Synthesis of triple-bond-containing 1-hydroxy-1,1-bisphosphonic acid derivatives to be used as precursors in "click" chemistry: Two examples

Article abstract of DOI:10.1021/jo500831r

The synthesis of novel (alkynyl-1-hydroxy-1,1-diyl)bisphosphonic acid tetramethyl esters (1a-c), their P,P'-dimethyl esters (2a-c), and two trimethyl ester derivatives (3a and 3b) is reported. The prepared compounds can be attached to many kinds of molecules containing azide (-N₃) functionalities using a "click" chemistry approach. As an example, bisphosphonate trimethyl ester 3a and P,P'-dimethyl ester 2b were attached to triethylene glycol to form triethylene glycol-bisphosphonate conjugates 4 and 5 as model compounds for further studies in, for example, nanoparticle targeting.

Full text of DOI:10.1021/jo500831r

Note
pubs.acs.org/joc
Synthesis of Triple-Bond-Containing 1‑Hydroxy-1,1-bisphosphonic
Acid Derivatives To Be Used as Precursors in “Click” Chemistry: Two
Examples
Petri A. Turhanen*
Biocenter Kuopio, School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland
S
* Supporting Information
ABSTRACT: The synthesis of novel (ω-alkynyl-1-hydroxy-1,1-
diyl)bisphosphonic acid tetramethyl esters (1a−c), their P,P′-
dimethyl esters (2a−c), and two trimethyl ester derivatives (3a
and 3b) is reported. The prepared compounds can be attached to
many kinds of molecules containing azide (−N3) functionalities
using a “click” chemistry approach. As an example, bisphosphonate
trimethyl ester 3a and P,P′-dimethyl ester 2b were attached to
triethylene glycol to form triethylene glycol−bisphosphonate
conjugates 4 and 5 as model compounds for further studies in, for example, nanoparticle targeting.
isphosphonates (BPs), which have been studied inten-
sively more than 50 years, are analogues of the naturally
chromium(III) from tannery effluents and aqueous solutions
based on solid BPs,22 (2) the first bisphosphonate hydro-
gelators as potential composers of biocompatible gels,23 and (3)
novel unexpected effects of BPs on plant growth that are
nonherbicidal.24 In addition, we discovered a method for
collecting metals from aqueous solutions using an insoluble BP
material.25 These highlight the enormous potential of BPs for
not only their medical uses but also their utilization in many
other unexpected fields.
B
occurring pyrophosphate, and they can be characterized by
their P−C−P backbone (Figure 1).1,2 During that time,
According to a literature search with SciFinder, there are
generally few “click” chemistry examples related to BPs,26−29
and only two examples of (ω-alkynyl-1-hydroxy-1,1-diyl)-
bisphosphonic acids have been reported.30,31 There are three
papers describing the conjugation of 1-hydroxy-1,1-bisphosph-
onates using the “click” chemistry approach, one of which
describes conjugation of azide-containing BP to antibacterial
agents.31−33 There are no examples of the synthesis of (ω-
alkynyl-1-hydroxy-1,1-diyl)bisphosphonic acid esters or their
conjugation via “click” chemistry. Tetraesters of 1-hydroxy-1,1-
bisphosphonic acids are sensitive toward undergoing a
rearrangement to form tetraalkyl phosphono phosphates if
any base and/or too-high temperatures are used in their
syntheses, as has been reported in the case of tetraesters of
etidronic acid34−38 (Figure 2). In fact, this was also a problem
Figure 1. Structure of pyrophosphate and general structure of
bisphosphonates.
according to a SciFinder search, approximately 17 000 different
BP structures in approximately 34 000 studies have been
published. At the beginning BPs were used as water softeners
since they inhibit the formation of calcium and magnesium
crystals, but as known in general, their very high affinity for the
bone mineral hydroxyapatite represents the basis for their
current main use today as drugs for the treatment of different
kinds of bone diseases, such as osteoporosis and Paget’s disease.
