Synthesis of N-(bisphosphonomethyl)-aza-15-Crown-5 and N- (bisphosphonomethyl)-aza-18-crown-6 ethers as artificial ion channels: An approach to channel-type molecular structures

Article abstract of DOI:10.1080/104265090969766

We report the synthesis and characterization of 2 new N- (bisphosphonomethyl)-aza-15-crown-5 1a and N-(bisphosphonomethyl)-aza-18-Crown-6 ethers 1b designed to further investigate the supramolecular assemblies based on exocyclic functional groups of crown ethers. Copyright Taylor & Francis LLC.

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Synthesis of N-
(bisphosphonomethyl)-
aza-15-Crown-5 and N-
(bisphosphonomethyl)-aza-18-
Crown-6 Ethers as Artificial
Ion Channels: An Approach
to Channel-Type Molecular
Structures
F. Fallouh a , D. Bernier b , D. Virieux b , H. J.
Cristau b & J. L. Pirat b
a Département de Chimie , Université de Damas ,
Syrie
b Laboratoire de Chimie Organique , France
Published online: 01 Feb 2007.
To cite this article: F. Fallouh , D. Bernier , D. Virieux , H. J. Cristau & J.
L. Pirat (2006) Synthesis of N-(bisphosphonomethyl)-aza-15-Crown-5 and N-
(bisphosphonomethyl)-aza-18-Crown-6 Ethers as Artificial Ion Channels: An Approach
to Channel-Type Molecular Structures, Phosphorus, Sulfur, and Silicon and the Related
Elements, 181:1, 219-225, DOI: 10.1080/104265090969766
To link to this article: http://dx.doi.org/10.1080/104265090969766
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Phosphorus, Sulfur, and Silicon, 181:219–225, 2006
Copyright © Taylor & Francis LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090969766
Synthesis of N-(bisphosphonomethyl)-aza-15-Crown-5
and N-(bisphosphonomethyl)-aza-18-Crown-6 Ethers
as Artificial Ion Channels: An Approach to Channel-Type
Molecular Structures
F. Fallouh
De´partement de Chimie, Universite´ de Damas, Syrie
D. Bernier
D. Virieux
H. J. Cristau
J. L. Pirat
Laboratoire de Chimie Organique, France
We report the synthesis and characterization of 2 new N-(bisphosphonomethyl)-aza-
15-crown-5 1a and N-(bisphosphonomethyl)-aza-18-Crown-6 ethers 1b designed to
further investigate the supramolecular assemblies based on exocyclic functional
groups of crown ethers.
Keywords Aza-18-Crown-6 ether; aza-15-Crown-5 ether; gem-bisphosphonates;
supramolecular assemblies
INTRODUCTION
The integration of macrocyclic ligands as aza-15-crown-5 or aza-18-
crown-6 ether substituents into a gem-bisphosphonic structure should
leads to a new class of compounds with a wide range of potential ap-
plications: osteoporosis and Paget disease treatment, extraction and
separation of isotopes, and complexing agents of actinides.1,2,3
Clearfield et al.4 described the synthesis of supramolecular assem-
blies based on exocyclic functional groups of crown ethers resulting in
unprecedented branched structures.
Received December 23, 2004; in final form February 1, 2005.
We are very grateful to Professor H. GROβ, who drawed our attention to the potential
interest of structures such as 1.
Address correspondence to H. J. Cristau, Laboratoire de Chimie Organique, UMR
5076 du CNRS, 8, Rue de l’Ecole Normale, 34 296 Montpellier Cedex, France. E-mail:
pirat@cit.enscm.fr
219

