Synthesis of functionalized bisphosphonates via click chemistry

Article abstract of DOI:10.1039/b705510b

An efficient general synthetic approach giving the possibility for facile, rapid and cheap access to a wide range of novel nitrogen-bisphosphonates (N-BPs) as potent drug candidates, based on the reaction of mono- and bis-propargyl-substituted bisphosphon

Full text of DOI:10.1039/b705510b

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of functionalized bisphosphonates via click chemistry
Hanna Skarpos,b Sergey N. Osipov,*a Daria V. Vorob’eva,a Irina L. Odinets,a Enno Lorkb and
Gerd-Volker Ro¨schenthaler*b
Received 3rd April 2007, Accepted 31st May 2007
First published as an Advance Article on the web 21st June 2007
DOI: 10.1039/b705510b
An efficient general synthetic approach giving the possibility for facile, rapid and cheap access to a wide
range of novel nitrogen-bisphosphonates (N-BPs) as potent drug candidates, based on the reaction of
mono- and bis-propargyl-substituted bisphosphonates with a variety of azides under Cu(I) catalysis
(“click” methodology), has been developed. The method allows the incorporation of two functionalities
into the N-BP molecule simultaneously, as well as to ligate in situ two N-BPs to one another via the
one-pot reaction of organic dibromides with propargyl-substituted bisphosphonates, generating both
the diazide and Cu(I) moieties.
geminal hydroxy group does not influence the ability of N-BPs
1. Introduction
to act at the cellular level, and (5) the introduction of lipophilic
groups into the N-BP backbone can significantly improve their
pharmacokinetics, increasing their availability in soft tissues.
Therefore, the purposeful synthesis of new members of the N-
BP family is of current interest for further development of more
potent drugs.
Bisphosphonates (BPs), being analogs of naturally occurring
diphosphates, are powerful inhibitors of bone resorption, and
some of them are currently clinically applied to treat malignant
hypercalcemia.1 For this reason, their main therapeutic uses are
in diseases connected with calcium disorders, such as Paget’s
disease, osteoporosis and bone tumoral metastasis.2 BPs are also
of interest in the context of cancer and immunotherapy, as they
possess potent effects against the parasites responsible for sleeping
sickness, Chagas’ disease, malaria and leishmaniasis.3
To date, most of the highly potent third-generation BP drugs
contain an additional moiety in the molecule, namely a nitrogen
heterocycle,4 as in risedronate and zoledronate (Fig. 1). These
cyclic nitrogen bisphosphonates (N-BPs) are up to 10 000-fold
more active1b than, for example, etidronate—the first BP used
for treating humans. These drugs act by directly and selectively
inhibiting the activity of osteoclasts, cells responsible for bone
resorption. The detailed inhibitory mechanism of N-BPs is well
documented in the literature.5,6
Modern drug discovery requires the identification and the op-
timization of synthetic routes to specifically acting low molecular
weight molecules. That is why simple methods that can quickly and
easily generate large libraries of compounds have become more
and more used.7 The “click” methodology recently introduced
by Sharpless et al.8 is one of these methods based on reactions
which are of wide scope, give high yields, and use highly energetic
reactants to form irreversible carbon–heteroatom bonds. The
Huisgen 1,3-dipolar cycloaddition9 perfectly illustrates this kind of
reaction. It consists of the ligation of azides and terminal alkynes
to give triazoles. As has been recently shown,10 under copper(I)
catalysis, the rate of this coupling event is dramatically accelerated
and only the corresponding 1,4-disubstituted regioisomer is ob-
tained. At the same time, 1,2,3-triazoles are versatile compounds,
which have been applied for a variety of purposes, including
as anticorrosive agents, dyes, agrochemicals and photographic
materials.11 Although the 1,2,3-triazole structural moiety does not
occur in nature, it features in diverse biologically active substances,
displaying anti-HIV and antimicrobial behavior as a selective b3-
adrenergic receptor agonist.12
Recently we have developed a simple method for the prepara-
tion of functionalized a-trifluoromethyl-substituted histidine aza
analogs via Cu(I)-catalyzed 1,3-dipolar Huisgen cycloaddition be-
tween a-propargyl-a-trifluoromethyl-a-amino esters and organic
azides.13 In this paper we disclose an efficient general approach
opening up the possibility for facile, rapid and cheap synthesis of
a wide range of novel N-BPs (e.g. aza-analogs of zoledronate—
the most potent drug to date among bisphosphonates1b) as potent
drug candidates based on “click” methodology.