In the literature there are hundreds of different BP applications,
such as combatting against parasitic diseases,3−8 the treatment
of atherosclerosis,9 and use as bone-imaging agents10 and bone-
targeting promoieties (e.g., as anti-inflammatory drugs11 and
bone metastases12). They can also be used in extraction of
actinide ions,13 as a new class of herbicides,14 and in studies for
crystal engineering.15 Furthermore, BPs have exhibited
interesting anticancer properties16 and have been claimed to
be important precursors in the preparation of nucleotide
analogues.17,18
Figure 2. Rearrangement of etidronic acid tetraesters to tetraalkyl
phosphono phosphates.
Our group has extensive experience related to BP synthesis in
recent years,19−21 and a while ago we devised three novel
applications for BPs: (1) a method for effective removal of
Received: April 14, 2014
© XXXX American Chemical Society
A
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Scheme 1. Synthesis of Novel BP Tetramethyl Esters 1a−c
Scheme 2. Synthesis of Novel BP P,P′-Dimethyl Esters 2a−c and Trimethyl Esters 3a−b
encountered in the synthesis of (ω-alkynyl-1-hydroxy-1,1-
diyl)bisphosphonic acid tetramethyl esters 1a−c described in
this study and will be discussed in more detail later in the paper.
The possibility of preparing BP tetraesters and partial esters
is of major importance. Tetraesters can function as protecting
groups when modifying the R1 and R2 groups of BPs39 (see
Figure 1), and if needed, they can be removed afterward to
produce the corresponding bisphosphonic acids by either acid
hydrolysis or a silylation/desilylation procedure under mild
conditions.40 In addition, these esters are much more lipophilic
than BP acids or salts, and this makes it possible to perform
syntheses and conjugations in organic solvents, which is
mandatory in some cases. In our ongoing study,41 we have
observed that BP partial esters have different affinities for
hydroxyapatite than the corresponding acids or salts, and there
are some unexpected results that may also open new targeting
possibilities (e.g., targeting those molecules to sites other than
bone) because BP acids and salts are very rapidly transported to
the bone surface when administered into the blood
circulation.42,43
Ethylene glycols (EGs) of different sizes have been used as
linkers to enhance and optimize the properties of mole-
cules.44−46 The most extensively used nonionic polymer in
polymer-based drug delivery research is poly(ethylene glycol)
(PEG).47 The role of PEG has proven to be crucial in the
evolution of drug delivery systems, especially for tumor
targeting and treatment. PEG-coated liposomal nanoparticles
have proved to be efficient drug delivery systems since they
achieve high circulation times, increased stability, decreased
systemic toxicity, and increased tumor accumulation.48 The
versatility that has been demonstrated with PEG will allow for
the exploration of novel uses and continuous improvements of
anticancer treatments.49
Perhaps the most practical way to prepare tetraesters of 1-
hydroxy-1,1-bisphosphonates is the reaction between equiv-
alent amounts of acyl chloride, trialkylphosphite, and
dialkylphosphite with or without a catalytic amount of
base.34,57,58 This was also the starting point when the
compounds reported here were synthesized (Scheme 1). ω-
Alkynoic acids were converted to the acid chlorides by the well-
known method that uses oxalyl chloride as the chlorinating
reagent, and subsequent addition of trimethylphosphite formed
the corresponding acylphosphonates as intermediate products.
Finally, 3 equiv of dimethylphosphite was added, and the
reaction mixture was stirred for about 4−11 days without
solvent at 40 °C to produce (ω-alkynyl-1-hydroxy-1,1-diyl)-
bisphosphonic acid tetramethyl esters 1a−c. The first synthesis
strategy was to use the standard method with equivalent
amounts of starting materials, but only a very small amount of
the desired product was obtained. When the temperature was
elevated to over 50 °C or a catalytic amount of base
(dibutylamine) was added to the reaction mixture, there was
isomerization of the product to the tetraalkyl phosphono
phosphate as revealed by the 31P NMR spectrum. (This is the
same phenomenon as shown in Figure 2 for etidronic acid
tetraalkyl ester; also see p S31 in the Supporting Information.
The proposed reaction mechanism has been reported else-
where.38) Therefore, the above-mentioned modified procedure
was developed (for a more detailed procedure, see the
Experimental Section).
