Symmetrical and asymmetrical bisphosphonate esters. Synthesis, selective hydrolysis, and isomerization

Article abstract of DOI:10.1007/s00706-005-0403-y

Two simple and efficient one-pot procedures for the synthesis of a series of α-branched N-heterocycle-substituted methane-1,1-bisphosphonates are outlined. In the first method, the parent halosubstrates were reacted with cyanomethylphosphonate followed by

Full text of DOI:10.1007/s00706-005-0403-y

Monatshefte f€ur Chemie 137, 105–116 (2006)
DOI 10.1007/s00706-005-0403-y
Symmetrical and Asymmetrical
Bisphosphonate Esters. Synthesis,
Selective Hydrolysis, and Isomerization
Wafaa M. Abdou1;ꢀ, Neven A. Ganoub1, Amin F. Fahmy2,
and Abeer A. Shaddy1
1
Department of Pesticide Chemistry, National Research Centre, Dokki,
12622, Cairo, Egypt
2
Department of Chemistry, Faculty of Science, Ain-Shams University, Cairo, Egypt
Received March 18, 2005; accepted (revised) May 11, 2005
Published online January 5, 2006 # Springer-Verlag 2006
Summary. Two simple and efficient one-pot procedures for the synthesis of a series of ꢀ-branched
N-heterocycle-substituted methane-1,1-bisphosphonates are outlined. In the first method, the parent
halosubstrates were reacted with cyanomethylphosphonate followed by reaction with dialkyl phospho-
nates to give asymmetrical or symmetrical bisphosphonates (BPs). In the second approach, the same
halocompounds were reacted with tetraethyl methyl-1,1-bisphosphonate to give the requisite BPs.
Partial and complete hydrolysis of the prepared BPs were also investigated. The products contain
functional groups advantageous for further synthetic modification as structural units for coupling with
the drug.
Keywords. Drug research; Carbanions; Methyl-1,1-bisphosphonates; Bone mineral affinity.
Introduction
Over the past few years, methyl-1,1-bisphosphonates (BPs) of type A (Formula 1)
have been receiving increased attention as a new class of pharmacological active
compounds [1]. Following the recent FDA approval of Pamidronate (Aredia+,
H2NH2CH2C–C(OH)[P(O)(OH)2]2) in 1995 [2], for multiple myeloma and breast
cancer bone disease, BPs have rapidly become the standard treatment for cancer-
linked hypercalcemia of malignancy and osteolytis bone disease, all over the world.
Notwithstanding, significant progress has been made in this area over the past
two decades, it is likely that realization of the full medicinal potential of both BPs
and their relevant bisphosphonic acids remains in the future pending on further
advances in drug design.
ꢀ
Corresponding author. E-mail: wabdou@intouch.com

106
W. M. Abdou et al.
Formula 1
Scheme 1
The marked structure-activity relationships observed among several BPs of
type A indicate that the pharmacophore required for maximal activity depends
not only upon the bisphosphonate moiety but also on key additional features,
especially nitrogen substitution in alkyl or heterocyclic side chains (R0 and R00
in A). For the reasons already mentioned, in a recent study [3] for developing
better drugs suitable for bone diseases, we described a facile and general method
for synthesis of several examples of N-heterocycle-substituted methyl-1,1-bisphos-
phonic acids C derived from the Michael addition reaction of the parent alkylidene
compounds B with tetraethyl methyl-1,1-bisphosphonate (1), followed by acid
hydrolysis (Scheme 1). Screening of some selected products has shown that these
compounds have potent cardiovascular and inflammatory activities, and are poten-
tially useful in the treatment of vascularhypertension.
As a sequel, we report herein two different one-pot procedures for the synthesis
of a series of symmetrical and asymmetrical ꢀ-branched methyl-1,1-bisphospho-
nates, bearing N-containing heterocycle species. Hydrolysis or partial hydrolysis of
the relevant phosphonate esters was also undertaken.
Results and Discussion
The first method involves a coupling reaction between halocompound D with the
lithium salt of diethyl cyanomethylphosphonate 2 to give the monophosphonate E.
Further displacement of the nitrile group by the phosphite moiety affords the
required bisphosphonate F (Scheme 2).
Accordingly, the general experimental procedure is as follows: the methylene
activated diethyl cyanomethylphosphonate 2 was treated with two equivalents LiH
in DMF at room temperature leading to the corresponding lithium salt. This in turn
was treated directly with the halogenated species in the presence of a further
equivalent LiH. The reaction mixture was refluxed for a proper time (TLC), poured
on water, and acidified. The product mixture was easily separated by solvent
extraction and purified. The phosphoryl carbanion of 2 was used in threefold excess
based on the corresponding halo compounds; otherwise the yields of the resulting
products decreased drastically.

