Synthesis of new functionalized mono- and diphosphonic acids with five-membered aza-heterocycles moieties

Article abstract of DOI:10.1002/hc.21353

The new functionalized hydroxymethylphosphonic and methylenediphosphonic acids are synthesized via unique reaction of tris(trimethylsilyl)phosphite and N-formyl derivatives of five-membered aza-heterocycles at the presence of effective catalyst—trimethylsilyl triflate.

Full text of DOI:10.1002/hc.21353

Received: 27 June 2016
DOI: 10.1002/hc.21353
Revised: 6 October 2016
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R E S E A R C H A R T I C L E
Synthesis of new functionalized mono- and diphosphonic acids
with five-membered aza-heterocycles moieties
Andrey A. Prishchenko
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Roman S. Alekseyev
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Mikhail V. Livantsov
Vladimir I. Terenin
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Olga P. Novikova Ludmila I. Livantsova
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Valery S. Petrosyan
Department of Chemistry, M.V. Lomonosov
Moscow State University, Moscow, Russia
Abstract
The new functionalized hydroxymethylphosphonic and methylenediphosphonic
acids are synthesized via unique reaction of tris(trimethylsilyl)phosphite and N-
formyl derivatives of five-membered aza-heterocycles at the presence of effective
catalyst—trimethylsilyl triflate.
Correspondence
Andrey A. Prishchenko, Department of Chemistry,
M.V. Lomonosov Moscow State University,
Moscow, Russia.
Email: aprishchenko@yandex.ru
Funding information
Russian Foundation for Basic Research, Grant/
Award Number: 14-03-00001, 15-03-00002 and
1
7-03-00169.
1
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INTRODUCTION
diphosphonic acids via addition of tris(trimethylsilyl)
phosphite to easily available N-formyl derivatives of five-
[
8]
The functionalized methylphosphonic and methylenedi-
phosphonic acids and their derivatives with aza-heterocyclic
moieties and various hydroxyl or amino groups present great
interest as promising polydentate ligands and organophospho-
rus biomimetics of hydroxyl or amino acids and natural py-
membered aza-heterocycles which are obtained by us
in situ. It is shown that this reaction proceeds only at the
[
5,9]
presence of effective catalyst—trimethylsilyl triflate
—under mild conditions to give phosphonates 1 and di-
phosphonates 2. The ratio of these compounds 1,2 depends
on the structure of aza-heterocycles, so phosphonate 1c
predominate for starting bulky N-formyl-3,5-dimetyl-1H-
pyrazole. An unusual variation in this reaction produces
simultaneously two types of target products 1,2 and com-
pares favorably with similar interaction of phosphites with
dialkylformamide dialkylacetals which always leads only
[
1–3]
rophosphates with multifactor activity.
These compounds
with stable P–C bonds interfere with various enzymatic
processes and possess the antibacterial, antiviral, antibiotic,
pesticidal, antitumor, and enzyme inhibitory properties. So
various derivatives of mono- and diphosphonic acids are
good complexones and promising plant growth regulators.
Also these diphosphonates with hard hydrolysable P–C–P
structure such as zoledronic, risedronic, and minodronic acids
are widely used in medicine as well known drugs—regulators
of calcium metabolism. Recently some of the N-substituted
aminomethylenediphosphonates have been synthesized by
us using various formamides and their derivatives like dial-
kylformamide dialkylacetals and ethoxymethylene imines as
well as trimethylsilyl esters of trivalent organophosphorus
[
5]
to aminomethylenediphosphonates. This process is re-
alized by us via one-pot synthesis of target products 1,2
directly from starting aza-heterocycles, formic acid, symm-
dicyclohexylcarbodiimide, and tris(trimethylsilyl) phos-
phite (Scheme 1).
In this way, N-formyl derivatives of five-membered aza-
heterocycles react with tris(trimethylsilyl) phosphite simi-
[
5]
larly to formamides of simple structure, and the role of
trimethylsilyl triflate as a catalyst is determined by the for-
[4–7]
acids with PH and POSiMe moieties.
