Synthesis of novel aminomethylenebisphosphonates and bisphosphonic acids, containing adamantyl fragment

Article abstract of DOI:10.1002/hc.20656

Novel aminomethylenebisphosphonates containing an adamantyl fragment were synthesized by a solvent-free, microwave-assisted, threecomponent reaction of amines, triethyl orthoformate, and O,O-diethyl phosphite. Several bisphophonic acids were prepared from

Full text of DOI:10.1002/hc.20656

Heteroatom Chemistry
Volume 22, Number 1, 2011
Synthesis of Novel
Aminomethylenebisphosphonates and
Bisphosphonic Acids, Containing Adamantyl
Fragment
Lidiya I. Minaeva,1 Ludmila S. Patrikeeva,1 Maria M. Kabachnik,1
Irina P. Beletskaya,1 Boris S. Orlinson,2 and Ivan A. Novakov2
1Department of Chemistry, M. V. Lomonosov Moscow State University, Moscow 119992, Russia
2Volgograd State Technical University, Volgograd 400131, Russia
Received 29 June 2010; revised 7 October 2010
been found to exhibit antibacterial [7,8], anticancer
ABSTRACT: Novel aminomethylenebisphospho-
[9], antiviral [10], herbicide [11], pesticide [12], and
nates containing an adamantyl fragment were syn-
many other activities [13,14]. A subclass of bispho-
thesized by a solvent-free, microwave-assisted, three-
sphonates, derivatives of aminomethylenebisphos-
component reaction of amines, triethyl orthoformate,
phonic acids, is practically used as medicine in the
and O,O-diethyl phosphite. Several bisphophonic
osteoporosis treatment [15,16], some of them are
acids were prepared from aminomethylenebisphos-
biologically tested as estradiol complexes for drug
phonates by the treatment with trimethylsilyl bromide
delivery purposes [17]. At the same time, it is well
ꢀ
C
followed by methanolysis.
2010 Wiley Periodicals,
known that different adamantane-containing com-
pounds were shown to have anti-influenza [18,19]
and anti-HIV activity [20,21] and activity against
epilepsy [22]. To our knowledge, only several exam-
ples of aminomethylenebisphosphonates containing
adamantyl fragment have yet been described in the
literature [10,23].
Inc. Heteroatom Chem 22:55–58, 2011; View this article
online at wileyonlinelibrary.com. DOI 10.1002/hc.20656
INTRODUCTION
Bisphosphonic acids and bisphosphonates are hy-
drolytically stable analogues of pyrophosphate in
which common P O P bonds are replaced by
the P C P fragments [1]. For over two decades,
these compounds have been employed as thera-
peutic agents for a treatment of bone disorders—
hypocalcaemia and osteoporosis [2–6]. Despite this,
in the course of investigation bisphosphonates have
RESULTS AND DISCUSSION
The simplest and most convenient procedure
for the preparation of aminomethylenebisphos-
phonates and bisphosphonic acids based on the
three-component reaction between a primary or a
secondary amine, triethyl orthoformate, and O, O-
diethyl phosphite, followed by acidic hydrolysis
[24–27].
In the present study, the three-component re-
action between aminoadamantanes 1a–d, triethyl
orthoformate, and O, O-diethyl phosphite was used
to obtain novel aminomethylenebisphosphonates
Correspondence to: Lidiya I. Minaeva; e-mail: lidusik7@yandex
.ru.
Contract grant sponsor: Russian Foundation of Basic Research.
Contract grant number: 08-03-00178.
2010 Wiley Periodicals, Inc.
c
ꢀ
55