An excess of dimethyl phosphite was used to drive the
reaction to completion so that no acyl phosphonate was left in
the reaction mixture (this was monitored via the 31P NMR
spectrum; see, e.g., the spectrum on page S31 in the Supporting
Information). Unfortunately, as can be seen in Scheme 1, the
yields of 1a−c were rather low as a result of partial
isomerization of the desired products to tetraalkyl phosphono
phosphates. It appeared that some of the product was
isomerized during the column chromatography purification,
which partly reduced the isolated yield. It was interesting to
note that the reaction mixture of 1a contained the greatest
amount of the rearranged product and the reaction mixture of
1c contained the least, even though the reactions were
performed under the same conditions, so it may be concluded
that there is some kind of effect of the triple bond on the
rearrangement process and that the effect is stronger when it is
closer to the BP part of the molecule.
Gold nanoparticles (GNPs) are widely used in many fields,
and the range of applications for GNPs is growing rapidly,
including photodynamic therapy, therapeutic agent delivery,
and diagnostics.50 BP-functionalized GNPs have recently been
reported to have the potential to improve clinical detection of
breast microcalcifications by mammography.51 We have
research experience related to silicon nanoparticles in our
group.52−54 GNPs are commercially available in the form of
PEGylated azides (PEG−N3),55 which makes them highly
interesting particles for different purposes should they be
conjugated with BPs by the “click” chemistry approach.56
B
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Scheme 3. Synthesis of TEG−N3 and of Novel TEG-Conjugated BP 4 Using “Click” Chemistry
Scheme 4. Synthesis of Novel TEG-Conjugated BP 5 Using “Click” Chemistry
(ω-Alkynyl-1-hydroxy-1,1-diyl)bisphosphonic acid P,P′-di-
methyl esters 2a−c were prepared in very high yields from
the corresponding tetramethyl esters 1a−c using the NaI/
acetone method59 (Scheme 2). The synthesis of trimethyl
esters 3a and 3b was much more challenging because one
would need to find a selective agent capable of removing only
one methyl group from tetramethyl esters 1a and 1b. We have
reported earlier59 about the selective synthesis of etidronic acid
trimethyl and triethyl esters using the KI/acetone system, but
in this case, this approach was not as selective as expected. The
logical way was to test the RbI/acetone system, and this was
observed to be more selective than KI/acetone, leading to very
reasonable yields of trimethyl esters 3a and 3b after isolation
(Scheme 2).
Since the raw product mixture in the case of 3a contained an
approximately 15% yield of the formed P,P′-dimethyl ester, a
few percent yield of rearranged product, and a few percent yield
of some monophosphorus species, it was purified by column
chromatography. Unfortunately the P,P′-dimethyl ester eluted
with the desired trimethyl ester 3a, so a further purification step
was required. The earlier experiences with the different
solubilities of the BP P,P′-dimethyl and trimethyl esters
suggested that it might be possible to separate trimethyl ester
3a from the corresponding P,P′-dimethyl ester by dissolving the
raw product in MeOH and crystallizing the P,P′-dimethyl ester
out of the MeOH solution, hoping that 3a would still remain
dissolved in MeOH. In the attempt to dissolve the raw mixture
into MeOH, another component was found to be totally
insoluble in MeOH, and surprisingly, it was the desired product
3a. One plausible explanation for this phenomenon is the
presence of very strong intra- or intermolecular hydrogen
bond(s) formed between the atoms capable of that in 3a in
solid form, so the methanol molecules could not solvate the
molecules of 3a, which is crucial for dissolution. It would be
very interesting to compare the crystal structures of 3a and the
corresponding P,P′-dimethyl ester and determine the absolute
reason for this unexpected situation. When trimethyl ester 3b
was synthesized the same procedure was also used successfully.
Since the ultimate goal was to prepare nanoparticles or
related molecules loaded with medicine targeting bone (or any
other calcium-containing target such as atherosclerotic
plaques9), triethylene glycol (TEG) was chosen as the model
compound to be conjugated with 3a and 2b using “click”
chemistry for the reasons presented in the introductory
discussed above. Commercially available TEG was readily
converted to the monoazide form (TEG−N3) via the tosyl
form (TEG−Ts) using the known method60 (Scheme 3)
before it was conjugated with 3a and 2b using solid copper as a
catalyst (Schemes 3 and 4).
The first attempt was to conjugate tetramethyl ester 1a to
TEG−N3 using perhaps the most common “click” chemistry
catalyst, CuSO4, but that was not successful under the
conditions used. When copper powder was added to the
reaction mixture of 1a and TEG−N3, the “click” reaction
worked well, but as expected, a yield of about 13% of the
formed conjugate was rearranged (the BP moiety became
isomerized as discussed earlier) according to the 31P NMR
spectrum, probably as a result of formation of the triazole ring
which could act as a base to catalyze the rearrangement process.
Since the goal was to produce lipophilic BP conjugates as
model compounds, one can conclude that conjugates 4 and 5
are excellent examples. Furthermore, it was very interesting to
note that conjugate 5 was able to chelate copper into its
structure, although this was not surprising because according to
our experience, even BP P,P′-diesters can coordinate metal
cations into their structures. This is not the case for BP
triesters, which chelate metals very poorly or not at all, as
observed for the case of conjugate 4. It is a well-known
phenomenon that when the metal cation is strongly
coordinated into the molecule, then the atoms involved in
the coordination have such long relaxation times that they are
hardly visible or not visible at all in NMR spectra.61 This was
observed when attempts were made to measure the 31P NMR
spectrum for 5, as no peaks were found. In addition, in the 13
C
NMR spectrum, the middle carbon (P−C−P), which already in
general has a long relaxation time, was not visible, and no
carbon−phosphorus couplings were detected. Interestingly, the
carbons from the triazole ring also were not visible, even when
tested with a 28 s relaxation delay and a very concentrated
sample, indicating that the triazole ring must take part in the
1
chelation process. The H NMR spectrum of 5 was also very
simple, and no couplings were observed, but it was fair enough
to confirm the structure when combined with MS and 13C
NMR results, especially when they were compared with the
NMR and MS spectra of 4. In the MS spectrum, a copper
complex peak for 5 was also observed. It would be very
interesting to determine the 3D crystal structure of 5 in the
future, if the compound could be crystallized. The 13C NMR
spectrum of 5 revealed six small carbon signals that did not
belong to conjugate 5 and probably originated from compound
C
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times with DCM (10 mL). The organic phases were dried over
TEG−NH2, which was formed in the reaction from TEG−N3
(reduction reaction); in the 1H NMR spectrum of 5 there was a
visible signal at ca. 3.05 ppm that was probably attributable to
the methylene protons next to the amino group
(−OCH2CH2NH2). On the basis of the signal intensities, it
can be said that the purity of compound 5 was approximately
85%, but because it was prepared as a model compound, that is
not very important in the further studies. Finally, it is worth
mentioning that the color of conjugate 5 in CD3OD in the
NMR tube was slightly fluorescent yellow, not blue or green as
could have been expected, and the same color remained even
when 7.6 M DCl was added and the pH was measured to be
≤1, which is evidence of the very strong copper complex of 5.
Actually, when attempts were made to measure, for example,
the 31P NMR spectrum for the above-mentioned acidic sample,
no visible signals could be observed.
In conclusion, three novel (ω-alkynyl-1-hydroxy-1,1-diyl)-
bisphosphonic acid tetramethyl esters (1a−c) were synthesized
and isolated in reasonable yields when their sensitivity to
isomerization is taken into account. In addition, three novel (ω-
alkynyl-1-hydroxy-1,1-diyl)bisphosphonic acid P,P′-dimethyl
esters (2a−c) and two trimethyl esters (3a and 3b) have
been reported. All of the prepared compounds are highly useful
as precursors for “click” chemistry, but if tetramethyl esters are
used in reactions, the tertiary hydroxyl group maybe protected
[e.g., by acylation (esterification)]37,38 against undergoing
rearrangement. Novel triethylene glygol−BP conjugates 4 and
5 were synthesized by the “click” chemistry approach as model
compounds for further studies (e.g., bone-targeted delivery
systems).
MgSO4 and evaporated to dryness. TEG−N3 (262 mg, 91%) was
1
present as a colorless oil. H NMR (CDCl3): δ 4.76−4.71 (m, 2H),
3.70−3.65 (m, 6H), 3.64−3.59 (m, 2H), 3.39 (t, 2H, 3J = 5.0), 2.28 (t,
3
2H, J = 6.3, OH).
