Efficient synthesis of racemic β-aminophosphonates via aza-Michael reaction in water

Article abstract of DOI:10.1016/j.tetlet.2008.08.015

Water as a solvent significantly accelerates the addition of various amines to diethyl vinylphosphonate to yield β-aminophosphonates without any catalyst compared to known procedures for such aza-Michael reactions. The products are obtained in quantitative yields and high purity over short reaction times. Using a reactant ratio (vinylphosphonate/amine) of 2:1 resulted in double phosphorylation of primary amines.

Full text of DOI:10.1016/j.tetlet.2008.08.015

Tetrahedron Letters 49 (2008) 6129–6133
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient synthesis of racemic b-aminophosphonates
via aza-Michael reaction in water
*
Ekaterina V. Matveeva, Pavel V. Petrovskii, Irina L. Odinets
A.N.Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilova Street, 28, 119991 Moscow GSP-1, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Water as a solvent significantly accelerates the addition of various amines to diethyl vinylphosphonate to
yield b-aminophosphonates without any catalyst compared to known procedures for such aza-Michael
reactions. The products are obtained in quantitative yields and high purity over short reaction times.
Using a reactant ratio (vinylphosphonate/amine) of 2:1 resulted in double phosphorylation of primary
amines.
Received 14 May 2008
Revised 30 July 2008
Accepted 5 August 2008
Available online 8 August 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Amines
Aza-Michael reaction
Vinylphosphonate
Water
b-Aminophosphonates
b-Aminophosphonic acid
The key role of naturally occurring amino acids in the chemistry
of life has led to the synthesis and investigation of the biological
activity of synthetic analogues. Among these, the so-called ‘phos-
phorus analogues’ have attracted particular attention due to their
diverse biological activity.1 In this area, derivatives of b-amino-
phosphonic acid, first isolated from Celiate protozoa by Horiguchi
and Kandatsu2 in 1959, are important. These compounds demon-
strate diverse biochemical properties such as antibacterial, anti-
HIV and protease-inhibiting activities.3 They also show complexing
properties which are advantageous for selective ionophores or
membrane carrier design.3b Hence, the development of procedures
for the efficient preparation of amino acid analogues including
asymmetric synthesis is currently of high importance.
Different methods such as carbon–phosphorus, carbon–carbon
or carbon–nitrogen bond formation reactions have been utilised
for the synthesis of b-aminophosphonic and phosphinic acid deriv-
atives. The aza-Michael addition is an important method for C–N
bond formation and involves the conjugate addition of N-nucleo-
philes to vinylphosphoryl compounds. In 1951, Pudovik4 reported
the addition of amines to vinylphosphonates to afford b-amino-
phosphonates, and work in this area has been further devel-
oped.1,3,5,6 Thus, secondary amines such as dimethylamine and
piperidine, being active nucleophiles, react exothermically with
diethyl vinylphosphonate in the absence of a solvent; however,
an additional 24 h are required for completion of the reaction along
with the use of 10–15% excess of the amine. Less active primary
amines and ammonia react only in the presence of basic catalysts
such as sodium or sodium alkoxides and require elevated temper-
atures and prolonged reaction times; arylamines do not add to
vinylphosphinates even under severe conditions. A wide range of
b-aminophosphonates have been prepared in good yields including
quaternary b-aminophosphonates, which are useful as synthetic
nonviral vector-mediated gene transfer agents,7 those bearing per-
fluoroalkyl groups,8 and phosphorylated analogues of putrescine
and spermidine,9 etc. However, despite satisfactory results, the
reported procedures used hazardous organic solvents, excess
amine and catalysts which are not desirable from a green chemis-
try point of view. Here, we report a very simple and high yielding
procedure for b-aminophosphonate synthesis in water without any
catalyst or organic co-solvent.
Organic reactions in water have received increased attention
due to environmental safety, low cost and the possibility to accel-
erate a variety of important reactions such as Diels–Alder, aldol,
alkylation reactions, Claisen rearrangements and so on.10 Recently,
the use of water as reaction medium for Michael reactions of
ketones and aldehydes with nitroolefins using diamine/TFA, (S)-
pyrrolidinesulfonamide or pyrrolidine–thiourea organocatalysts11
as well as amine additions to activated non-phosphorylated
alkenes without any catalyst12 was reported. Possibly due to the
fact that water has an adverse effect on organophosphorus
reactants due to side reactions, for example, hydrolysis, it has not
found wide application as a medium in organophosphorus chemis-
try with examples being restricted to Wittig reactions.13
We have found that various primary and secondary alkylamines
add smoothly and rapidly to diethyl vinylphosphonate in water
* Corresponding author. Fax: +7 499 135 5085.
