Synthesis of new five-membered N-heterocycle derivatives of mono- and bis-phosphonic acids

Article abstract of DOI:10.1016/j.mencom.2017.01.029

The new functionalized hydroxymethylphosphonic and methylenebis(phosphonic) acids are synthesized via reaction of tris(trimethylsilyl) phosphite and N-formyl derivatives of five-membered N-heterocycles in the presence of trimethylsilyl triflate.

Full text of DOI:10.1016/j.mencom.2017.01.029

Mendeleev
Communications
Mendeleev Commun., 2017, 27, 90–92
Synthesis of new five-membered N-heterocycle
derivatives of mono- and bis-phosphonic acids
Andrey A. Prishchenko,* Mikhail V. Livantsov, Olga P. Novikova,
Ludmila I. Livantsova and Valery S. Petrosyan
Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation.
E-mail: aprishchenko@yandex.ru
DOI: 10.1016/j.mencom.2017.01.029
O
OH
P(OH)2
The new functionalized hydroxymethylphosphonic and
methylenebis(phosphonic) acids are synthesized via reaction
of tris(trimethylsilyl) phosphite and N-formyl derivatives of
five-membered N-heterocycles in the presence of trimethyl-
silyl triflate.
HetNCHP(OH)2
O
HetNH
HetNCH
P(OH)2
O
Me
N ,
N
N
N
N
N
HetN =
,
,
N
Me
N
N
Methylphosphonic and methylenebis(phosphonic) acids and their
derivatives functionalized with N-heterocycle moieties and hydroxyl
or amino groups are of interest as promising polydentate ligands
and organophosphorus biomimetics of hydroxy or amino acids
and natural pyrophosphates with multifactor activity.1 These
Herein, we propose a convenient access to new five-membered
N-heterocycle derivatives of mono- and bis-phosphonic acids
by addition of tris(trimethylsilyl) phosphite to readily available
9
N-formylated five-membered N-heterocycles which are obtained
–4
in situ. This reaction proceeds only in the presence of effective
6
,10
compounds with stable P–C bonds interfere with various enzymatic
catalyst, trimethylsilyl triflate,
under mild conditions to give
processes and possess antibacterial, antiviral, antibiotic, pesticidal,
antitumor and enzyme inhibitory properties. Various derivatives
of mono- and bis-phosphonic acids are good complexones and
promising plant-growth regulators. Bis-phosphonates with hardly
hydrolysable P–C–P unit such as zoledronic, risedronic and
minodronic acids are used in medicine as regulators of calcium
metabolism. Recently we prepared some N-substituted (amino-
methylene)bis(phosphonates) by reaction of formamides or their
equivalents with trimethylsilyl esters of trivalent organophosphorus
phosphonates 1 and bis-phosphonates 2, the ratio of products 1, 2
depending on the structure of N-heterocycle used (Scheme 1).
Phosphonate 1c predominates in case of bulky N-formyl-3,5-di-
methyl-1H-pyrazole. The current version of this reaction yields
simultaneously two types of products 1, 2. This is superior to
6
similar procedure using phosphites and various alkylform-
amides affording only (aminomethylene)bis(phosphonates). In the
experiment, products 1, 2 are obtained in one-pot directly from
N-heterocycles, formic acid, symm-dicyclohexylcarbodiimide
(DCC), and tris(trimethylsilyl) phosphite (see Scheme 1).†
Apparently, in the course of the reaction, N-formyl derivatives
HetNCHO react with tris(trimethylsilyl) phosphite similarly to
5–8
acids bearing PH or POSiMe moieties.
3
P(OSiMe3)3,
HCOOH, DCC
CF3SO2OSiMe3
6
HetNH
HetNCHO
formamides of simple structure, with the catalytic role of tri-
2
0 °C
40 °C
methylsilyl triflate being the generation of highly reactive inter-
O
6
mediate salts (Scheme 2). The ability of substituted (trimethyl-
OSiMe3
P(OSiMe3)3,
CF3SO2OSiMe3
0 °C
P(OSiMe3)2
siloxymethyl)phosphonates 1 to remain steady under the process
HetN–CH–P(OSiMe3)2
HetNCH
4
†
Starting trimethylsilyl esters of phosphorous acid were prepared as
–
(Me3Si)2O
P(OSiMe3)2
O
12–14
reported.
