Synthesis of new functionalized aryl and pyridyl aminomethylenebisphosphonic acids and their derivatives via silicon-assisted methodology

Article abstract of DOI:10.1016/j.jorganchem.2020.121177

The new convenient synthesis of functionalized aryl and pyridyl aminomethylenebisphosphonic acids and their derivatives has been developed via silicon-assisted methodology. New functionalized aminomethylenebisphosphonic acids containing pyridines moieties were obtained using unique reaction of tris(trimethylsilyl) phosphite with N-formyl aminopyridines and trimethylsilyl triflate as a catalyst under mild conditions. Intermediates – tetra(trimethylsilyl) aminomethylenebisphosphonates formed, were converted to the target acids by further treatment with methanol excess. In contrast the corresponding tetraethyl aminomethylenebisphosphonates were synthesized under heating (130 °C) of four component mixture (diethyl trimethylsilyl phosphite, triethyl orthoformate, aryl- or pyridylamine, and diethyl phosphite) in the presence of zinc chloride catalyst. The catalytic schemes of target substances formation are proposed and thoroughly discussed.

Full text of DOI:10.1016/j.jorganchem.2020.121177

Journal Pre-proof
Synthesis of new functionalized aryl and pyridyl aminomethylenebisphosphonic acids
and their derivatives via silicon-assisted methodology
Andrey A. Prishchenko, Roman S. Alekseyev, Mikhail V. Livantsov, Olga P. Novikova,
Ludmila I. Livantsova, Valery S. Petrosyan
PII:
S0022-328X(20)30078-4
DOI:
https://doi.org/10.1016/j.jorganchem.2020.121177
JOM 121177
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 26 November 2019
Revised Date: 7 February 2020
Accepted Date: 8 February 2020
Please cite this article as: A.A. Prishchenko, R.S. Alekseyev, M.V. Livantsov, O.P.
Novikova, L.I. Livantsova, V.S. Petrosyan, Synthesis of new functionalized aryl and pyridyl
aminomethylenebisphosphonic acids and their derivatives via silicon-assisted methodology, Journal of
Organometallic Chemistry (2020), doi: https://doi.org/10.1016/j.jorganchem.2020.121177.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of
record. This version will undergo additional copyediting, typesetting and review before it is published
in its final form, but we are providing this version to give early visibility of the article. Please note that,
during the production process, errors may be discovered which could affect the content, and all legal
disclaimers that apply to the journal pertain.
© 2020 Published by Elsevier B.V.

Synthesis
of
new
functionalized
aryl
and
pyridyl
aminomethylenebisphosphonic acids and their derivatives via silicon-
assisted methodology
This article is dedicated to the 120th anniversary of academician Alexander
N. Nesmeyanov
Andrey A. Prishchenko*, Roman S. Alekseyev, Mikhail V. Livantsov, Olga P. Novikova,
Ludmila I. Livantsova, Valery S. Petrosyan
Department of Chemistry, M.V. Lomonosov Moscow State University, Moscow119991, Russia
*Corresponding author.
E-mail address: aprishchenko@yandex.ru (A. A. Prishchenko)
Ms. Ref. No.: JORGANCHEM-D-19-00738
Received
26 November 2019
ABSTRACT
The new convenient synthesis of functionalized aryl and pyridyl aminomethylenebisphosphonic
acids and their derivatives has been developed via silicon-assisted methodology. New
functionalized aminomethylenebisphosphonic acids containing pyridines moieties were obtained
using unique reaction of tris(trimethylsilyl) phosphite with N-formyl aminopyridines and
trimethylsilyl triflate as a catalyst under mild conditions. Intermediates – tetra(trimethylsilyl)
aminomethylenebisphosphonates formed, were converted to the target acids by further treatment
with methanol excess. In contrast the corresponding tetraethyl aminomethylenebisphosphonates
were synthesized under heating (130 °C) of four component mixture (diethyl trimethylsilyl
phosphite, triethyl orthoformate, aryl- or pyridylamine, and diethyl phosphite) in the presence of
zinc chloride catalyst. The catalytic schemes of target substances formation are proposed and
thoroughly discussed.
Keywords:
aryl and pyridyl moieties
functionalized aminomethylenebisphosphonic acids
trimethylsilyl phosphites
trimethylsilyl triflate
zinc chloride