E-mail address: odinets@ineos.ac.ru (I. L. Odinets).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.015

6130
E. V. Matveeva et al. / Tetrahedron Letters 49 (2008) 6129–6133
R1
was complete for Et2NH and n-BuNH2, but for sterically hindered
tert-butylamine the yield of the final product 1b was 78% after
70 h at rt. It should be noted that without water, active amines
such as diethylamine did not add to the vinylphosphonate at room
temperature even over long reaction times. Elongation of the alkyl
chain in the alkylamine resulted in a decrease in reactivity, and at
room temperature, long-chain aliphatic dialkylamines (>C8) did
not react with vinylphosphonate in water. Aromatic amines and
amino acids and their esters did not react, possibly due to a
decrease in their nucleophilic properties.
If more than one amine functionality was present in the starting
reactant, addition to the vinylphosphonate in water proceeded
readily with participation of all the amine functionalities. Thus,
reaction with ethylenediamine, meta-xylylenediamine and tris(2-
aminoethylamine) resulted in bis(aminophosphonates) 3a,c and
tris(aminophosphonate) 3b in almost quantitative yields (Table 1,
entries 13–15).
NH
O
P
R1
R2
O
R2
OEt
OEt
(EtO)2P
N
r.t.
H2O,
1a-f, 2a-d, 3a-c
Scheme 1.
(Scheme 1). The difference in chemical shifts of the phosphorus
substrate and the product allows easy monitoring of the reaction
by 31P NMR spectroscopy. Both the nucleophilic and steric proper-
ties of the amine influence the reaction rate which decreased in the
series: Alk2NH > AlkNH2 > ArCH2NH2 and with an increase in the
bulkiness of the substituents on the nitrogen atom of the amine.
Among secondary amines, cyclic examples such as piperidine and
morpholine were more active than their acyclic analogues (Table
1).
At room temperature, the reaction of (EtO)2P(O)CH@CH2 with
piperidine was complete (quantitative) in 7 min (Table 1, entry
10, compound 2b), while the yields of the corresponding b-amino-
phosphonates over the same period of time were 73%, 25% and 5%
for reaction with diethylamine, n-butylamine and tert-butylamine,
respectively (Table 1, entries 1, 2 and 8). After 45 min, the reaction
To reduce the reaction time, elevated temperatures can be used
and no side reactions were observed even at reflux. At 100 °C the
reactions with benzylamine and N(CH2CH2NH2)3 were complete
in 45 min; however, with tBuNH2 and PhCH(CH3)NH2, 3 h were
required to afford the products in high yields (Table 2).
When the starting reactants were used in the ratio 1:1, only
mono adducts were formed in the case of primary amines and no
traces of the corresponding bis-addition products were observed.
However, use of the reactants in the ratio (EtO)2P(O)CH@CH2/
amine=1:2 allowed double phosphorylation of primary amines
(Table 3). To the best of our knowledge, no examples of such reac-
tions have been observed previously under common reaction con-
ditions. According to 31P NMR monitoring, the reaction proceeded
via a stepwise process giving firstly the mono adducts followed by
addition to a second molecule of vinylphosphonate. In the case of
aza-Michael reactions of non-phosphorylated activated alkenes in
water,12 double addition to primary amines was not observed.
The amount of water used did not influence the reaction rate
significantly. The use of 2 ml of water per 1 mmol of amine was
appropriate. All the reactions were very clean and often did not
require further purification. Moreover, as the final b-aminophos-
phonates are very soluble in water, extraction of the product into
DCM or CHCl3 led to partial loss of the compound (ca. 15–25%).