1
a–d
O
Bis(trimethylsilyl) [(1H-imidazol-1-yl)(trimethylsiloxy)methyl]phos-
phonate 1a and tetrakis(trimethylsilyl) (1H-imidazol-1-ylmethylene)-
N
2
a–d
a HetN =
b HetN =
bis(phoshonate) 2a. A solution of DCC (14.4 g, 0.07 mol) in CH Cl
3
MeOH 10–20 °C
2
2
N
4 MeOH 10–20 °C
(20 ml) was added under stirring to a solution of 1H-imidazole (3.4 g,
0
.05 mol) and formic acid (2.8 g, 0.06 mol) in CH Cl2 (50 ml). The
O
P(OH)2
2
N
N
mixture was stirred for 6 h and left for 12 h. The precipitate was filtered off,
the filtrate was added to a solution of tris(trimethylsilyl) phosphite (44.8 g,
OH
HetN–CH–P(OH)2
O
HetNCH
P(OH)2
0.15 mol), and a solution of trimethylsilyl triflate (2.9 g, 0.013 mol) in
Me
CH Cl (10 ml) was added to this mixture. The mixture was heated in a
2
2
boiling water bath to complete the removal of low-boiling compounds
and then distilled to give phosphonate (1.8 g) 1a, yield 9%, bp 102°C
(1 Torr) and bis-phosphonate (22.0 g) 2a, yield 83%, bp 126°C (1 Torr).
3
a–d
O
c HetN =
d HetN =
N
Me
4a–d
N
1
For 1a: H NMR (400 MHz, CDCl ) d: –0.38 (s, Me SiO), –0.24 (s,
3
3
N
2
2
Me Si), 5.22 (d, a-CH, J 4.8 Hz), 6.57 and 7.15 (both s, CHHet).
C NMR (100 MHz, CDCl ) d: 1.62 (s, Me Si), –0.25 and 0.05 (both s,
3 3
2Me Si), 76.47 (d, a-C, J 213.2 Hz), 106.61, 139.80, 146.52 (all s,
CHet). P NMR (162 MHz, CDCl ) d: –4.02 (s). Found (%): C, 39.42;
3 PH
N
1
3
1
N
3 PC
31
3
Scheme 1
H, 7.83. Calc. for C H N O PSi (%): C, 39.57; H, 7.92.
13
31
2
4
3
©
2017 Mendeleev Communications. Published by ELSEVIER B.V.
–
90 –
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.

Mendeleev Commun., 2017, 27, 90–92
OSiMe3
The resulting compounds 1–4 can be used in the synthesis of
new types of organophosphorus substances, including both hetero-
cyclic fragments and phosphonic groups. These compounds are
promising precursors for multitarget drug discovery, perspective
plant-growth regulators as well as effective polydentate ligands
for various metal complexes with versatile properties.
In conclusion, we have proposed the convenient methods of
synthesis of new functionalized mono- and bis-phosphonic acids
equipped with five-membered N-heterocycle moieties via the
unique reaction of tris(trimethylsilyl) phosphite with N-formylated
N-heterocycles catalyzed by trimethylsilyl triflate.
CF3SO2OSiMe3
HetNCHO
HetNCH
11
OSO2CF3
P(OSiMe3)3
HetN CHOSiMe3
CF3SO3
1 + 2
–
CF3SO2OSiMe3
Scheme 2
conditions is obviously determined by the size of the heterocyclic
moiety which prevents further substitution of trimethylsiloxy
group at a-C of phosphonates 1.