Graphical abstract:
1. Introduction
In the last few decades the chemistry of bisphosphonic acids has been developed rapidly due to
its great synthetic and biological significance. Functionalized methylenebisphosphonic acids and
their derivatives were widely investigated among bisphosphoryl compounds. The latter
intensively used as promising polydentate ligands and organophosphorus biomimetics of natural
pyrophosphates with multifactorial activity. These substances include stable P-C-P scaffold with
two non-hydrolysable P-C bonds and interfere with various biochemical processes, so they
demonstrate the properties of herbicides, pesticides, antibiotics, antiviral and antitumor agents
and enzyme inhibitors [1]. The series of functionalized bisphosphonic acids and their derivatives
are effective ligands, so these compounds are widely used as recognized drugs – regulators of
calcium metabolism [2], also some of them with similar structure are of particular interest as
effective antioxidants and cytoprotectors [3]. The subclass of bisphosphonic acids –
aminomethylenebisphosphonic acids are excellent chelators for heavy metal detoxification [4]
and promising radiopharmaceuticals [5]. The diverse biological activity of these acids is firstly
determined by a favorable combination of methylenebisphosphonates, hydroxyl, amine, and N-
heterocyclic moieties [1]. So zoledronic and risedronic acids as the most successful examples
with imidazole and pyridine moieties are widely used in medicine as well-known regulators of
calcium metabolism [6]. Thus the search of new synthetic routes to new types of functionalized
aminomethylenebisphosphonic acids and their derivatives is an area of active study.
2. Results and discussion
Here we report about new convenient synthesis of functionalized aryl and pyridyl
aminomethylenebisphosphonic acids and their derivatives via silicon-assisted methodology using
highly reactive trimethylsilyl phosphites, various formic acid derivatives, and the effective

catalysts – trimethylsilyl triflate or zinc chloride. The organosilicon applied synthesis of
functionalized organophosphorus acids and their derivatives is a convenient method for creating
Р-С bonds; recently this methodology has been successfully developed and became modern
trend in organophosphorus chemistry [7]. It should be noted the trimethylsilyl phosphites readily
add to the carbonyl group of aldehydes and ketones with P-C bond formation, nevertheless the
addition of trimethylsilyl phosphites to the inactive carbonyl group of various formamides was
not known before our investigations [7a,b,i].
We were first to find that various formamides readily react with tris(trimethylsilyl) phosphite
excess only in the presence of trimethylsilyl triflate as effective catalyst to give various
aminomethylphosphonates and aminomethylenebisphosphonates containing N-heterocycles and
amino acids fragments [8]. However, the use of five-membered N-heterocycles in the above
reaction results in mixture of two products which were separated by distillation [8a]. Here we
have
developed
the
new
convenient
one-pot
synthesis
of
functionalized
aminomethylenebisphosphonic acids with pyridines moieties – promising structural analogues of
risedronic acid as recognized drug. The synthesis of the target substances – acids 3 involves
three steps. Initially the starting aminopyridines were easily transformed to the corresponding N-
formyl derivatives 1 in situ under the action of formic acid and dicyclohexylcarbodiimide
(DCC). The further interaction of N-formyl derivatives 1 and tris(trimethylsilyl) phosphite
proceeds under mild conditions only in the presence of an effective catalyst – trimethylsilyl
triflate to yield tetra(trimethylsilyl) aminomethylenebisphosphonates 2 as intermediates (Scheme
1).
Scheme 1 Synthesis of tetra(trimethylsilyl) aminomethylenebisphosphonates 2 as intermediates.
Reagents and conditions: (a) XNH2 (0.05 mol), HCOOH (0.07 mol), DCM (50 mL), DCC (0.07
mol in 20 mL DCM), 20 °C, 8 h, then 20 °C, 12 h; (b) (TMSO)3P (0.15 mol), TMSOTf (0.015
mol), DCM (10 mL).
Undoubtedly the catalytic effect of trimethylsilyl trifluoromethanesulfonate is connected with its
ability to generate highly electrophilic iminium intermediates A1,2 (Scheme 2). It should be
mentioned that previously trimethylsilyl triflate was successfully used by us earlier as a catalyst

for the activation of imines and some formamides double bonds [7c,8]. The process proceeds
rather rapidly at 20 °C with immediate formation of methylenebisphosphonates 2 in contrast to a
similar reaction of N-formyl derivatives containing five-membered N-heterocycles [8a].
Scheme
2
The proposed mechanism for the synthesis of tetra(trimethylsilyl)
aminomethylenebisphosphonates 2.
Bisphosphonates 2 were easily transformed to the corresponding aminomethylenebisphosphonic
acids 3 by methanolysis. The trimethylsilyl groups of bisphosphonates 2 were removed under
mild conditions in order to prevent the P-C bond break in the bisphosphonic acids 3 formed (cf.
Ref. [8a]). So the treatment of bisphosphonates 2 with the methanol excess under mild
conditions resulted in the water-soluble acids 3 in high yields (Scheme 3).