Lyophilisation of the crude reaction mixture followed by additional
purification (if necessary) using flash chromatography gave the
best results. It should be mentioned that the compounds form
stable solvates with CHCl3 or hydrates (compounds 3c, 4a,b,d
and 1b,d, respectively), which lost the solvent molecule only under
prolonged drying in vacuo (1 Hg) at ca. 100 °C. The formation of
strong solvates with CHCl3 serving as a proton donor for amino-
phosphonates has been reported in the literature.14
Table 1
Aza-Michael reaction of diethyl vinylphosphonate and various amines in water
according to Scheme 1
Entry
1
Amine
Product
Time
Yielda (%)
nBuNH2
1a
7 min
45 min
1.5 h
45 min
3 h
25
70
93 (65)b
2
tBuNH2
1b
5
18
70 h
78 (68)b
3
4
5
nHexNH2
nOctNH2
1c
1d
1e
45 min
3 h
45 min
3 h
45 min
3 h
77
Quant (95)
75
Quant (94)
35
75
96 (92)
PhCH2NH2
24 h
6
PhCH(CH3)NH2
1f
45 min
24 h
9
79
48 h
Quant (92)
7
8
PhNH2
Et2NH
—
2a
No reaction
7 min
45 min
73
96 (92)
No reaction
9
Oct2NH
—
Despite the reaction rate for the aza-Michael addition in water
at room temperature with vinylphosphonate being a little bit
lower compared with other activated alkenes bearing more acidic
10
2b
7 min
Quant (95)
NH
11
2c
7 min
45 min
50
O
O
NH
Quant (95)
Table 2
12
13
14
2d
3a
3b
45 min
5 h
45 min
48 h
42
NH
Influence of reaction temperature on the rate of the aza-Michael addition in water
88 (75)b
25
Entry
1
Amine
Product
Temperature (°C)
Time
Yielda (%)
H2NCH2CH2NH2
N(CH2CH2NH2)3
Quant (97)
72
tBuNH2
1b
20
3 h
18
3 h
100
100
20
100
20
100
100
20
45 min
3 h
65
100
35
100
9
75
100
20
100
20 h
Quant (92)
2
3
PhCH2NH2
1e
1f
45 min
45 min
45 min
45 min
3 h
15
3c
45 min
3 h
20 h
52
86
PhCH(CH3)NH2
NH2
NH2
Quant (96)
Yield according to 31P NMR spectroscopy. Isolated yield after lyophilization
a
4
N(CH2CH2NH2)3
3b
45 min
45 min
shown in brackets.
100
b
Work-up comprised extraction with DCM followed by chromatographic
Yield according to 31P NMR spectroscopy.
a
purification.

E. V. Matveeva et al. / Tetrahedron Letters 49 (2008) 6129–6133
6131
Table 3
Synthesis of bis(diethylphosphorylethyl) substituted amines 4a-d
O
O
O
H2O
r.t.
EtO
2
P
RNH2
(EtO)2P
N
R
P(OEt)2
+
EtO
4a-d
Entry
1
Amine
Product
Time
Yielda (%)
O
O
45 min
24 h
48 h
2
70
96 (87)
nBuNH2
(EtO)2P
N
nBu
P(OEt)2
4a
P(O)(OEt)2
P(O)(OEt)2
(EtO)2(O)P
2
H2NCH2CH2NH2
72 h
96 h
120 h
90 (71)
90 (85)
90 (83)
N
N
(EtO)2(O)P
(EtO)2(O)P
4b
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
N
NH2
N
NH2
N
N
3
4c
N
H2N
(EtO)2(O)P
P(O)(OEt)2
(EtO)2(O)P
P(O)(OEt)2
P(O)(OEt)2
4
N
N
4d
NH2
NH2
(EtO)2(O)P
a
Yield according to 31P NMR spectroscopy. Isolated yield after extraction with CH2Cl2 and further chromatographic purification shown in brackets.
substituents, that is,
a
,b-unsaturated carboxylic esters, ketones,
nate. The reported procedure being extremely simple opens wide
possibilities for the design of molecular sensors and oligodentate
ligands bearing b-aminophosphonate moieties.
nitriles and amides,12 it proceeds much faster in comparison with
known procedures for b-aminophosphonate synthesis (Table 4).
It seems reasonable that acceleration of the aza-Michael addi-
tion in water is promoted by both hydrogen bond formation
between the H-atom of water and the oxygen atom of the phos-
phoryl moiety increasing the electrophilic character of the b-car-
bon atom and between the H-atom of the amine and the oxygen
atom of water resulting in increased amine nucleophilic properties.
In conclusion, we have demonstrated that water activates the
aza-Michael addition between amines and diethyl vinylphospho-
General procedure for the synthesis of diethyl 2-amino-
ethylphosphonates: To a solution of the amine (1 mmol) in water
(2 ml) at room temperature was added the appropriate stoichio-
metric amount of diethyl vinylphosphonate. The mixture was stir-
red over the time mentioned in the Tables 1–3 either at room
temperature or at reflux if desired. In the case of quantitative reac-
tion, lyophilisation of the crude reaction mixture afforded the pure
product. Otherwise, the reaction solution was extracted with
Table 4
Synthesis of b-aminophosphonates under various conditions
Amine
Solvent
Catalyst
Reaction conditions
Isolated yield (%)
nBuNH2
Excess amine
Water
Excess amine
Water
Excess amine
Water
Excess diethyl vinylphosphonate
Water
MeONa
—
EtONa
—
EtONa
—
EtONa
—
Reflux, 4 h
rt, 1.5 h
Reflux, 20 h
r.t., 70 h
Reflux, 5 h
rt, 24 h
rt, 96 h, then 100 °C, 30 min
rt, 48 h
7515
88
—
tBuNH2
15
68
PhCH2NH2
H2NCH2CH2NH2
Et2NH
7515
92
6416
89
Excess amine
Water
Na
—
90 °C, 5 h
rt, 45 min
6617
92
Excess amine
Water
—
rt, 24 h
rt, 7 min
5618
95
NH
Excess amine
Water
—
—
70 °Ca
rt, 45 min
806
95
O
NH
a
Reaction time not quoted.