Symmetrical and Asymmetrical Bisphosphonate Esters
107
Scheme 2
Following this procedure, 3-chlorophenanthro[9,10-e]-1,2,4-triazine (4a) (or
3-chloro-5,6-diphenyl-1,2,4-triazine (4b)) was treated with 2 (three equivalents)
in refluxing DMF containing excess of LiH (twice equivalents of 2) to give the
corresponding diethyl 3-cyanomethylphosphonates 5a (74%) or 5b (71%) as the
sole reaction product (Scheme 3). A similar behavior was observed when 4a and
4b were allowed to react with alkylidenephosphoranes [4a]. Furthermore, reactions
of 4a and 4b with cyclic and acyclic trialkyl phosphites, as well as dialkyl phos-
phonates have been previously studied by us [4b].
Structure 5 was found to be present in two tautomeric isomers 5A { 5B
as indicated by the NMR spectra. The 31P NMR spectrum of 5a showed
1
two resonances at ꢁ ¼ 32.83 and 33.94 ppm (3:1 ratio). The H NMR spectrum
of 5a (DMSO-d6) showed the exocyclic methine proton of 5aA as a doublet
(2JPH ¼ 22.2 Hz) at 4.43 ppm. The presence of an exocyclic methine proton was
also attested to a doublet (1JPC ¼ 144 Hz) at 51.6 (HC-P) in the 13C NMR
spectrum of 5a, a value that coincides with an expected shift for a deshielded
methane-carbon due to the electron withdrawing cyano and phosphonate groups.
Furthermore, the doublet (1JPC ¼ 203 Hz) at 73.4 ppm was assigned for ¼ C-P
1
(5aB). However, the weak signals for the NH in the H NMR (ꢁ ¼ 12.34 ppm)
and IR spectra (ꢂꢀ¼ 3453 cmꢁ1) indicate that 5aA is the predominant tautomer.
When the phosphonate 5a was treated with one equivalent of dimethyl phos-
phonate (3a), the reaction was completed by boiling the reactants in toluene
containing 10 cm3 of a NaOH solution (0.5 M) for 24 h. The reaction yielded a
colorless crystalline material of diethyl dimethyl phenanthro[9,10-e]-1,2,4-tri-
azine-3-methane-1,1-bisphosphonate (6a, 62% based on 5a), via elimination of
HCN [7a], according to Scheme 3. A similar treatment of 5a with diethyl phos-
1
phonate (3b) led to the tetraethyl derivative 6b (74%). The H and 13C NMR
spectra of 6b are similar to those of 6a except for the ester group, which displays
characteristic resonances. Parallel compounds 6c (68%) and 6d (72%) were
likewise obtained by treating 5b with dialkyl phosphonates 3a and 3b under the
same reaction conditions (Scheme 3). The bisphosphonate tautomerism 6aA–
6dA { 6aB–6dB (3:1 ratio as being indicated from the 31P NMR spectra) is
unambiguously supported by the spectral data. The IR spectra of compounds

108
W. M. Abdou et al.
Scheme 3
6a–6d exhibited the presence of NH stretching vibration bands (ꢂ3420 cmꢁ1). The
distinguishing features in the 13C NMR spectra of 6a and 6b were the presence of
signals at ꢁ ꢂ 36 (t, JPC ¼ ꢂ140 Hz, ꢀ-CHP, 6A) and ꢂ54 (t, JPC ꢂ 200 Hz, ¼ C-P,
6B) ppm [7]. Furthermore, the 31P NMR spectra of BPs 6a–6d showed two doub-
lets (JPP ¼ 6 Hz) for P–C–P around ꢁ ꢂ 22 and 24 ppm [8].
Similar to 6, this synthesis was extended to tetraalkyl 1,3-dimethyluracil-5-
methane-1,1-bisphosphonates 10a and 10b in 61% and 65% yields. Thus, applica-
tion of 2 to 5-bromo-1,3-dimethyluracil (8a) afforded the expected diethyl 1,3-
dimethyluracil-5-cyanomethylphosphonate (9) in 69% yield (Scheme 4). The
structure of 9 was substantiated from elemental analysis and spectral properties.

Symmetrical and Asymmetrical Bisphosphonate Esters
109
Scheme 4
No reaction was observed, as stated before [5], when 5-bromouracil (8b) was
treated with the same reagent 2 in boiling DMF containing LiH, even after 3 days.
The reactions of uracils with different ter- and pentavalent phosphorus reagents
have been previously studied [5, 6].
When 9 was reacted with dialkyl phosphonates 3a or 3b in toluene containing
0.5 M sodium hydroxide solution it afforded the required bisphosphonates 10a or
10b (Scheme 4). The 31P NMR spectrum of 10b revealed only one signal at
ꢁ ¼ 20.67 ppm [9].
Furthermore, 6a–6d, 10a, and 10b could be obtained in better yields when the
sodium salt of 3a or 3b was added directly to the crude product mixture resulting
from the reaction of 4a, 4b, or 8a with 2.
In one of our previous studies [5], we reported that treatment of 2-chloroisatin
(12) with phosphonate 2 (4 mol equivalents) in the presence of NaH (twice equiva-
lents of 2) in boiling THF for 14 h led to the formation of the phosphono-substi-
tuted furan 14 (55%) via the nonisolable intermediate 13a (Scheme 5, pathway i).
In the present investigation, an experiment to slow down the above reaction for
isolating the intermediate was undertaken. Thus, 13b could be isolated in 48%
yield along with 14 in 12% yield by allowing 12 to react with 2 in the presence
of EtONa at room temperature for 48 h. On the same ground, when 13b was treated
with 3a or 3b in a way analogous to the one described for 5, tetraalkyl isatin-2-
methane-1,1-bisphosphonates 15a and 15b were obtained (Scheme 5, pathway ii).
Notably, in contrast to 5 and 6, the products 13b and 15 were present exclusively in
one isomeric form as there was no indication for the presence of an exocyclic
methine proton in the 1H or 13C NMR spectra of these species (see Experimental).
In the second method, we have applied another Horner-Wittig reagent, tetra-
ethyl methyl-1,1-bisphosphonate (1) to the same halosubstrates D whereupon the
BPs F (R ¼ Et) were produced (Scheme 6).