3
[
5]
mation of highly reactive intermediate salts (Scheme 2).
The ability to save substituted trimethylsiloxymethylphos-
phonates 1 in process conditions is obviously determined
by the volume of the heterocyclic moiety that prevents fur-
2
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RESULTS AND DISCUSSION
1
Now we propose the convenient routes to new five-
membered aza-heterocycles derivatives of mono- and
ther substitution of trimethylsiloxy group at C in phospho-
nates 1.
Heteroatom Chemistry 2016; 1–5
wileyonlinelibrary.com/journal/hc
© 2016 Wiley Periodicals, Inc.
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1

2
PRISHCHENKO Et al.
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HCOOH,
P(OSiMe ) ,
3 3
(
c-C H N=) C,
CF SO SiMe ,
6
11
2
3
3
3
2
0°C
40°C
1
HetNCHO
HetNC HP(O)(OSiMe )
3 2
HetNH
-
(c-C H NH) CO
6 11 2
OSiMe3
P(OSiMe ) ,
3
3
1a-d
CF SO SiMe ,
3
3
3
4
0°C
1
HetNC H[P(O)(OSiMe ) ]
3
2 2
-
(Me Si) O
3
2
2a-d
N
N
N
N
N
(d).
(b),
(c),
N
(a),
HetN =
N
N
N
SCHEME 1 Synthesis of phosphonates 1
and diphosphonates 2
OSiMe3
+
CF SO SiMe
HetN=CHOSiMe
P(OSiMe3)3
- CF SO SiMe
3
3
3
3
3
SCHEME 2 The possible routes
of the formation of phosphonates 1 and
diphosphonates 2
HetNCH
1 + 2
HetNCHO
-
3
CF SO3
3
3
OSO CF
2
3
3
1
MeOH,
0-20°C
(
XO) POSiMe ,
2
3
1
Me SiCl, CH Cl ,
4
3
2
2
1
a-d
a-d
HetNC HP(O)(OH)2
OH
1,2
-
3 MeOSiMe3
0°C
- n EtOSiMe3
- HetNSiMe3
HetNCH(OEt)2
3
a-d
4
1
MeOH,
0-20°C
(
XO) PCH(OEt)2
2
1
2
HetNC H[P(O)(OH)2]2
O
a,b
-
4 MeOSiMe3
5
N
4
a-d
(
a),
N (b); X = Me3Si (a), Et (b).
HetN =
N
N
N
N
N
(b),
(c),
N
N (d).
HetN =
(a),
N
N
N
N
SCHEME 4 Synthesis of dialkoxymethylphosphonates 5
SCHEME 3 Synthesis of acids 3, 4
3
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CONCLUSIONS
Trimethylsilyl esters 1,2 readily react with excess metha-
nol under mild conditions to form water-soluble functionalized
mono- or diphosphonic acids, respectively, 3,4 (Scheme 3).
The resulting compounds 1-4 can be used for the synthe-
sis of new types of organophosphorus substances, including
both heterocyclic fragments and phosphonic groups. These
compounds are promising precursors for multitarget drug
discovery, perspective plant growth regulators, as well as ef-
fective polydentate ligands for various metal complexes with
versatile properties.
Thus, we have proposed the convenient methods of synthe-
sis of new functionalized mono- and diphosphonic acids with
five-membered aza-heterocycles moieties via the unique re-
action of tris(trimethylsilyl) phosphite with N-formyl aza-
heterocycles catalyzed by trimethylsilyl triflate.
4
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EXPERIMENTAL
1
13
31
It should be noted that, unlike diethyl acetal formamides,
which react readily with esters of phosphorous acid to form
The H, C, and P NMR spectra were registered on a
Bruker Avance-400 spectrometer (400, 100, and 162 MHz,
[
10]
1
13
N-substituted aminomethylenediphosphonates,
reaction
respectively) against TMS ( H and C) and 85% H PO in
3 4
3
1
of readily available N-diethoxymethyl derivatives of aza-
D O ( P). All reactions were carried out under dry argon
2
[
11–13]
heterocycles
withtris(trimethylsilyl) phosphite proceeds
in anhydrous solvents. The starting trimethylsilyl esters of
trivalent phosphorus acids were prepared as described in
via rupture of C–N bonds and leads to diethoxymethylphos-
Woniak and Chojnowski[ and Romanenko et al.