6132
E. V. Matveeva et al. / Tetrahedron Letters 49 (2008) 6129–6133
1
CH2Cl2 (3 Â 5 ml), the combined extracts were dried over Na2SO4
and evaporation of the solvent under reduced pressure to dryness
afforded the crude final product with purity >95% according to
NMR data. Further purification by column chromatography (SiO2,
CHCl3/ethanol, 100:6) gave pure b-aminophosphonates as oils after
evaporation of the appropriate fractions (according to TLC and 31P
NMR data) in vacuum (20 Hg, 60 °C, 3 h).
In some cases (compounds 1c and 4c), elemental analysis data
were obtained for free phosphonous acids (prepared via reaction
with trimethylsilyl bromide in chloroform followed by the treat-
ment with aq MeOH) as hydrobromides or as hydrobromide-
hydrates.
3JPC = 5.9 Hz, CH3 in Et), 23.88 (s, CH3), 26.96 (d, JPC = 139.4 Hz,
CH2–P), 40.78 (s, CH2–NH), 57.71 (s, CH), 61.21 (s, OCH2), 61.29
(s, OCH2), 126.28 (s, meta-C in C6H5), 126.73 (s, para-C in C6H5),
128.16 (s, ortho-C in C6H5), 144.56 (s, ipso-C in C6H5). IR (KBr)
m
/cmÀ1: 1021 (P–O–C), 1270 (P@O). Elemental analysis data were
obtained for the corresponding solid hydrochloride obtained by
treatment with HCl/Et2O; mp 142 °C (hydroscopic). Anal. Calcd
for C14H25ClNO3PÁ0.3H2O: C, 51.30; H, 7.89; N, 4.27; P, 9.45. Found:
C, 51.28; H, 7.42; N, 4.23; P, 9.27.
Diethyl 2-(4-oxo-1-piperidinyl)ethylphosphonate (2d): Synthe-
sized from 4-piperidone hydrochloride monohydrate in the
presence of potassium carbonate. Yield 75% (after column
chromatography), pale yellow oil. 31P NMR (162 MHz, CDCl3): d
Physicochemical constants and spectral data of known com-
pounds (1a,6 1e,15 2a,6 2b,18 2c,6 3a16) correlate well the literature
data.
29.8. 1H NMR (400 MHz, CDCl3): d 1.25 (t, JHH = 6.3 Hz, 3H, CH3),
3
3
1.26 (t, JHH = 7.0 Hz, 3H, CH3), 1.87–1.98 (m, 2H, CH2–P), 2.38–
Diethyl 2-(tert-butylamino)ethylphosphonate (1b): Yield 68%
(purified by column chromatography), pale yellow oil. 31P NMR
(121 MHz, CDCl3): d 30.4. 1H NMR (300 MHz, CDCl3): d 1.07 (s,
2.39 (m, 4H, CH2 in piperidone), 2.69–2.75 (m, 6H, CH2–N, CH2 in
piperidone), 3.99–4.05 (m, 4H, OCH2). 13C NMR (101 MHz, CDCl3):
3
1
d 15.99 (d, JPC = 5.9 Hz, CH3), 23.84 (d, JPC = 139.7 Hz, CH2–P),
40.60 (s, CH2 in piperidone), 50.18 (s, CH2–N), 52.04 (s, CH2 in pip-
eridone), 61.07 (s, OCH2), 61.14 (s, OCH2), 207.91 (s, C@O). IR (thin
3
9H, CH3 in tBu), 1.29 (t, JHH = 7.1 Hz, 6H, CH3 in Et), 1.90 (dt,
3
2JPH = 18 Hz, JHH = 7.3 Hz, 2H, CH2–P), 2.38 (br s, 1H, NH), 2.81
3
3
(dt, JPH = 14.9 Hz, JHH = 7.3 Hz, 2H, CH2–NH), 4.02–4.11 (m, 4H,
layer) m
/cmÀ1: 1022 (P–O–C), 1234 (P@O), 1729 (C@O). Anal. Calcd
OCH2). 13C NMR (101 MHz, CDCl3): d 15.87 (d, JPC = 5.6 Hz, CH3
for C11H22NO4P: C, 50.18; H, 8.42; N, 5.32; P, 11.76. Found: C,
49.93; H, 8.58; N, 5.18; P, 11.44.