110
W. M. Abdou et al.
Scheme 5
Scheme 6
Scheme 7
The BPs 6b (60%), 6d (63%), 10b (66%), and 15b (67%) were available,
unequivocally, by one step synthesis from the reaction of the proper halo sub-
strate 4a, 4b, 8a, or 12 with 1. The reactions were carried out in alcoholic
sodium ethoxide solution at reflux temperature (ꢃ15 h, TLC) (Scheme 7). The
products were found to be identical in all aspects with compounds described
above.
As recent structure-activity studies in several pharma laboratories have identi-
fied impressively distinct therapeutic characteristics from 1,1-bisphosphonic acid
to 1,1-bisphosphonate ester counterparts [10], we also present in this report our
preparation of substituted-1,1-bisphosphonic acids. Thus, e.g. hydrolysis [7] of the

Symmetrical and Asymmetrical Bisphosphonate Esters
111
Scheme 8
bisphosphonates 6a and 10b with concentrated HCl gives the corresponding 1,1-
bisphosphonic acid 7 (83%) (Scheme 3) and 11 (85%) (Scheme 4).
In another experiment, we applied the acid hydrolysis to the monophosphonate
9, as a representative example. Cyanomethylphosphonic acid 16 was allowed to
react with 3b using the previous reaction conditions to furnish the partially hydro-
lyzed bisphosphonate 17 in 55% yield, based on 9 (Scheme 8).
Biological Evaluation
Finally, to predict the effect on bone resorption of these new BPs, the examples 6a,
6b, 10a, 10b, 7, 11, and 17 were evaluated in vitro [12] and in vivo [13]. All tested
compounds inhibited in vitro osteoclast mediated pit formation for up to 76% at
10ꢁ8 M. Different side chain substitutions resulted in marked differences in the
antiresorptive potency. In vivo BPs 6a, 6b, and 17 inhibited unstimulated bone
resorption at a relatively high dose of 2ꢄ200 mg=kg for up to 60%, whereas the
effects with 7, 10a, 10b, and 11 were 10 times stronger. These data indicate that the
effects of these new compounds are only moderate when compared to Risedronate.
Thus, the results obtained are encouraging for further optimization of the antire-
sorptive properties of these compounds.
Conclusion
Halo compounds were elaborated as valuable and versatile candidates for the pro-
duction of ꢀ-N-heterocycle – substituted methane-1,1-bisphosphonates. The two
reported one-pot procedures for the generation of BPs are derived from the treat-
ment of the halo substrates with Horner-Wittig reagents. However, despite the first
process includes two steps, namely the reaction of the halo compound with cya-
nomethylphosphonate followed by treatment of the resulting mixture in situ with
dialkyl phosphonates, this procedure is highly advantageous due to the easily
accessible and low cost starting materials. In addition, the two steps of this process
allow the possibility of preparing a variety of asymmetrical BPs as well as partially
hydrolyzed products. On the other hand, the second one-pot procedure for the
synthesis of BPs, by treatment of the halo species with tetraethyl methyl-1,1-
bisphosphonate is a straightforward, simple, and smooth one reaction step, with
total avoidance of any further reaction. Moreover, the better yields of the obtain-
able BPs, in question, are the distinct advantage of the latter method. Its major
drawback is, however, the high cost of 1, and the reported methods of preparing
such reagents are very long and low yielding [11].