Scheme 3 Synthesis of aminomethylenebisphosphonic acids 3. Reagents and conditions:
bisphosphonate 2 (0.05 mol), Et2O (30 mL), MeOH (20 mL), 20 °C, 12 h.
We also suggested new synthetic route to functionalized tetraethyl aminomethylenebisphospho-
nates with aryl and pyridyl moieties 4,5, which are of interest as stable polydentate ligands and
biologically active substances. It is important to note these compounds are rather difficultly
available by other methods where the yields are low or moderate [9]. It should be emphasized
that it was not possible to obtain tetraethyl esters 4,5 under conditions similar to the synthesis of
tetra(trimethylsilyl) ethers of aminomethylenebisphosphonic acids 2. Thus, according to the data
31
of P NMR spectra, in the reaction mixtures there are no signals corresponding to compounds
4,5, and a signal of diethyl trimethylsilyl phosphate (δР -9.3 ppm) appears. Thus, in this case,
unlike tris trimethylsilyl phosphite, diethyl trimethylsilyl phosphite is easily oxidized by the
catalyst - trimethylsilyl triflate to form diethyl trimethylsilyl phosphate, which leads to the
disappearance of the catalyst in the reaction mixture.
To synthesize the target bisphosphonates 4,5 we were the first using four component mixture
containing sufficiently nucleophilic diethyl trimethylsilyl phosphite, triethyl orthoformate, aryl-
or pyridylamine, and diethyl phosphite in the presence of an effective catalyst – zinc chloride.
The reaction proceeds under heating (110-130 °C) with simultaneous distillation of
ethoxytrimethylsilane and leads to bisphosphonates 4,5 in high yields. It should be noted that in
spite of diethyl phosphite formation in the process as a result of released ethanol interaction with
the starting diethyl trimethylsilyl phosphite, the preliminary entering of diethyl phosphite excess
into the mixture 20% increases the yields of bisphosphonates 4,5 (Scheme 4).

Scheme 4 Synthesis of tetraethyl aminomethylenebisphosphonates 4,5. Reagents and conditions:
XNH2 (0.02 mol), HC(OEt)3 (0.024 mol), (EtO)2POTMS (0.07 mol), (EtO)2P(O)H (0.024 mol)
and ZnCl2 (0.001 mol), 110-130 ºС, 1 h.
High yields of diphosphonates 4,5 were achieved due to the unique catalytic activity of zinc
chloride which could generate both electrophilic iminium salts B1,2 and increase the
nucleophilicity of the starting diethyl trimethylsilyl phosphite upon cleavage of the Si-O bond
with the formation of the zinc diethyl phosphite salt [9a] (Scheme 5).
XNH2
ZnCl2
HC(OEt)2
HC(OEt)3
XNHCH(OEt)2
(EtO)2POTMS
[EtOZnCl2]
- EtOH, -ZnCl2
ZnCl2
XNH=CHOEt
[EtOZnCl2]
XNHCHOEt
[EtOZnCl2]
B1
O
XNH CH-P(OEt)2
OEt
OTMS
XNH CH-P(OEt)2
- EtOTMS, -ZnCl2
OEt
[EtOZnCl2]
XNH=CHP(OEt)2
XNHCHP(OEt)2
(EtO)2POTMS
ZnCl2
O
O
[EtOZnCl2]
B2
[EtOZnCl2]
NHX
NHX
P(OEt)2
(EtO)2P
P(OEt)2
OTMS
(EtO)2P
- EtOTMS, -ZnCl2
O
O
O
4,5
[EtOZnCl2]