3
in Et), 26.46 (d, JPC = 139.4 Hz, CH2–P), 28.12 (s, CH3 in tBu),
1
t
35.79 (s, CH2–NH), 50.34 (s, C in Bu), 61.04 (s, OCH2), 61.08 (s,
OCH2). IR (thin layer)
Diethyl
[6-{2-[2-(diethoxyphosphinyl)ethyl]aminoethyl}-12-
m
/cmÀ1: 1029 (P–O–C), 1235 br (P@O),
ethoxy-12-oxido-13-oxa-3,6,9-triaza-12-phosphapentadec-1-yl]phos-
phonate (3b): Yield 92% (after freeze-drying), pale-yellow oil. 31P
NMR (162 MHz, CDCl3): d 30.5. 1H NMR (400 MHz, CDCl3): d 1.29
3298, 3468 (N–H). Anal. Calcd for C10H24NO3PÁ0.17H2O: C, 49.99;
H, 10.21; P, 12.89. Found: C, 50.14; H, 10.15; P, 12.44.
3
2
3
Diethyl 2-(hexylamino)ethylphosphonate (1c): Yield 95% (after
freeze-drying), pale-yellow oil. 31P NMR (121 MHz, CDCl3): d
30.8. 1H NMR (400 MHz, CDCl3): d 0.80–0.83 (m, 3H, CH3 in Hex),
1.22–1.29 (m, 12H, CH3 in Et, CH2 in Hex), 1.38–1.43 (m, 2H, CH2
(t, JHH = 7.1 Hz, 18H, CH3 in Et), 2.07 (dt, JPH = 18.4 Hz, JHH =
7.8 Hz, 6H, CH2–P), 2.57–2.68 (m, 12H, N–CH2CH2–N), 2.77–2.82
(m, 6H, CH2–N), 4.06–4.14 (m, 12H, OCH2). 13C NMR (75 MHz,
C6D6): d 16.38 (d, 3JPC = 5.7 Hz, CH3 in Et), 26.86 (d, 1JPC = 137.9 Hz,
CH2–P), 43.77 (s, CH2–N), 47.44 (s, N–CH2CH2–N), 54.82 (s, N–
CH2CH2–N), 60.93 (s, OCH2), 61.01 (s, OCH2). IR (thin layer)
2
3
in Hex), 1.92 (dt, JPH = 18.3 Hz, JHH = 7.3 Hz, 2H, CH2–P), 2.53 (t,
3
3
3H, JHH = 7.2 Hz, CH2N in Hex), 2.84 (dt, JPH = 14.8 Hz,
3JHH = 7.3 Hz, 2H, CH2–NH), 3.99–4.19 (m, 4H, OCH2). 13C NMR
m
/cmÀ1: 1036 (P–O–C), 1244br (P@O), 3400 (N–H). Anal. Calcd
3
(101 MHz, CDCl3): d 13.32 (s, CH3), 15.74 (d, JPC = 6.3 Hz, CH3 in
Et), 21.88 (s, CH2), 25.78 (d, JPC = 139.3 Hz, CH2–P), 26.31 (s,
CH2), 29.29 (s, CH2), 31.06 (s, CH2), 42.69 (d, JPC = 3.7 Hz, CH2–
for C24H57N4O9P3: C, 45.14; H, 9.00; P, 14.55. Found: C, 44.81;
H, 8.73; P, 14.32.
1
2
1,3-Bis{[(diethoxyphosphoryl)ethyl]aminomethyl}benzene
(3c):
NH), 48.95 (s, CH2), 60.73 (s, OCH2), 60.79 (s, OCH2). IR (KBr)
Yield 96% (after freeze-drying), pale yellow oil. 31P NMR
m
/cmÀ1: 1214 (P@O). Elemental analysis data were obtained for
(121 MHz, CDCl3): d 31.5. 1H NMR (400 MHz, CDCl3): d 1.26 (t,
2
3
the corresponding phosphonous acid hydrobromide, mp 195 °C.
Anal. Calcd for C8H20NO3PÁ1HBrÁ0.6H2O: C, 31.94; H, 7.44; N,
4.65; P, 10.29. Found: C, 31.66; H, 6.96; N, 4.55; P, 10.62.