112
W. M. Abdou et al.
Experimental
All melting points were recorded on an Electrothermal 9100 melting point apparatus. IR spectra (KBr)
were recorded on a Jasco FT=IR 300E spectrophotometer. The 1H and 13C NMR spectra were recorded
on a Varian MERCURY 300 MHz (75 MHz) spectrometer. The 31P NMR spectra were run on a Varian
CFT-20 relative to external H3PO4 (75%). The mass spectra were recorded on a Finnigan SSQ 7000
(EI 70 eV) spectrometer. The starting halo compounds 4a, 4b [14], 8a [15], and 12 [16] were prepared
according to the reported procedures. Satisfactory elemental analyses and molecular weight measure-
ments (MS) were obtained for all new compounds.
Preparation of the Phosphonates 5a, 5b, and 9
A solution of LiH (9M) in 20cm3 DMF was treated with 1.6g 2 (9.0mmol) followed by 9 M LiH in
15cm3 DMF and 0.8 g (3.0mmol) triazines 4a, 4b, or 0.8 g (3.63 mmol) uracil 8a. After evolution of
H2 had ceased off, the suspension was stirred at rt for further 30 min and then heated under reflux for
the appropriate time (for 4a, 4b: 8 h; 8a: 5 h). The product mixture was concentrated and the excess of
LiH was quenched carefully with 50 cm3 ice=H2O followed by acidification with conc HCl, solvent
extraction (CHCl3), drying, and evaporation. The resulting residue was crystallized from the proper
solvent to give 5a, 5b, and 9.
No reaction was observed when 5-bromouracil (8b) was reacted with 2 in DMF containing LiH
using the same procedure as for 8a.
Diethyl phenanthro[9,10-e]-1,2,4-triazine-3-cyanomethylphosphonate (5a, C21H19N4O3P)
Pale yellow crystals (0.9g, 74%), mp 252–254ꢅC (EtOH); 1H NMR (DMSO-d6): ꢁ ¼ 1.05, 1.11 (2dt,
JHH ¼ 6.8, JPH ¼ 2.3 Hz, 2OCCH3), 3.78, 4.01 (2dq, JPH ¼ 10.8Hz, 2OCH2), 4.43 (d, JPH ¼ 22.2Hz,
ꢀ-HC-P, 5aA), 7.44–7.61 (m, 4H-Ar), 7.76–7.80 (m, 2H-Ph), 8.48–8.62 (m, 1H-Ph), 8.88–9.02 (m,
1H-Ph), 12.34 (br, NH, 5aB) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 15.4, 16.1 (2s, 2OCH2CH3), 51.6 (d,
JPC ¼ 144 Hz, ꢀ-HC-P, 5aA), 73.4 (d, JPC ¼ 203 Hz, ¼C-P, 5aB), 62.6, 63.1 (d, JPC ¼ 5 Hz, OCH2),
117.3 (CN), 120.4, 122.3, 123.0, 123.8, 124.8, 128.6, 128.8, 133.3, 133.7 (C-Ph) ppm; 31P NMR
(DMSO-d6): ꢁ ¼ 32.83, 33.94 (2s, 3:1 ratio) ppm; MS: m=z (%) ¼ 406 (8) [Mþ], 404 (14), 380 (31),
ꢀ
269 (22), 243 (100); IR (KBr): u ¼ 3453 (NH), 2224 (CN), 1667 (C¼C, exocyclic), 1228, 1268 (P¼O),
1059 (P–O–C) cmꢁ1
.
Diethyl 5,6-diphenyl-1,2,4-triazine-3-cyanomethylphosphonate (5b, C21H21N4O3P)
Pale yellow crystals (866mg, 71%); mp 246–248ꢅC (EtOH); 1H NMR (DMSO-d6): ꢁ ¼ 1.09, 1.24 (2dt,
JHH ¼ 6.8, JPH ¼ 2.5 Hz, 2OCCH3), 3.84, 3.97 (2dq, JPH ¼ 11Hz, 2OCH2), 4.28 (d, JPH ¼ 21.3Hz,
ꢀ-HC-P, 5bA), 7.44–7.61 (m, 4H-Ph), 7.76–7.80 (m, 2H-Ph), 8.21–8.27 (m, 2H-Ph), 8.40–8.78
(m, 2H-Ph), 11.88 (br, NH, 5bB) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 15.4, 16.6 (2s, OCH2CH3), 53.6
(d, JPC ¼ 141 Hz, ꢀ-HC-P, 5bA), 72.5 (d, JPC ¼ 185 Hz, ¼C-P, 5bB), 61.8, 62.4 (2d, JPC ¼ 5 Hz,
OCH2), 117.7 (CN), 118.6, 119.4, 122.5, 123.4, 123.8, 124.3, 124.8, 128.5, 133.6, 134.5 (C-Ph)
31
ppm; P NMR (DMSO-d6): ꢁ ¼ 32.6, 33.45 (2s, 3:1 ratio) ppm; MS: m=z (%) ¼ 408 (11) [Mþ],
ꢀ
406 (18), 382 (28), 271 (36), 245 (100); IR (KBr): u ¼ 3433 (NH), 2237 (CN), 1655 (C¼C, exocyclic),
1235, 1267 (P¼O), 1080 (P–O–C) cmꢁ1
.
Diethyl 1,3-dimethyluracil-5-cyanomethylphosphonate (9, C12H18N3O5P)
Yellow leaflets (790 g, 69%); mp 165–167ꢅC (CHCl3); 1H NMR (DMSO-d6): ꢁ ¼ 1.16, 1.27
(2dt, JHH ¼ 6.8, JPH ¼ 1.8 Hz, 2OCCH3), 3.25 (s (br), 2NCH3), 3.83 (d, JPH ¼ 22.2 Hz, ꢀ-HC-P),
3.87, 4.11 (2dq, JPH ¼ 10.4Hz, 2OCH2), 7.62 (s, 6-CH) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 15.6, 15.8
(2s, 2CH3CH2O), 33.1, 34.2 (2s, 2N-CH3), 52.2 (d, JPC ¼ 148 Hz, ꢀ-HC-P, 9), 62.3, 62.8 (2OCH2),
117.5 (d, JPC ¼ 7 Hz, CN), 143.1 (6-C), 155.4 (5-C), 152.5, 163.4 [2d, C-2(O), C-4(O)] ppm; 31P NMR
(DMSO-d6): ꢁ ¼ 33.62 ppm; MS: m=z (%) ¼ 313 (37) [Mþ-2], 289 (17), 285 (58), 233 (100), 178 (8);
ꢁ1
ꢀ
IR (KBr): u ¼ 2235 (CN), 1690, 1674 (2C¼O), 1235 (P¼O), 1083 (P–O–C) cm
.

