A simple, novel and convenient method for the synthesis of 1-aminophosphinic acids: synthesis of a novel C2-symmetric phosphinic acid pseudodipeptide

Article abstract of DOI:10.1016/j.tetlet.2009.01.055

A simple, efficient and novel method has been developed for the synthesis of 1-aminophosphinic acids from simple starting materials. Treatment of aromatic aldehydes with ammonia and hypophosphorus acid gives novel C₂-symmetric 1-aminoarylmethylphosphinic acids. The synthesis of novel C₂-symmetric phosphinic acid pseudodipeptides is also discussed.

Full text of DOI:10.1016/j.tetlet.2009.01.055

Tetrahedron Letters 50 (2009) 1450–1452
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A simple, novel and convenient method for the synthesis of 1-aminophosphinic
acids: synthesis of a novel C2-symmetric phosphinic acid pseudodipeptide
*
Babak Kaboudin , Fariba Saadati
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Gava Zang, Zanjan 45195-1159, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple, efficient and novel method has been developed for the synthesis of 1-aminophosphinic acids
from simple starting materials. Treatment of aromatic aldehydes with ammonia and hypophosphorus
acid gives novel C2-symmetric 1-aminoarylmethylphosphinic acids. The synthesis of novel C2-symmetric
phosphinic acid pseudodipeptides is also discussed.
Received 2 November 2008
Revised 23 December 2008
Accepted 13 January 2009
Available online 19 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Phosphinic acids are of growing importance in understanding
and modulating biological processes.1 In recent years, the synthesis
of a-substituted phosphoryl derivatives (phosphonic and phosphi-
and also side reactions. On the other hand, the key step in the
one-pot synthesis of 1-aminoalkylphosphinic acids is nucleophilic
addition of an amine to a carbonyl compound followed by addition
of hyphophosphorus acid to the resulting imine. Therefore, the for-
mation of 1-hydroxyalkylphosphinic acids frequently accompanies
the formation of 1-aminoalkylphosphinic acids.12 Hydrophosph-
inylation of N,N0-arylidene bisamides has been reported as a new
method for the synthesis of 1-aminophosphinic acids.13 However,
this method also has problems, and includes difficulties in the
preparation of starting materials and requires harsh reaction con-
ditions for hydrolysis of the amide intermediate to the amine
product.
Diimines serve as good precursors for the synthesis of numer-
ous organic compounds, especially heterocyclic compounds.14,15
These, easily accessible precursors can be produced by the reaction
of aromatic aldehydes with ammonia solution. Recently, we re-
ported the reaction of diimines with diethyl phosphite for the pre-
partion of bis(1-diethoxyphosphorylalkyl)amines.16 As part of our
efforts to introduce novel methods for the synthesis of organo-
phosphorus compounds,17 herein we report a new method for
nic acids) has attracted significant attention, due to their biological
activities with broad application as enzyme inhibitors, antimetab-
olites and antibiotics.2 Among
a-functionalized phosphinic acids,
a-aminoalkylphosphinic derivatives have potential biological
activities, such as anti-bacterial,2 herbicidal3 and fungicidal.4 1-
Aminoalkylphosphinic acids, the phosphinic acid analogues of 1-
amino carboxylic acids, are an important class of compounds that
exhibit a variety of interesting and useful properties. In addition,
the structure of the phosphinic functional group mimics the tran-
sition state of peptide hydrolysis, and the symmetric nature of
the phosphinic acid derivatives is expected to be of benefit in their
binding to the homodimer of HIV-protease having C2-axis
symmetry.
A phosphinic moiety (–PO2–CH2–) is considered a mimic of the
tetrahedral transition state of peptide bond hydrolysis and due to
this, phosphinate pseudopeptides have attracted considerable
interest providing a wide range of potent inactivators of proteolytic
enzymes, particularly metalloproteases.5 In contrast to the widely
studied 1-aminoalkylphosphonic acid derivatives,6–9 relatively few
papers have reported the chemistry of 1-aminoalkylphosphinic
the synthesis of a-aminophosphinic acids and novel C2-symmetric
phosphinic acid pseudodipeptides. We have found that reaction of
aromatic aldehydes with ammonia solution followed by reaction
with hypophosphorus acid gives 1-aminophosphinic acids in good
yields (Scheme 1).