14]
[15]
phonates 5 in high yields (Scheme 4).

PRISHCHENKO Et al.
3
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Anal. Calcd for C H N O PSi C 45.92; H 7.48. Found: C
1
7
33
2
4
3
4
1
.1
|
Bis(trimethylsilyl) 1H-imidazol-
4
5.81; H 7.40.
-yl(trimethylsiloxy)methylphosphonate
(
1a) and tetra(trimethylsilyl) 1H-imidazol-1-
ylmethylenediphoshonate (2a)
4.3
Tetra(trimethylsilyl) 1H-benzimidazol-
|
1
-ylmethylenediphosphonate (2b)
A solution of symm-dicyclohexylcarbodiimide (14.4 g,
1
0
.07 mol) in CH Cl (20 mL) was added under stirring to
Yield 62%, bp 139°C (1 mm Hg). H NMR (400 MHz,
2
2
a solution of 1H-imidazole (3.4 g, 0.05 mol) and formic
CDCl ), δ, ppm: −0.38 and −0.31 (both s, 18H, 2 Me Si),
3
3
2
1
acid (2.8 g, 0.06 mol) in CH Cl (50 mL). The mixture was
−0.16 (s, Me Si), 3.55 (t, 1H, J =16.8 Hz, C H), and 6.65-
2
2
3 PH
1
3
stirred for 6 hours and left for 12 hours, then the precipi-
tate is filtered off, the resulting solution was added to a so-
lution of tris(trimethylsilyl) phosphite (44.8 g, 0.15 mol),
and a solution of trimethylsilyl triflate (2.9 g, 0.013 mol)
in CH Cl (10 mL) was added to this mixture. The mix-
7.55 (m, CH ). C NMR (100 MHz, CDCl ), δ, ppm: 1.10
Het 3
1
1
(s, 4 Me Si), 68.11 (d, J =167.3 Hz, C ), 112.46, 119.92,
3
PC
3
1
122.13, 122.75, 139.71, 141.75, and 145.46 (all s, C ).
P
Het
NMR (162 MHz, CDCl ), δ, ppm: −0.58 (s). Anal. Calcd for
3
C H N O P Si C 41.36; H 7.29. Found: C 41.26; H 7.20.
2
2
20 42
2
6
2
4
ture was heated in a boiling water bath to complete the
stripping of low-boiling compounds and then distilled to
give 1.8 g of phosphonate 1a, yield 9%, bp 102°C (1 mm
Hg) and diphosphonate (22.0 g) 2a, yield 83%, bp 126°C
4
.4
|
Bis(trimethylsilyl) 3,5-dimethyl-
1
H-pyrazol-1-yl(trimethylsiloxy)
methylphosphonate (1c)
(
1 mm Hg).
1
Yield 86%, bp 106°C (1 mm Hg). H NMR (400 MHz,
CDCl ), δ, ppm: −0.38 and −0.31 (both s, 18H, 2 Me Si),
3
3
4
.1.1
|
Phosphonate 1a
−
0.16 (s, 9H, Me Si), 1.71 and 1.99 (both s, 2 Me), 5.36 (s,
3
1
2
1
13
H NMR (400 MHz, CDCl ), δ, ppm: −0.38 (s, 9H, Me SiO),
CH ), 5.40 (d, J =7.2 Hz, C H). C NMR (100 MHz,
Het PH
3
3
2
1
−
0.24 (s, 18H, 2 Me Si), 5.22 (d, 1H, J =4.8 Hz, C H),
CDCl ), δ, ppm: −1.62 (s, Me Si), −0.25 and 0.05 (both
3
PH
3
3
1
3
6
.57 and 7.15 (both s, CH ). C NMR (100 MHz, CDCl ),
s, 2 Me Si), 10.77 and 12.36 (both s, 2 Me), 81.19 (d,
Het
3
3
1
1
δ, ppm: 1.62 (s, Me Si), −0.25 and 0.05 (both s, 2 Me Si),
J =214.1 Hz, C ), 106.61, 139.80, and 146.52 (all s, C ).