Trimethylsilyl esters 1, 2 readily react with excess methanol
under mild conditions to form water-soluble functionalized mono-
‡
(1H-Imidazol-1-ylmethylene)bis(phosphonic) acid 4a. A solution of
bis-phosphonate 2a (10.6 g, 0.02 mol) in diethyl ether (15 ml) was added
to methanol (40 ml) under stirring and cooling to 10°C, the mixture was
‡
or diphosphonic acids 3, 4, respectively (see Scheme 1).
refluxed, the solvent was removed. White crystals were kept in vacuum
1
(
(
7
1 Torr) to give 4.7 g of acid 4a, yield 97%, mp 174–176°C. H NMR
1
For 2a: H NMR (400 MHz, CDCl ) d: –0.15 (s, 2Me Si), –0.14 (s,
3
3
2
400 MHz, D O–pyridine-d ) d: 3.33 (t, a-CH, J 16.0 Hz), 6.55 and
.85 (2s, CHHet). C NMR (100 MHz, D O–pyridine-d ) d: 66.26 (t,
a-C, J 139.9 Hz), 117.83 and 132.43 (2s, CHet). P NMR (162 MHz,
D O–pyridine-d ) d: 14.66 (s). Found (%): C, 19.69; H, 3.28. Calc. for
2
13
2
5
PH
2
(
1
–
Me Si), 3.55 (t, a-CH, J 17.2 Hz), 6.57 and 7.15 (2s, CHHet). C NMR
3 PH
13
1
2 5
100 MHz, CDCl ) d: 0.47 (s, 4Me Si), 67.80 (t, a-C, J 168.2 Hz),
21.00 and 134.69 (both s, CHet). P NMR (162 MHz, CDCl ) d:
0.32 (s). Found (%): C, 36.12; H, 7.52. Calc. for C H N O P Si (%):
C, 36.21; H, 7.60.
Phosphonates 1b–d and bis-phosphonates 2b–d were prepared similarly.
Bis(trimethylsilyl) [(1H-benzimidazol-1-yl)(trimethylsiloxy)methyl]-
phosphonate 1b. Yield 30%, bp 110°C (1 Torr). H NMR (400 MHz,
CDCl ) d: –0.44 (s, Me Si), –0.25 (s, 2Me Si), 5.58 (d, a-CH, J 4.4 Hz),
.70–7.45 (m, CHHet). C NMR (100 MHz, CDCl ) d: –0.22 (s, Me Si),
.11 (s, 2Me Si), 75.50 (d, a-C, J 214.1 Hz), 110.40, 120.23, 122.51,
23.19, 139.62, 143.28, 145.74 (all s, CHet). P NMR (162 MHz, CDCl3)
d: –3.47 (s). Found (%): C, 45.81; H, 7.40. Calc. for C H N O PSi (%):
C, 45.92; H, 7.48.
Bis(trimethylsilyl) [(2,4-dimethyl-1H-pyrazol-1-yl)(trimethylsiloxy)-
methyl]phosphonate 1c. Yield 86%, bp 106°C (1 Torr). H NMR
400 MHz, CDCl ) d: –0.38 and –0.31 (2s, 2Me Si), –0.16 (s, Me Si),
.71 and 1.99 (2s, 2Me), 5.36 (s, CHHet), 5.40 (d, a-CH, J 7.2 Hz).
C NMR (100 MHz, CDCl ) d: –1.62 (s, Me Si), –0.25 and 0.05 (2s,
Me Si), 10.77 and 12.36 (2s, 2Me), 81.19 (d, a-C, JPC 214.1 Hz),
06.61, 139.80, 146.52 (all s, CHet). P NMR (162 MHz, CDCl ) d:
3.35 (s). Found (%): C, 42.49; H, 8.28. Calc. for C H N O PSi (%):
C, 42.62; H, 8.35.
Bis(trimethylsilyl) [(1H-benzotriazol-1-yl)(trimethylsiloxy)methyl]-
phosphonate 1d. Yield 59%, bp 108°C (1 Torr). H NMR (400 MHz,
CDCl ) d: –0.36 (s, Me Si), –0.05 (s, 2Me Si), 6.26 (d, a-CH, J 6.4 Hz),
.99–7.76 (m, C H ). C NMR (100 MHz, CDCl ) d: –0.93 (s, Me Si),
0.75 (s, Me Si), –0.43 (s, Me Si), 80.73 (d, a-C, JPC 213.2 Hz),
13.37, 119.20, 124.17, 127.30, 131.84, 146.45 (all s, CHet). P NMR
162 MHz, CDCl ) d: –4.81 (s). Found (%): C, 43.03; H, 7.16. Calc. for
C H N O PSi (%): C, 43.12; H, 7.24.
etrakis(trimethylsilyl) (1H-benzimidazol-1-ylmethylene)bis(phosphonate)
b. Yield 62%, bp 139°C (1 Torr). H NMR (400 MHz, CDCl ) d: –0.38
3 3 PC
1
31
31
PC
3
2
5
16
40
2
6
2
4
C H N O P (%): C, 19.85; H, 3.33.