Thus, the reaction of benzaldehyde, chosen as a model com-
pound, with ammonia followed by treatment with hypophospho-
rus acid was studied under various reaction conditions. When
the reaction was conducted under reflux for 10 h using 5 equiv of
acids, although there is evidence that
a-aminophosphinic acids
are pharmaceutically active. Synthetic routes to 1-aminoalkyl-
phosphinic acids involve Mannich-type reaction of amines with
aldehydes in the presence of anhydrous hypophosphorus acid
and prolonged heating of anhydrous hypophosphorus acid with a
Schiff’s base.10 The addition of hypophosphorus acid to structurally
diverse imines appears to be a general method for the preparation
of N-substituted 1-aminoalkanephosphinic acids.11 However, both
of these methods have drawbacks, such as harsh reaction condi-
tions, anaerobic and anhydrous conditions, long reaction times
O
H
N
O
P
H
1) NH4OH (aq)/reflux/5 h
2) H3PO2/2-12 h
P
H
ArCHO
HO
OH
Ar Ar
1
2
* Corresponding author. Tel.: +98 241 4153220; fax: +98 241 4214949.
E-mail address: kaboudin@iasbs.ac.ir (B. Kaboudin).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.055

B. Kaboudin, F. Saadati / Tetrahedron Letters 50 (2009) 1450–1452
1451
Ph
O
O
P
H
O
P
H
O
P
H
H
N
H
N
N
N
1) NH4OH(aq)
2) H3PO2
Ph
P
H
+
HO
OH HO
OH
PhCHO
Ph
Ph Ph
Ph Ph
(R*,S*)-2a
(R*,R*)-2a
1a
Scheme 2.
H3PO2 (anhydrous), the 31P NMR spectrum of the product exhibited
two major peaks at d 17.85 and 17.58 due to the diastereoisomers
of 2a. The 1H NMR spectrum exhibited two doublets at d 4.16 and
3.79 indicative of HC–P coupling (JHP = 13.5 Hz). Two doublets at d
6.88 and 6.83 were indicative of H–P coupling (JHP = 552 Hz). Due
to the presence of two stereogenic carbons bonded to a phosphorus
atom, and due to the prototopic transfer of the acidic proton
between the phosphoryl (P@O) and acidic (P–OH) sites, these com-
pounds exist as two diastereomeric forms: one meso-compound
These results prompted us to extend this process to phosphorus
acid for the synthesis of 1-aminophosphonic acids (Scheme 3). Ini-
tially, we carried out the reaction of benzaldehyde 1a with ammo-
nia in the presence of phosphorus acid under reflux conditions.
Unfortunately, the reaction failed, and no product was detected
after 24 h at reflux.
Phosphorus–carbon bond formation via Michael addition is a
useful method for the synthesis of phosphinic acid dipeptides with
application in organic synthesis and bioorganic chemistry. A novel
C2-symmetric phosphinic acid dipeptide was synthesized by Mi-
chael addition of 2a to methyl acrylate. 1-Aminophosphinic acid
2a (single diastereoisomer) was activated by silylation with
HMDS18 then reacted with methyl acrylate to afford adduct 3a in
85% yield (Scheme 4).
In summary, the simple work-up, mild reaction conditions,
good yields and clean reactions with no tar formation make this
method an attractive and useful contribution to present methodol-
ogies.19 A novel C2-symmetric phosphinic acid dipeptide was also
synthesized by Michael addition of 2a to methyl acrylate.20 Further
investigations on the stereochemistry of the products and their
complexation ability are now in progress.
(R ,S -2a) and one racemic pair (S*,S* or R*,R*-2a), as shown in
Scheme 2. When the mixture of diastereoisomers 2a was washed
with a solvent mixture of ethanol/water (9:1) and dried in air at
room temperature, a single diastereoisomer was obtained. As we
were unable to obtain an X-ray crystal of the two diastereoisomers
of 2a, their unambiguous stereochemical assignments have not
been determined. It should be noted that when the reaction was
carried out with 50% hypophosphorus acid, 1-hydroxyphenyl
methylphosphinic acid was obtained as the major product.
This process was applied successfully to other aromatic alde-
hydes as summarized in Table 1. Substituted benzaldehydes re-
acted with ammonia followed by reaction with hypophosphorus
acid to afford the desired products 2b–f in moderate to good yields.
2-Naphthalene carbaldehyde also reacted with hypophosphorus
acid in the presence of ammonia to give compound 2g in 40% yield.
Reaction of aliphatic aldehyde 1h with hypophosphorus acid in the
presence of ammonia gave an unidentified mixture of products.
*
*
Acknowledgement
The Institute for Advanced Studies in Basic Sciences (IASBS) is
thanked for supporting this work.
References and notes
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Table 1
Synthesis of 1-aminophosphinic acids 2 from aldehydes
Entry
Ar
Reaction time (h)
Yielda (%)
a
b
c
d
e
f
C6H5-
10
11
12
12
11
2
48
71
61
45
64
42
40
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p-ClC6H4-
p-FC6H4-
p-MeOC6H4-
p-MeC6H4-
o-FC6H4-
_
´
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g
h
2-Naphthyl
n-C6H13
8
—
b
-
—
a
Isolated yields of mixtures of two diastereoisomers.
Unknown products obtained.
b
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1263–1270.
O
O
H
N
1) NH4OH (aq)/reflux/5 h
2) H3PO3/24 h
P(OH)2
(HO)2P
PhCHO
Ar Ar
1a
Scheme 3.
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Lett. 2001, 42, 5561–5563.
O
P
H
N
O
O
H
N
O
P
1) HMDS, 110 °C
MeO
P
OMe
O
P
H
H
OMe
OH
2)
OH
OH
OH
O
Ph Ph
Ph Ph
O
3a
2a
Scheme 4.

1452
B. Kaboudin, F. Saadati / Tetrahedron Letters 50 (2009) 1450–1452
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Haemers, A. Synthesis 1994, 23–24.
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Am. Chem. Soc. 1990, 112, 4976–4977.
62.1 (m, CHP), 127.0, 127.5, 127.7, 128.5, 128.7, 128.9, 134.9, 136.5; 31P NMR
(D2O/H3PO4-101.2 MHz): 17.58, 17.85 (40:60) ppm; IR (KBr): 3650–2120 (–
OH), 1250 (P@O), 1055–710 (P–O) cmꢀ1; Anal. Calcd for C14H17NO4P2: C, 51.68;
H, 5.27; N, 4.31. Found: C, 51.55; H, 5.20; N, 4.56. Compound 2b: white solid,
single diastereoisomer, mp: 240–242 °C; 1H NMR (D2O/TMS-250 MHz): 3.79
(2H, d, J = 14.0 Hz, –CHP), 6.84 (2H, d, JHP = 552 Hz), 6.91 (4H, d, J = 7.2 Hz), 7.21
(4H, d, J = 7.2 Hz); 13C NMR (D2O–NaOD/TMS-62.9 MHz): 59.2–61.5 (m, CHP),
128.7, 130.1 (d, JCP = 5.7 Hz), 132.8 (d, JCP = 3.1 Hz), 133.4 (d, JCP = 3.8 Hz); 31P
NMR (D2O/H3PO4-101.2 MHz): 17.37 ppm; IR (KBr): 3650–2120 (–OH), 1250
(P@O), 1080–750 (P–O) cmꢀ1; Anal. Calcd for C14H15Cl2NO4P2. C, 42.75; H,
3.85; N, 3.56. Found: C, 42.56; H, 3.80; N, 3.52. Compound 2c: white solid,
single diastereoisomer, mp: 230–232 °C; 1H NMR (D2O/TMS-250 MHz): 3.98
(2H, d, J = 13.5 Hz, –CHP), 6.99 (2H, d, JHP = 552 Hz), 7.01–7.15 (m, 8H); 31P
NMR (D2O/H3PO4-101.2 MHz): 17.22 ppm; IR (KBr): 3650–2120 (ꢀOH), 1240
(P@O), 1180–580 (P–O) cmꢀ1 13C NMR (D2O-NaOD/TMS-62.9 MHz): 60.1 (dd,
;
JCP = 98.5 and 14.1 Hz), 115.4 (d, JCP=21.4 Hz), 130.1–130.5 (m, Ar), 162.1 (d,
JCP = 243.2 Hz), Anal. Calcd for C14H15F2NO4P2: C, 46.53; H, 4.19; N, 3.88.
