Organosilicon based synthesis of new functionalized aminomethylenediphosphonates with moieties of amino acids

Article abstract of DOI:10.1016/j.jorganchem.2018.07.007

The new functionalized aminomethylenediphosphonates with moieties of various amino acids are synthesized via unique reaction of tris(trimethylsilyl) phosphite and N-formyl amino acids at the presence of effective catalyst – trimethylsilyl triflate under m

Full text of DOI:10.1016/j.jorganchem.2018.07.007

Journal of Organometallic Chemistry 871 (2018) 36e39
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Organosilicon based synthesis of new functionalized
aminomethylenediphosphonates with moieties of amino acids
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, Moscow, 119991, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
The new functionalized aminomethylenediphosphonates with moieties of various amino acids are
synthesized via unique reaction of tris(trimethylsilyl) phosphite and N-formyl amino acids at the pres-
ence of effective catalyst e trimethylsilyl triflate under mild conditions. The further treatment of ami-
nomethylenediphosphonates with the methanol excess resulted in the water-soluble functionalized
aminomethylenediphosphonic acids.
Received 8 June 2018
Received in revised form
29 June 2018
Accepted 6 July 2018
Available online 7 July 2018
© 2018 Elsevier B.V. All rights reserved.
This article is dedicated to Professor
ꢀ
Armando Jose Latourrette de Oliveira
Pombeiro
Keywords:
Tris(trimethylsilyl) phosphite
N-formyl amino acids
Trimethylsilyl triflate
Functionalized
aminomethylenediphosphonic acids
1. Introduction
regulator of calcium metabolism, and some of the compounds with
similar structure are used as effective functionalized antioxidants
The functionalized organophosphorus derivatives of amino-
carboxylic acids and their corresponding peptides are the perspec-
tive organophosphorus biomimetics of natural phosphates and
amino acids. These compounds are well known structural compo-
nents of cells such as lipids and proteins. Many of these substances
including non-hydrolysable P-C bonds interfere with various
biochemical processes and possess a variety of biological activities
[1e6]. Several phosphorus containing peptides with proline moi-
eties have attached attention in the capacity of the competitive in-
hibitors of human immunodeficiency virus protease [7,8].
and cytoprotectors [9e18]. Aminomethylenediphosphonic acids as
a subclass of diphosphonic acids are good complexones and effec-
tive ligands. So the aminomethylenediphosphonates are excellent
chelators for heavy metal detoxification due to their coordination
abilities over a broad range of pH [19e25].
However, the aminomethylenediphosphonic acids containing
both P-C-P groups and moieties of amino acids are practically un-
available. Thus the search for convenient methods of synthesis of
new types of functionalized aminomethylenediphosphonic acid is
an area of active study.
Also numerous methylenediphosphonic acids and their de-
rivatives present great interest as effective polydentate ligands and
biomimetics of natural pyrophosphates with multifactor activity.
These compounds with stable P-C-P bonds possess a wide range of
biomedical applications. So zoledronic acid as the most successful
example is widely used in medicine as well known-drug e
Recently we synthesized aminomethylenediphosphonic acid
with proline moiety using tris(trimethylsilyl) phosphite [26]. It
should be noted that organosilicon synthons with highly reactive Si-
O-P groups are widely used for creating of P-C bonds and synthesis of
numerous functionalized organophosphorus compounds [27,28].
Also we developed the convenient synthetic methods for preparing
of the some aminomethylenediphosphonates via applications of
trimethylsilyl esters of trivalent phosphorus acids in organosilicon-
mediated synthesis [29e31]. Also we first showed that various
formamides reacts readily with tris(trimethylsilyl) phosphite excess
* Corresponding author.
E-mail address: aprishchenko@yandex.ru (A.A. Prishchenko).
https://doi.org/10.1016/j.jorganchem.2018.07.007
0022-328X/© 2018 Elsevier B.V. All rights reserved.