3JHH = 7.0 Hz, 12H, CH3), 2.01 (dt, JPH = 18.4 Hz, JHH = 7.4 Hz, 2H,
3
3
CH2–P), 2.90 (dt, JPH = 14.6 Hz, JHH = 7.4 Hz, 4H, CH2–NH), 3.77
(s, 4H, CH2–Ar), 4.00–4.09 (m, 8H, OCH2), 7.20–7.31 (m, 4H,
3
Diethyl 2-(octylamino)ethylphosphonate (1d): Yield 94% (after
freeze-drying), pale yellow oil. 31P NMR (121 MHz, CDCl3): d
30.7. 1H NMR (400 MHz, CDCl3): d 0.78–0.82 (m, 3H, CH3 in Oct),
C6H4). 13C NMR (101 MHz, CDCl3): d 15.20 (d, JPC = 6.2 Hz, CH3),
1
25.15 (d, JPC = 139.0 Hz, CH2–P), 41.49 (s, CH2_N), 52.16 (s, CH2–
Ar), 60.15 (s, OCH2), 60.22 (s, OCH2), 124.56 (s, C5), 125.51 (s, C4,
3
1.19–1.22 (m, 10 H, CH2 in Hex), 1.25 (t, JHH = 7.1 Hz, 6H, CH3 in
C6), 127.18 (s, C2), 139.01 (s, C1, C3). IR (thin layer) /cmÀ1: 1029
m
2
Et), 1.39–1.42 (m, 2H, CH2 in Oct), 1.92 (dt, JPH = 18.3 Hz,
(P–O–C), 1238 br (P@O), 3304, 3465 (N–H). This product was sig-
nificantly retained on silica gel if purified by column chromatogra-
phy, such purification decreased the yield up to 20% and gave the
chloroform solvate. Anal. Calcd for C20H38N2O6P2Á0.8CHCl3: C,
44.61; H, 6.98. Found: C, 44.48; H, 7.08.
3
3JHH = 7.4 Hz, 2H, CH2–P), 2.52 (t, 3H, JHH = 7.2 Hz, CH2N in Oct),
3
3
2.83 (dt, JPH = 14.8 Hz, JHH = 7.4 Hz, 2H, CH2–NH), 3.99–4.15 (m,
4H, OCH2). 13C NMR (101 MHz, CDCl3): d 13.52 (s, CH3 in Oct),
3
15.89 (d, JPC = 6.3 Hz, CH3 in Et), 22.09 (s, CH2 in Oct), 25.93 (d,
1JPC = 138.9 Hz, CH2–P), 26.78 (s, CH2 in Oct), 28.69 (s, CH2 in
Diethyl 2-[butyl{2-(diethoxyphosphinyl)ethyl}amino]ethylphosph-
onate (4a): Yield 87% (after column chromatography), pale yellow
oil. 31P NMR (162 MHz, CDCl3): d 30.7. 1H NMR (400 MHz, CDCl3):
d 0.87 (t, 3JHH = 7.2 Hz, 3H, CH3 in Bu), 1.16–1.23 (m, 2H, CH2–CH3),
Oct), 28.95 (s, CH2 in Oct), 29.46 (s, CH2 in Oct), 31.26 (s, CH2 in
2
Oct), 42.82 (d, JPC = 3.7 Hz, CH2–NH), 49.09 (s, NH–CH2 in Oct),
60.90 (s, OCH2), 60.97 (s, OCH2). IR (thin layer)
(P–O–C), 1242 (P@O), 3306, 3464 (N–H). Anal. Calcd for
m
/cmÀ1: 1031
3
1.27 (t, JHH = 7.1 Hz, 12H, CH3 in Et), 1.32–1.39 (m, 2H, CH2–
2
3
C
14H32NO3PÁ0.7H2O: C, 55.01; H, 11.00; N, 4.59. Found: C, 55.06;
CH2CH3), 1.84 (dt, JPH = 19.0 Hz, JHH = 8.0 Hz, 2H, CH2–P), 1.86
2
3
H, 10.69; N, 4.14.
(dt, JPH = 19.2 Hz, JHH = 8.2 Hz, 2H, CH2–P), 2.33-2.36 (m, 2H, N–
CH2 in Bu), 2.68-2.74 (m, 4H, CH2–N), 4.00–4.07 (m, 8H, OCH2).
13C NMR (101 MHz, CDCl3): d 13.70 (s, CH3 in Bu), 16.20 (d,
3JPC = 6.2 Hz, CH3 in Et), 20.27 (s, CH2CH3), 22.87 (d, 1JPC = 137.5 Hz,
CH2–P), 28.80 (s, CH2–CH2CH3), 46.18 (s, CH2–N), 52.28 (s, N–CH2
Diethyl 2-[(1-phenylethyl)amino]ethylphosphonate (1f): Yield
92% (after freeze-drying), pale yellow oil. 31P NMR (162 MHz,
CDCl3): d 30.7. 1H NMR (400 MHz, CDCl3): d 1.25 (td, 3JHH = 7.0 Hz,
3
4JPH = 3.1 Hz, 6H, CH3 in Et), 1.34 (d, JHH = 6.6 Hz, 3H, CH3), 1.92
2
3
(dt, JPH = 18 Hz, JHH = 7.2 Hz, 2H, CH2–P), 2.37 (br s, 1H, NH),
in Bu), 61.32 (s, OCH2), 61.39 (s, OCH2). IR (thin layer) m :
/cmÀ1
3
2.65-2.73 (m, 2H, CH2–NH), 3.76 (q, JHH = 6.6 Hz, 1H, CH), 3.99–
1032 (P–O–C), 1247 br (P@O). Anal. Calcd for C16H37NO6P2Á
0.4CHCl3: C, 43.85; H, 8.39; N, 3.12. Found: C, 43.90; H, 8.60; N,
2.90.
3
4.07 (m, 4H, OCH2), 7.22 (br t, JHH = 4.4 Hz, 1H, para-H in C6H5),
7.28–7.29 (m, 4H, C6H5). 13C NMR (101 MHz, CDCl3): d 16.08 (d,

E. V. Matveeva et al. / Tetrahedron Letters 49 (2008) 6129–6133
6133
Diethyl [3,6-bis{2-(diethoxyphosphinyl)ethyl}-9-ethoxy-9-oxido-
10-oxa-3,6-diaza-9-phosphadodec-1-yl]phosphonate (4b): Yield 71%
(after column chromatography), pale yellow oil. 31P NMR
(162 MHz, CDCl3): d 30.3. 1H NMR (400 MHz, CDCl3): d 1.28 (t,
for C32H64N2O2P4Á0.6CHCl3: C, 45.30; H, 7.50; P, 14.33. Found: C,
45.39; H, 7.53; P, 14.02.
Acknowledgement
2
3
3JHH = 7.1 Hz, 24H, CH3 in Et), 1.85 (dt, JPH = 19.2 Hz, JHH
=
8.1 Hz, 8H, CH2–P), 2.46 (s, 4H, NCH2CH2N), 2.70–2.75 (m, 8H,
This work was supported by the Russian Foundation of Basic
Research (Grant No. 08-03-00766).
CH2–N), 4.01–4.10 (m, 16H, OCH2). 13C NMR (101 MHz, CDCl3): d
3
1
16.38 (d, JPC = 6.2 Hz, CH3 in Et), 26.42 (d, JPC = 139.4 Hz, CH2–
P), 48.77 (s, CH2–N), 51.65 (s, N–CH2CH2–N), 61.57 (s, OCH2),
References and notes
61.63 (s, OCH2). IR (thin layer)
m
/cmÀ1: 1031 (P–O–C), 1247 br
(P@O). Anal. Calcd for C26H60N2O12P4Á1.5CHCl3: C, 36.87; H, 6.92;
1. Aminophosphonic and Aminophosphinic Acids. Chemistry and Biological Activity;
Kukhar, V. P., Hudson, H. R., Eds.; John Wiley & Sons Ltd: Chichester, 2000.
2. Horiguchi, M.; Kandatsu, M. Nature 1959, 184, 901.
3. (a) Palacios, F.; Alonso, C.; de los Santos, J. M. Chem. Rev. 2005, 105, 899 and
references cited therein; (b) Gumienna-Kontecka, E.; Galezowska, J.; Drag, M.;
Lataika, R.; Kafarski, P.; Kozlowski, H. Inorg. Chim. Acta 2004, 357, 1632; (c)
Rahman, M. S.; Oliano, M.; Kuok, H. K. Tetrahedron: Asymmetry 2004, 15, 1835.
4. Pudovik, A. N. Dokl. Akad. Nauk USSR 1951, 80, 65.
5. Gubnitskaya, E. S.; Peresypkina, L. P.; Samaray, L. I. Russ. Chem. Rev. 1990, 59,
807 and references cited therein.
6. Cherkasov, R. A.; Galkin, V. I.; Khusainova, N. G.; Mostovaya, O. A.; Garifzyanov,
A. R.; Nuriazdanova, G. Kh.; Krasnova, N. S.; Berdnikov, E. A. Russ. J. Org. Chem.
2005, 41, 1481.
P, 13.83. Found: C, 36.85; H, 6.84; P, 13.77.