3
3
PC
Het
1
1
31
7
6.47 (d, J 213.2 Hz, C ), 106.61, 139.80, and 146.52 (all
P NMR (162 MHz, CDCl ), δ, ppm: −3.35 (s). Anal. Calcd
PC
3
3
1
s, C ). P NMR (162 MHz, CDCl ), δ, ppm: −4.02 (s).
for C H N O PSi C, 42.62; H, 8.35. Found: C, 42.49; H,
15 35 2 4 3
Het
3
Anal. Calcd for C H N O PSi : C 39.57; H 7.92. Found:
C 39.42; H 7.83.
8.28.
1
3
31
2
4
3
4
.5
|
Tetra(trimethylsilyl) 3,5-dimethyl-1H-
4
.1.2
|
Diphosphonate 2a
pyrazol-1-ylmethylenediphosphonate (2c)
1
1
H NMR (400 MHz, CDCl ), δ, ppm: −0.15 (s, 18H, 2
Yield 7%, bp 129°C (1 mm Hg). H NMR (400 MHz,
3
2
Me Si), −0.14 (s, 18H, 2 Me Si), 3.55 (t, 1H, J =17.2 Hz,
CDCl ), δ, ppm: −0.12 and −0.16 (both s, 36H, 4 Me Si),
3
3
PH
3
3
1
13
2
C H), 6.57 and 7.15 (both s, CH ). C NMR (100 MHz,
1.80 and 2.01 (both s, 6H, 2 Me), 3.58 (t, 1H, J =17.2 Hz,
Het
PH
1
1
13
CDCl ), δ, ppm: 0.47 (s, 4 Me Si), 67.80 (t, J =168.2 Hz,
C H), 5.36 (s, CH ). C NMR (100 MHz, CDCl ), δ, ppm:
Het 3
3
3
PC
1
31
C ), 121.00 and 134.69 (both s, C ). P NMR (162 MHz,
0.35 (s, 4 Me Si), 10.80 and 12.40 (both s, 2 Me), 68.09 (t,
Het
3
1
3
1
CDCl ) δ: −0.32 (s). Anal. Calcd for C H N O P Si : C
J =168.2 Hz, C ), 106.68, 139.86, and 146.57 (all s, C ).
3
16 40
2
6
2
4
PC
Het
1
3
6.21; H 7.60. Found: C 36.12; H 7.52.
P NMR (162 MHz, CDCl ), δ, ppm: −0.30 (s). Anal. Calcd
3
Phosphonates 1b-d and diphosphonates 2b-d were pre-
for C H N O P Si C 38.69; H 7.94. Found: C 38.52; H
7.86.
1
8
44
2
6
2
4
pared similarly.
4
.2
|
Bis(trimethylsilyl) 1H-benzimidazol-1-
4.6
Bis(trimethylsilyl) 1H-benzotriazol-1-
|
yl(trimethylsiloxy)methylphosphonate (1b)
yl(trimethylsiloxy)methylphosphonate (1d)
1
1
Yield 30%, bp 110°C (1 mm Hg). H NMR (400 MHz,
Yield 59%, bp 108°C (1 mm Hg). H NMR (400 MHz,
CDCl ), δ, ppm: −0.44 (s, 9H, Me Si), −0.25 (s, 18H, 2
CDCl ), δ, ppm: −0.36 (s, 9H, Me Si), −0.05 (s, 18H, 2
3
3
3
3
2
1
2
1
Me Si), 5.58 (d, 1H, J =4.4 Hz, C H), and 6.70-7.45 (m,
Me Si), 6.26 (d, 1H, J =6.4 Hz, C H), and 6.99-7.76 (m,
3
PH
3 PH
1
3
13
CH ). C NMR (100 MHz, CDCl ), δ, ppm: −0.22 (s,
4H, C H ). C NMR (100 MHz, CDCl ), δ, ppm: −0.93
6 4 3
Het
3
1
1
Me Si), 1.11 (s, 2 Me Si), 75.50 (d, J =214.1 Hz, C ),
(s, Me Si), −0.75 (s, Me Si), −0.43 (s, Me Si), 80.73 (d,
3
3
PC
3 3 3
1
1
1
10.40, 120.23, 122.51, 123.19, 139.62, 143.28, and 145.74
J =213.2 Hz, C ), 113.37, 119.20, 124.17, 127.30, 131.84,
PC
3
1
31
(
all s, C ). P NMR (162 MHz, CDCl ), δ, ppm: −3.47 (s).