Fig. 1
The results obtained to date regarding the inhibitory potency of
N-BPs indicate that: (1) the presence of two geminal phosphonate
groups is responsible for interaction with the molecular target,
(2) the presence of a basic nitrogen in the heterocyclic side
chain affects potency, (3) the 3-dimensional orientation of this
basic nitrogen atom is critical for effective inhibition, (4) the
aA. N. Nesmeyanov Institute of Organoelement Compounds, Russian
Academy of Sciences, 28 Vavilova, 119991, Moscow, Russia. E-mail:
osipov@ineos.ac.ru
2. Results and discussion
bInstitute for Inorganic & Physical Chemistry, University of Bremen,
Leobener Strasse., D-28334, Bremen, Germany. E-mail: gvr@chemie.uni-
bremen.de
Despite the synthesis of propargyl-substituted bisphosphonate 2
based on the alkylation of methylene bisphosphonate by propargyl
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bromide (with deprotonation by NaH) being reported in the
literature,14 in our experience this reaction is accompanied by sub-
stantial double alkylation (up to 35% of 3). Moreover, separation
of mono- and dipropargyl-substituted bisphosphonates 2 and 3
using column chromatography is not effective due to the similar Rf
values of these compounds. Therefore, we developed an alternative
method for the preparation of 2, which comprises selective
addition of sodium acetylenide to ethylidene bisphosphonate 4.
This reaction gives excellent results even on a multi-gram scale
(Scheme 1). After ordinary work-up the product 2 obtained in
92% yield does not require additional purification and can be used
directly in further transformations.
It should be noted that alkylation of methylene bisphosphonate
1 by 2 equivalents of propargyl bromide using deprotonation with
NaH in THF is a facile route to disubstituted bisphosphonate 3,
as described by Choi et al.15
Thus, having in hand the mono- and dipropargyl-substituted
bisphosphonates 2 and 3, we investigated the possibility of their ap-
plication in cycloadditions with a variety of azide-functionalized
substrates. To the best of our knowledge, the alkene–azide type of
1,3-dipolar addition has not yet been applied in bisphosphonate
chemistry.
Scheme 2
The structure of bisphosphonate 6 was confirmed by X-ray
data (Fig. 2). Molecules in the crystal have an approximately
C2 symmetry (a two-fold axis passes through the C9 atom). The
principal geometrical parameters of 6 are within the range of
standard values.
In the standard procedure for regioselective Cu(I)-catalyzed
alkyne–azide coupling, the catalyst can be directly introduced as a
Cu(I) salt or generated in situ by reduction of Cu(II) salts,16 usually
in organic–aqueous systems. For the synthesis of the N-BPs 5
from propargyl-substituted bisphosphonate 2, we have applied
both of the above-mentioned procedures, namely: A) use of CuI as
a catalyst in an organic solvent (THF) in the presence of an organic
base (DIPEA); and B) generation of Cu(I) in situ from CuSO4 and
sodium ascorbate in a water–alcohol medium (Table 1).
1,3-Dipolar Huisgen cycloaddition of propargyl-containing
bisphosphonate 2 with various azides was found to proceed
smoothly at room temperature to afford functionalized 1,2,3-
triazoles 5a–f in high yields after 68 h. Even highly functionalised
azides (Table 1, entries 5 and 6) are good partners for propargyl-
bisphosphonate 2 in these copper-catalyzed reactions. In spite of
the fact that both methods give good-to-excellent results, method
B is preferable due to a simpler isolation procedure (in the majority
of cases column chromatography was not required).