56 Minaeva et al.
and aminomethylenebisphosphonic acids, contain-
ing a biologically active adamantyl fragment. The
reaction was carried out under microwave irradia-
tion (400 W, 150◦C) under solvent-free conditions
without added catalyst during 25–45 min (Eq. (1)).
Aminomethylenebisphosphonates 2a–d were iso-
lated in good yields (62–90%) by column chromatog-
raphy on silica gel. It should be emphasized that a
common process carried out under heating condi-
tions (150◦C, 4–5 h) resulted in the reduced product
yields due to thermal instability of the imine-type
intermediate forming in the process [28].
thoformate and O, O-diethyl phosphite was used to
give bisphosphonate 4 in high yield (Eq. (2)). The
structure and composition of compound 4 were con-
1
firmed by the H and 13C NMR spectra and elemen-
tal analysis data (Tables 1 and 2). When the reaction
was performed with equimolar amounts of amine 3,
triethyl orthoformate, and O, O-diethyl phosphite,
only the formation of compound 4 was noted. No
phosphorylation at a single amino group was found.
P(O)(OEt)2
NH2
2(EtO)3CH
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
N
H
+
MW
+
H
R
NH2
4(EtO)2P(O)H
NH2
R
N
P(O)(OEt)2
P(O)(OEt)2
(2)
MW
N
(EtO)3CH
H
+
3
4
2(EtO)2P(O)H
To obtain aminomethylenebisphosphonic acids
5a,b,d, the well-known procedure for alkoxy groups
removal from phosphorus esters was used [30,31].
The method is based on the interaction be-
tween aminomethylenebisphopsonates 2a,b,d and
trimethylsilyl bromide followed by the treatment
with methanol and propylene oxide at room tem-
perature (Eq. (3)). The yields of corresponding acids
5a,b,d were found to be 85–95%. In the 31P NMR
spectra, compounds’ 5a,b,d exhibit chemical shifts
in the 10.8–13.2 ppm region (Table 1).
1
2
R= H (2a), Ph (2b)
(1)
R
R
P(O)(OEt)2
A
NH2
A
N
P(O)(OEt)2
H
MW
(EtO)3CH
+
2(EtO)2P(O)H
1
2
R
P(O)(OEt)2
R
P(O)(OH)2
P(O)(OH)2
A= OCH2 (2c), CH2 (2d)
R= H (2c), Me (2d)
(CH2)n
N
P(O)(OEt)2
(CH2)n
N
H
H
1. TMSBr, CH2Cl2, 40oC
Aminomethylenebisphosphonates 2a–d were ade-
2. MeOH, r.t.
3. propylene oxide
1
quately characterized by means of H, 13C, and 31P
NMR spectroscopy and elemental analysis. In the
1H NMR spectra, chemical shifts of CHP fragments
were in 3.09–3.33 ppm area and were shown to
2
5
n= 0 (2a), 0 (2b), 1 (2d)
R= H (2a), Ph (2b), Me (2d)
2
be triplets with JPH = 21–25 Hz. These data are
in accordance with the data reported for the usual
aminomethylenebisphosphonates [28,29] (Table 1).
In 13C NMR spectra, carbon atoms connected with
In summary, we synthesized the new class of amin-
omethylenebisphosphonates containing adamantyl
fragment in a three-component reaction under mi-
crowave irradiation and in solvent-free conditions.
The corresponding aminomethylenebisphosphonic
acids were obtained by the established protecting
group removal method.
1
two P-atoms are triplets with JPC = 142–146 Hz
in the 51.17–58.26 ppm area (Table 1). 31P NMR
spectra of bisphosphonates 2b and 2d were found
to show two phosphorus signals of the AB type
with P P chemical coupling constant equal to 41.0–
42.1 Hz (Table 1). Apparently, the presence of the
bulky methylenebisphosphonate fragment slows ro-
tation around a C N bond, this leads to nonequiva-
lence of the two phosphorus atoms (each atom is in
different chemical environment) and the formation
of two conformers in solution.
EXPERIMENTAL
All reactions were carried out under microwave ir-
radiation at 400 W using a domestic oven (Dae-
woo, KOR-4125G). H, 13C, and 31P NMR spectra
1
In reaction with amine 3, containing 2 equiv
amino groups, a double excess of the triethyl or-
were recorded at room temperature on a Bruker
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Novel Aminomethylenebisphosphonates and Bisphosphonic Acids, Containing Adamantyl Fragment 57
TABLE 1 Reaction Time, Yields, and NMR Spectral Data for the PC1H(NC2)P Fragments (δ, ppm; J, Hz) of Compounds 2, 4,
and 5a
Compound
Reaction Time (min)
Yield (%)
δ(H) C1H t
2JPH
δ(C1)t
1JPC
δ(C2) s
δ
P
2a
2b
2c
2d
4
5a
5b
5d
35
45
25
28
30
3 h
3 h
3 h