Scheme
5
The
proposed
mechanism
for
the
synthesis
of
tetraethyl
aminomethylenebisphosphonates 4,5 using diethyl trimethylsilyl phosphite.
It is important to note that the use of the three-component mixture without diethyl trimethylsilyl
phosphite significantly reduces yield of bisphosphonates 4 and 5, and the temperature of the
reaction mixture has to be raised up to 150 ºС (Scheme 6).
Scheme 6 Synthesis of tetraethyl aminomethylenebisphosphonates 4,5 using diethyl phosphite.
Reagents and conditions: XNH2 (0.02 mol), HC(OEt)3 (0.024 mol), (EtO)2P(O)H (0.024 mol)
and ZnCl2 (0.001 mol), 140-150 ºС, 1 h.
Obviously the above results are connected both with reduced nucleophilitciy of the starting
diethyl phosphite and with low electrophilicity of intermediate imines C1,2 formed as result of
decomposition of the zinc chloride complexes at high temperature. Further subsequent addition
of diethyl phosphite to imines C1,2 proceeds under heating and results in bisphosphonates 4 and
5 (Scheme 7).

Scheme
7
The
proposed
mechanism
for
the
synthesis
of
tetraethyl
aminomethylenebisphosphonates 4,5 using diethyl phosphite.
Indeed, the interaction of diethyl phosphite with specially prepared imines C1a,b was realized
under the same conditions and led to bisphosphonates 4a,b in moderate yields. These results
confirm the proposed reaction route (Scheme 8).
Scheme 8 Synthesis of tetraethyl aminomethylenebisphosphonates 4a,b via imidoformates
C1a,b. Reagents and conditions: compound C1a,b (0.02 mol), (EtO)2P(O)H (0.024 mol) and
ZnCl2 (0.001 mol), 140-150 ºС, 1 h.
At the same time the interaction of imines C1a,b and the mixture of tris(trimethylsilyl) phosphite
and bis(trimethylsilyl) phosphite (three component system) proceeds at higher temperature and
the yields of the target bisphosphonates 6a,b are very high (Scheme 9).
Scheme 9 Synthesis of tetra(trimethylsilyl) aminomethylenebisphosphonates 6a,b via
imidoformates C1a,b. Reagents and conditions: compound C1a,b (0.02 mol), (TMSO)3P (0.015
mol), (TMSO)2P(O)H (0.015 mol) and ZnCl2 (0.001 mol), 150-160 ºС, 1 h.
We emphasize that the small amounts of complexes of the initial catalyst - zinc chloride and
resulting compounds 4-6 are easily separated upon their recrystallization or distillation.
Bisphosphonates 6 were easily transformed to bisphosphonic acids 7 by methanolysis similar to
bisphosphonates 2 (Scheme 10).

Scheme 10 Synthesis of aminomethylenebisphosphonic acids 7 via methanolysis. Reagents and
conditions: 2 (0.05 mol), Et2O (30 mL), MeOH (20 mL), rt, 12 h.
It should be noted that the obtained functionalized aminomethylenebisphosphonic acids and their
derivatives 2-7 are quite stable; unlike hydroxymethylenebisphosphonates esters, they are not
capable to phosphonate-phosphate rearrangement with a cleavage of the P-C bond.
The structures of functionalized aminomethylenebisphosphonic acids and their derivatives 2-7
were confirmed by the 1H, 13C, 31P NMR spectra and high resolution mass spectra (HRMS) (see
Supporting information) where the characteristic signals of the corresponding fragments were
observed. Note that the protons exchange in aminomethylenebisphosphonic acids 3 leads to the
broadening of signals in the NMR spectra, so the spectra of acids 3 were registered in two
13
different types of solvents – D2O + D2SO4 and DMSO-d6 + Et3N, but the C NMR spectra of
acids 3 were registered using only the mixture of solvents DMSO-d6 + Et3N (see supplementary
data).
3. Conclusions
In summary, we have developed an efficient silicon-assisted methodology using highly reactive
trimethylsilyl phosphites, formic acid derivatives, and trimethylsilyl triflate or zinc chloride as
effective catalysts and have provided an access to various functionalized aryl and pyridyl
aminomethylenebisphosphonic acids and their derivatives in excellent yields. The proposed
mechanism for the reaction include the formation of highly reactive iminium salts and was
discussed and probed in detail. The resulting substanses are of great practical interest because
they are structural analogues of well-known drugs and may be considered as promising
polydentate ligands in coordination chemistry.
4. Experimental
1
31
The H, 13C and P NMR spectra were registered at room temperature on a Bruker Avance-400
spectrometer (400, 100, and 162 MHz, respectively) against TMS as internal standard (1H and
13C) and 85% H3PO4 in D2O as external standard (31P). Chemical shifts (δ) were given in ppm
and coupling constants (J) in Hz. High resolution mass spectra (HRMS) were measured on a