Symmetrical and Asymmetrical Bisphosphonate Esters
113
Preparation of the Phosphonates 13b and 14
A solution of EtONa in EtOH prepared by dissolving 690 mg (30 mmol) sodium in 10 cm3 abs
ethanol was added to a stirred solution of 2.64 g 2 (15 mmol) in 15 cm3 ethanol. The stirring was
continued for 20 min and then a solution of 0.8 g 12 (4.8 mmol) in 10 cm3 ethanol was added. The
reaction mixture was stirred at rt for 48 h. After removing the solvent, 50 cm3 dist H2O were added
and then extracted with CHCl3, dried, and the solvent was evaporated. The resulting residue was
chromatographed on silica gel using n-hexane=CHCl3 as the eluent. Fractions up to 2:8 (v=v)
afforded 13b.
Diethyl isatin-2-cyanomethylphosphonate (13b, C14H15N2O4P)
Orange crystals (710 mg, 48%); mp 153–155ꢅC (CH2Cl2); 1H NMR (DMSO-d6): ꢁ ¼ 1.09, 1.16 (2dt,
JHH ¼ 6.6, JPH ¼ 2.3 Hz, 2OCCH3), 3.85, 4.0 (2dq, JPH ¼ 10.3Hz, 2OCH2), 6.92 (d, JHH ¼ 7.3 Hz, 1H-
Ph), 7.62 (d, JHH ¼ 7.3 Hz, 2H-Ph), 7.88 (d, JHH ¼ 2.6 Hz, 1H-Ph), 10.58 (br, NH) ppm; 13C NMR
(DMSO-d6): ꢁ ¼ 13.9, 15.2 (2s, 2OCCH3), 73.5 (d, JPC ¼ 208 Hz, ¼C-P), 62.3, 63.1 (2d, JPC ¼ 5 Hz,
2OCH2), 117.3 (CN), 111.3, 121.2, 122.8, 124.2, 127.6, 144.7 (C-Ph), 151.7 (N–C¼C), 165.7 (C¼O)
31
ppm; P NMR (DMSO-d6): ꢁ ¼ 31.21, 33.9 (2s) ppm; MS: m=z (%) ¼ 306 (15) [Mþ], 305 (13)
þ
þ
ꢀ
[M -1], 304 (18) [M -2], 280 (71), 278 (26), 252 (100), 169 (21), 143 (35); IR (KBr): u ¼ 3442
(NH), 2218 (CN), 1745 (C¼O), 1628 (C¼C, exocyclic), 1255 (P¼O), 1110 (P–O–C) cmꢁ1
.
Elution with pure CHCl3 gave in addition yellow crystals, 179 mg (12%), of the known furan 14;
mp 155–157ꢅC (CH2Cl2) [Ref [5] 155–157ꢅC (CH2Cl2)], identical IR, and MS spectra.
Preparation of Bisphosphonates 6a–6d, 10a, 10b, 15a, and 15b
A mixture of 2.0mmol 5a, 5b, 9, or 13 and 2.2 mmol 3a or 3b in 20cm3 toluene and 10 cm3 NaOH
(0.5M), was heated under reflux for 15–20 h (TLC). After evaporation the crude product was crystal-
lized from the appropriate solvent to afford 6a–6d, 10a, 10b, 15a, or 15b.
Diethyl dimethyl phenanthro[9,10-e]-1,2,4-triazine-3-methane-1,1-bisphosphonate
(6a, C22H25N3O6P2)
Colorless needles (670 mg, 62% based on 5a, 45% based on 4a); mp 174–175ꢅC (benzene); 1H NMR
(DMSO-d6): ꢁ ¼ 1.20, 1.36 (2dt, JHH ¼ 6.6, JPH ¼ 2.5 Hz, 2OCCH3), 3.46 (d, JPH ¼ 11.6 Hz, 2OCH3),
3.84, 4.08 (2dq, JPH ¼ 10.3Hz, 2OCH2), 4.48 (d, JPH ¼ 21.8Hz, HC-P, 6aA), 7.26, 7.76 (2d,
JHH ¼ 5.2 Hz, 4H-Ph), 8.24 (d, JHH ¼ 5.4 Hz, 2H-Ph), 8.87 (d, JHH ¼ 5.5 Hz, 1H-Ph), 9.01 (d,
JHH ¼ 5.5 Hz, 1H-Ph), 12.08 (br, NH, 6aB) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 15.6, 16.3 (2s,
2OCH2CH3), 36.6 (t, JPC ¼ 144 Hz, ꢀ-HC-P, 6aA), 54.2 (d, JPC ¼ 196 Hz, ¼CP, 6aB), 58.3, 58.8
(2m, POCH3), 62.5, 62.8 (2s, 2OCH2), 120.2, 121.2, 122.8, 123.8, 124.4, 124.6, 128.5, 128.7,
133.5, 133.8 (C-Ph) ppþm; 31P NMR (DMSO-d6): ꢁ ¼ 23.54, 26.2 (2d, JPP ¼ 6 Hz, 3:1 ratio) ppm;
ꢀ
MS: m=z (%) ¼ 487 [M -2], 376 (21), 352 (28), 243 (100); IR (KBr): u ¼ 3442 (NH), 1655 (C¼C),
1233, 1270 (2P¼O), 1070, 1038 (2P–O–C) cmꢁ1
.
Tetraethyl phenanthro[9,10-e]-1,2,4-triazine-3-methane-1,1-bisphosphonate
(6b, C24H29N3O6P2)
1
Colorless crystals (0.8g, 74% based on 5a, 51% based on 4a); mp 168–170ꢅC (EtOH); H NMR
(DMSO-d6): ꢁ ¼ 1.21, 1.36 (2dt, JHH ¼ 7.4, JPH ¼ 2.2 Hz, 4OCCH3), 3.99–4.22 (2q (m), 4OCH2), 4.38
(d, JPH ¼ 22.1 Hz, ꢀ-HC-P, 6bA), 7.45–7.63 (m, 4H-Ph), 7.76–7.82 (m, 2H-Ph), 8.48–8.62 (m,
1H-Ph), 8.88–9.02 (m, 1H-Ph), 12.56 (br, NH, 6bB) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 15.8, 16.6,
17.4 (3s, 4CH3CH2O), 36.4 (t, JPC ¼ 138 Hz, ꢀ-HCP, 6bA), 53.5 (d, JPC ¼ 208 Hz, ¼C-P, 6bB),
62.7, 63.0, 63.4 (3s, 4OCH2), 120.3, 121.6, 122.3, 122.8, 123.6, 124.2, 124.6, 128.1, 128.4, 133.6,
134.2 (C-Ph) ppm;þ31P NMR (DMSO-d6): ꢁ ¼ 22.7, 24.3 (2d, JPP ¼ 6 Hz, 3:1 ratio) ppm; MS: m=z
þ
ꢀ
(%) ¼ 517 (<5) [M ], 514 (23) [M -3], 380 (100), 243 (48); IR (KBr): u ¼ 3412 (NH), 1635 (C¼C),
1237, 1262 (2P¼O), 1150 (P–O–C) cmꢁ1
.