73
62
90
88
67
85
92
95
3.15
3.09
3.33
3.30
3.18
2.99
2.94
3.08
21.7
21.9
21.5
22.2
21.6
18.4
18.9
19.1
55.47
58.26
54.43
51.17
53.22
–
143.9
154.2
146.6
146.1
147.1
–
52.70
54.13
50.52
52.49
51.55
–
19.4
20.04b
19.7
20.0b
18.9
10.8
10.9
13.2
–
–
–
–
–
–
aAll signals of alkyl, adamantyl, and ethoxy groups are in the standard areas. In the 1H NMR spectra, the CH3 fragment for compounds: 2a,
3
3
3
3
3
1.31 t, JHH 4.8; 2b, 1.27 t, JHH 6.1; 2c, 1.29 t, JHH 7.1; 2d, 1.31 t, JHH 4.8; 4, 1.20 t, JHH 6.0; the POCH2 fragment for compounds: 2a,
3
4.18 m; 2b, 4.13 m; 2c, 3.44 m; 2d, 4.17 m; 4, 4.07 m; the NCH2 fragment for compounds: 2a, 2.45 s; 2c, 2.91 t, JHH 5.1; the NCH(Ph)
3
fragment for compound: 2b, 2.81 s; the NCHC fragment for compound 2d, 2.34 m; the NCH2C fragment for compound 4, 2.73 t, JHH 5.5;
the COCH2 fragment for compound 2c, 3.44 t, JHH 5.1; the CCH2C fragment for compound 4, 1.25 t, JHH 5.5. In the 13C NMR spectra,
the adamantyl fragment for compounds: 2a, 28.33, 33.67, 37.12, 40.44; 2b, 28.06, 36.35, 38.54, 40.15; 2c, 30.41, 36.42, 41.50, 71.88; 2d,
28.62, 32.23, 37.00, 42.85; 4, 28.94, 32.47, 36.50, 42.10; the CH3 fragment for compounds: 2a, 16.42; 2b, 16.50; 2c, 16.43; 2d, 16.30; 4,
16.35; fragment POCH2 for compounds: 2a, 62.70; 2b, 73.53; 2c, 62.81; 2d, 62.80; 4, 61.75; the NCH2 fragment for compound 2a, 62.70; the
NCH(Ph) fragment for compound: 2b, 65.22; the COCH2 fragment for compound 2c, 76.81; the CCH2C fragment for compound 4, 44.52; the
NCHC fragment for compound 2d, 52.49.
3
3
bAB system2JPP for compounds: 2b, 42.1; 2d, 41.4.
DPX-400 spectrometer (400.13, 100.61, and 161.98
MHz, respectively) in CDCl3 or D2O against TMS (1H
and 13C) and 85% H3PO4 in D2O (31P). Analytical thin
layer chromatography (TLC) was carried out with
“Silufol” silica gel plates (supported on aluminum);
The revelation was done by chemical staining (iodine
vapor). Column chromatography was performed us-
ing silica gel 60 (230–400 mesh, Merk). All reagents,
except commercial products of satisfactory qual-
ity were purified with literature procedures prior
to use.
O,O,O,O-Tetraethyl Adamantylmethylaminom-
ethylenebisphosphonate (2a). A mixture of 1.65 g
of adamantylmethylamine 1a, 2.23 g of triethyl
orthoformate, and 5.52 g of O, O-diethyl phos-
phite in a 20-mL flask was exposed to microwave
irradiation for 35 min. The aminomethylenebispho-
sphonate 2a was purified by chromatography on
silica gel (CHCl3–MeOH 50:1) to give 3.29 g of the
product.
The compounds 2b–d were prepared similarly.
Octaethyl [Adamantane-1,3-diylbis(ethane-2,1-
diylimino)]bis (methylenebisphosphonate) (4).
A
mixture of 1.23 g of adamantane-1,3-diylbis(ethane-
2,1-dyilamine) 3, 4.46 g of triethyl orthoformate, and
11.04 g of O, O-diethyl phosphite in a 50-mL flask
was exposed to microwave irradiation for 30 min.
The aminomethylenebisphosphonate 4 was purified
by chromatography on silica gel (CHCl3–MeOH
50:1) to give 5.31 g of the product.
N-Methylaminomethylenedisphosphonic
(5a). To a stirred solution of 2.25 g of O,O,
O,O-tetraethyl adamantylmethylaminomethyle-
Acid
nebisphosphonate 2a in 20 mL of methylene chlo-
ride, a solution of 3.8 g of trimethylsilyl bromide
in 5 mL of methylene chloride was added dropwise
TABLE 2 Elemental Analyses Data of Synthesized Compounds
Calcd. (%)
Found (%)
Compound
Empirical Formula
Formula Weight
C
H
C
H
2a
2b
2c
2d
4
5a
5b
5d
C20H39NO6P2
C26H43NO6P2
C21H41NO7P2
C22H43NO6P2
C32H66N2O12P4
C14H29NO6P2
C20H33NO6P2
C16H33NO6P2
451.47
527.57
481.50
479.52
794.76
369.33
445.42
397.39
53.21
59.19
52.38
55.10
48.36
45.43
53.93
48.36
8.71
8.22
8.58
9.04
8.37
7.91
7.47
8.37
53.16
59.10
52.31
55.09
48.31
45.39
53.88
48.33
8.72
8.16
8.57
9.13
8.35
7.88
7.45
8.34
Heteroatom Chemistry DOI 10.1002/hc

58 Minaeva et al.
at 0◦C. Then the reaction mixture was heated up
to 40◦C for 3 h. The solvent was removed at 20◦C,
and 10 mL of propylene oxide was added. Acid
5a precipitated as white crystals to give 1.44 g of
product.
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Heteroatom Chemistry DOI 10.1002/hc