Bruker micrOTOF II instrument using electrospray ionization (ESI) in positive or negative
mode. Melting points were determined in open capillaries and are not corrected. Chemicals were
purchased from common commercial suppliers (Sigma-Aldrich and Acros Organics) and used as
delivered. All reactions were carried out under dry argon in anhydrous solvents. Imidoformates
C1a,b were prepared according to reported procedure [10].
Organosilicon applied synthesis of aminomethylenebisphosphonic acids 3. General Procedure.
A solution of dicyclohexylcarbodiimide (0.07 mol) in CH2Cl2 (20 mL) was added dropwise at 20
°С under stirring to a mixture of aminopyridine (0.05 mol) and formic acid (0.06 mol) in CH2Cl2
(50 mL). The mixture was stirred for 8 hours and left for 12 hours at room temperature, then the
formed precipitate is filtered off, the resulting solution was added to a solution of
tris(trimethylsilyl) phosphite (0.15 mol), and a solution of trimethylsilyl triflate (0.015 mol) in
CH2Cl2 (10 mL) was added to this mixture. The reaction mixture was heated in a boiling water
bath to complete the removal of low-boiling compounds in vacuum 0.5 mm Hg. The residue
containing the intermediate bisphosphonates 2 was dissolved in 30 mL of ether, and methanol
(20 mL) was added dropwise to a solution under stirring. The reaction mixture was stirred for 8
hours and left for 24 hours. White powder was filtered off and kept in vacuum 0.5 mm Hg to
give acids 3. Bisphosphonic acids 7a,b were prepared similarly from bisphosphonates 6a,b.
Tetraethyl aminomethylenebisphosphonates 4,5. General Procedure.
A mixture of amine (0.02 mol), triethyl orthoformate (0.024 mol), diethyl (trimethylsilyl)
phosphite (0.07 mol), diethyl phosphite (0.024 mol) and zinc chloride (0.001 mol) was heated at
110 – 130 °С with distilling off ethoxytrimethylsilane for 1 h and then the product was distilled
or recrystallized from a mixture of hexane and diethyl ether (9 : 1) to give bisphosphonates 4,5.
Bisphosphonates 6a,b were prepared by similar procedure.
Acknowledgments
This study was supported by Russian Foundation for Basic Research, grant number 17-03-00169
and Russian Science Foundation, grant number 19-73-00245.
Appendix A. Supplementary data
Supplementary data related to this article can be found at https:
References