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W. M. Abdou et al.
Diethyl dimethyl 5,6-diphenyl-1,2,4-triazine-3-methane-1,1-bisphosphonate
(6c, C22H27N3O6P2)
1
Colorless crystals (708mg, 68% based on 5b, 48% based on 4b); mp 188–190ꢅC (EtOH); H NMR
(CDCl3): ꢁ ¼ 1.13, 1.25 (2dt, JHH ¼ 6.8, JPH ¼ 3.5 Hz, 4OCCH3), 3.66 (d, JPH ¼ 11.8Hz, 2OCH3),
3.89, 3.99 (2dq, JHH ¼ 6.8, JPH ¼ 4.5Hz, 2OCH2), 4.46 (d, JPH ¼ 18.86 Hz, ꢀ-HC-P, 6cA), 7.37–7.68
(m, 4H-Ph), 7.88–8.18 (m, 2H-Ph), 8.21–8.27 (m, 2H-Ph), 8.40–8.65 (m, 2H-Ph), 11.82 (br, NH, 6cB)
ppm; 13C NMR (CDCl3): ꢁ ¼ 15.23, 16.12 (2s, 2OCCH3), 34.1 (t, JPC ¼ 148 Hz, ꢀ-HC-P, 6cA), 52.3
(d, JPC ¼ 203 Hz, ¼CP, 6cB), 58.2, 58.8 (2m, 2POCH3), 61.8, 63.6 (2s, 2OCH2), 118.4, 119.2, 121.7,
122.6, 123.4, 123.8, 124.5, 124.6, 128.5, 128.8, 133.3, 133.9 (C-Ph) ppm; 31P NMR (CDCl3):
ꢁ ¼ 24.36, 25.94 (2d, JPP ¼ 6 Hz, 3:1 ratio) ppm; MS: m=z (%) ¼ 491 (<5) [Mþ], 489 (13), 378
ꢀ
(38), 370 (27), 354 (100), 352 (88), 245 (40); IR (KBr): u ¼ 3458 (NH), 1655 (C¼C), 1256, 1262
(2P¼O), 1068, 1152 (2P–O–C) cmꢁ1
.
Tetraethyl 5,6-diphenyl-1,2,4-triazine-3-methane-1,1-bisphosphonate (6d, C24H31N3O6P2)
1
Colorless crystals (793mg, 72% based on 5b, 51% based on 4b); mp 162–164ꢅC (EtOH); H NMR
(DMSO-d6): ꢁ ¼ 1.23, 1.38 (2dt, JHH ¼ 7.2, JPH ¼ 2.6 Hz, 4CCH3), 3.86–4.04 (2dq (m), 4OCH2), 4.35
(d, JPH ¼ 20.8 Hz, ꢀ-HC-P, 6dA), 7.34-7.61 (m, 4H-Ar), 7.86–8.09 (m, 2H-Ph), 8.23–8.28 (m, 2H-Ph),
8.41–8.63 (m, 2H-Ph), 12.69 (br, NH, 6dB) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 14.8, 15.1, 16.8 (3s,
4CH3CH2O), 33.7 (t, JCP ¼ 138 Hz, ꢀ-HCP, 6dA), 51.8 (d, JPC ¼ 200 Hz, ¼C-P, 6dB), 62.2, 62.8, 63.4
(3s, 4OCH2), 118.6, 119.0, 120.8, 121.6, 122.4, 123.5, 123.7, 124.3, 124.7, 128.5, 129.1, 133.3, 134.2
(C-Ph) ppm; 31P NMR (DMSO-d6): ꢁ ¼ 20.55, 23.32 (2d, JPP ¼ 6 Hz, 3:1 ratio) ppm; MS: m=z
þ
ꢀ
(%) ¼ 519 (8) [M ], 518 (6), 517 (13), 382 (25), 380 (22), 245 (100); IR (KBr): u ¼ 3408 (NH),
1652 (C¼C), 1234, 1256 (2P¼O), 1156, 1085 (2P–O–C) cmꢁ1
.
Diethyl dimethyl 1,3-dimethyluracil-5-methane-1,1-bisphosphonate (10a, C13H24N2O8P2)