Procedure for the Preparation of Tetramethyl Ester 1a. 4-
Pentynoic acid (1.11 g, 11.3 mmol) was dissolved in dry DCM (15
mL), and two drops of DMF were added. The reaction mixture was
then stirred at 40−45 °C. Oxalyl chloride (1000 μL, 1.5 g, 1.05 equiv,
11.8 mmol) was added in portions into the reaction mixture, and after
its total addition the reaction mixture was refluxed for 1 h. The
reaction mixture was cooled to about 0 °C, and distilled trimethyl
phosphite (1420 μL, 1.49 g, 12.0 mmol) was added. The reaction
mixture stirred for 2 h at room temperature, and then all volatile
fractions were removed by evaporation in vacuo. Distilled dimethyl
phosphite (3250 μL, 3.9 g, ca. 3 equiv, 35.4 mmol) was added, and the
reaction mixture was stirred for 7 days at 40 °C. Again all of the
volatile fractions were removed by evaporation in vacuo. Diethyl ether
(20 mL) and hexane (5 mL) were added to the residue with vigorous
stirring, and the mixture was placed in the freezer (about −18 °C).
After a few hours, two phases were separated, and after few days,
compound 1a crystallized out in the lower phase. The crystals were
separated, washed with diethyl ether, and dried in vacuo. The product
1a (1.02 g, 30%) was obtained as colorless crystals.
Procedure for the Preparation of Tetramethyl Ester 1b. This
was prepared similarly to 1a, starting from 5-hexynoic acid (1.26 g,
11.2 mmol), except that the reaction time was 4 days instead of 7 days
and the crude product was purified by column chromatography using
EtOAc/MeOH (8:2) as the eluent. 1b (1.20 g, 34%) was obtained as a
yellow viscous oil.
Procedure for Preparation of Tetramethyl Ester 1c. This was
prepared similarly to 1a, starting from 6-heptynoic acid (1.42 g, 11.3
mmol), except that the reaction time was 11 days instead of 7 days and
the crude product was purified by column chromatography using
EtOAc/MeOH (8:2) as the eluent. 1c (1.51 g, 41%) was obtained as a
slightly yellow viscous oil.
EXPERIMENTAL SECTION
■
1
General Methods. H, 31P, and 13C NMR spectra were recorded
Procedure for the Preparation of P,P′-Dimethyl Ester 2a.
Tetramethyl ester 1a (200 mg, 0.67 mmol) was dissolved in dry
acetone (6 mL), and dry NaI (205 mg, 2.05 equiv, 1.37 mmol) was
added. The mixture stirred overnight at 50 °C, and the precipitate was
filtered, washed with acetone, and dried in vacuo. The product 2a (203
mg, 96%) was obtained as a white powder.
on a 500 MHz spectrometer operating at 500.1, 202.5, and 125.8
MHz, respectively. The solvent residual peaks were used as standards
for 1H and 13C measurements in CDCl3 and CD3OD (7.26 and 77.16
ppm for CDCl3 and 3.31 and 49.00 ppm for CD3OD, respectively),62
1
in D2O in H measurements (4.79 ppm), and trimethylsilylpropionic
acid sodium salt (TSP) in 13C measurements (0.00 ppm); 85% H3PO4
Procedure for the Preparation of Trimethyl Ester 3a.
Tetramethyl ester 1a (200 mg, 0.67 mmol) was dissolved in dry
acetone (5 mL), and RbI (142 mg, 1 equiv, 0.67 mmol) was added.
The mixture was stirred overnight at 50 °C and then evaporated to
dryness, dissolved in 1 M HCl (1.5 mL), and evaporated to dryness
again. The crude product was first purified by column chromatography
using EtOAc/MeOH (2:8) as the eluent, and if the collected product
still contained the corresponding P,P′-dimethyl ester, then it was
dissolved in MeOH and the white solids were separated and dried in
vacuo. The product 3a (122 mg, 64%) was obtained as a white solid.
Procedure for the Preparation of TEG−BP Conjugate 4.