220
F. Fallouh et al.
FIGURE 1
The main goal of this study is to synthesise new structures as 1
to afterwards investigate the supramolecular assemblies based on exo-
cyclic functional groups of crown ethers with better chelating properties
than Clearfield structures owing to the bisphosphonic ligand and the
variation of the length between the nitrogen atom and the methylene
bisphosphonic group.
In this article, we report the first synthesis of 1,1-bis(diethylphos-
phono)-1-(4ꢀ,7ꢀ,10ꢀ,13ꢀ-tetraoxa-1ꢀ-azacyclopentadec-1ꢀ-yl)methane 1a
and the 1,1-bis(diethylphosphono)-1-(4ꢀ,7ꢀ,10ꢀ,13ꢀ,16ꢀ-pentaoxa-1ꢀ-aza-
cyclooctadec-1ꢀ-yl) methane 1b (Figure 1).
RESULTS AND DISCUSSION
Synthesis of Crown Ethers
The first step is the preparation of 1-aza-[15-5]-crown ether 2a
and 1-aza-[18-6]-crown ether 2b (Scheme 1). The tosylation of the
tri- or tetraethylene glycol was performed in good yield (>90%)
using p-toluenesulfonylchloride in THF and a solution of KOH in
water.5
The monoaza-[15-5]- and [18-6]-crown ethers 2a and 2b then
were obtained in moderated yields (25–50%) using the one-step
synthesis described by Maeda and colleagues6 by the treatment
of di(2-hydroxyethyl)amine with the corresponding tosylates in
tBuONa/tBuOH.

An Approach to Channel-Type Molecular Structures
221
SCHEME 1 Preparation of 1-aza-[15-5]-crown ether 2a and 1-aza-[18-6]-
crown ether 2b.5,6
Synthesis of Substituted Crown Ether Gem-bisphosphonates
The crown ether-substituted methane-gem-bisphosphonic esters 1a
and 1b were synthesized starting from crown ethers, triethylo-
rthoformate, and diethyl phosphite. The reaction, performed at 140–
160◦C, in closed Wheaton tubes (5 mL) under dry nitrogen atmosphere,
without solvent, allowed, in one step, to get the crown ether-substituted
methane-gem-bisphosphonic esters 1a and 1b (Scheme 2). Purifications
were achieved by chromatography on alumina to give the compounds
with 40–49% yields.
SCHEME 2 Synthesis of crown ethers-subtituted gem-bisphosphonates 1a
and 1b.
In summary, we described in this article the first synthesis of crown
ether-substituted gem-bisphosphonic ethyl esters. The synthesis of
crown ether-subtituted homologs 1, with a variation of the length be-
tween the nitrogen atom and the bisphosphonic groups, as well as the
investigations of the supramolecular assemblies of these structures are
in progress.

222
F. Fallouh et al.
EXPERIMENTAL PART
All reactions involving air- or moisture-sensitive reagents or interme-
diates were carried out under dry nitrogen in flame-dried glassware.
Reagents and solvents were distilled before use and stored under ni-
trogen over sodium wires (THF) or molecular sieves (dichloromethane).
All reactions were monitored by 31P NMR. NMR spectra were recorded
on BRUKER AC 200, or 250 (1H frequency: 200.13 or 250.13 MHz; 13
C
frequency: 50.32 or 62.89 MHz, 31P frequency: 81.02 or 101.25 MHz, re-
spectively). Chemical shifts are given in δ units with respect to TMS (1H,
13C NMR) or H3PO4 85% (31P), and coupling constants are expressed
in Hz.
Triethylene Glycol Di(toluene-p-sulphonate)
In a 250-mL flask containing 100 mL of THF, were added p-
toluenesulfonylchloride (42.0 g, 220 mmol) (recrystallized in pentane)
and triethylene glycol (11.0 g, 73.2 mmol). A solution of KOH (26.2 g
in 25 mL of water, 467 mmol) is added. The addition was performed
for 3 h at 0◦C. After this addition, the mixture was allowed to stand to
ambient temperature for 7 h. Then the reaction is poured into 150 mL
of a mixture of ice/CH2Cl2 (70/30). The water phase was extracted 3
times with 50 mL of CH2Cl2. The organic phases, dried over MgSO4
and evaporated under vacuum, gave 31.3 g (68.3 mmol) of a yellow oil
(yield = 93%).
1H NMR (CDCl3, 200 MHz): δ = 7.74 (d, J = 8.2, 4H, Har), 7.30
(d, J = 8.2, 4H, Har), 4.10 (t, J = 4.7, 4H, TsO-CH ), 3.61 (t, J =
2
4.7, 4H, TsO-CH2 CH –), 3.48 (s, 8H, O CH CH O), 2.40 (s, 6H,
2
2
2
CH ) 13C NMR (CDCl3, 50 MHz): δ = 144.9 (Car), 129.8 (Car), 70.6 (TsO-
3
CH2 CH2 O ), 69.3 (O CH2 CH2-O-), 68.7 (TsO-CH2 CH2-O-).
Tetraethylene Glycol Di(toluene-p-sulphonate)
In a 250-mL flask containing 100 mL of THF, p-toluenesulfonicchloride
(41.4 g, 217 mmol) (recrystallized in pentane) and tetraethylene glycol
(14.1 g, 72.6 mmol) were added. Then is added a to solution of KOH
(26.2 g in 25 mL of water, 467 mmol). The addition was performed for
3 h at 0◦C. After this addition, the mixture was allowed to stand to am-
bient temperature for 7 h. Then the reaction is poured into 150 mL of a
mixture of ice/CH2Cl2 (70/30). The water phase was extracted 3 times
with 50 mL of CH2Cl2. The organic phases, dried over MgSO4 and evap-
orated under vacuum, gave 35 g of a yellow oil (yield = 96%).
1H NMR (CDCl3, 200 MHz): δ = 7.74 (d, J = 8.2, 4H, Har), 7.29 (d,
J = 8.2, 4H, Har), 4.11 (t, J = 4.7, 4H, TsO-CH ), 3.63 (t, J = 4.7, 4H,
2