4
8
2
6 2
Acids 3a–d, 4b–d were prepared similarly.
(1H-Imidazol-1-yl)(hydroxy)methyl]phosphonic acid 3a. Yield 96%,
[
1
mp 144–145°C (decomp.). H NMR (400 MHz, D O–pyridine-d ) d: 6.81
1
2
5
2
13
(
d, a-CH, J 4.2 Hz), 6.57 and 7.92 (2s, CHHet). C NMR (100 MHz,
D O–pyridine-d ) d: 78.81 (d, a-C, J 180.4 Hz), 117.96 and 132.86
2s, CHet). P NMR (162 MHz, D O–pyridine-d ) d: 7.47 (s). Found (%):
C, 26.86; H, 3.88. Calc. for C H N O P (%): C, 26.98; H, 3.96.
2
PH
3
3
1
3
PH
1
3
2
5
PC
6
1
1
3
3
31
(
1
2 5
3
PC
31
4
7
2
4
[
(1H-Benzimidazol-1-yl)(hydroxy)methyl]phosphonic acid 3b. Yield
17
33
2
4
3
1
9
4%, mp 157–159°C (decomp.). H NMR (400 MHz, D O–pyridine-d )
2 5
2
3
4
d: 5.15 (d, a-CH, J 6.4 Hz), 7.17 (dd, J 16.0 Hz, J 3.2 Hz), 7.47
dd, J 16.0 Hz, J 3.2 Hz), 7.57 (s, CHHet). C NMR (100 MHz,
D O–pyridine-d ) d: 78.85 (d, a-C, JPC 170.0 Hz), 114.16, 125.86,
PH
HH
HH
3
4
13
(
HH HH
1
1
2
5
(
31
3
3
3
1
6
29.74, 138.52 (all s, CHet). P NMR (162 MHz, D O–pyridine-d ) d:
2 5
2
1
PH
.88 (s). Found (%): C, 41.97; H, 3.91. Calc. for C H N O P (%): C, 42.12;
8 9 2 4
13
3
3
H, 3.98.
1
2
1
–
3
[
(2,4-Dimethyl-1H-pyrazol-1-yl)(hydroxy)methyl]phosphonic acid
3c. Yield 97%, mp 357–359°C (decomp.). H NMR (400 MHz, D O–
pyridine-d ) d: 1.86 and 2.20 (2s, 2Me), 4.92 (d, a-CH, J 6.0 Hz),
.64 (s, CHHet). C NMR (100 MHz, D O–pyridine-d ) d: 10.47 and
2.44 (2s, 2Me), 88.18 (d, a-C, J 191.4 Hz), 103.71, 144.05 (all s,
CHet). P NMR (162 MHz, D O–pyridine-d ) d: 10.42 (s). Found (%):
C, 34.78; H, 5.30. Calc. for C H N O P (%): C, 34.96; H, 5.38.
[(1H-Benzotriazol-1-yl)(hydroxy)methyl]phosphonic acid 3d. Yield
31
3
1
2
15
35
2
4
3
2
5
PH
13
5
1
2 5
1
PC
1
31
2
5
2
3
3
3
PH
6 11 2 4
1
3
6
–
1
6 4 3 3
1
1
3
3
95%, mp 105–107°C (decomp.). H NMR (400 MHz, DMSO-d ) d:
6
31
2
3
4
6.43 (d, a-CH, J
7.2 Hz), 7.41 (dd, CH , J 6.4 Hz, J 3.2 Hz),
HH HH
PH
Het
13
(
7.89 (dd, CHHet, 3J 6.4 Hz, J 3.2 Hz). C NMR (100 MHz, DMSO-d6)
4
3
HH HH
1
16
32
3
4
3
d: 79.96 (d, a-C, J 187.7 Hz), 114.92, 118.84, 125.42, 126.86, 131.87,
PC
T
45.86 (all s, CHet). 31P NMR (162 MHz, DMSO-d ) d: 10.62 (s).
1
6
1
2
3
Found (%): C, 36.55; H, 3.48. Calc. for C H N O P (%): C, 36.70; H, 3.52.
(1H-Benzimidazol-1-ylmethylene)bis(phosphonic) acid 4b. Yield 98%,
mp 348–350°C (decomp.). H NMR (400 MHz, DMSO-d ) d: 4.18 (t,
a-CH, J 16.0 Hz), 7.18 (dd, CH , J 6.0 Hz, J 3.2 Hz), 7.46 (dd,
CHHet, J 6.0 Hz, J 3.2 Hz), 7.56 (s, CHHet). C NMR (100 MHz,
HH HH
DMSO-d ) d: 66.86 (d, a-C, J 142.1 Hz), 113.79, 125.73, 129.59, 138.88
all s, CHet). P NMR (162 MHz, DMSO-d ) d: 15.63 (s). Found (%):
6
C, 32.74; H, 3.40. Calc. for C H N O P (%): C, 32.89; H, 3.45.
(2,4-Dimethyl-1H-pyrazol-1-ylmethylene)bis(phosphonic) acid 4c.
Yield 98%, mp 357–359°C (decomp.). H NMR (400 MHz, DMSO-d –
pyridine-d ) d: 1.82 and 2.14 (2s, 2Me), 3.97 (t, a-CH, J 15.6 Hz),
5.60 (s, CHHet). C NMR (100 MHz, DMSO-d –pyridine-d ) d: 10.44
and 12.34 (2s, 2Me), 55.57 (t, a-C, J 181.7 Hz), 105.63, 140.83 (all s,
PC
CHet). P NMR (162 MHz, DMSO-d –pyridine-d ) d: 15.03 (s). Found (%):
7 8 3 4
2
and –0.31 (2s, 2Me Si), –0.16 (s, Me Si), 3.55 (t, a-CH, J 16.8 Hz),
.65–7.55 (m, CHHet). C NMR (100 MHz, CDCl ) d: 1.10 (s, 4Me Si),
8.11 (d, a-C, J 167.3 Hz), 112.46, 119.92, 122.13, 122.75, 139.71,
41.75, 145.46 (all s, CHet). P NMR (162 MHz, CDCl ) d: –0.58 (s).
3
3
PH
13
6
6
1
1
3
3
6
1
2
3
4
PC
PH Het HH
HH
13
31
3
4
3
Found (%): C, 41.26; H, 7.20. Calc. for C H N O P Si (%): C, 41.36;
1
20
42
2
6
2
4
6 PC
H, 7.29.
31
(
Tetrakis(trimethylsilyl) (2,4-dimethyl-1H-pyrazol-1-ylmethylene)bis-
phosphonate) 2c. Yield 7%, bp 129°C (1 Torr). H NMR (400 MHz,
8 10 2 6 2
1
(
1
CDCl ) d: –0.12 and –0.16 (2s, 4Me Si), 1.80 and 2.01 (2s, 2Me), 3.58
3
3
6
2
13
2
(
0
1
–
t, a-CH, J 17.2 Hz), 5.36 (s, CHHet). C NMR (100 MHz, CDCl ) d:
PH
3
5
PH
1
13
.35 (s, 4Me Si), 10.80 and 12.40 (2s, 2Me), 68.09 (t, a-C, J 168.2 Hz),
06.68, 139.86, 146.57 (all s, CHet). P NMR (162 MHz, CDCl ) d:
0.30 (s). Found (%): C, 38.52; H, 7.86. Calc. for C H N O P Si (%):
3
PC
6 5
31
1
3
31
18
44
2
6
2
4
6 5
C, 38.69; H, 7.94.
C, 26.49; H, 4.52. Calc. for C H N O P (%): C, 26.68; H, 4.48.
6 12 2 6 2
Tetrakis(trimethylsilyl) (1H-benzotriazol-1-ylmethylene)bis(phosphonate)
(1H-Benzotriazol-1-ylmethylene)bis(phosphonic) acid 4d. Yield
1
1
2
(
(
1
d. Yield 30%, bp 133°C (1 Torr). H NMR (400 MHz, CDCl ) d: –0.11
96%, mp 355–357°C (decomp.). H NMR (400 MHz, DMSO-d –
3
6
2
13
2
3
s, 4Me Si), 3.75 (t, a-CH, J 16.8 Hz), 7.17–7.83 (m, C H ). C NMR
pyridine-d ) d: 3.88 (t, a-CH, J 17.2 Hz), 8.01 (d, J 8.2 Hz), 8.95
(d, J 8.2 Hz). C NMR (100 MHz, DMSO-d –pyridine-d ) d: 65.28
HH 6 5
3
PH
6
1
4
5 PH HH
3
13
100 MHz, CDCl ) d: 0.01 (s, 4Me Si), 67.71 (t, a-C, J 168.2 Hz),
3
3
PC
10.50, 114.55, 119.44, 126.22, 129.93, 140.27 (all s, CHet). 3 P NMR
1
1
(t, a-C, J 150.2 Hz), 113.61, 118.64, 124.03, 125.42, 126.86, 138.69
PC
(
162 MHz, CDCl ) d: –0.47 (s). Found (%): C, 39.03; H, 7.01. Calc. for
(all s, CHet). 31P NMR (162 MHz, DMSO-d –pyridine-d ) d: 16.41 (s).
3
6
5
C H N O P Si (%): C, 39.22; H, 7.10.
Found (%): C, 28.56; H, 3.14. Calc. for C H N O P (%): C, 28.68; H, 3.09.
7 9 3 6 2
19
41
3
6
2
4
–
91 –

Mendeleev Commun., 2017, 27, 90–92
This work was supported by the Russian Foundation for Basic
Research (grant nos. 14-03-00001 and 15-03-00002).
7 A. A. Prishchenko, M. V. Livantsov, O. P. Novikova, L. I. Livantsova,
I. S. Ershov and V. S. Petrosyan, Heteroat. Chem., 2015, 26, 101.
A. A. Prishchenko, M. V. Livantsov, O. P. Novikova, L. I. Livantsova,
G. M. Averochkin and V. S. Petrosyan, Heteroat. Chem., 2015, 26, 405.
A. R. Katriztky, H.-X. Chang and B. Yang, Synthesis, 1995, 503.
8
9
References
1
Aminophosphonic and Aminophosphinic Acids. Chemistry and Biological
Activity, eds. V. P. Kukhar and H. R. Hudson, Wiley, New York, 2000.
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, G. Schreiber, Y. Seltenmeyer and J. R. Green, J. Med. Chem.,
10 A. D. Dilman and S. L. Ioffe, Chem. Rev., 2003, 103, 733.
11 A. A. Prishchenko, M. V. Livantsov, O. P. Novikova, L. I. Livantsova,
and V. S. Petrosyan, Russ. Chem. Bull., Int. Ed., 2016, 65, 1846 (Izv.
Akad. Nauk, Ser. Khim., 2016, 1846).
12 A. A. Prishchenko, M. V. Livantsov, O. P. Novikova, L. I. Livantsova
and V. S. Petrosyan, Heteroat. Chem., 2009, 20, 319.
13 L. Wo z´ niak and J. Chojnowski, Tetrahedron, 1989, 45, 2465.
14 V. D. Romanenko, M. V. Shevchuk and V. P. Kukhar, Curr. Org. Chem.,
2011, 15, 2774.
2
2
002, 45, 3721.
O. I. Kolodiazhnyi, Russ. Chem. Rev., 2006, 75, 227 (Usp. Khim., 2006,
5, 254).
3
7
4
5
A. Mucha, P. Kafarski and L. Berlicki, J. Med. Chem., 2011, 54, 5955.
A. A. Prishchenko, M. V. Livantsov, O. P. Novikova, L. I. Livantsova and
V. S. Petrosyan, Russ. Chem. Bull., Int. Ed., 2016, 65, 228 (Izv. Akad. Nauk,
Ser. Khim., 2016, 228).
6
A. A. Prishchenko, M. V. Livantsov, O. P. Novikova, L. I. Livantsova,
I. S. Ershov and V. S. Petrosyan, Heteroat. Chem., 2013, 24, 355.
Received: 12th May 2016; Com. 16/4969
–
92 –