Fig. 2 A general view of 6, representing atoms by thermal ellipsoids
˚
(p = 50%). The disorder is omitted for clarity. Selected bond lengths (A):
P1–C9 1.837(4), P2–C9 1.837(4), P1–O1 1.458(3), P2–O4 1.456(3), C9–C10
1.572(5), C9–C20 1.571(5), C10–C11 1.503(5), C20–C21 1.500(5); bond
angles (◦): P1–C9–P2 109.7(2), P1–C9–C10 108.1(3), P1–C9–C20 109.3(3),
P2–C9–C20 107.7(3), P2–C9–C10 109.7(2), C10–C9–C20 112.8(3).
In a similar manner, Huisgen copper-catalyzed 1,3-dipolar
cycloaddition of bisphosphonate 3 with azides was accomplished
using method B (being more preferable in terms of purification)
to afford the corresponding bistriazols 6 and 7 in a good yield
(Scheme 2).
It should be noted that such a 1,3-cycloaddition can also be
performed as a one-pot reaction starting from organic bromides
and sodium azide (generation of the corresponding azide in situ
normally takes about 12 hours) followed by propargyl-substituted
Scheme 1
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Table 1 Reaction of 2 with alkynes
Entry
1
R–N3
Product
Methoda
Yield (%)
A
B
79
87
2
A
B
73
80
3
4
A
B
81
85
B
72
5
6
B
B
68
92
a Method A: CuI (10 mol%), DIPEA (3 equiv.), THF. Method B: CuSO4 (5 mol%), sodium ascorbate (30 mol%), H2O–t-BuOH.
bisphosphonate addition (Scheme 3). Thus, the above-mentioned
bisphosphorylated triazole 5b was obtained starting directly from
benzyl bromide, while for the synthesis of tetraphosphonates 8
and 9 isomeric bis(bromomethyl)benzenes were used. Due to
the complexing ability of the methylenebisphosphonate moiety
towards metals, under these one-pot conditions tetraphosphonates
8 and 9 form strong chelates with sodium bromide (the side
product of the reaction), and these complexes were isolated after
column chromatography (Scheme 3).
To obtain free N-BP 11, the N-pivaloylmethyl derivative 5d
was selected as the most suitable precursor. We found that the
pivaloylmethyl group could be selectively removed under basic
conditions for few minutes at room temperature in methanol to
afford 10 in good yield. Finally, hydrolysis of the ester groups at the
phosphorus atoms was quantitatively performed by treatment of
10 with trimethylsilyl bromide in chloroform followed by treatment
with aqueous MeOH (Scheme 4).
Scheme 3
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(200.13 MHz, CDCl3) d: 1.31 (t, 12H, CH3, 3JHH = 7.2 Hz), 2.03
(s, 1H, C≡H), 2.61–2.92 (m, 3H, CHP + CH2), 4.22–4.28 (m,
3
8H, OCH2); 13C (50.32 MHz, CDCl3) d: 16.7 (d, CH3, JCP
=
6.1 Hz), 39.6 (CH, t, 1JCP = 134.3), 63.3 (d, OCH2, 2JCP = 6.5 Hz),
70.4 (HC≡), 81.6 (t, CH2C≡, 3JCP = 9.4). IR (thin layer) m/cm−1:
=
1025 (P–O–C), 1249 (P O), 2120 (C≡C). HRMS: calculated for
C12H26O6P2 (M+) 326.1048, found 326.1040.
Tetraethyl hepta-1,6-diyne-4,4-diyldiphosphonate (3)
Scheme 4
Obtained according to the procedure described in ref. 15. Yield
78% (white crystals), mp 57–61 ◦C. 31P NMR (80.99 MHz, CDCl3)
1
Conclusion
d: 22.9. H NMR (200.13 MHz, CDCl3) d: 1.34 (t, 12H, CH3,
3
3JHH = 7.0), 2.04 (s, 1H, C≡H), 2.90 (dt, 4H, CH2, JHH = 3.1,
In conclusion, we have developed an efficient general synthetic
approach giving the possibility for the facile, rapid and cheap
synthesis of a wide range of novel N-BPs as potent drug candidates
based on “click” methodology. The method allows the incorpora-
tion of two functionalities into the N-BP molecule simultaneously,
as well as the ligation of two N-BPs to one another by a one-
pot reaction of organic dibromides with propargyl-substituted
bisphosphonates, generating both the diazide and Cu(I) moiety
in situ.