A.A. Prishchenko et al. / Journal of Organometallic Chemistry 871 (2018) 36e39
37
only in the presence of trimethylsilyl triflate as effective catalyst to
give corresponding aminomethylenediphosphonates with N-het-
erocycles moieties in high yield [26].
In this article we synthesized the new amino-
methylenediphosphonic acids with moieties of various amino acids
directly from available N-formyl amino acids which are well-known
synthons in the chemistry of amino acids [32e36].
process is realized by us as one-pot synthesis of target products 3
directly from starting N-formyl amino acids and tris(trimethylsilyl)
phosphite, but the synthesis of diphosphonates 3 was followed by
the trimethylsilylation of starting formamides 1a-f containing un-
protected carboxyl groups with the formation of intermediates e
trimethylsilyl esters 2a-f (Scheme 1).
It should be noted that some of these esters 2a,b,f were specially
obtained by us via the interaction of the starting formamides 1a,b,f
and bis(trimethylsilyl)amine, and their further reaction with tris(-
trimethylsilyl) phosphite under similar conditions also leads to
diphosphonates 3a,b,f in high yields (Scheme 2).
It is known that trimethylsilyl triflate was successfully used as a
catalyst for the activation of double bonds [26,37]. Evidently, in this
way the catalytic effect of trimethylsilyl triflate is similarly con-
nected with its ability to generate highly reactive electrophilic
carbonio-immonium ions as intermediates in the course of this
reaction (Scheme 3).
2. Results and discussion
Now we propose the convenient routes to new amino-
methylenediphosphonic acids with moieties of various amino acids
via reaction of tris(trimethylsilyl) phosphite to easily available N-
formyl derivatives of amino acids which we obtained by treatment
of amino acids with formic acid according to the usual methods
described in Refs. [32e35]. We demonstrate that this reaction
proceeds only at the presence of effective catalyst e trimethylsilyl
triflate under mild conditions to give target diphosphonates 3. This
The obtained trimethylsilyl diphosphonates
3 are easily
Scheme 1. Synthesis of aminomethylenediphosphonates 3a-f.
Scheme 2. Synthesis of aminomethylenediphosphonates 3a,b,f via specially obtained trimethylsilyl esters 2a,b,f.
Scheme 3. The possible route of formation of aminomethylenediphosphonates 3a-f.
Scheme 4. Synthesis of aminomethylenediphosphonic acids 4a-f via methanolysis of corresponding trimethylsilyl diphosphonates 3a-f.

38
A.A. Prishchenko et al. / Journal of Organometallic Chemistry 871 (2018) 36e39
converted to the corresponding acids 4. So, trimethylsilyl esters 3
readily react with methanol excess under mild conditions to form
water-soluble functionalized aminomethylenediphosphonic acids
4 as white crystals (Scheme 4).
impurity was converted to phosphorous acid and removed during
the synthesis of the corresponding acid 4a (cf. in Ref. [13]).
Diphosphonates 3b-f were prepared similarly (see supplemen-
tary data).
The structures of diphosphonic acids and their precursors 2e4
with moieties of amino acids were confirmed by the 1H, 13C, 31P
NMR spectra where the characteristic signals of corresponding
moieties were observed. The numbers of the carbon atoms used for
the description of the 1H, 13C NMR spectra for compounds 2e4 in
the experimental section are shown in the Schemes 1e4.
b. Trimethylsilyl trifluoromethanesulfonate (0.004 mol, 0.89 g),
was added with the stirring to solution of tris(trimethylsilyl)
phosphite (0.06 mol, 17.9 g) and trimethylsilyl N-formylglycinate 2a
(0.02 mol, 3.5 g) in methylene chloride (10 mL). Diphosphonate 3a
(11.5 g, yield 94%), was obtained similarly to example a.
Diphosphonates 3b,f were prepared similarly.
3. Conclusions
4.3. N-(Diphosphonomethyl)glycine 4a
Summarizing, we have confirmed convenient methods for
synthesis of new functionalized aminomethylenediphosphonic
acids and their derivatives with various amino acids moieties via
the unique reaction of tris(trimethylsilyl) phosphite with N-formyl
amino acids catalyzed by trimethylsilyl triflate. The resulting
compounds are the promising synthons for preparation of func-
tionalized organophosphorus substances with various amino acids
and peptides moieties. Also these compounds are the perspective
polydentate ligands and biologically active substances with versa-
tile properties.
Methanol (10 mL) was added to solution of diphosphonate 3a
(0.016 mol, 9.8 g) in ether (15 mL) under stirring and cooling to
10ꢀС, The mixture was kept at 20ꢀС for 12 h, then white crystals
were filtered, washed with cold ether (10 mL), and kept in vacuum
0.5 mm Hg for 0.5 h to give 4.0 g of acid 4a, yield 95%, mp 192ꢀС
2
(decomp.). 1H NMR (400 MHz, D2O),
d
, ppm: 3.33 t (С1Н, JPH
18.4 Hz), 3.75 s (С2Н2). 13C NMR (100 MHz, D2O),
d
, ppm: 47.1 s (С2),
52.8 t (С1, JPC 126.2 Hz), 168.5 s (CO). 31P NMR (D2O, 162 MHz),
d,
1
ppm: 7.4 (s). HRMS (ESI), m/z [M-H]þ, calcd 248.9764, found
248.9751. Anal. Calcd for C3H9NO8P2 (%): С, 14.47; Н, 3.64. Found: С,
14.22; Н, 3.68.
4. Experimental
Diphosphonic acids 4b-f were prepared similarly (see supple-
mentary data).
The 1H, 13C and 31P NMR spectra were registered 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). High resolution mass spectra (HRMS)
were measured on a Bruker micrOTOF II instrument using elec-
trospray ionization (ESI).
Acknowledgments
We thank the Russian Foundation for Basic Research for finan-
cial support (grant numbers 17-03-00169).
All reactions were carried out under dry argon in anhydrous
solvents. The starting tris(trimethylsilyl) phosphite was prepared as
described in Refs. [27,28]. The starting N-formyl amino acids were
prepared as described in Refs. [32e36].
Appendix A. Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.jorganchem.2018.07.007.
4.1. Trimethylsilyl N-formylglycinate 2a
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