Diethyl [6-{2-[bis[2-(diethoxyphosphinyl)ethyl]aminoethyl}-3,9-bis-
[2-(diethoxyphosphinyl)ethyl]-12-ethoxy-12-oxido-13-oxa-3,6,9-tria-
za-12-phosphapentadec-1-yl]phosphonate (4c): Yield 85% (after col-
umn chromatography), pale yellow oil. 31P NMR (162 MHz, CDCl3):
d 30.4. 1H NMR (400 MHz, CDCl3): d 1.26 (t, 3JHH = 7.0 Hz, 36H, CH3
in Et), 1.84 (dt, 2JPH = 19.2 Hz, 3JHH = 8.0 Hz, 12H, CH2–P), 2.25–2.53
(m, 12H, N–CH2CH2–N), 2.67–2.73 (m, 12H, CH2–N), 3.98–4.08 (m,
3
24H, OCH2). 13C NMR (101 MHz, D2O): d 15.91 (d, JPC = 5.6 Hz,
1
CH3 in Et), 24.45 (d, JPC = 136.6 Hz, CH2–P), 42.05 (s, CH2–N),
7. Guénin, E.; Hervé, A.-C.; Floch, V.; Loisel, S.; Yaouanc, J.-J.; Clément, J.-C.; Ferec,
C.; des Abbayes, H. Angew. Chem., Int. Ed. 2000, 39, 629.
8. Cen, W.; Shen, Y. J. Fluorine Chem. 1995, 72, 107.
9. Mortier, J.; Fortineau, A.-D.; Vaultier, M. Phosphorus, Sulfur, Silicon 1999, 149,
221.
45.64 (s, N–CH2CH2–N), 53.28 (s, N–CH2CH2–N), 63.33 (s, OCH2),
63.39 (s, OCH2). IR (thin layer,
1246br (P@O). Anal. for the corresponding tris(phosphonous
acid) trihydrobromide, mp 163 °C. Anal. Calcd for C18H48N4O18
m
/cmÀ1): 1031 (P–O–C),
-
10. Lindström, U. M. Chem.Rev. 2002, 102, 2751.
11. (a) Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F. J. Am.
Chem. Soc. 2006, 128, 4966; (b) Zu, L.; Wang, J.; Li, H.; Wang, W. Org. Lett. 2006,
8, 3077; (c) Cao, Y.-L.; Lai, Y.-Y.; Wang, X.; Li, Y.-L.; Xiao, W.-J. Tetrahedron Lett.
2007, 48, 21.
12. Ranu, B. C.; Banerjee, S. Tetrahedron Lett. 2007, 48, 141.
13. El-Batta, A.; Jiang, C.; Zhao, W.; Anness, R.; Cooksy, A. L.; Bergdahl, M. J. Org.
Chem. 2007, 72, 5244.
14. Ovchinnikov, V. V.; Sagdeev, E. V.; Stoikov, I. I.; Safina, Yu. G.; Sopin, V. F. Russ J.
Gen. Chem. 1998, 68, 1488.
15. Gubnitskaya, E. S.; Peresypkina, L. P. Zh. Obshch. Khim. 1989, 59, 556.
16. Medved’, T. Ya.; Dyatlova, N. M.; Markhaeva, V. P.; Rudomino, M. V.; Churilina,
N. V.; Polokarpov, Yu. M.; Kabachnik, M. I. Bull. Acad. Sci. USSR Div. Chem. Sci.
1976, 25, 992.
P6Á3HBr: C, 20.84; H, 4.96; N, 5.40. Found: C, 20.78; H, 5.04; N,
5.05.
1,3-Bis{(N,N-bis[(diethoxyphosphoryl)ethyl])aminomethyl}benzene
(4d): Yield 83% (after column chromatography), pale-yellow oil.
31P NMR (162 MHz, CDCl3): d 30.4. 1H NMR (400 MHz, CDCl3): d
3
2
1.27 (t, JHH = 7.1 Hz, 24H, CH3), 1.92 (dt, JPH = 19.3 Hz,
3JHH = 8.1 Hz, 8H, CH2–P), 2.77 (dt, JPH = 8.0 Hz, JHH = 7.9 Hz, 8H,
CH2–N), 3.53 (s, 4H, CH2–Ar), 3.99–4.07 (m, 16H, OCH2), 7.17–
7.21 (m, 4H, C6H4). 13C NMR (101 MHz, CDCl3): d 15.74 (d,
3
3
3JPC = 5.9 Hz, CH3), 22.54 (d, JPC = 137.5 Hz, CH2–P), 45.66 (s,
1
CH2_N), 56.75 (s, CH2–Ar), 60.79 (s, OCH2), 60.85 (s, OCH2),
126.93 (s, C5), 127.60 (s, C4, C6), 128.35 (s, C2), 137.98 (s, C1, C3).
17. Tawney, P. O.; Passaic, N. J. U.S. Patent 2570,503, 1951; Chem. Abstr. 1952, 46,
3556e.
18. Pudovik, A. N.; Denisowa, G. M. Zh. Obshch. Khim. 1953, 23, 263; Pudovik, A. N.;
Denisowa, G. M. Chem. Abstr. 1954, 48, 2572i.
IR (thin layer, m
/cmÀ1): 1031 (P–O–C), 1248 br (P@O). Anal. Calcd