2JHP = 15.9 Hz), 4.23 (quintet, 8H, OCH2). 13C (50.32 MHz,
3
CDCl3) d: 14.3 (d, CH3, JCP = 6.1 Hz), 19.0 (CH2), 41.7 (t,
1
2
C(CH2)2, JCP = 133.8 Hz), 61.1 (d, OCH2, JCP = 7.2 Hz), 69.6
(HC≡), 76.8 (t, CH2C≡, 3JCP = 10.9 Hz). IR (thin layer) m/cm−1:
=
1025 (P–O–C), 1255 (P O), 2120 (C≡C). HRMS: calculated for
C15H26O6P2 (M+) 364.1205, found 364.1204.
Procedures for the synthesis of triazoles
Method A. A mixture of organic azide (1.0 mmol), acetylene
2 (1.0 mmol), DIPEA (2.0 mmol) and CuI (0.1 mmol) in THF
(10 mL) was stirred at r.t. for 68 h. The resulting reaction mixture
was treated with 1 N HCl (15 mL), and extracted with ether (3 ×
15 mL). The combined organic layers were dried over MgSO4 and
filtered. The solvent was removed under reduced pressure and the
crude product was purified by flash chromatography on silica gel
(acetone–petroleum ether).
Experimental
General remarks
Solvents were freshly distilled from the appropriate drying agents
before use. All other reagents were recrystallized or distilled
when necessary. Syntheses of mono- and bispropargyl substituted
bisphosphonates 2 and 3 were performed under an atmosphere of
dry nitrogen. Analytical TLCs were performed with Merck silica
gel 60 F254 plates. Visualization was accomplished by UV light or
spraying by Ce(SO4)2 solution in H2SO4. Flash chromatography
was carried out using Merck silica gel 60 (230–400 mesh ASTM).
Melting points were determined with an Electrothermal IA9100
digital melting point apparatus and are uncorrected. NMR spectra
were obtained on Bruker DPX-200 (1H, 200.13, 31P, 80.99, 19F,
188.31, and 13C, 50.32 MHz) and Bruker Avance-300 (1H, 300.13,
31P, 121.49 and 13C, 75.47 MHz) spectrometers using the residual
proton signals of the deuterated solvent as an internal standard
(1H, 13C) relative to TMS, H3PO4 (31P) or CFCl3 (19F) as external
standards. High-resolution mass spectra were obtained on a
Varian MAT CH7A instrument at 70 eV. IR spectra were recorded
using a thin layer of the sample on a Fourier-transform “Magna-
IR750” (Nicolet) spectrometer (resolution 2 cm−1, 128 scans).
Method B. The organic azide (2.0 mmol) and acetylene 2
(2.0 mmol) were suspended in 1 : 4 H2O–t-BuOH (8 mL). To
this was added CuSO4·5H2O (5 M solution, 0.1 mmol, 5 mol%)
and sodium ascorbate (0.6 mmol). The mixture was stirred at
r.t. for 24 h, after which time TLC (silica, acetone–petroleum
ether) indicated complete conversion. The resulting solution was
concentrated under reduced pressure (rotary evaporator). The
residue was dissolved in 30 mL of brine and then extracted with
ethyl acetate (3 × 30 mL). The combined organic layers were
washed with 5% aq. NH4OH (2 × 10 mL), dried over MgSO4,
filtered, and the solvent removed under vacuum to give analytically
pure product.
Tetraethyl 2-(1-phenyl-1H-1,2,3-triazol-4-yl)ethane-1,
1-diyldiphosphonate (5a)
Tetraethyl but-3-yne-1,1-diyldiphosphonate (2)
Yield 87%, colorless oil. 31P NMR (80.99 MHz, CDCl3) d: 23.7. 1H
NMR (200.13 MHz, CDCl3) d: 1.31 (t, 12H, CH3, 3JHH = 7.1 Hz),
3.03 (tt, 1H, CHP, 3JHH = 6.4, 2JHP = 23.1 Hz), 3.40 (dt, 2H, CH2,
3JHH = 6.4, 3JHP = 16.0 Hz), 4.22–4.31 (m, 8H, OCH2), 7.45–7.55
(m, 5H, arom), 7.71 (s, 1H, CH). 13C (50.32 MHz, CDCl3) d: 16.7
(d, CH3, 3JCP = 3.0 Hz), 16.8 (d, CH3, 3JCP = 2.5 Hz), 22.6 (CH2),
To a solution of ethylidenbisphosphonate 1 (10 g, 34.4 mmol)
in dry THF (100 mL) a slurry of sodium acetylenide in xylene
(9.1 mL, 18% solution) was added dropwise at −15 ◦C. The
reaction mixture was allowed to warm to r.t. and stirred overnight.
To the reaction solution, ether (100 mL) and 1 N HCl (50 mL)
were added. The organic layer was washed with 1 N HCl (50 mL),
brine (2 × 50 mL) and dried over magnesium sulfate. After
evaporation of the solvent under reduced pressure, the product
was used for subsequent reactions without purification. Yield 92%
1
37.1 (t, CP, JCP = 132.9 Hz), 62.9 (OCH2), 63.3 (OCH2), 120.8
=
=
(CH ), 128.9, 128.6, and 130.2 (CHAr), 137.6 (CArN), 146.9 (C ).
−1
=
=
IR (thin layer) m/cm : 1023 (P–O–C), 1255 (P O), 1597 (C C),
+
=
1500 (N N). HRMS: calculated for C18H29N3O6P2 (M ) 445.1532,
(colorless oil). 31P NMR (80.99 MHz, CDCl3) d: 22.8. H NMR
found 445.1543.
1
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Tetraethyl 2-(1-benzyl-1H-1,2,3-triazol-4-yl)ethane-1,
1-diyldiphosphonate (5b)
Tetraethyl (2-{1-[3-(hydroxymethyl)-5-(5-methyl-2,4-dioxo-3,
4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl]-1H-1,2,3-
triazol-4-yl}ethane-1,1-diyl)diphosphonate (5f)
Yield 89%, colorless oil. 31P NMR (80.99 MHz, CDCl3) d: 23.6. 1H
NMR (200.13 MHz, CDCl3) d: 1.3 (t, 12H, CH3, 3JHH = 6.5 Hz),
2.91 (tt, 1H, CHP, 3JHH = 6.3, 2JHP = 23.0 Hz), 3.32 (dt, 2H, CH2,
3JHH = 6.4, 3JHP = 15.9 Hz), 4.21–4.26 (m, 8H, OCH2), 5.52 (s, 2H,
CH2), 7.30–7.33 (m, 5H, arom.), 7.52 (s, 1H, CH). 13C (50.32 MHz,
Yield 92%, oil. 31P NMR (80.99 MHz, CDCl3): d 24.73. 1H NMR
(200.13 MHz, CDCl3) d: 1.28–1.35 (m, 12H, CH3), 1.96 (s, 3H,
CH3), 2.97–3.00 (m, 3H, CH2CH), 3.35–3.37 (m, 3H, CH2CH),
3.86 (dm, 1H, CH), 4.09–4.12 (dm, 1H, CH2), 4.16–4.18 (m, 8H,
OCH2), 4.39–4.42 (m, 1H, CH2), 5.35–5.39 (m, 1H, CH), 6.20–
1
CDCl3) d: 16.7 (CH3), 22.6 (CH2), 37.1 (t, CP, JCP = 132.9 Hz),
55.2 (NCH2), 62.9 (d, OCH2, 2JCP = 6.5 Hz), 63.2 (d, OCH2, 2JCP
=
=
6.24 (m, 1H, CH), 7.43 (s, 1H, CH), 7.75 (s, 1H, CH), 8.55
(br s, 1H, NH). 13C (50.32 MHz, CDCl3) d: 12.9 (CH3), 16.7 and
=
6.2 Hz), 122.6 (CH ), 128.5 and 128.6 and 129.4 (CAr), 135.3 (CAr),
−1
16.8 (CH3CH2O), 22.5 (CH2), 37.0 (t, CP, 1J = 133.6 Hz), 59.3
=
=
145.9 (C ). IR (thin layer) m/cm : 1024 (P–O–C), 1248 (P O),
CP
2
=
=
1498 (N N), 1555 (C C). HRMS: calculated for C19H31N3O6P2
(M+) 459.1688, found 459.1685.
(CHN), 60.8 (CH2OH), 63.3 (dd, OCH2, JCP = 6.5 Hz), 85.5
=
=
(NCH), 87.5 (CHCH2OH), 111.2 ( CCH3), 123.6 (NCH C),
=
=
137.6 ( CH2N), 145.5 and 145.6 and 145.7 (CAr), 151.0 (C O),
=
164.8 (C O). Calculated for C22H37N5O10P2: C, 44.48; H, 6.23; N,
11.79. Found: C, 44.35; H, 6.24; N, 11.58.
Tetraethyl 2-[1-(4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononyl)-1H-
1,2,3-triazol-4-yl]ethane-1,1-diyldiphosphonate (5c)
Tetraethyl 1,3-bis(1benzyl-1H-1,2,3-triazol-4-yl)propane-2,
Yield 92%, colorless oil. 31P NMR (80.99 MHz, CDCl3) d: 23.7. 1H
NMR (200.13 MHz, CDCl3) d: 1.31 (t, 12H, CH3, 3JHH = 7.0 Hz),
2.41–2.93 (m, 3H, CHP + CH2), 3.40 (dt, 2H, CH2, 3JHH = 6.1 Hz,
3JHP = 16.1 Hz), 4.22–4.31 (m, 8H, OCH2), 4.72 (t, 2H, CH2,
3JHH = 7.2 Hz), 7.61 (s, 1H, CH), (m). 19F NMR (188.34 MHz,
CDCl3) d: −81.9 (m, 3F, CF3), −114.3 (m, 2F, CF2CH2), −123.0
(m, 2F, CF2CF3), −124.0 (m, 2F, CH2CF2CF2CF2), −124.6 (m,
2F, CH2CF2CF2), −127.2 (m, 2F, CF2CF2CF3). 13C (50.32 MHz,
2-diyldipshopshonate (6)
◦
Yield 88%, white crystals, mp 86–88 C. 31P NMR (80.99 MHz,
1
CDCl3) d: 25.1. H NMR (200.13 MHz, CDCl3) d: 1.33 (t, 12H,
CH3, 3JHH = 7.3 Hz), 3.32 (dd, 4H, CH2, 3JHP(1) = 16.0 Hz 3JHP(2)
=
12.2 Hz), 4.21–4.27 (m, 8H, OCH2), 5.52 (s, 4H, CH2), 7.30–7.35
(m, 10H, arom.), 7.91 (s, 2H, CH). 13C (50.32 MHz, CDCl3) d:
3
3
16.6 (d, CH3, JCP = 3.3 Hz), 16.7 (d, CH3, JCP = 3.1 Hz), 26.6
1
(PCH2), 47.6 (t, CP, JCP = 130.9), 54.2 (NCH2), 63.1 & 63,2
3
3
CDCl3) d: 16.6 (d, CH3, JCP = 3.0 Hz), 16.8 (d, CH3, JCP
=
=
=
(POCH2), 125.0 (CH ), 128.5 and 128.9 and 129.4 (CHAr), 135.6
2.5 Hz), 22.5, 32.2 (t, CH2CF2, 2JCF = 21.7 Hz), 37.0 (t, CP, 1JCP
+
=
(ipso-CAr), 143.4 (C ). HRMS: calculated for C29H40N6O6P2 (M )
133.1 Hz), 42.5 (NCH2), 62.9 (d, OCH2, 2JCP = 6.5 Hz), 63.3 (d,
630.2484, found 630.2480.
OCH2, 2JCP = 6.2 Hz), 109.3, 121.1 (CH ), 123.4, 145.9 (C ). IR
=
=
−1
=
(thin layer) m/cm : 1028 (P–O–C), 1241 (P O), 1367 and 1394
X-Ray crystallography. Crystals of 6 suitable for X-ray diffrac-
tion were grown from diethyl ether. Crystallographic data for 6
(C29H40N6O6P2) at 173(2) K: Crystal size 0.42 × 0.30 × 0.22 mm,
=
(CH2), 1550 (C C), 3460. HRMS: calculated for C20H28N3O6P2F13
(M+) 715.1245, found 715.1235.
¯
triclinic, space group P1, a = 8.615(6), b = 12.829(4), c =
◦
˚
14.996(5) A, a = 88.06(3), b = 78.28(4), c = 75.70(4) , V =
3
ꢀ
˚
1572.3(13) A , Z = 2 (Z = 1), M = 630.61, dcalc = 1.332 g
m−3, l(MoKa) = 1.90 cm−1, F(000) = 668. The intensities of
6834 reflections were measured with an Siemens P4 diffractometer
tert-Butyl {4-[2,2-bis(diethoxyphosphoryl)ethyl]-1H-1,2,
3-triazol-1-yl}acetate (5d)
Yield 64%, oil. 31P NMR (121.49 MHz, CDCl3): d 22.4. 1H NMR
◦
˚
at 173(2) K (k(MoKa) = 0.71072 A, 2h < 50 , 2h-scans), and
5524 independent reflections (Rint = 0.0273) were used in the
further refinement. The structure was solved by direct methods and
refined by the full-matrix least-squares technique against F2 in the
anisotropic-isotropic approximation. Analysis of Fourier density
synthesis revealed that the ethyl groups (C(3)–C(4) and C(7)–
C(8)) are disordered over two positions with equal occupancies.
The positions of the hydrogen atoms were calculated from a
geometrical point of view. The refinement converged to wR2 =
0.1940 and GOF = 1.035 for all independent reflections (R1 =
0.0702 was calculated based on F for 3621 observed reflections
with I > 2r(I)). All calculations were performed using SHELXTL
PLUS 5.0.17 CCDC reference number 645541. For crystallographic
data in CIF or other electronic format see DOI: 10.1039/b705510b
(300.13 MHz, CDCl3): d 1.23 (s, 9H, CH3), 1.34 (t, 12H, CH3,
3JHH = 7.08 Hz), 2.97–3.04 (m, 1H, CH), 3.38 (dt, 2H, CH2, 3JHH
=
16.20 Hz), 4.15–4.22 (m, 8H, OCH2), 6.24 (s, 2H, CH2), 7.76 (s,
1H, CH). Calculated for C18H35N3O8P2: C, 44.75; H, 7.24; N, 8.70.
Found: C, 44.67; H, 7.31; N, 8.49.
Tetraethyl 2-[1-(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)-
1H-1,2,3-triazol-4-yl]ethane-1,1-diyldiphosphonate (5e)
Yield 66%, oil. 31P NMR (121.49 MHz, CDCl3): d 22.33. 1H NMR
(300.13 MHz, CDCl3): d 1.28–1.40 (m, 12H, CH3), 1.93 (s, 3H,
CH3), 2.11 (d, 9H, CH3, 3JHH = 11.2 Hz), 2.89–3.09 (m, 1H, CH),
3.32–3.47 (m, 2H, CH2), 4.01–4.29 (m, 8H, OCH2, 3H), 5.28 (t,
1H, CH, 3JHH = 10.05 Hz), 5.45 (t, 1H, CH, 3JHH = 9.12 Hz), 5.54
Tetraethyl 1,3-bis[1-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)-
1H-1,2,3-triazol-4yl]propane-2,2-diyldiphosphonate (7)