Trimethyl ester 3a (40 mg, 0.14 mmol) was dissolved in 2 mL of
EtOH/H2O (1:1), and copper powder (19 mg, 0.30 mmol) and TEG-
N3 (25 mg, 1 equiv, 0.14 mmol) were added. The mixture was stirred
overnight at room temperature and then evaporated to dryness. The
residue was dissolved in DCM (ca. 5 mL) and filtered through Celite.
Then MeOH (ca. 5 mL) was poured through the Celite and
evaporated to dryness in vacuo. Product 4 (36 mg, 56%) was obtained
as a slightly blue syrup (indicative of the presence of copper cations).
Procedure for the Preparation of TEG−BP Conjugate 5.
Dimethyl ester 2b (50 mg, 0.15 mmol) was dissolved in 2 mL of
MeOH/H2O (1:1), and copper powder (29 mg, 0.46 mmol) and
TEG-N3 (29 mg, 1.1 equiv, 0.17 mmol) were added. The mixture was
stirred overnight at 50 °C and then cooled to room temperature,
acidified with 2 M HCl, and evaporated to dryness. The residue was
dissolved in DCM (ca. 5 mL) and filtered through Celite.
Subsequently approximately 5 mL of DCM/MeOH (1:1) was poured
through the Celite and evaporated to dryness in vacuo. The crude
was used as an external standard for 31P measurements. The JHP
n
couplings were calculated from proton spectra and all J values are
given in hertz. The nJCP couplings were calculated from carbon spectra,
and the coupling constants in hertz are given in parentheses. Mass
spectra were recorded on a quadrupole time-of-flight mass
spectrometer using electrospray ionization (ESI) with positive
ionization mode for compounds 1a−c and negative ionization mode
for 2a−c, 3a, 3b, 4, and 5. The purity of the products was determined
from the 1H and 31P NMR spectra and was ≥95% unless stated
otherwise.
Procedure for the Preparation of 2-(2-(2-Azidoethoxy)-
ethoxy)ethanol (TEG−N3). The procedure reported elsewhere was
1
followed with slight modifications, and all of the H and 13C NMR
spectra were comparable to those reported elsewhere.60 Triethylene
glycol (900 μL, 1.012 g, 6.74 mmol) was dissolved in dry DCM (30
mL) and cooled to about −5 °C. Ag2O (2.34 g, 10.10 mmol, 1.5
equiv), TsCl (1.41 g, 7.40 mmol, 1.1 equiv), and dry KI (225 mg, 1.36
mmol, 0.2 equiv) were added, and the reaction mixture was stirred for
30 min at about −5 °C. Subsequently, the reaction mixture was filtered
through Celite and evaporated to dryness. The crude product was
purified by silica column chromatography using EtOAc as the eluent.
2-(2-(2-Hydroxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate
(TEG−Ts) (1.07 g, 52% yield) was present as a colorless oil.
TEG−Ts (500 mg, 1.64 mmol) was dissolved in dry acetonitrile (10
mL), and NaN3 (160 mg, 2.46 mmol, 1.5 equiv) was added. The
reaction mixture was then refluxed for 40 h. After the mixture was
cooled, water (10 mL) was added, and the mixture was extracted three
D
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3
4
product was dissolved in MeOH (8 mL), and about 1 g of Dowex
50WX8-200 ion-exchange resin was added. The mixture was stirred for
0.5 h at room temperature. The Dowex was filtered and washed with
MeOH before being stirred with 2 M HCl (ca. 5 mL) for 15 min at
room temperature. The Dowex was filtered, and the fitrate was
evaporated to dryness in vacuo. The product 5 (47 mg, 59%) was
obtained as a yellow syrup, and its purity was approximately 85%.
Tetramethyl (1-Hydroxypent-4-yne-1, 1-diyl)-
OCH3), 3.68 (d, 3H, JHP = 13.0, OCH3), 2.38 (t, 1H, J = 2.5), 2.26
(td, 2H, 4J = 2.5), 2.03−2.14 (m, 2H), 1.75−1.85 (m, 2H). 13C NMR
1
1
(D2O): δ 88.2, 77.8 (dd, JCP = 144.9, JCP′ = 151.2, P−C−P), 72.5,
57.04 (d, 3JCP = 7.8, OCH3), 56.96 (d, 3JCP = 7.9, OCH3), 55.7 (d, 3JCP
= 6.7, OCH3), 36.4, 25.3 (t, ∑2JCP = 6.4), 21.0. 31P NMR (D2O): δ
2
−
27.76 (d, JPP = 30.5), 15.78 (d). MS (ESI−): calcd for C9H17O7P2
[M − H]− 299.0450, found 299.0440.