Found: C, 46.56; H, 4.12; N, 3.72. Compound 2d: white solid, single
diastereoisomer, mp: 212–214 °C; 1H NMR (D2O/TMS-250 MHz): 3.63 (s, 6H),
3.73 (2H, d, J = 14.5 Hz, –CHP), 6.86 (2H, d, JHP = 550 Hz), 6.82 (4H, d, J = 8.0 Hz),
6.90 (4H, d, J = 8.0 Hz); 31P NMR (D2O/H3PO4-101.2 MHz): 17.81 ppm; IR (KBr):
3650–2320 (ꢀOH), 1248 (P@O), 1150–650 (P–O) cmꢀ1
;
13C NMR (D2O–NaOD/
TMS-62.9 MHz): 55.3, 59.2–61.5 (m, CHP), 114.8, 120.4, 130.1 (d, JCP = 5.5 Hz),
159.7; Anal. Calcd for C16H21NO6P2: C, 49.86; H, 5.50; N, 3.64. Found: C, 49.71;
H, 5.43; N, 3.52. Compound 2e: white solid, mixture of two diastereoisomers;
1H NMR (D2O/TMS-250 MHz): 2.07, 2.10 (s, 6H), 3.72, 4.12 (2H, 2d, J = 14.0 Hz,
ꢀCHP), 6.83, 6.88 (2H, 2d, JHP = 551 Hz), 6.75–7.17 (8H, m); 31P NMR (D2O/
H3PO4-101.2 MHz): 17.86, 18.12 ppm; IR (KBr): 3650–2220 (ꢀOH), 1251
(P@O), 1185–610 (P–O) cmꢀ1 13C NMR (D2O–NaOD/TMS-62.9 MHz): 20.1,
;
60.0–62.1 (m, CHP), 128.4 (d, JCP = 5.7 Hz), 128.8 (d, JCP = 5.7 Hz), 129.0, 129.2,
131.6, 133.3, 137.6 (d, JCP = 3.1 Hz), 137.9 (d, JCP = 3.1 Hz). Anal. Calcd for
C16H21NO4P2: C, 54.38; H, 5.99; N, 3.96. Found: C, 54.30; H, 5.85; N, 4.05.
Compound 2f: white solid, single diastereoisomer, mp: 226–228 °C; 1H NMR
(D2O/TMS-250 MHz): 4.15 (2H, d, J = 14.7 Hz, ꢀCHP), 6.90 (2H, d,
JHP = 557.5 Hz), 6.75–7.85 (m, 8H); 31P NMR (D2O/H3PO4-101.2 MHz):
16. (a) Kaboudin, B.; Moradi, K. Synthesis 2006, 2339–2342; (b) Kaboudin, B.; Jafari,
E. Synthesis 2006, 3063–3066.
17. (a) Kaboudin, B. Chem. Lett. 2001, 880–881; (b) Kaboudin, B.; Nazari, R.
Tetrahedron Lett. 2001, 42, 8211; (c) Kaboudin, B.; Nazari, R. Synth. Commun.
2001, 31, 2245–2250; (d) Kaboudin, B. Tetrahedron Lett. 2002, 43, 8713–8714;
(e) Kaboudin, B. Tetrahedron Lett. 2003, 44, 1051–1053; (f) Kaboudin, B.;
Rahmani, A. Synthesis 2003, 2705–2708; (g) Kaboudin, B.; Saadati, F. Synthesis
2004, 1249–1252; (h) Kaboudin, B.; Rahmani, A. Org. Prep. Proced. Int 2004, 36,
82–86; (i) Kaboudin, B.; Moradi, K. Tetrahedron Lett. 2005, 46, 2989–2991; (j)
Kaboudin, B.; Haghighat, H. Tetrahedron Lett. 2005, 46, 7955–7957; (k)
Kaboudin, B.; Haghighat, H.; Yokomatsu, T. J. Org. Chem. 2006, 71, 6604–
6606; (l) Kaboudin, B.; Karimi, M. Bioorg. Med. Chem. Lett. 2006, 16, 5324–5327;
(m) Kaboudin, B.; Farjadian, F. Beilstein J. Org. Chem 2006, 2, 4; (n) Yamagishi,
T.; Kusano, T.; Kaboudin, B.; Yokomatsu, T.; Sakuma, C.; Shibuya, S. Tetrahedron
2003, 59, 767–772; (o) Kaboudin, B.; Haruki, T.; Yamaghishi, T.; Yokomatsu, T.
Tetrahedron 2007, 63, 8199–8205; (p) Kaboudin, B.; Haruki, T.; Yamagishi, T.;
Yokomatsu, T. Synthesis 2007, 3226–3232; (q) Kaboudin, B.; Haghighat, H.;
Yokomatsu, T. Tetrahedron: Asymmetry 2008, 19, 862–866.
15.95 ppm; IR (KBr): 3650–2120 (ꢀOH), 1240 (P@O), 1180–580 (P–O) cmꢀ1
;
13C NMR (D2O–NaOD/TMS-62.9 MHz): 60.1 (dd, JCP = 98.5 and 14.1 Hz), 116.1
(d, JCP = 21.4 Hz), 125.3–130.5 (m, Ar), 161.1 (d, JCP = 242.0 Hz), Anal. Calcd for
C14H15F2NO4P2: C, 46.53; H, 4.19; N, 3.88. Found: C, 46.50; H, 4.15; N, 3.75.