and 146.45 (all s, C ). P NMR (162 MHz, CDCl ), δ,
Het
3
Het
3

4
PRISHCHENKO Et al.
|
ppm: −4.81 (s). Anal. Calcd for C H N O PSi C 43.12; H
7
1
6
32
3
4
3
4
.11
|
3,5-Dimethyl-1H-pyrazol-1-
.24. Found: C 43.03; H 7.16.
yl(hydroxy)methylphosphonic acid (3c)
1
Yield 97%, mp 357-359°C (decomposition). H NMR
4
1
.7
|
Tetra(trimethylsilyl) 1H-benzotriazol-
(
4
400 MHz, D O-Py-d ), δ, ppm: 1.86 and 2.20 (both s, 2 Me),
2 5
-ylmethylenediphosphonate (2d)
2
1
13
.92 (d, J =6.0 Hz, C H), and 5.64 (s, CH ). C NMR
PH Het
1
Yield 30%, bp 133°C (1 mm Hg). H NMR (400 MHz,
(100 MHz, D O-Py-d ), δ, ppm: 10.47 and 12.44 (both s, 2
2
5
1
1
CDCl ), δ, ppm: −0.11 (s, 36H, 4 Me Si), 3.75 (t, 1H,
Me), 88.18 (d, J =191.4 Hz, C ), 103.71 and 144.05 (both
3
3
PC
2
1
13
31
J =16.8 Hz, C H), and 7.17-7.83 (m, 4H, C H ). C NMR
s, C ). P NMR (162 MHz, D O-Py-d ), δ, ppm: 10.42
PH
6
4
Het
2
5
(
100 MHz, CDCl ), δ, ppm: 0.01 (s, 4 Me Si), 67.71 (t,
(s). Anal. Calcd for C H N O P C 34.96; H 5.38. Found: C
3
3
6 11 2 4
1
1
J =168.2 Hz, C ), 110.50, 114.55, 119.44, 126.22, 129.93,
34.78; H 5.30.
PC
3
1
and 140.27 (all s, C ). P NMR (162 MHz, CDCl ), δ,
Het
3
ppm: −0.47 (s). Anal. Calcd for C H N O P Si C 39.22;
1
9
41
3
6
2
4
4
.12
|
1H-Benzotriazol-1-yl(hydroxy)
H 7.10. Found: C 39.03; H 7.01.
methylphosphonic acid (3d)
1
Yield 95%, mp 105-107°C (decomposition). H NMR
4
.8
|
1H-Imidazol-1-
2
(
400 MHz, DMSO-d ), δ, ppm: 6.43 (d, 1H, J =7.2 Hz,
6
PH
ylmethylenediphosphonic acid (4a)
1
3
4
C H), 7.41 (dd, J =6.4 Hz, J =3.2 Hz), and 7.89 (dd,
HH
HH
3
4
13
A solution of diphosphonate 2a (10.6 g, 0.02 mol) in ether
J =6.4 Hz, J =3.2 Hz), both CH . C NMR (100 MHz,
HH HH Het
1
1
(
15 mL) was added to methanol (40 mL) under stirring and
DMSO-d ), δ, ppm: 79.96 (d, J =187.7 Hz, C ), 114.92,
6 PC
31
cooling to 10°C, a mixture was refluxed, and the solvent was
removed. White crystals were kept in vacuum 1 mm Hg to
118.84, 125.42, 126.86, 131.87, and 145.86 (all s, C ).