Methyl Hydrogen (1-(Dimethoxyphosphoryl)-1-hydroxy-3-
(1-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)-
propyl)phosphonate (4). 1H NMR (D2O/CD3OD): δ 7.88 (s, 1H),
4.58 (t, 2H, 3J = 4.8), 3.95 (t, 2H, 3J = 4.8), 3.87 (d, 3H, 3JHP = 10.5),
1
bisphosphonate (1a). Colorless crystals, mp 62−64 °C. H NMR
(CDCl3): δ 3.90−3.85 (m, 12H), 2.58−2.52 (m, 2H), 2.36−2.25 (m,
2H), 1.98 (t, 1H, 4J = 2.5). 13C NMR (CDCl3): δ 84.0, 74.7 (t, 1JCP
=
3
3
3
152.9, P−C−P), 69.0, 54.51 (t, ∑2JCP = 6.2, 2C, OCH3), 54.47 (t,
∑2JCP = 6.8, 2C, OCH3), 33.0, 13.4 (t, 2JCP = 7.0). 31P NMR (CDCl3):
δ 22.07. MS (ESI+): calcd for C9H19O7P2 [M + H]+ 301.0606, found
301.0604.
3.86 (d, 3H, JHP = 10.5), 3.70 (d, 3H, JHP = 10.0), 3.67 (t, 2H, J =
3
4.5), 3.66−3.59 (m, 4H), 3.54 (t, 2H, J = 4.8), 3.09−2.95 (m, 2H),
2.38−2.22 (m, 2H). 13C NMR (CD3OD): δ 149.2, 123.9, 75.7 (dd,
P−C−P, ∑1 JCP and CP′ = 142.9), 73.6, 71.43, 71.37, 70.4, 62.2, 51.3,
34.5, 20.9. 31P NMR (CD3OD): δ 28.45 (d, JPP = 43.3), 14.38 (d).
2
Tetramethyl (1-Hydroxyhex-5-yne-1,1-diyl)bisphosphonate
−
MS (ESI−): calcd for C14H28N3O10P2 [M − H]− 460.1250, found
1
3
(1b). H NMR (CDCl3): δ 3.88−3.81 (m, 12H), 3.48 (t, 1H, JHP
=
3
4
460.1230.
10.0, OH), 2.20 (td, 2H, J = 7.0, J = 2.5), 2.16−2.05 (m, 2H), 1.94
(t, 1H, 4J = 2.5), 1.87−1.80 (m, 2H). 13C NMR (CDCl3): δ 83.8, 75.0
(t, 1JCP = 152.0, P−C−P), 69.0, 54.4 (t, ∑2JCP = 7.0, 2C, OCH3), 54.3
(t, ∑2JCP = 7.2, 2C, OCH3), 33.4, 22.4 (t, 2JCP = 5.8), 18.9. 31P NMR
(CDCl3): δ 22.77. MS (ESI+): calcd for C10H21O7P2 [M + H]+
315.0763, found 315.0763.
Dimethyl (1-Hydroxy-4-(1-(2-(2-(2-hydroxyethoxy)ethoxy)-
ethyl)-1H-1,2,3-triazol-4-yl)butane-1,1-diyl)bisphosphonate
1
Monocopper Salt (5). H NMR (CD3OD): δ 8.62 (br, 1H), 4.75
(br, 2H), 3.94 (br, 2H), 3.82−3.69 (br, 6H), 3.69−3.62 (br, 2H),
3.62−3.57 (br, 2H), 3.57−3.52 (br, 2H), 3.50−3.43 (br, 2H), 2.95−
2.80 (br, 2H), 2.13−1.94 (br, 4H). 13C NMR (CD3OD): δ 73.7, 71.6,
71.4, 69.4, 62.1, 55.4, 34.2, 24.9, 23.6. MS (ESI−): calcd for
Tetramethyl (1-Hydroxyhept-6-yne-1, 1-diyl)-
1
bisphosphonate (1c). H NMR (CDCl3): δ 3.89−3.81 (m, 12H,
−
C14H28N3O10P2 [M − H]− 460.1250, found 460.1265.