An Approach to Channel-Type Molecular Structures
223
TsO CH2 CH ), 3.51 (s, 8H, O CH CH O), 2.40 (s, 6H, CH ) 13
C
2
2
2
3
NMR (CDCl3, 50 MHz): δ = 144.8 (Car), 132.9 (Car), 129.8 (CHar), 127.9
(CHar), 70.7 (TsO CH2 CH2 O ), 70.5 and 69.3 (O CH2 CH2 O-),
68.6 (TsO CH2 CH2 O ).
1-Aza [15-5] Crown ether 2a
At room temperature, in a 2-L flask, containing sodium terbutoxide
(prepared by a 12-h reaction of Na [8.8 g, 383 mmol] in 1.5 L of tBuOH,
at 50◦C), were added drop by drop, simultaneously, triethylene glycol
di(toluene-p-sulphonate) (32 g, 69.8 mmol) in 100 mL of dioxane and
diethanolamine (8.10 g, 77.0 mmol) in 100 mL of tBuOH.
After the addition, the reaction was continued for 3 h at 40◦C. Then
the reaction mixture was filtered and the solvent was evaporated. Wa-
ter (80 mL) was added to the residue and the solution was extracted
once with hexane to remove hexane-soluble materials and then was
extracted several times with dichloromethane. The dichloromethane
extracts were combined, the solvent was evapored, and the residue was
distilled (kugelrohr) to give a colorless liquid (4.55 g, Yield = 25%).
1H NMR (CDCl3, 200 MHz): δ = 3.38 and 3.49 (m, 16H, OCH ), 2.86
2
(bs, 1H, NH), 2.58 (m, 4H, NCH ).
2
13C NMR (CDCl3, 50 MHz): δ = 70.1, 69.8, 69.7 (OCH2), 48.8 (NCH2).
1-Aza [18-6] Crown ether 2b
At room temperature, in a 2-L flask containing tBuOK (30.7
g, 274 mmol) in 1.5-L of tBuOH, triethylene glycol di(toluene-p-
sulphonate) (46 g, 91.5 mmol) are added simultaneously, drop by drop,
in 100 mL of dioxanne and diethanolamine (9.6 g, 91.3 mmol) in 100
mL of tBuOH.
After the addition, the reaction was continued for 1 h at 40◦C. Then
the reaction mixture was filtered and the solvent was evaporated. Water
(30 mL) was added to the residue and the solution was extracted once
with hexane to remove hexane-soluble materials and then it was ex-
tracted several times with dichloromethane. The dichloromethane ex-
tracts were combined, the solvent was evapored off, and the residue was
distilled (kugelrohr) to give a white solid (5.86 g, Yield = 24%). m.p. =
48◦C.
1H NMR (CDCl3, 200 MHz): δ = 3.61 (m, 20H, OCH ), 2.78 (m, 4H,
2
NCH ), 1.14 (s, 1H, NH)
2
13C NMR (CDCl3, 50 MHz): δ = 70.7, 70.5, 70.4, 70.2 (OCH2), 49.1
(NCH2).