P
Het
NMR (162 MHz, DMSO-d ), δ, ppm: 10.62 (s). Anal. Calcd
6
1
give 4.7 g acid 4a, yield 98%, and mp 174-176°C. H NMR
for C H N O P C, 36.70; H, 3.52. Found: C 36.55; H 3.48.
7
8
3
4
2
(
400 MHz, D O-Py-d ), δ, ppm: 3.33 (t, 1H, J =16.0 Hz,
2
5
PH
1
13
C H), 6.55 and 7.85 (both s, CH ). C NMR (100 MHz,
Het
4
.13
|
1H-Benzimidazol-1-
1
1
D O-Py-d ), δ, ppm: 66.26 (t, J =139.9 Hz, C ), 117.83
2
5
PC
ylmethylenediphosphonic acid (4b)
3
1
and 132.43 (both s, C ). P NMR (162 MHz, D O-Py-d ),
Het
2
5
1
δ, ppm: 14.66 (s). Anal. Calcd for C H N O P C 19.85; H
Yield 98%. mp 348-350°C (decomposition). H NMR
4
8
2
6 2
2
3
.33. Found: C 19.69; H 3.28.
Acids 3a-d and 4b-d were prepared similarly.
(400 MHz, DMSO-d ), δ, ppm: 4.18 (t, 1H, J =16.0 Hz,
6
PH
1
3
4
C H), 7.18 (dd,
J
=6.0 Hz,
J
=3.2 Hz), 7.46 (dd,
HH
HH
3
4
13
J
=6.0 Hz, JHH=3.2 Hz), 7.56 (s, CH ). C NMR
HH
Het
1
(
100 MHz, DMSO-d ), δ, ppm: 66.86 (d, J =142.1 Hz,
6
PC
4
.9
|
1H-Imidazol-1-yl(hydroxy)
1
31
C ), 113.79, 125.73, 129.59, and 138.88 (all s, C ).
P
Het
methylphosphonic acid (3a)
NMR (162 MHz, DMSO-d ), δ, ppm: 15.63 (s). Anal. Calcd
6
1
Yield 96%, mp 144-145°C (decomposition). H NMR
for C H N O P C 32.89; H 3.45. Found: C 32.74; H 3.40.
8
10
2
6 2
2
(
400 MHz, D O-Py-d ), δ, ppm: 6.81 (d, 1H, J =4.2 Hz,
2
5
PH
1
13
C H), 6.57 and 7.92 (both s, CH ). C NMR (100 MHz,
Het
4
.14
|
3,5-Dimethyl-1H-pyrazol-1-
1
1
D O-Py-d ), δ, ppm: 78.81 (d, J =180.4 Hz, C ), 117.96
2
5
PC
ylmethylenediphosphonic acid (4c)
3
1
and 132.86 (both s, C ). P NMR (162 MHz, D O-Py-d ),
Het
2
5
1
δ, ppm: 7.47 (s). Anal. Calcd for C H N O P C,26.98; H
Yield 98%, mp 357-359°C (decomposition). H NMR
4
7
2
4
3
.96. Found: C 26.86; H 3.88.
(400 MHz, DMSO-d - Py-d ), δ, ppm: 1.82 and 2.14 (both
6
5
2
1
s, 6H, 2 Me), 3.97 (t, 1H, J =15.6 Hz, C H), and 5.60 (s,
PH
1
3
CH ). C NMR (100 MHz, DMSO-d - Py-d ), δ, ppm:
Het
6
5
4
.10
|
1H-Benzimidazol-1-yl(hydroxy)
1
1
1
1
0.44 and 12.34 (both s, 2 Me), 55.57 (t, J =181.7 Hz, C ),
PC
methylphosphonic acid (3b)
31
05.63, and 140.83 (all s, C ). P NMR (162 MHz, DMSO-
Het
1
Yield 94%, mp 157-159°C (decomposition). H NMR
d - Py-d ), δ, ppm: 15.03 (s). Anal. Calcd for C H N O P C
6
5
6
12
2
6 2
2
(
400 MHz, D O-Py-d ), δ, ppm: 5.15 (d, 1H, J =6.4 Hz,
26.68; H 4.48. Found: C 26.49; H 4.52.
