2004, 60, 877.
(c) Kaboudin, B.; Haruki, T.; Yamaghishi, T.; Yokomatsu,
T. Tetrahedron 2007, 63, 8199. (d) Kaboudin, B.; Haruki,
T.; Yamagishi, T.; Yokomatsu, T. Synthesis 2007, 3226.
(10) Drag, M.; Oleksyszyn, J. Tetrahedron Lett. 2005, 46, 3359.
(11) For example, see: (a) Corey, E. J.; Grogan, M. J. Org. Lett.
1999, 1, 157. (b) Uchida, H.; Shimizu, T.; Reddy, P. Y.;
Nakamura, S.; Toru, T. Synthesis 2003, 1236. (c) Kaboudin,
B.; Saadati, F. Heterocycles 2005, 65, 353.
acids via the reaction of easily available α-hydroxyalkyl-
phosphinic acids with diimines. The reaction gave a mix-
ture of two diastereomeric forms of α-amino-α′-
hydroxyalkylphosphinic acids. The difference in solubili-
ty in organic solvents due to polarity allowed us to readily
separate the diastereoisomers. Fast reaction rates, mild re-
action conditions, good yields, a simple workup, clean re-
actions with no protection or deprotection steps, and
simple separation of diastereoisomers make this method
an attractive and a useful contribution to current method-
ology. We have also developed an efficient method for the
synthesis of bis(α-aminoalkyl)phosphinic acids via treat-
ment of [α-hydroxy-(o-chlorophenyl)methyl]phosphinic
acid or [α-hydroxy-(α-naphthyl)methyl]phosphinic acid
with diimines in the presence of TMSCl at reflux toluene
for 24 hours in good yields.23
(12) Kupfer, R.; Brinker, U. H. J. Org. Chem. 1996, 61, 4185.
(13) (a) Kaboudin, B.; Saadati, F. Tetrahedron Lett. 2009, 50,
1450. (b) Kaboudin, B.; Saadati, F.; Yokomatsu, T. Synlett
2010, 1837. (c) Kaboudin, B.; Saadati, F.; Golshan, A.;
Abdollahi, H.; Yokomatsu, T. J. Chem. Eng. Data 2011, 56,
3651.
Acknowledgment
The authors gratefully acknowledge support by the Institute for Ad-
vanced Studies in Basic Sciences (IASBS) Research Council under
grant No. G2010IASBS120.
(14) For example, see recent papers: (a) Kaboudin, B.; Alaie, S.;
Yokomatsu, T. Tetrahedron: Asymmetry 2011, 22, 1813.
(b) Kaboudin, B.; Malekzadeh, L. Synlett 2011, 2807.
(15) Vassliou, S.; Kosikowska, P.; Grabowiecka, A.; Yiotakis,
A.; Kafarski, P.; Berlicki, L. J. Med. Chem. 2010, 53, 5597.
(16) Hunter, D. H.; Sim, S. K. Can. J. Chem. 1972, 50, 669.
(17) Hexamethyldisilizane (HMDS) has been used as an activator
for the phosphinic acids. For example, see: (a) Matziari, M.;
Georgiadis, D.; Dive, V.; Yiotakis, A. Org. Lett. 2001, 3,
659. (b) Kaboudin, B.; Saadati, F.; Yokomatsu, T.
Phosphorus, Sulfur Silicon Relat. Elem. 2011, 186, 804.
(18) Boyd, E. A.; Corless, M.; James, K.; Regan, A. C.
Tetrahedron Lett. 1990, 31, 2933.
(19) For example, see: (a) Cox, P. B.; Loh, V. M.; Monteils, C.
Jr.; Baxter, A. D.; Boyd, E. A. Tetrahedron Lett. 2001, 42,
125. (b) Buchardt, J.; Meldal, M. J. Chem. Soc., Perkin
Trans. 1 2000, 3306.
(20) For example, see: (a) Kaboudin, B.; Moradi, K. Synthesis
2006, 2339. (b) Kaboudin, B.; Jafari, E. Synthesis 2006,
3063. (c) Sardarian, A. R.; Kaboudin, B. Tetrahedron Lett.
1997, 38, 2543. (d) Soroka, M.; Kolodziejczyk, K.
Tetrahedron Lett. 2003, 44, 1863. (e) Kaboudin, B.; Moradi,
K. Tetrahedron Lett. 2005, 46, 2989.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
maotrin
r
t
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Trimethylsilyl chloride (6 mmol, 0.75 mL) was added
dropwise to a suspension of 1-hydroxy-H-phosphinic acid (2
mmol) in anhyd toluene (10 mL) under argon, and the
mixture was stirred at 0 °C for 30 min. A solution of diimine
(3 mmol) in toluene (5 mL) was added to the reaction
mixture, and the mixture was stirred at reflux for 4 h. EtOH
(5 mL) was added to this mixture, and the mixture was
stirred at reflux for 1 h, during which time a white solid
precipitated. This was collected by filtration, washed with
EtOH (2 mL), and air drying to give a mixture of diastereo-
isomers of α-amino-α′-hydroxyphosphinic acid in 41–83%
yield. All products gave satisfactory spectral data in
accordance with the assigned structures.
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α-Amino(phenyl)methyl[α′-hydroxy(phenyl)methyl]-
Synlett 2012, 23, 1965–1969
© Georg Thieme Verlag Stuttgart · New York

LETTER
phosphinic Acid (3a)
Nuclephilic Addition of α-Hydroxy-H-phosphinic Acids to Diimines
1969
127.0–127.5 (Ar), 127.6 (d, JPC = 4.0 Hz), 127.7 (d, JPC = 4.0
Hz), 128.1 (d, JPC = 1.0 Hz), 128.3 (d, JPC = 2.0 Hz), 128.4
(d, JPC = 1.0 Hz), 138.6 (d, JPC = 3.0 Hz), 138.8 (d, JPC = 2.0
Hz), 139.1 (d, JPC = 2.0 Hz) ppm. 31P NMR (162 MHz, D2O–
H3PO4): δ = 32.90, 33.37 ppm. HRMS: m/z calcd for
C14H15NO3PNa2 [M + 2Na+]: 322.0585; found: 322.0581.
White solid, mixture of two diastereoisomers. 1H NMR (400
MHz, D2O): δ = 4.02 (d, 1 H, J = 12.4 Hz), 4.08 (d, 1 H, J =
8.8 Hz), 4.60 (d, 1 H, J = 4.8 Hz), 4.85 (d, 1 H, overlap with
D2O signal), 7.19–7.45 (m, 20 H) ppm. 13C NMR (100 MHz,
D2O–TMS): δ = 54.0 (d, JPC = 89.0 Hz), 54.2 (d, JPC = 88.0
Hz), 72.2 (d, JPC = 101.0 Hz), 72.4 (d, JPC = 102.0 Hz),
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1965–1969

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