3
3
(t, 1H, CH, JHH = 9.12 Hz), 5.89 (d, 1H, JHH = 9.12 Hz), 7.76
(s, 1H, CH). Calculated for C26H43N3O15P2: C, 44.64; H, 6.15; N,
6.01. Found: C, 44.15; H, 6.14; N, 5.58.
Yield 92%, white crystals, mp 126–129 ◦C. 31P NMR (80.99 MHz,
1
CDCl3) d: 29.8. H NMR (200.13 MHz, CDCl3) d: 1.30 (t, 12H,
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CH3, 3JHH = 7.1 Hz), 2.91–2.95 (m, 4H, CH2), 3.41 (dd, 4H, CH2,
3JHP = 16.0 Hz), 4.21–4.27 (m, 8H, OCH2), 4.73 (t, 4H, CH2,
3JHH = 7.4 Hz), 8.01 (s, 2H, CH), (m). 19F NMR (188.31 MHz,
CDCl3) d: −76.9 (3F, m, CF3), −110.3 (2F, m, CF2CH2), −117.9
(2F, m, CF2CF3), −118.9 (2F, m, CH2CF2CF2CF2), −119.6 (2F,
m, CH2CF2CF2), −122.2 (2F, m, CF2CF2CF3). 13C (50.32 MHz,
d 3.15–3.07 (m, 2H, CH2), 3.88–3.84 (m, 1H, CH), 7.61 (s, 1H, CH).
Calculated for C4H9N3O6P2: C, 18.67; H, 3.50; N, 16.33. Found:
C, 18.69; H, 3.52; N, 16.21.
Acknowledgements
2
CDCl3) d: 16.6 (d, CH3, JCP = 6.2 Hz), 26.5 (PCCH2), 30.4 (t,
This work was supported by the Deutsche Forschungsgemein-
schaft (DFG no. 436 RUS 113/905/0-1) and the Russian Foun-
dation of Basic Research (grant no. 06-03-04003).
CH2CF2, 2JCF = 21.9 Hz), 41.6 (t, CP, 1JCP = 133.1), 42.7 (NCH2),
63.4 (d, OCH2, 2JCP = 7.2 Hz), 109.3–121.1, 125.6 (CH ), 142.7,
=
=
143.5 (C ). Calculated for C31H34N6O6P2F26: C, 32.59; H, 3.00.
Found: C, 32.28; H, 3.21.
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Yield 67%, colorless oil. 31P NMR (CD3CN) d: 29.3. H NMR
(CD3CN) d: 1.13–1.18 (m, CH3, 24H), 3.00–3.05 (m, CHP + CH2,
6H), 3.85–4.04 (m, OCH2, 16H), 5.48 (s, CH2, 4H), 7.32 (s, Ha, 4H),
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=
=
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5.55.
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3-triazol-4,1-diyl))bis(ethane-2,1,1-triyl]tetraphosphonate (9)
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Yield 65%, colorless oil. 31P NMR (CD3CN) d: 24.0. H NMR
3
(CD3CN) d: 1.30–1.33 (m, CH3, 24H, JHH = 7.3 Hz), 2.93–
2.96 (m, CHP + CH2, 6H), 3.82–4.13 (m, OCH2, 16H), 5.50
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Tetraethyl [2-(1H-1,2,3-triazol-4-yl)ethane-1,
1-diyl]bis(phosphonate) (10)
To a solution of 5d (0.48 g, 0.9 mmol) in MeOH (3.6 mL), NaOH
(1 M aq. solution, 3.6 mL) was added. The reaction mixture was
stirred at r.t. for 3 h and subsequently neutralized with 1 N HCl
(5 mL), diluted with H2O (20 mL) and extracted three times with
ethyl acetate (45 mL). The organic layer was dried over MgSO4
and evaporated under vacuum to yield the product in pure form.
Yield 65%, oil. 31P NMR (121.49 MHz, CDCl3): d 22.4. 1H NMR
(300.13 MHz, CDCl3): d 1.35 (t, 12H, CH3, 3JHH = 7.08 Hz), 2.93–
3.01 (m, 1H, CH), 3.36–3.42 (m, 2H, CH2), 4.17–4.23 (m, 8H,
3
OCH2), 5.77 (s, 1H, NH), 7.61 (d, 1H, CH, JHH = 10.95 Hz).
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2366 | Org. Biomol. Chem., 2007, 5, 2361–2367
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