Pale yellow crystals (608mg, 61% based on 9, 42% based on 8a); mp 130–132ꢅC (cyclohexane); 1H
NMR (DMSO-d6): ꢁ ¼ 1.09, 1.14 (2dt, JHH ¼ 6.6, JPH ¼ 2.4 Hz, 2OCCH3), 3.19, 3.28 (2s, 2NCH3),
3.42, 3.45 (2d, JPH ¼ 10.8Hz, 2OCH3), 3.85, 3.98 (2dq, JPH ¼ 11.7Hz, 2OCH2), 4.32 (d,
JPH ¼ 22.4Hz, ꢀ-HC-P), 7.58 (s, 6-CH) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 11.9, 15.8 (2s, 2OCCH3),
33.2, 34.6 (2s, 2NCH3), 38.6 (t, JPC ¼ 155 Hz, ꢀ-HC-P), 58.2, 58.8 (2d, 2POCH3), 61.6, 62.5 (2s,
2OCH2), 141.4 (6-C), 155.1 (5-C), 152.8, 163.4 [2d, C-2(O), C-4(O)] ppm; 31P NMR (DMSO-d6):
ꢁ ¼ 27.62, 21.59 (2d, JPP ¼ 6 Hz) ppm; MS: m=z (%) ¼ 397 (<5) [Mþ-1], 393 (15), 368 (11), 364 (10),
ꢀ
314 (100), 289 (59), 261 (35), 258 (20), 178 (15); IR (KBr): u ¼ 1690, 1668 (2C¼O), 1248, 1258
(2P¼O), 1085, 1105 (2P–O–C) cmꢁ1
.
Tetraethyl 1,3-dimethyluracil-5-methane-1,1-bisphosphonate (10b, C15H28N2O8P2)
Pale yellow needles (694 mg, 65% based on 9, 45% based on 8a); mp 118–120ꢅC (cyclohexane); 1H
NMR (DMSO-d6): ꢁ ¼ 1.25, 1.36 (2dt, JHH ¼ 6.8, JPH ¼ 2.4 Hz, 4OCCH3), 3.13, 3.27 (2s, 2NCH3),
3.84, 3.98 (2dq, JPH ¼ 11.2Hz, 4OCH2), 4.18 (d, JPH ¼ 23.3Hz, ꢀ-HC-P), 7.64 (s, 6-CH) ppm;
13C NMR (DMSO-d6): ꢁ ¼ 15.2, 16.2, 16.7 (3s, 4CH3CH2O), 32.4, 32.8 (2NCH3), 38.4
(t, JPC ¼ 142 Hz, ꢀ-HC-P), 61.8, 62.4, 63.3 (3s, 4OCH2), 143.6 (6-C), 154.6 (5-C), 153.1, 162.6
[2d, C-2(O), C-4(O)] ppm; 31P NMR (DMSO-d6): ꢁ ¼ 20.67, 1.25 (2s) ppm; MS: m=z (%) ¼ 425
(11) [Mþ-1], 424 (13), 423 (15), 396 (11), 314 (100), 389 (82), 259 (66), 178 (11); IR (KBr):
ꢁ1
ꢀ
u ¼ 1701, 1680 (2C¼O), 1254, 1266 (2P¼O), 1100 (P–O–C) cm
.
Diethyl dimethyl isatin-2-methane-1,1-bisphosphonate (15a, C15H21NO7P2)
Straw yellow needles (514mg, 57% based on 13b, 27% based on 12); mp 122–124ꢅC (cyclohexane);
1H NMR (DMSO-d6): ꢁ ¼ 1.2, 1.23 (2dt, JHH ¼ 6.6, JPH ¼ 2.5 Hz, 2OCCH3), 3.31 (2dt, JPH ¼ 11.3Hz,
2OCH3), 4.05 (dq, JPH ¼ 10.6 Hz, 2OCH2), 6.92 (d, JHH ¼ 7.3 Hz, 1H-Ph), 7.68 (d, JHH ¼ 7.3 Hz,
2H-Ph), 7.89 (d, JHH ¼ 2.6 Hz, 1H-Ph), 10.59 (br, NH) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 13.6, 14.6