Compound 2g: white solid, single diastereoisomer, mp: 212–214 °C; 1H NMR
(D2O/TMS-250 MHz): 4.13 (2H, d, J = 13.2 Hz, –CHP), 7.13 (2H, d, JHP = 551 Hz),
6.90–7.80 (m, 12H), 6.90 (2H, d, J = 8.0 Hz); 31P NMR (D2O/H3PO4-101.2 MHz):
17.80 ppm; IR (KBr): 3650–2100 (ꢀOH), 1248 (P@O), 1050–750 (P–O) cmꢀ1
;
13C NMR (D2O–NaOD/TMS-62.9 MHz): 61.2 (dd, JCP = 97.5 and 13.8 Hz), 126.1–
126.5 (m, Ar) 127.6, 128.0 (d, JCP = 7.0 Hz), 128.2, 132.5, 132.6 132.9; Anal.
Calcd for C22H21NO4P2: C, 62.10; H, 4.98; N, 3.29. Found: C, 61.97; H, 5.03; N,
3.22.
20.
A mixture of phosphinic acid 2a (one diastereoisomer, 1 mmol) and
18. Matziari, M.; Georgiadis, D.; Dive, V.; Yiotakis, A. Org. Lett. 2001, 3, 659–662.
19. The aldehyde (3 mmol) was added to ammonium hydroxide (30%, 15 mL), and
the solution was stirred for 5 h at reflux. During this time, a white precipitate
formed. The precipitate was removed by filtration and dried. The solid was
dissolved in 5 mL of ethanol, and anhydrous hypophosphorus acid (5 mmol)
was added to this mixture and the resulting solution was stirred for 2–12 h at
reflux. The solvent was evaporated and the mixture was dissolved in acetone
by heating. Dropwise addition of water gave the crude product as a white solid.
The crude product was washed with ethanol and dried in air at room
temperature to give product 2 in 40–71% yield. The solid product was washed
with ethanol/water (50 ml, 9:1) and dried in air at room temperature to give a
single diastereoisomer. All products gave satisfactory spectral data in accord
with the assigned structures. Analytical and spectral data for compounds 2:
Compound 2a: white solid, mixture of two diastereoisomers; 1H NMR (D2O/
TMS-250 MHz): 3.79, 4.16 (2H, 2d, J = 13.5 Hz, –CHP), 6.83, 6.88 (2H, 2d,
JHP = 552 Hz), 6.85–7.40 (10H, m); 13C NMR (D2O-NaOD/TMS-62.9 MHz): 60.0–
1,1,1,3,3,3-hexamethyldisilazane (5 mmol, 1 mL) was heated at 110 °C for
2 h under Ar. The mixture was cooled to rt. Methyl acrylate (2 mmol,
0.18 mL) was added dropwise and the resulting mixture was stirred at 60 °C
for 12 h. Absolute EtOH (10 mL) was added and the mixture was cooled to rt
slowly. The solvent was removed under vacuum. The residue was treated
with a solution of sodium bicarbonate (5%, 10 mL) and extracted with ethyl
acetate (3 ꢁ 10 mL). The aqueous solution was acidified with HCl (5%), and
extracted with CHCl3 (4 ꢁ 10 mL). The combined organic layers were washed
with brine, dried over Na2SO4 and evaporated under reduced pressure to
give 3a as a white solid in 85% yield. Mp: 95–96 °C; 1H NMR (DMSO/TMS-
250 MHz): 1.55–1.90 (m, 4H), 2.20–2.40 (m, 4H), 3.54 (s, 8H), 5.10–5.75 (br
s, NH), 7.10–7.40 (m, 10H); 31P NMR (DMSO/H3PO4-101.2 MHz): 43.68 ppm;
13C NMR (DMSO/TMS-62.9 MHz): 21.8 (d, JCP = 93.7 Hz), 26.6, 52.0, 59.9 (dd,
JCP = 99.8 and 13.3 Hz), 127.2–129.5 (m, Ar), 135.6, 172.9 (d, JCP = 16.1 Hz);
Anal. Calcd for C22H29NO8P2: C, 53.10; H, 5.89; N, 2.82. Found: C, 53.05; H,
5.80; N, 2.65.