OCH3), 3.19 (t, 1H, 3JHP = 10.5, OH), 2.22 (td, 2H, 3J = 7.5, 4J = 2.5),
2.07−1.96 (m, 2H), 1.93 (t, 1H, 4J = 2.5), 1.75−1.66 (m, 2H), 1.59−
1.52 (m, 2H). 13C NMR (CDCl3): δ 84.3, 75.1 (t, 1JCP = 152.0, P−C−
P), 68.4, 54.35 (t, ∑2JCP = 7.1, 2C, OCH3), 54.26 (t, ∑2JCP = 7.2, 2C,
ASSOCIATED CONTENT
■
S
* Supporting Information
2
OCH3), 33.8, 29.1, 22.4 (t, JCP = 5.7), 18.3. 31P NMR (CDCl3): δ
1H, 13C, and 31P NMR spectra of 1a−c, 2a−c, 3a, 3b, 4, and 5.
This material is available free of charge via the Internet at
http://pubs.acs.org.
22.95. MS (ESI+): calcd for C11H22O7P2Na [M + Na]+ 351.0738,
found 351.0740.
Dimethyl (1-Hydroxypent-4-yne-1,1-diyl)bisphosphonate
1
Disodium Salt (2a). Mp >300 °C. H NMR (D2O): δ 3.70−3.65
(m, 6H, OCH3), 2.58−2.53 (m, 2H), 2.39 (t, 1H, 4J = 2.5), 2.27−2.17
AUTHOR INFORMATION
1
(m, 2H). 13C NMR (D2O): δ 89.1, 77.6 (t, JCP = 143.4, P−C−P),
■
2
71.9, 55.3 (t, ∑2JCP = 6.4, 2C, OCH3), 36.9, 16.2 (t, JC−P = 7.0). 31P
Corresponding Author
*E-mail: petri.turhanen@uef.fi.
NMR (D2O): δ 19.74. MS (ESI−): calcd for C7H13O7P2 [M − H]−
271.0137, found 271.0130.
Notes
Dimethyl (1-Hydroxyhex-5-yne-1,1-diyl)bisphosphonate
The authors declare no competing financial interest.
Disodium Salt (2b). Prepared similarly to 2a, obtained as a white
1
powder, 95% yield, mp >300 °C. H NMR (D2O): δ 3.67−3.62 (m,
6H, OCH3), 2.38−2.36 (m, 1H), 2.28−2.22 (m, 2H), 2.06−1.95 (m,
ACKNOWLEDGMENTS
■
1
2H), 1.85−1.78 (m, 2H). 13C NMR (D2O): δ 88.9, 78.2 (t, JCP
=
143.5, P−C−P), 69.0, 55.2 (t, ∑2JCP = 6.2, 2C, OCH3), 37.2, 25.7 (t,
2JCP = 5.8), 21.2. 31P NMR (D2O): δ 20.38. MS (ESI−): calcd for
This research was supported by strategic funding of the
University of Eastern Finland. The author thanks Mrs. Maritta
Salminkoski for her expert technical assistance and Dr. Janne
Mauritz Weisell for performing MS measurements. The author
−
C8H15O7P2 [M − H]− 285.0293, found 285.0292.
Dimethyl (1-Hydroxyhept-6-yne-1,1-diyl)bisphosphonate
Disodium Salt (2c). Prepared similarly to 2a, obtained as a white
also thanks Professor Jouko Vepsalainen for his guidance all
̈
̈
1
powder, 93% yield, mp >300 °C. H NMR (D2O): δ 3.70−3.64 (m,
these years.
4
3
4
6H, OCH3), 2.39 (t, 1H, J = 2.5), 2.28 (td, 2H, J = 7.5, J = 2.5),
2.00−1.89 (m, 2H), 1.74−1.66 (m, 2H), 1.62−1.53 (m, 2H). 13C
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■
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dx.doi.org/10.1021/jo500831r | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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