[1] a) D. Seebach, Angew. Chem. Int. Ed. 29 (1990) 1320-1367; b) S.C. Fields, Tetrahedron 55
(1999) 12237-12273; c) R. Graham, G. Russell, Phosphorus, Sulfur and Silicon 144-146
(1999) 793-820; d) E. Brauer, Analogue-based Drug Discovery (Eds.: J. Fischer,
C.R.Ganellin), Wiley-VCH, Weinheim (2006); e) V.P. Kukhar and H.R. Hudson,
Aminophosphonic and Aminophosphinic Acids. Chemistry and Biological Activity, (Ed.:
V.P. Kukhar and H.R. Hudson) Wiley-VCH, New York (2000) 634 pp; f) O.I.
Kolodiazhnyi, Rus. Chem. Rev. 75 (2006) 254-282; g) V.P Kukhar, V.D. Romanenko in
Amino Acids, Peptides and Proteins in Organic Synthesis, Vol. 2 (Ed.: A.B. Hughes),
Wiley-VCH, Weinheim (2009) pp. 189-260; h) X. Liu , X.-R. Zhang, G.M. Blackburn,
Phosphorus, Sulfur and Silicon 144-146 (1999) 541-544; i) K.W. Pankiewicz, K.B. Lesiak,
K.A. Watanabe, Sulfur and Silicon 144-146 (1999) 671-674; j) B.Z. Leder, H.M.
Kronenberg, Gastroenterology 119 (2000) 866-869; k) P. Kafarski, B. Lejczak, Phosphorus,
Sulfur and Silicon 63 (1991) 193-215; l) T. Galaka, B.N. Falcone, C. Li, S.H. Szajnman,
S.N.J. Moreno, R. Docampo, J.B. Rodriguez, Bioorg. Med. Chem. 27 (2019) 3663–3673.
[2] a) E.V. Giger, B. Castagner, J.-C. Leroux, J. Control. Release 167 (2013) 175-178; b) R.
Burgada, T. Bailly, M. Lecouvey, V. Larue, Y. Leroux, Eur. J. Org. Chem. (2001) 349-352;
c) M. Lecouvey, I. Mallard, T. Bailly, R. Burgada, Y. Leroux, Tetrahedron Lett. 42 (2001)
8475–8478; d) E. Guenin, E. Degache, J. Liquier, M. Lecouvey, Eur. J. Org. Chem. (2004)
2983-2987; e) L. Widler, K. A. Jaeggi, J.R. Green, Phosphorus, Sulfur and Silicon 144-146
(1999) 5-8; f) 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, J.R. Green, J. Med. Chem. 45 (2002) 3721-3738; g) S.M. Krasovskaya, L.D.
Uzhinova, M.Y. Andrianova, A.A. Prishchenko, M.V. Livantsov, Biomaterials 12 (1991)
817-820; h) J. Gałęzowska, H. Czapor-Irzabek, R. Janicki, E. Chmielewska,, T. Janek, New J.
Chem. 41 (2017) 10731-10741.
[3] a) A.A. Prishchenko, M.V. Livantsov, O.P. Novikova, L.I. Livantsova, V.S. Petrosyan,
Heteroatom Chem. 23 (2012) 32-40; b) A.A. Prishchenko, M.V. Livantsov, O.P. Novikova,
L.I. Livantsova, E.R. Milaeva, Heteroatom Chem. 19 (2008) 490-494; c) N.T. Berberova,
V.P. Osipova, M.N. Kolyada, N.A. Antonova, N.S. Zefirov, E.R. Milaeva, S.I. Filimonova,
Yu.A. Gracheva, A.A. Prishchenko, M.V. Livantsov, L.I. Livantsova, O.P. Novikova, Patent
RU 2405032 C 1, Rus. Patent Bull 2010, 33; d) N.T. Berberova, I.M. Chernushkina, V.P.
Osipova, M.N. Kolyada, Yu.I. Pimenov, Yu.A. Gracheva, A.A. Prishchenko, M.V.
Livantsov, L.I. Livantsova, O.P. Novikova, E.R. Milaeva, N.S. Zefirov, Patent RU 2457240
C 2, Rus. Patent Bull 2012, 21.