2
5
PH
1
3
4
C H), 7.17 (dd,
J
16.0 Hz,
J
3.2 Hz), 7.47 (dd,
HH
HH
3
4
13
J
16.0 Hz, J 3.2 Hz), 7.57 (s), all CH
.
C NMR
HH
HH
Het
4
.15
|
1H-Benzotriazol-1-
1
(
100 MHz, D O-Py-d ), δ, ppm: 78.85 (d, J =170.0 Hz,
2
5
PC
ylmethylenediphosphonic acid (4d)
Yield 96%, mp 355-357°C (decomposition). H NMR
(400 MHz, DMSO-d - Py-d ), δ, ppm: 3.88 (t, 1H,
1
31
C ), 114.16, 125.86, 129.74, and 138.52 (all s, C ).
P
Het
1
NMR (162 MHz, D O-Py-d ), δ, ppm: 6.88 (s). Anal. Calcd
for C H N O P C 42.12; H 3.98. Found: C 41.97; H 3.91.
2
5
8
9
2
4
6
5

PRISHCHENKO Et al.
5
|
2
1
3
J =17.2 Hz, C H), 8.01 (d, J =8.2 Hz), and 8.95 (d,
HH
ACKNOWLEDGMENTS
PH
HH
3
13
J
=8.2 Hz). C NMR (100 MHz, DMSO-d - Py-d ),
6 5
We thank Russian Foundation for Basic Research for finan-
cial support (Grants Numbers 14-03-00001, 15-03-00002,
and 17-03-00169).
1
1
δ, ppm: 65.28 (t, J =150.2 Hz, C ), 113.61, 118.64,
PC
3
1
1
24.03, 125.42, 126.86, and 138.69 (all s, C ). P NMR
Het
(
162 MHz, DMSO-d - Py-d ), δ, ppm: 16.41 (s). Anal.
6 5
Calcd for C H N O P C 28.68; H 3.09. Found: C 28.56;
7
9
3
6 2
H 3.14.
REFERENCES
[
1] V. P. Kukhar, H. R. Hudson, Aminophosphonic and Aminophosphinic Acids:
Chemistry and Biological Activity, Wiley, New York, USA 2000, p. 634.
4
.16
|
Bis(trimethylsilyl)
[
2] L. Widler, K. A. Jaeggi, M. Glatt, K. Müller, R. Bachmann, M. Bisping, A.-
R. Born, R. Cortesi, G. Guiglia, H. Jeker, R. Klein, U. Ramseier, J. Schmid,
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diethoxymethylphosphonate (5a)
A
mixture of N-diethoxymethyl 1H-imidazole (4 g,
.024 mol), tris(trimethylsilyl) phosphite (18 g, 0.061 mol),
and chlorotrimethylsilane (5 g, 0.046 mol) in CH Cl
[
[
0
4] A. A. Prishchenko, M. V. Livantsov, O. P. Novikova, L. I. Livantsova, V. S.
Petrosyan, Russ. Chem. Bull. 2016, 65, 228.
2
2
[
[
5] A. A. Prishchenko, M. V. Livantsov, O. P. Novikova, L. I. Livantsova, I. S.
Ershov, V. S. Petrosyan, Heteroat. Chem. 2013, 24, 355.
(
20 mL) was refluxed for 1 h, then slowly heated with solvent
distillation in a boiling water bath, the residue was distilled
6] A. A. Prishchenko, M. V. Livantsov, O. P. Novikova, L. I. Livantsova, I. S.
Ershov, V. S. Petrosyan, Heteroat. Chem. 2015, 26, 101.
to give 5.8 g of phosphonate 5a, yield 74 %, and bp 104°C
1
(
2 mm Hg). H NMR (400 MHz, CDCl ), δ, ppm: 0.03 (s,
H, Me Si), 0.97 (t, 6H, J =6.8 Hz, 2 CH ), 3.38-3.55
[7] A. A. Prishchenko, M. V. Livantsov, O. P. Novikova, L. I. Livantsova, G. M.
Averochkin, V. S. Petrosyan, Heteroat. Chem. 2015, 26, 405.
3
3
9
3
HH
3
2
1
13
[8] A. R. Katriztky, H.-X. Chang, B. Yang, Synthesis 1995, 503.
(
m, 4H, 2 CH O), and 4.34 (d, 1H, J =5.2 Hz, C H).
C
2
PH
[
9] A. D. Dilman, S. L. Ioffe, Chem. Rev. 2003, 103, 733.
NMR (100 MHz, CDCl ), δ, ppm: 0.67 (s, 2 Me Si), 14.85
3
3
[10] A. A. Prishchenko, M. V. Livantsov, O. P. Novikova, L. I. Livantsova, V. S.
(
s, 2Me), 63.97 and 64.08 (both s, 2 CH O), and 98.97 (d,
J =216.0 Hz, C ). P NMR (162 MHz, CDCl ), δ, ppm:
Petrosyan, Heteroat. Chem. 2009, 20, 352.
2
1
1
31
[
11] N. J. Curtius, R. S. Brown, J. Org. Chem. 1980, 45, 4038.
PC
3
[
16]
[12] A. R. Katriztky, J. J. Slawinski, F. Brunner, S. J. Gorun, Chem. Soc. Perkin
Trans. 1989, 1, 1139.
−3.58 (s) (cf ).
[
13] S. Ohta, M. Matsukawa, N. Ohashi, K. Nagayama, Synthesis 1990, 78.
Phosphonate 5b was obtained similarly.
[14] L. Woniak, J. Chojnowski, Tetrahedron 1989, 45, 2465.
15] V. D. Romanenko, M. V. Shevchuk, V. P. Kukhar, Curr. Org. Chem. 2011,
[
1
5, 2774.
4
.17
|
Diethyl diethoxymethylphosphonate
[16] M. V. Livantsov, M. V. Proskurnina, A. A. Prishchenko, I. F. Lutsenko,
Russ. J. Gen. Chem. 1984, 54, 2504.
(
5b)
[
17] A. A. Prishchenko, M. V. Livantsov, S. A. Moshnikov, I. F. Lutsenko, Russ.
1
Yield 78%, bp 93°C (2 mm Hg). H NMR (400 MHz,
CDCl ), δ, ppm: 0.81 (t, 6H, J =6.8 Hz, 2 CH ), 0.91
J. Gen. Chem. 1910, 1987, 57.
3
3
HH
3
3
(
t, 6H, J =7.2 Hz, 2 CH ), 3.10-3.50 (m, 4H, 2 CH O),
HH 3 2
How to cite this article: Prishchenko AA, Alekseyev RS,
Livantsov MV, Novikova OP, Livantsova LI, Terenin VI, and
Petrosyan VS. Synthesis of new functionalized mono- and
diphosphonic acids with five-membered aza-heterocycles moieties.
Heteroatom Chem. 2016;00:1–5. doi: 10.1002/hc.21353.
2
3
.60-3.80 (m, 4H, 2 CH O), 4.32 (d, 1H, J =4.8 Hz,
2 PH
1
13
C H). C NMR (100 MHz, CDCl ), δ, ppm: 14.62 (s,
3
3
3
2
Me), 15.93 (d, J =5.5 Hz, Me), 62.41 (d, J =6.5 Hz,
PC
PC
2
CH O), 63.99 (d, J =10.1 Hz, CH O), and 98.59 (d,
2
PC
2
1
1
31
J =207.7 Hz, C ). P NMR (162 MHz, CDCl ), δ, ppm:
3.63 (s) (cf ).
PC
3
[
17]
1