224
F. Fallouh et al.
1,1-Bis(diethylphosphono)-(4ꢀ,7ꢀ,10ꢀ,13ꢀ-tetraoxa-1ꢀ-
azacyclopentadec-1ꢀ-yl)methane 1a
General Procedure
Under dry nitrogen atmosphere, in a closed Wheaton tube (5 mL),
without solvent, 1-aza [15-5] crown ether (0.50 g, 2.28 mmol), tri-
ethylorthoformate (0.60 mL, 0.53 g, 3.61 mmol) and diethyl phosphite
(0.56 mL, 0.60 g, 4.35 mmol) were added. The reaction mixture was
heated at 150–160◦C for 2–3 h.
Then, triethylorthoformate was evapored under vaccum at
90◦C. Purification was achieved by chromatography on alumina
(CH3CN/CH2Cl2: 0/100 → 40/60) to give 0.46 g a yellow oil (0.91 mmol,
Yield = 25%).
31P (DMSO-d6), 101 MHz): δ = 20.3.
1H NMR (CDCl3, 200 MHz): δ = 4.17 (m, 8H, OCH CH3), 3.58 (m,
2
3
2
16H, OCH ), 3.38 (t, 1H, JPH = 25.2, PCHP), 3.09 (t, JHH = 6.1, 4H,
2
OCH2CH N), 1.28 (t, 3JHH = 7.03, 12H, OCH2CH3).
2
13C NMR (CDCl3, 50 MHz): δ = 71.1, 70.9, 70.4, 70.0 (OCH2
1
crown ether), 62.8 and 62.2 (OCH2CH3), 60.8 (PCHP, t, JCP
=
140), 55.5 (OCH2CH2N), 16.3 (OCH2CH3). HRMS(FAB+): calcd for
C19H42NO10P2: 506.2284. Found: 506.2304.
1,1-Bis(diethylphosphono)-(4ꢀ,7ꢀ,10ꢀ,13ꢀ,16ꢀ-pentaoxa-1ꢀ-
azacyclooctadec-1ꢀ-yl)methane 1b
Under dry nitrogen atmosphere, in a closed Wheaton tube (5 mL), with-
out solvent, 1-aza [18-6] crown ether (0.44 g, 1.67 mmol), triethylortho-
formate (0.50 mL, 0.45 g, 3.01 mmol) and diethyl phosphite (0.41 mL,
0.44 g, 3.18 mmol) were added. The reaction mixture was heated at
150–160◦C for 2–3 h.
Then, triethylorthoformate was evapored under vaccum at
90◦C. Purification was achieved by chromatography on alumina
(CH3CN/CH2Cl2: 0/100 → 40/60) to give 0.45 g of yellow oil (0.82 mmol,
Yield = 49%).
31P (DMSO-d6, 101 MHz): δ = 20.4.
1H NMR (CDCl3, 200 MHz): δ = 4.04 (m, 8H, OCH CH3), 3.48 (m,
2
3
2
20H, OCH ), 3.41 (t, 1H, JPH = 24.8, PCHP), 2.97 (t, JHH = 5.8, 4H,
2
OCH2CH N), δ = 1.18 (t, 3JHH = 6.0 Hz, 12H, OCH2CH ).
2
3
13C NMR (CDCl3, 50 MHz): δ = 71.7, 70.8, 70.5, 70.4, 69.7 (OCH2
1
crown ether), 62.8 and 62.2 (OCH2CH3), 61.8 (PCHP, t, JCP
=
142), 54.2 (OCH2CH2N), 16.3 (OCH2CH3). HRMS(FAB+): calcd for
C21H46NO11P2: 550.2546. Found: 550.2567.

An Approach to Channel-Type Molecular Structures
225
REFERENCES
[1] H.-J. Cristau, D. Virieux, P. Mouchet, and A. Fruchier, Eur. J. Org. Chem., 7, 1561
(1999).
[2] H. J. Cristau, D. Virieux, J. F. Dozol, and H. Rouquette, J. Radioanalytical Nuclear
Chem., 241, 543 (1999).
[3] H. Fleisch, Medicina, 57, 65 (1997).
[4] C. V. K. Sharma and A. Clearfield, J. Am. Chem. Soc., 122, 1558 (2000).
[5] Y. Chen and G. L. Baker, J. Org. Chem., 64, 6870 (1999).
[6] H. Maeda, Y. Nakatsuji, and M. Okahara, J. Chem. Soc., Chem. Commun., 10, 471
(1981).