[4] a) E.P. Chmielewska, P. Kafarski, Molecules 21 (2016) 1-26; b) J. Gałęzowska, H Czapor-
Irzabek, E.P. Chmielewska, P. Kafarski, T. Janek, New J. Chem. (2018) 1-15; c) E.
Matczak-Jon, B. Kurzak, W. Sawka-Dobrowolska, Polyhedron 31 (2012) 176-187; d) A.
Dobosz, J. Spychała, T. Ptak, G. Maciejewska, E. Chmielewska, P. Kafarski, P. Mlynarz,
Inorg. Chim. Acta 435 (2015) 82-93; e) A. Dobosz, J. Spychała, T. Ptak, E. Chmielewska,
G. Maciejewska, P. Kafarski, P. Mlynarz, Coord. Chem. Rev. 327-328 (2016) 271-286.
[5] a) F. Hosain, R.P. Spencer, H.M. Couthon, G. L. Sturtz, J. Nucl. Med. 37 (1996) 105-107; b)
G. Sturtz, H. Couthon, O. Fabulet, M. Mian, S. Rosini, Eur. J. Med. Chem. 28 (1993) 899-
903; c) G. Sturtz, G. Appere, K. Breistol, O. Fodstad, G. Schwartsmann, H.R. Hendriks,
Eur. J. Med. Chem. 27 (1992) 825-833; d) A. Gonzalez, L.J. Wilson, W. Wu, G.H.
Nancollas, Bioorg. Med. Chem. 10 (2002) 1991-1997; e) J.J. Vepsäläinen, Curr. Med.
Chem. 12 (2002) 1201-1208.
[6] a) F.H. Ebetino, Phosphorus, Sulfur and Silicon 144-146 (1999) 9-12; b) N.G. Almstead,
S.M. Dansereau, M.D. Francis, C.M. Snider, F.H. Ebetino , Phosphorus, Sulfur and Silicon
144-146 (1999) 325-328; c) M.L. Peters, M. Leonard, A.A. Licata, Cleve. Clin. J. Med. 68
(2001) 945-951; d) T. Kowalik-Jankowska, M. Pietruszka, Ju. Jezierska, E. Matczak-Jon, P.
Kafarski, Polyhedron 30 (2011) 1274-1280; e) F.H. Ebetino, L.A. Jamieson, Phosphorus,
Sulfur and Silicon 51-52 (1990) 23-26.
[7] a) V.D. Romanenko, M.V. Shevchuk, V.P. Kukhar, Current. Org. Chem. 15 (2011) 2774-
2801; b) L. Wozniak, J. Chojnowski, Tetrahedron 45 (1989) 2465-2524; c) A.A.
Prishchenko, M.V. Livantsov, O.P. Novikova, L.I. Livantsova, I.S. Ershov, V.S. Petrosyan,
Heteroat. Chem. 26 (2015) 101-105; d) A.A. Prishchenko, M.V. Livantsov, O.P. Novikova,
L.I. Livantsova, G.M. Averochkin, V.S. Petrosyan, Heteroat. Chem. 26 (2015) 405-410; e)
A.A. Prishchenko, R.S. Alekseyev, M.V. Livantsov, O.P. Novikova, L.I. Livantsova, V.S.
Petrosyan, Inorg. Chim. Acta 484 (2019) 319-321; f) A.A. Prishchenko, M.V. Livantsov,
O.P. Novikova, L.I. Livantsova, V.S. Petrosyan, Heteroat. Chem. 27 (2016) 381-388; g) J.
Dussart, N. Guedeney, Ju. Deschamp, M. Monteil, O. Gager, Th. Legigan, E. Migianu-
Griffoni, M. Lecouvey, Org. Biomol. Chem. 16 (2018) 6969–6979; h) A.A. Prishchenko,
M.V. Livantsov, O.P. Novikova, L.I. Livantsova, V.S. Petrosyan, Heteroat. Chem. 29 (2018)
e21419; i) U. Schollkopf, I. Hoppe, A. Thiele, Liebigs Ann. Chem. (1985) 555-559.
[8] a) A.A. Prishchenko, R.S. Alekseyev, M.V. Livantsov, O.P. Novikova, L.I. Livantsova, V.S.
Petrosyan, J. Organomet. Chem. 867 (2018) 149-154; b) A.A. Prishchenko, R.S. Alekseyev,
M.V. Livantsov, O.P. Novikova, L.I. Livantsova, V.S. Petrosyan, J. Organomet. Chem. 871
(2018) 36-39.

[9] a) A.A. Prishchenko, M.V. Livantsov, V.S. Petrosyan, Russ. J. Gen. Chem. 64 (1994) 1316-
1330; b) A.A. Prishchenko, M.V. Livantsov, O.P. Novikova, L.I. Livantsova, Russ. J. Gen.
Chem. 79 (2009) 1936-1938; c) E. Dabrowska, A. Burzynska, A. Mucha, E. Matczak-Jon,
W. Sawka-Dobrowolska, L. Berlicki, P. Kafarski, J. Organomet. Chem. 684 (2009) 3806-
3813; d) D. Kantoci, J.K. Denike, W.J. Wechter, Synth. Commun. 26 (1996) 2037-2043; e)
V.I. Krutikov, A.V. Erkin, P.A. Pautov, M.M. Zolotukhina, Russ. J. Gen. Chem. 73 (2003)
205-210; f) V. D. Romanenko, V.P. Kukhar, ARKIVOC iv (2012) 127-166; g) E. Balint, A.
Tajti, A. Dzielak, G. Haegele, G. Keglevich, Beilstein J. Org. Chem. 12 (2016) 1493–1502.
[10] a) R.M. Roberts, J. Am. Chem. Soc. 71 (1949) 3848-3849; b) R.M. Roberts, P.J. Vogt, Org.
Synth. 35 (1955) 65.

The new functionalized aminomethylenediphosphonates with moieties of various aryl and
pyridyl are synthesized via unique reaction of highly reactive trimethylsilyl phosphites, formic
acid derivatives, and trimethylsilyl triflate or zinc chloride as effective catalysts. The catalytic
schemes of the target compounds synthesis include the formation of highly reactive iminium
salts and were discussed and confirmed in detail. The resulting substanses are of great practical
interest because they are structural analogues of well-known drugs and may be considered as
promising polydentate ligands in coordination chemistry.

Declaration of interests
V ☐The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
☐ The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: