Synthesis and reactivity of alkyl-1,1,1-trisphosphonate esters

Article abstract of DOI:10.1021/jo201523w

The α-trisphosphonic acid esters provide a unique spatial arrangement of three phosphonate groups and may represent an attractive motif for inhibitors of enzymes that utilize di- or triphosphate substrates. To advance studies of this unique functionality,

Full text of DOI:10.1021/jo201523w

ARTICLE
pubs.acs.org/joc
Synthesis and Reactivity of Alkyl-1,1,1-trisphosphonate Esters
Jacqueline P. Smits and David F. Wiemer*
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294, United States
S Supporting Information
b
ABSTRACT: The α-trisphosphonic acid esters provide a unique spatial arrangement of three phosphonate
groups and may represent an attractive motif for inhibitors of enzymes that utilize di- or triphosphate
substrates. To advance studies of this unique functionality, a general route to alkyl derivatives of the parent
system (R = H) has been developed. A set of new α-alkyl-1,1,1-trisphosphonate esters has been prepared
through phosphinylation and subsequent oxidation of tetraethyl alkylbisphosphonates, and the reactivity of
these new compounds has been studied in representative reactions that afford additional examples of this
functionality.
’ INTRODUCTION
The geminal bisphosphonate moiety is found in a number of
drugs that are in widespread clinical use, including alendronate
(1, Fosamax), risedronate (2, Actonel), and zoledronate (3,
Zometa) (Figure 1).1 The clinical applications of these com-
pounds in treatment of various diseases of the bone,1 together
with the prevalence of di- and triphosphate intermediates in
metabolism, have encouraged studies of many other bisphos-
phonates, and there are numerous reports on their chemical
synthesis2 and biological activity.3 In sharp contrast to the
Figure 1. Bis- and trisphosphonates.
extensive work with geminal bisphosphonates, there are very
’ RESULTS AND DISCUSSION
few reported studies of aryl- or alkyl-1,1,1-trisphosphonate esters
(4). Phosphonate esters often are prepared through reaction of a
trialkyl phosphite with an alkyl halide, but simple alkyl halides are
not very reactive in this classical MichaelisÀArbuzov synthesis,
and chloroform does not react with triethyl phosphite even under
forcing conditions.4 However, trichloromethylamine is known to
react with triethyl phosphite to afford the aminotrisphosphonate
55 through a reaction sequence now assumed to be based on
eliminationÀaddition reactions.6 A similar strategy with a qui-
none methide was used to prepare the aryl trisphosphonate 6,7
and ultimately the parent compound 7 was prepared through
addition to tetraethyl diazo-bisphosphonate.6 The parent tris-
phosphonate 7 also has been prepared via CÀP bond formation.
In this case, the anionic bisphosphonate proved unreactive with
diethyl chlorophosphate, but phosphinylation of the bisphos-
phonate anion followed by oxidation to the phosphonate was
successful,6 a strategy that already had been applied to prepara-
tion of β-keto phosphonates from ketone and ester enolates.8
However, apart from some intriguing studies by Blackburn et al.,
who prepared adenosine esters derived from compound 7 and its
halogenated analogues,9 little has been done with trisphospho-
nates for some time. The limited information available on
trisphosphonate esters and our longstanding interest in CÀP
bond formation10 led us to investigate the synthesis and reactivity
of this functionality.
One might reasonably assume that the shortest route from
tetraethyl methylenebisphosphonate (8) to a family of alkyl
trisphosphonates would involve preparation of the parent tris-
phosphonate 7 followed by alkylation. To explore this possibility,
compound 7 was prepared starting with the literature approach
that employed phosphinylation of tetraethyl methylenebispho-
sphonate, but followed by oxidation of the presumed phosphi-
nate intermediate with hydrogen peroxide8b,10b rather than air
(Scheme 1).6 This modified procedure gave an improved yield
(48% vs 32% in the original report6) when the methylene-
1
bisphosphonate is thoroughly dried (vide infra), and the H,
13C, and 31P spectra of the material prepared this way matched
literature data.6 Attempted reaction of the methylenebisphos-
phonate anion with diethyl chlorophosphate was not successful
under the same reaction conditions.
Upon treatment of compound 7 with NaH, formation of the
anion was strongly suggested by a downfield shift in the 31P NMR
spectrum (from 14 to 32 ppm). However, addition of benzyl
bromide did not induce any further change in the 31P NMR
shift, nor did addition of the less sterically encumbered alkylating
agent allyl bromide. Presumably the limited reactivity of the
anion under these conditions is a consequence of the fact that the
Received: July 21, 2011
Published: September 14, 2011
r
2011 American Chemical Society
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Scheme 1. Strategies for Trisphosphonate Synthesis
Table 1. Synthesis of α-Alkyl-1,1,1- trisphosphonates
carbanionic center is both well stabilized and considerably
hindered. Several experiments were conducted to determine
the approximate acidity of compound 7. For example, the 31P
NMR resonance observed for the anion at 32 ppm persisted even
after addition of water or saturated NH4Cl to the NMR sample.
Only after addition of acetic acid was a resonance representing
the neutral compound 7 again observed at 14 ppm. Titration of
the trisphosphonate ester 7 with NaOH gave a pKa of ∼6.5,
suggesting that the negative charge is highly delocalized and that
this ester should be viewed as a strong carbon acid.
To explore alternate approaches to these compounds, tetra-
ethyl benzylbisphosphonate 9 was prepared by alkylation of
bisphosphonate 8.2c,d No evidence for CÀP bond formation
could be detected by 31P NMR upon treatment of compound 9
with NaH and diethyl chlorophosphate, but reactions that
employed diethyl chlorophosphite as the electrophile6,8 were
more encouraging. After treatment of bisphosphonate 9 with
NaH and diethyl chlorophosphite, exposure to air under stan-
dard conditions afforded just trace amounts of the desired
trisphosphonate. However, when reaction of the bisphosphonate
9 with NaHMDS and diethyl chlorophosphite at 0 °C was
followed by treatment with H2O2, an exothermic reaction
ensued. A new product was detected by TLC analysis, and
analysis of the reaction mixture by 31P NMR revealed a new
resonance at 18 ppm. After isolation of this product via column
a In this case, the bisphosphonate was prepared via conjugate addition of
sodium acetylide to vinyl bisphosphonate.2a
Scheme 2. Reactions of Trisphosphonate 11
1
chromatography, the H NMR spectrum displayed a notable
phosphorus coupling to the benzylic hydrogens (q, J = 15.8 Hz).
The 13C NMR spectrum was even more striking, with observable
couplings to 31P throughout the spectrum and a resonance for the
quaternary carbon that appeared as a clear quartet (JCP = 118 Hz).
On the basis of these data, as well as a consistent elemental
analysis, the product was assigned the structure of trisphos-
phonate 10.
The three-step protocol of alkylation, phosphinylation, and
oxidation proved to be successful with several other alkyl halides,
but the isolated yields initially were modest (<20%). Addition of
excess base did not result in increased yields. Elemental analyses
of alkylbisphosphonates have consistently revealed the presence
of water, suggesting that hydroxide generated in situ might
complicate formation of the desired intermediate in this case.
Thorough drying of the alkylated bisphosphonates via azeotopic
distillation with either benzene or toluene prior to deprotonation
and phosphinylation resulted in a dramatic increase in reaction
yields. Ultimately this strategy resulted in conversions ranging
from 64% to 86% by 31P NMR, with isolated yields typically just
slightly lower. This methodology was then applied to the
synthesis of a variety of alkyl trisphosphonates with good isolated
yields (Table 1). Furthermore, there is at least the potential to
recover the alkylbisphosphonate in the cases of lower conversion,
and that decision can be based on inspection of the 31P NMR
spectrum of the reaction mixture (∼18 ppm for trisphosphonate
10 versus ∼23 ppm for the bisphosphonate 9).
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Scheme 3. Reactions of Trisphosphonate 14
Scheme 4. A Click Reaction with Trisphosphonate 16
Scheme 5. Hydrolysis of Trisphosphonate 11
Because so few alkyl-1,1,1-trisphosphonates are known, it was
unclear whether it would be possible to carry out various
functional group transformations in the presence of this group.
Some reactions proved to be routine while others were not. For
example, treatment of allyltrisphosphonate 11 with hydrogen
over Pd/C resulted in selective reduction of the olefin to afford
the saturated compound 15 in good yield (Scheme 2). However,
some oxidative transformations proved to be more problematic.
After treatment of the allyl trisphosphonate 11 with ozone under
typical conditions,11 some evidence for formation of the desired
aldehyde 17 was obtained, including a resonance appropriate for
the aldehyde hydrogen in the 1H NMR spectrum. However, this
material was obtained in low yield, and there was detectable
dephosphorylation to a bisphosphonate. Attempts to avoid
decomposition by treatment with a limited amount of ozone
under Rubin conditions12 also resulted in decomposition of the
allyltrisphosphonate. Similar observations were found upon
attempted epoxidation. Treatment of allyl trisphosphonate 11
with m-CPBA resulted in the disappearance of the resonances for
the olefinic hydrogens, but again only low amounts of material
that appeared to be the epoxide 18 were obtained, and decom-
position to a bisphosphonate may be competitive.
In this case, attempted cross metathesis of compound 14 with 2-
methyl-2-butene proceeded smoothly and gave the expected trisub-
stituted olefin 21 in high yield (87%, Scheme 3). In a similar sense,
treatment of olefin 14 with 9-BBN followed by standard oxidative
workup gave the primary alcohol 22 in reasonable yield (57%).
While metathesis reactions of the trisphosphonate 11 may be
limited in their ability to afford a diverse array of new trisphos-
phonates, this is clearly a promising approach with more distal
olefins such as compound 14. Another approach to facile
preparation of compound libraries is based on the 1,3-dipolar
cycloaddition of azides with acetylenes (or click chemistry).14
Somewhat to our surprise given the results with the metathesis
reaction, the copper-catalyzed reaction of the acetylene trisphos-
phonate 16 with benzyl azide proceeded smoothly to give the
triazole 23 in 85% yield (Scheme 4). This reaction clearly
demonstrates that the trisphosphonate group will tolerate stan-
dard conditions for this cycloaddition and strongly suggests that
more distal acetylenes would react at least as well.
As one might expect, the trisphosphonate functionality is of
considerable size, and several attempted reactions appeared to be
difficult due to steric hindrance. For example, the allyl trisphos-
phonate 11 did not undergo hydroboration readily upon treat-
ment with 9-BBN, but treatment with borane in THF resulted in
conversion to the primary alcohol 19 in reasonable yield. The
trisphosphonate group was not significantly impacted by this
oxidative workup with H2O2, as might be expected given that
hydrogen peroxide was used during the trisphosphonate synthe-
sis. Cross metathesis reactions of trisphosphonate 11 also may be
affected by the size and proximity of the trisphosphonate moiety.
Attempted cross metathesis with 2-methyl-2-butene and the
Grubbs second generation catalyst gave the unexpected cis and
trans 1,2-disubstituted olefins 20 as the major product, and only a
small amount of the expected trisubstituted alkene 12.13 The
identity of the olefins 20 was established unequivocally when the
cross metathesis reaction of trisphosphonate 11 with 2-butene
also gave a mixture of the same cis and trans olefins 20.
Hydrolysis of these trisphosphonate esters could provide a
variety of salts depending upon the extent of ester hydrolysis.
Initial attempts to bring about complete hydrolysis of benzyl
trisphosphonate 10 by treatment with HCl under reflux resulted
in decomposition.15 Even though the corresponding benzylbis-
phosphonate 9 undergoes complete hydrolysis under parallel
conditions,2d the more relevant comparison may be with the
parent trisphosphonate 7, which also was reported to undergo
decomposition when subjected to acid hydrolysis.6 Treatment of
trisphosphonate 11 with TMSBr and collidine (Scheme 5)16
resulted in the formation of the TMS esters, as monitored by 31
P
NMR spectroscopy. Addition of 1 N NaOH to a solution of the
TMS ester led to complete hydrolysis and formation of the mixed
sodium and collidinium salt17 (24), which could be isolated by
standard workup.
In conclusion, these studies have led to a more efficient
synthesis of hexaethyl methanetrisphosphonate than in the
original report6 and determined that this compound should be
viewed as a strong carbon acid. They also have established a
general strategy for preparation of alkyl-1,1,1-trisphosphonates
from the corresponding alkyl-1,1-bisphosphonates through
phosphinylation and oxidation with hydrogen peroxide. As long
The importance of steric factors in the reactivity of compound
11 may be clarified by consideration of the reactivity of trisphos-
phonate 14, which can be viewed as a less sterically congested
analogue where the number of methylene carbons between the
double bond and the trisphosphonate group has been increased.
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as steric factors from the bulky trisphosphonate group are
considered, alkyl-1,1,1-trisphosphonates can undergo a variety
of functional group transformations, although they are sensitive
to some oxidative conditions. In particular, steric factors already
have led to an interesting variation on the Grubbs metathesis
where a disubstituted olefin was observed as the major product
from metathesis with 2-methyl-2-butene rather than the expected
trisubstituted alkene. Furthermore, the ability of an acetylene
trisphosphonate to undergo click chemistry suggests that li-
braries of trisphosphonates should be readily available. Thus it
appears likely that further studies of alkyl-1,1,1-trisphosphonates
will unveil other new chemistry and that screening of trisphos-
phonate libraries could be used to identify biologically active
compounds of this general structure. Investigations along these
lines are continuing and will be reported in due course.
EtOAc) gave the desired trisphosphonate 10 as a clear oil (432 mg,
61%): 1H NMR δ 7.60À7.57 (m, 2H), 7.23À7.20 (m, 3H), 4.24À4.13
(m, 12H), 3.59 (q, JPH = 15.8 Hz, 2H), 1.27 (t, J = 8.9 Hz, 18H); 13
C
NMR (100 MHz) δ 136.3 (q, JPC = 5.9 Hz), 132.5 (2C), 126.9 (2C),
126.6, 63.4 (m, 6C), 52.8 (q, JPC = 117.8 Hz), 36.1 (q, JPC = 5.1 Hz), 16.3
(m, 6C); 31P NMR (121 MHz, CDCl3) +17.7 ppm; HRMS calcd for
C20H37O9NaP3 (M + Na)+, 537.1548, found 537.1553. Anal. Calcd for
C20H37O9P3 H2O: C, 45.12; H, 7.38. Found: C, 45.26; H, 7.57.
3
3-Butenylidynetrisphosphonic Acid, Hexaethyl Ester (11).
According to the general procedure for synthesis of alkylated trisphos-
phonates, allylbisphosphonate20 (985 mg, 3.0 mmol) was treated with
NaHMDS (4.5 mL, 4.5 mmol) and ClP(OEt)2 (1.29 g, 8.2 mmol), and
then after 30 min H2O2 (3.50 mL, 31 mmol) was added to the reaction
mixture. After standard workup the product was purified via column
chromatography on silica gel (0 to 40% EtOH in EtOAc), and
1
compound 11 was isolated as a clear oil (987 mg, 71%): H NMR δ
6.32À6.18 (m, 1H), 5.15À5.05 (m, 2H), 4.34À4.14 (m, 12H), 2.92 (qd,
JPH = 9.0 Hz, J = 6.6 Hz, 2H), 1.34 (t, J = 7.2 Hz, 18H); 13C NMR δ
134.4 (q, JPC = 6.3 Hz), 117.1, 63.4 (m, 6C), 50.5 (q, JPC = 119.8 Hz),
35.0 (q, JPC = 5.5 Hz), 16.5 (m, 6C); 31P NMR +18.0 ppm; HRMS calcd
for C16H35O9NaP3 (M + Na)+, 487.1392, found 487.1407. Anal. Calcd
’ EXPERIMENTAL SECTION
General Procedures. Both THF and Et2O were distilled from
sodium and benzophenone immediately prior to use. All nonaqueous
reactions were performed with either oven-dried or flame-dried glass-
ware under an argon atmosphere. Flash chromatography was performed
on silica gel with an average particle size of 40À63 μm. The 1H NMR
spectra were recorded at 300 MHz (75 MHz for 13C) with CDCl3 as
solvent and (CH3)4Si as internal standard unless otherwise noted. The
1H NMR spectra recorded in D2O used residual H2O (4.80 ppm) as a
reference, and 1,4-dioxane (67.0 ppm) was used as a reference for these
13C NMR spectra. Chemical shifts of 31P NMR spectra are reported in
ppm relative to H3PO4 as an external standard. Elemental analyses were
performed at a commercial facility. High resolution mass spectral
analysis was performed with a quadrupole time-of-flight hybrid mass
spectrometer with the capacity for positive and negative ionization
modes. Electrospray ionization was employed with acetonitrile or
aqueous (24) solutions.
Methylidynetrisphosphonic Acid, Hexaethyl Ester (7).
Tetraethyl methylenebisphosphonate (251 mg, 0.87 mmol) was dis-
solved in benzene (5 mL) and then concentrated in vacuo to remove
traces of water. After three such cycles, the residue was dissolved in THF
(10 mL) and cooled to 0 °C in an ice bath. A solution of NaHMDS in
THF (1.0 M, 1.3 mL, 1.3 mmol) was added, and the mixture was allowed
to stir at 0 °C for 30 min after which ClP(OEt)2 (340 mg, 2.17 mmol)
was added. After an additional 30 min, H2O2 (2.0 mL, 17.6 mmol) was
very slowly added dropwise to the vessel. The reaction mixture was
allowed to stir for 1 h, then diluted with brine, and extracted with
CH2Cl2. The organic portions were combined, dried (MgSO4), and
filtered, and the filtrate was concentrated in vacuo. Final purification via
flash chromatography (silica gel, 0 to 50% EtOH in EtOAc) gave the
desired trisphosphonate 7 as a light yellow oil (176 mg, 48%). Both 31P
and 1H NMR data were consistent with previously reported values.5b,6
2-Phenylethylidynetrisphosphonic Acid, Hexaethyl Ester
(10). General procedure for the synthesis of alkyl trisphosphonates. A
sample of tetraethyl benzylbisphosphonate (9)18,19 (518 mg, 1.37
mmol) was dissolved in benzene (5 mL) and then concentrated in
vacuo. After three such cycles, the residue was dissolved in THF
(6.4 mL) and cooled to 0 °C in an ice bath. A solution of NaHMDS
in THF (1.0 M, 2.1 mL, 2.1 mmol) was added, and the mixture was
allowed to stir at 0 °C for 30 min, after which ClP(OEt)2 (437 mg, 2.74
mmol) was added. After an additional 30 min, excess H2O2 (2.0 mL,
∼30% by titration) was slowly added dropwise (5À10 min) to the
vessel. The reaction mixture was allowed to stir for 1 h, then diluted with
brine, and extracted with CH2Cl2. The organic portions were combined,
dried (MgSO4), and filtered, and the filtrate was concentrated in vacuo.
Final purification via flash chromatography (silica gel, 0 to 30% EtOH in
for C16H35O9P3 H2O: C, 39.84; H, 7.73. Found: C, 40.19; H, 7.83.
3
4-Methyl-3-pentenylidynetrisphosphonic Acid, Hexaethyl
Ester (12). According to the general procedure for synthesis of alkylated
trisphosphonates, prenylbisphosphonate2e (494 mg, 1.39 mmol) was
treated with NaHMDS (2.10 mL, 2.1 mmol) and ClP(OEt)2 (472 mg,
2.77 mmol). After 30 min H2O2 (2.00 mL, 17.6 mmol) was added to the
reaction mixture. The product 12 was purified bycolumn chromatography
on silica gel (0 to 30% EtOH in EtOAc) and was isolated as a faint yellow
oil (461 mg, 68%): 1H NMR δ 5.67 (t, J = 6.6 Hz, 1H), 4.29À4.17 (m,
12H), 2.86 (qd, JPH = 15.9 Hz, J = 6.6 Hz, 2H), 1.72 (s, 3H), 1.64 (s, 3H),
1.36À1.30 (m, 18H); 13C NMR δ 132.5, 120.2 (q, JPC = 6.1 Hz),
63.4À63.3 (m, 6C), 50.4 (q, JPC = 117.6 Hz), 29.5, (q, JPC = 5.4 Hz), 26.0,
17.9, 16.5À16.3 (m, 6C); 31P NMR (121 MHz, CDCl3) +18.6 ppm;
HRMS calcd for C18H40O9P3 (M + H)+, 493.1885, found 493.1883.
(3E)-4,9-Dimethyl-3-nonadienylidynetrisphosphonic Acid,
Hexaethyl Ester (13). According to the general procedure for syn-
thesis of alkylated trisphosphonates, geranylbisphosphonate3c (249 mg,
0.6 mmol) was treated with NaHMDS (1.00 mL, 1.0 mmol) and
ClP(OEt)2 (125 mg, 0.8 mmol), and then after 30 min H2O2 (1.00 mL,
8.8 mmol) was added to the reaction mixture. After standard workup, the
product 13 was purified by column chromatography on silica gel (0 to
30% EtOH in EtOAc) and was isolated as a faintly yellow oil (208 mg,
63%): 1H NMR δ 5.72 (t, J = 6.3 Hz, 1H), 5.13 (t, J = 6.2 Hz, 1H), 4.25
(q, J = 7.1 Hz, 12H), 2.87 (qd, JPH = 16.2, J = 7.1 Hz, 2H), 2.09À2.03 (m,
4H), 1.68 (s, 3H), 1.63 (s, 3H), 1.60 (s, 3H), 1.33 (t, J = 6.6 Hz, 18H);
13C NMR δ 135.8, 131.1, 124.1, 119.8 (q, JPC = 6.2 Hz), 63.1 (m, 6C),
50.2 (q, JPC = 119.6 Hz), 39.9, 29.2 (q, JPC = 5.6 Hz), 26.5, 25.5, 17.4,
16.3À16.2 (m, 6C), 16.1; 31P NMR +18.6 ppm; HRMS calcd for
C23H48O9P3 (M + H)+, 561.2511, found 561.2529. Anal. Calcd for
C23H47O9P3 H2O: C, 47.75; H, 8.54. Found: C, 47.98; H, 8.44.
3
Tetraethyl 6-Hepten-1,1-bisphosphonate. Tetraethyl methy-
lenebisphosphonate (5.31 g, 18.4 mmol) was added dropwise to a
stirring suspension of NaH (810 mg, 20.2 mmol) in THF (10 mL). After
30 min, 6-bromo-1-hexene (3.00 g, 18.4 mmol) was added, and the
mixture was heated at reflux overnight. After the reaction mixture had
cooled to room temperature, saturated NH4Cl was added, and the
organic and aqueous portions were separated. The aqueous portion was
extracted with Et2O, and the organic layers were combined, dried
(MgSO4), and concentrated in vacuo. The resulting oil was purified
via flash chromatography (silica gel, 10% EtOH in hexanes), and the
desired bisphosphonate was isolated in 46% yield (3.10 g): 1H NMR δ
5.84À5.73 (m, 1H), 5.03À4.92 (m, 2H), 4.23À4.12 (m, 8H), 2.27 (tt,
JPH = 24.3 Hz, J = 6.3 Hz, 1H), 2.01À1.83 (m, 4H), 1.64À1.54 (m, 2H),
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1.45À1.32 (m, 14H); 13C NMR δ 138.6, 114.3, 62.4À62.1 (m, 4C),
36.6 (t, JPC = 132.5 Hz), 28.5 (2C), 25.3, 16.3À16.2 (m, 4C); 31P NMR
+23.9 ppm; HRMS calcd for C15H33O6P2 (M + H)+, 371.1752, found
371.1745.
aqueous portions were retained and extracted with CH2Cl2. The organic
portions were combined, dried (MgSO4), and concentrated in vacuo.
The resulting oil was purified via flash chromatography (silica gel, 0 to
45% EtOH in EtOAc) to obtain compound 19 as a clear oil (66 mg,
1
62%): H NMR δ 4.33À4.20 (m, 12H), 3.64 (t, J = 5.7 Hz, 2H),
6-Heptenylidynetrisphosphonic Acid, Hexaethyl Ester
(14). According to the general procedure for synthesis of alkylated
trisphosphonates, tetraethyl 6-hepten-1,1-bisphosphonate (508 mg,
1.37 mmol) was treated with NaHMDS (2.06 mL, 2.06 mmol) and
ClP(OEt)2 (438 mg, 2.75 mmol), and then H2O2 (2.00 mL, 17.6 mmol)
was added. After standard workup the product 14 was purified by
column chromatography on silica gel (0 to 30% EtOH in EtOAc) and
was isolated as a faintly yellow oil (435 mg, 78%): 1H NMR (CDCl3) δ
5.89À5.75 (m, 1H), 5.04À4.92 (m, 2H), 4.29À4.19 (m, 12H),
2.11À2.00 (m, 4H; 2 exchange with D2O), 1.91À1.80 (m, 2H)
1.43À1.13 (m, 22H); 13C NMR (CDCl3) δ 138.8, 114.2, 63.4À63.1
(m, 6C), 50.6 (q, JPC = 119.3 Hz), 33.4, 30.8 (q, JPC = 5.3 Hz), 29.3, 25.2
(q, JPC = 5.0 Hz), 16.5À16.2 (m, 6C); 31P NMR (121 MHz, CDCl3)
+18.7 ppm; HRMS calcd for C19H41O9NaP3 (M + Na)+, 529.1861,
found 529.1867.
2.30À2.05 (m, 7H; 2 exchange with D2O), 1.35 (t, J = 6.6 Hz, 18H); 13
NMR δ 63.5À63.4 (m, 6C), 63.0, 51.6 (q, JPC = 119.8 Hz), 33.0 (q, JPC
C
=
5.5 Hz), 19.2 (q, JPC = 5.2 Hz), 16.4 (m, 6C); 31P NMR +18.8 ppm;
HRMS calcd for C16H37O10NaP3 (M + Na)+, 505.1497, found
505.1503.
3-Pentenylidynetrisphosphonic Acid, Hexaethyl Ester
(20) and Compound 12. Grubbs second generation catalyst (4.9 mg,
3 mol %) was dissolved in 2-methyl-2-butene (1 mL) and placed in a
1-dram vial. The trisphosphonate 11 (88.3 mg, 0.2 mmol) was added to
this mixture, along with an additional 1 mL of 2-methyl 2-butene. The
vial was sealed, and the reaction was allowed to stir at 40 °C overnight.
After the solvent was removed in vacuo, the resulting oil was purified via
flash chromatography (silica gel, 0 to 30% EtOH in EtOAc). The
reaction products (76 mg, 83% total) were isolated as an inseparable
mixture of cis and trans isomers of compound 20 (68%, 1.2:4.3 isomer
ratio) and prenyl trisphosphonate 12 (15%, 1:5.5 ratio with respect to
olefins 20). The 31P, 1H, and 13C NMR spectra were consistent with a
mixture of compounds 20 and 12, both of which had been prepared
independently.
Compound 20 via Metathesis with 2-Butene. Grubbs second
generation catalyst (2.3 mg, 6 mol %) was dissolved in CH2Cl2 (0.5 mL)
and placed in a 1-dram vial, and trisphosphonate 11 (24 mg, 0.1 mmol)
was added to this mixture. After 2-butene was added to the vessel via
balloon, the vessel was sealed, and the reaction was allowed to stir at
40 °C overnight. The volatile materials were removed in vacuo, and the
resulting oil was purified via flash chromatography (silica gel, 0 to 30%
EtOH in EtOAc). The olefins 20 were isolated as a mixture of trans and
cis isomers (19 mg, 78%) in a 2.8:1 ratio. For the trans isomer: 1H NMR
(500 MHz, CDCl3) δ 5.85 (dt, J = 14.0, 7.0 Hz, 1H), 5.57À5.50 (m,
1H), 4.29À4.18 (m, 12H), 2.89À2.84 (m, 2H), 1.67 (dd, J = 7.0, 1.5 Hz,
3H), 1.35À1.32 (m, 18H); 13C NMR (125 MHz, CDCl3) δ 128.0, 126.7
Butylidynetrisphosphonic Acid, Hexaethyl Ester (15). Ac-
cording to the general procedure for synthesis of alkylated trisphos-
phonates, propylbisphosphonate19,21 (292 mg, 0.9 mmol) was treated
with NaHMDS (1.30 mL, 1.3 mmol) and ClP(OEt)2 (346 mg, 2.2
mmol). After 30 min H2O2 (2.00 mL, 17.6 mmol) was added to the
reaction mixture. Standard workup and purification via column chro-
matography on silica gel (0 to 35% EtOH in EtOAc) gave compound 15
1
as a clear oil (324 mg, 79%). Both the 31P and H NMR spectra are
consistent with material prepared via hydrogenation of compound 11
(vide infra).
3-Butyn-1-ylidynetrisphosphonic Acid, Hexaethyl Ester
(16). According to the general procedure for synthesis of alkylated
trisphosphonates, propargylbisphosphonate22 (291 mg, 0.9 mmol) was
treated with NaHMDS (0.9 mL, 0.9 mmol) and ClP(OEt)2 (280 mg,
1.8 mmol), and then after 30 min H2O2 (2.00 mL, 17.6 mmol) was added
to the reaction mixture. After standard workup the product was purified
via column chromatography on silica gel (0 to 30% EtOH in EtOAc),
and compound 16 was isolated as a clear oil (243 mg, 59%): 1H NMR δ
4.33À4.21 (m, 12H), 3.03 (qd, JPH = 14.7 Hz, J = 3.3 Hz 2H), 2.09À2.07
(m, 1H), 1.34À1.32 (m, 18H); 13C NMR δ 79.9 (q, JPC = 9.1 Hz), 70.5,
63.9À63.6 (m, 6C), 49.7 (q, JPC = 120.0 Hz), 21.0 (q, JPC = 5.6 Hz),
16.4À16.3 (m, 6C); 31P NMR +16.7 ppm; HRMS calcd for
C16H34O9P3 (M + H)+, 463.1416, found 463.1420.
(q, JPC = 6.3 Hz), 63.4À63.3 (6C), 50.7 (q, JPC = 119.5 Hz), 33.9 (q, JPC
=
5.3 Hz), 17.9, 16.5À16.3 (6C); 31P NMR (121 MHz, CDCl3) +18.4
ppm. For the cis isomer: 1H NMR (500 MHz, CDCl3), δ 5.94À5.92 (m,
1H), 5.57À5.50 (m, 1H), 4.29À4.18 (m, 12H), 2.89À2.84 (m, 2H),
1.64 (dd, J = 7.0, 1.0 Hz, 3H), 1.35À1.32 (m, 18H); 13C NMR (125
MHz, CDCl3) 126.1 (q, JPC = 6.0 Hz), 125.0, 63.5À63.4 (6C), 50.1 (q,
JPC = 119.6 Hz), 28.3 (q, JPC = 8.0 Hz), 16.5À16.3 (6C), 12.9; 31P NMR
(121 MHz, CDCl3) +18.5 ppm; HRMS calcd for C17H37O9NaP3 (M +
Trisphosphonate 15 via Catalytic Hydrogenation of Com-
pound 11. Trisphosphonate 11 (96 mg, 0.2 mmol) in EtOH (5 mL)
was treated with Pd/C (23 mg, 0.2 mmol) under an H2 atmosphere.
After 12 h the reaction mixture was filtered through Celite, and the
filtrate was collected and concentrated in vacuo. The resulting oil was
purified using flash chromatography (silica gel, 0 to 25% EtOH in
EtOAc) to obtain compound 15 as a clear oil (81 mg, 84%): 1H NMR δ
4.30À4.18 (m, 12H), 2.18À1.77 (m, 4H), 1.34 (t, J = 6.6 Hz, 18H), 0.91
(t, J = 6.9 Hz, 3H); 13C NMR δ 63.4 (m, 6C), 51.6 (q, JPC = 119.8 Hz),
Na)+, 501.1548, found 501.1554. Anal. Calcd for C17H37O9P3 H2O: C,
3
41.13; H, 7.92. Found: C, 41.35; H, 7.91.
7-Methyl-6-octenylidynetrisphosphonic Acid, Hexaethyl
Ester (21). Grubbs second generation catalyst (3.1 mg, 3 mol %) was
dissolved in 2-methyl-2-butene and placed in a 1-dram vial, and trisphos-
phonate 14 (62 mg, 0.12 mmol) was added along with an additional
1 mL of 2-methyl-2-butene. The vial was sealed, and the reaction was
allowed to stir at 40 °C overnight. After concentration in vacuo, the
resulting oil was purified via flash chromatography (silica gel, 0 to 30%
EtOH in EtOAc), and the desired product 21 was isolated as an oil (57
mg, 87%): 1H NMR δ 5.12 (t, J = 6.0 Hz, 1H), 4.19À4.31 (m, 12H),
1.96À2.24 (m, 6H), 1.77À1.88 (m, 2H), 1.68 (3H), 1.57 (3H), 1.34 (t,
J = 6.6 Hz, 18H); 13C NMR δ 131.2, 124.7, 63.5À63.2 (m, 6C), 50.7 (q,
JPC = 119.4 Hz), 31.0À30.9 (m), 30.9, 27.8, 25.7, 25.4 (q, JPC = 5.2 Hz),
17.6, 16.4À16.2 (m, 6C); 31P NMR +18.8 ppm; HRMS calcd for
C21H46O9P3 (M + H)+, 535.2355, found 535.2357.
33.0 (q, JPC = 5.5 Hz), 19.2 (q, JPC = 5.2 Hz), 16.4 (m, 6C), 15.0; 31
P
NMR +18.8 ppm; HRMS calcd for C16H37O9NaP3 (M + Na)+,
489.1548, found 489.1564. Anal. Calcd for C16H37O9P3 H2O: C,
3
39.67; H, 8.11. Found: C, 39.66; H, 8.02.
4-Hydroxybutylidynetrisphosphonic Acid, Hexaethyl Es-
ter (19). Trisphosphonate 11 (102 mg, 0.22 mmol) was dried under
vacuum in the presence of P2O5 overnight. The remaining oil was
dissolved in THF (5 mL) and placed into an ice bath. To the reaction
flask was added BH3 THF (1 M in THF, 0.45 mL, 0.45 mmol), and the
3
mixture was allowed to stir. After 1.5 h, MeOH (2 mL) was added to the
flask, followed by NaOH (3M, 0.5 mL, 1.5 mmol) and then H2O2
(0.3 mL, 2.7 mmol), and the resulting mixture was heated at 50 °C
for 1 h. The reaction mixture was washed with saturated NaCl, and the
7-Hydroxyheptylidynetrisphosphonic Acid, Hexaethyl Es-
ter (22). Trisphosphonate 14 (109 mg, 0.2 mmol) was dried overnight
under vacuum in the presence of P2O5. The remaining oil was dissolved
in THF (5 mL) and placed into an ice bath. To the reaction flask was
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The Journal of Organic Chemistry
ARTICLE
added 9-BBN (0.5 M in THF, 1.0 mL, 0.5 mmol), and the mixture was
allowed to stir. After 1.5 h, MeOH (2 mL) was added to the flask,
followed by NaOH (3 M, 0.5 mL, 1.5 mmol) and then H2O2 (0.5 mL,
4.4 mmol), and the resulting mixture was heated at 50 °C for 1 h. The
reaction mixture was washed with saturated NaCl, and the aqueous
portions were retained and extracted with CH2Cl2. The organic portions
were combined, dried (MgSO4), and concentrated in vacuo. The
resulting oil was purified via flash chromatography (silica gel, 0 to
40% EtOH in EtOAc) to obtain compound 22 as a clear oil (64 mg,
’ ACKNOWLEDGMENT
Financial support from the NIH Predoctoral Training Pro-
gram in the Pharmacological Sciences (2 T32 GM067795), the
U.S. Department of Education (GAANN award P200A070526),
and the Roy J. Carver Charitable Trust as a Research Program of
Excellence is gratefully acknowledged.
’ REFERENCES
1
57%): H NMR δ 4.30À4.17 (m, 12H), 3.63 (t, J = 6.3 Hz, 2H),
(1) For an excellent review of the chemistry and biological activity of
bisphosphonates, see: Ebetino, F. H.; Hogan, A.-M.; Sun, S.; Tsoumpra,
M.; Duan, A.; Triffitt, J. T.; Kwaasi, A. A.; Dunford, J. E.; Barnettt, B. L.;
Oppermann, U.; Lundy, M. W.; Boyde, A.; Kashemirov, B. A.; McKenna,
C. E.; Russell, R. G. G. Bone 2011, 49, 20–33.
2.18À2.03 (m, 3H), 1.90À1.82 (m, 2H), 1.60À1.53 (m, 2H),
1.44À1.28 (m, 22); 13C NMR δ 63.5À63.2 (m, 6C), 62.8, 50.6
(q, JPC = 119.5 Hz), 32.7, 30.8 (q, JPC = 5.3 Hz), 30.3, 25.5 (q, JPC = 5.3
Hz), 25.3, 16.5À16.2 (6C); 31P NMR +18.8 ppm; HRMS calcd for
C19H43O10NaP3 (M + Na)+, 547.1967, found 547.1991.
(2) For representative syntheses of bisphosphonates via addition to
alkylidene bisphosphonates, see: (a) Sturtz, G.; Guervenou, J. Synthesis
1991, 661. (b) Hutchinson, D. W.; Thornton, D. M. J. Organomet. Chem.
1988, 346, 341. For synthesis via alkylation of methylenebisphospho-
nates, see:(c) Kosolapoff, G. M. J. Am. Chem. Soc. 1953, 75, 1500–1501.
(d) Quimby, O. T.; Curry, J. D.; Nicholson, D. A.; Prentice, J. B.; Roy,
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A. J.; Hohl, R. J.; Wiemer, D. F. Bioorg. Med. Chem. 2006, 14, 4130–4136.
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Bioorg. Med. Chem. 2010, 18, 7212–7220. For a synthesis via two CÀP
bond formations and lead references to other strategies, see:(g) Du, Y.;
Jung, K. Y.; Wiemer, D. F. Tetrahedron Lett. 2002, 43, 8665–8668.
(3) For representative reports of biologically active bisphos-
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F. H.; Xia, Z.; Russell, R. G. G.; Coxon, F. P.; Roelofs, A. J.; Rogers, M. J.;
McKenna, C. E. Bioconjugate Chem. 2008, 19, 2308–2310. (b) Singh,
A. P.; Zhang, Y.; No, J. H.; Docampo, R.; Nussenzweig, V.; Oldfield, E.
Antimicrob. Agents Chemother. 2010, 54, 2987–2993. (c) Holstein, S. A.;
Cermak, D. M.; Wiemer, D. F.; Lewis, K.; Hohl, R. J. Bioorg. Med. Chem.
1998, 6, 687–694. (d) Wiemer, A. J.; Yu, J. S.; Lamb, K. M; Hohl, R. J.;
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therein.
1-Benzyl-4-[2,2,2-tris(diethyoxyphosphinyl)ethyl-1H-1,2,
3-triazole (23). Benzyl bromide (182 mg, 1.1 mmol) was added to a
suspension of sodium azide (83 mg, 1.3 mmol) in DMF (5 mL), and the
resulting mixture was allowed to stir. After 10 min, trisphosphonate 16
(164 mg, 0.4 mmol) was added along with 0.1 mL of CuSO4 (5 M),
sodium ascorbate (43 mg, 0.2 mmol), and a solution of tBuOH in water
(1:4 ratio, 5 mL), and the reaction mixture was allowed to stir at room
temperature. After 24 h EDTA and 1 M NH4OH were added, the
resulting solution was placed in a continuous liquidÀliquid extractor and
extracted for 4 h with EtOAc. The organic portion was retained and
concentrated in vacuo. The resulting oil was purified via flash chromatog-
raphy (silica gel, 0 to 50% EtOH in EtOAc) to provide the desired triazole
23 (179 mg, 85%): 1H NMR δ 7.95 (s, 1H), 7.35À7.31 (m, 5H), 5.47 (s,
2H), 4.22À4.07 (m, 12H), 3.66 (q, JPH = 15.9 Hz, 2H), 1.26À1.21(m,
18H); 13CNMR δ143.3 (q, JPC = 7.4 Hz), 135.2, 128.9 (2C), 128.4, 128.0
(2C), 124.7, 63.7À63.4 (m, 6C), 53.9, 50.6 (q, JPC = 119.2 Hz), 27.9, (q,
JPC = 5.5 Hz), 16.4À16.1 (m, 6C); 31P NMR +17.6 ppm; HRMS calcd for
C23H40N3O9NaP3 (M + Na)+, 618.1875, found 618.1893.
3-Butenylidynetrisphosphonic Acid, Pentasodium, 2,4,6-
Trimethylpyridinium Salt (24). A solution of 2,4,6-collidine (524 mg,
4.3 mmol) and TMSBr (568 mg, 4.3 mmol) was allowed to stir in an
ice bath. After 20 min, trisphosphonate 11 (75 mg, 0.2 mmol) was added,
and the reaction was allowed to stir for 24 h with periodic monitoring by
31P NMR spectroscopy. Once the reaction was complete, it was diluted
by addition of toluene, the solvent was removed in vacuo, and aqueous
sodium hydroxide (1.5 mmol, 9 equiv) was added. The mixture was
allowed to stir overnight and again was monitored by 31P NMR. The
reaction mixture then was lyophilized, and the resulting solid was dissolved
in a minimum amount of water, then slowly poured into cold acetone,
and kept at 40 oC overnight. The resulting precipitate was filtered and
washed with cold acetone. The remaining residue was dissolved in water
and lyophilized to afford compound 24 as a flocculent white residue (51 mg,
60%): 1H NMR (D2O) δ 7.43 (s, 2H), 6.19À6.10 (m, 1H), 5.23À5.05
(m, 2H), 2.92À 2.85 (m, 2H), 2.93 (s, 6H), 2.50 (s, 3H); 13C NMR
(D2O) δ 164.1 (2C), 155.8, 139.1À139.0 (m), 129.2, 121.6 (2C), 52.3 (q,
JPC = 103.6 Hz), 38.6, 25.3 (2C), 22.5; 31P NMR (121 MHz, D2O) +17.5
ppm; HRMS calcd for C4H10O9P3 (M À H)À, 294.9538, found 294.9542.
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’ AUTHOR INFORMATION
Corresponding Author
*E-mail: david-wiemer@uiowa.edu.
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