Symmetrical and Asymmetrical Bisphosphonate Esters
115
(2s, 2OCCH3), 51.8 (d, JPC ¼ 196 Hz, C-P), 55.6 (d, JPC ¼ 7.2 Hz, 2OCH3), 60.3, 61.4 (d,
JPC ¼ 7.2 Hz, 2OCH2), 114, 117, 122.4, 124.5, 127.4, 143.8 (C-Ph), 150.2 (N-C¼C), 165.6 (C¼O)
ppm; 31P NMR (DMSO-d6): ꢁ ¼ 26.35, 35.12 (2d, JPP ¼ 6.8 Hz) ppm; MS: m=z (%) ¼ 389 (13) [Mþ],
ꢀ
388 (13), 333 (27), 305 (100), 280 (44), 143 (28); IR (KBr): u ¼ 3442 (NH), 1744 (C¼O), 1623
(C¼C), 1248, 1251 (2P¼O), 1024, 1066 (2P–O–C) cmꢁ1
.
Tetraethyl isatin-2-methane-1,1-bisphosphonate (15b, C17H25NO7P2)
Straw yellow needles (589 mg, 61% based on 13b, 29% based on 12); mp 111–113ꢅC (cyclohex-
ane); 1H NMR (DMSO-d6): ꢁ ¼ 1.11, 1.16 (2dt, JHH ¼ 7.4, JPH ¼ 2.4 Hz, 4OCCH3), 3.83, 4.05
(2dq, JPH ¼ 11.2 Hz, 4OCH2), 6.9 (d, JHH ¼ 7.3 Hz, 1H-Ph), 7.62 (d, JHH ¼ 7.3 Hz, 2H-Ph), 7.99 (d,
JHH ¼ 2.6 Hz, 1H-Ph), 10.6 (br, NH) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 13.6, 15.1 (2s, OCCH3), 52.6
(d, JPC ¼ 201 Hz, ¼C-P), 62.6, 63.2 (2d, JPC ¼ 7.2 Hz, OCH2), 115, 117, 121.6, 122.6, 126.8, 144.1
(C-Ph), 153.3 (N-C¼C), 167.1 (C¼O) ppm; 31P NMR (DMSO-d6): ꢁ ¼ 25.6, 31.8 (2d,
JPP ¼ 6.5 Hz) ppm; MS: m=z (%) ¼ 417 (<5) [Mþ], 416 (21), 389 (13), 361 (42), 305 (100),
ꢀ
280 (62), 143 (41); IR (KBr): u ¼ 3424 (NH), 1730 (C¼O), 1623 (C¼C), 1248, 1251 (2P¼O)
1024, 1086 (2P–O–C) cmꢁ1
.
In an alternative, 0.8 g 4a, 4b (3.0mmol) or 0.8 g 8a (3.63mmol) were treated with a solution of
1.6 g 2 (9.0mmol) in DMF containing 144mg (18.0mmol) of a slurry of LiH dispersion (60% in
paraffin oil) and the mixture was refluxed for ꢂ8 h (TLC). The reaction procedure and workup were as
mentioned above. The crude residue of 5a, 5b, or 9 produced was treated, in situ, with 2.2 mmol 3a or
3b in 20cm3 toluene containing 10cm3 NaOH (0.5M). The reaction mixture was heated under reflux
for 20h (TLC). After evaporation of the volatile materials, the crude product was crystallized from the
appropriate solvent to afford 6a (720mg, 49%), 6b (880mg, 57%), 6c (750mg, 51%), 6d (825mg,
53%), 10a (697 mg, 48%), or 10b (790mg, 51%); yields based on the halo compounds. They were
proved to be identical with the above isolated compounds.
Preparation of 6b, 6d, 10b, and 15b
A solution of 1.4 g 1 (5.0mmol) in 10 cm3 absolute ethanol was added at 0ꢅC to a stirred solution of
20cm3 EtOH containing 230 mg Na (10.0 mmol). After the addition was completed (1h), a solution of
2.5 mmol 4a, 4b, 8a, or 12 in 5 cm3 EtOH was added and the resulting mixture was heated under reflux
forꢃ15 h (TLC). The mixture was worked up as described for the reaction of 2 with 12. The residue
was crystallized from the appropriate solvent to give 6b (60%), 6d (63%), 10b (66%), and 15b (67%),
which were identical with the products previously obtained.
Preparation of Bisphosphonic Acids 7 and 11
The phosphonates 6a (0.5g, 1.02 mmol) or 10b (0.5g, 1.17 mmol) were dissolved in 15cm3 conc HCl
and the mixture was heated under reflux for 12h. Then the solution was decolorized with activated C,
then filtered, and evaporated to dryness under reduced pressure. After addition of 5 cm3 EtOH the solid
was filtered off and washed twice with ether to yield the phosphonic acids 7 or 11.
Phenanthro[9,10-e]-1,2-4-triazine-2-methane-1,1-bisphosphonic acid (7, C16H13N3O6P2)
1
White material (340mg, 83%), mp >300ꢅC (EtOH=H2O, 1=1, v=v); H NMR (D2O): ꢁ ¼ 4.41 (d,
JPH ¼ 22.1Hz, HC-P), 7.26–8.96 (m, 8H-Ph) ppm; 31P NMR (D2O): ꢁ ¼ 22.4, 24.1 ppm; MS (EI): m=z
þ
þ
ꢀ
(%) ¼ 404 (8) [M -1], 401 (44) [M -4]; IR (KBr): u ¼ 3350 br (OH), 1658 (N¼N), 1200 (P¼O)
cmꢁ1
.
1,3-Dimethyluracil-5-methanephosphonic acid (11, C7H12N2O8P2)
1
White material (310 mg, 85%), mp 293–295ꢅC (acetone=H2O, 1=1, v=v); H NMR (D2O): ꢁ ¼ 2.99,
3.17 (2s, 2NCH3), 7.42 (s, 6-CH) ppm; 13P NMR (D2O): ꢁ ¼ 22.8, 23.6ppm; MS (EI): m=z (%) ¼ 314
þ
þ
ꢁ1
.
ꢀ
(<5) [M ], 310 (53) [M -4]; IR (KBr): u ¼ 3200 br (OH), 1690 (C¼O), 1210 (P¼O) cm

116
W. M. Abdou et al.: Symmetrical and Asymmetrical Bisphosphonate Esters
Preparation of 16 and the Partially Hydrolyzed Bisphosphonate 17
A solution of 630 mg 9 (2mmol) in 20cm3 conc HCl was heated under reflux for 20h, followed by the
above-described workup to give 16.
1,3-Dimethyluracil-5-cyanomethylphosphonic acid (16, C8H10N3O5P)
Pale yellow crystals (426 mg, 82%), mp >300ꢅC (EtOH=H2O, 1=1, v=v); 1H NMR (D2O): ꢁ ¼ 3.41 (s
(br), 2N-CH3), 3.87 (d, JHP ¼ 21.2 Hz, ꢀ-HC-P), 7.59 (s, 6-CH) ppm; 31P NMR (D2O): ꢁ ¼ 32.41 ppm;
þ
ꢀ
MS (EI): m=z (%) ¼ 259 (59) [M ]; IR (KBr): u ¼ 3190 w, 2950 (P-OH), 2230 (CN), 1690 (C¼O),
1230 (P¼O) cmꢁ1
.
1,3-Dimethyluracil-5-methane-1-diethoxyphosphono-1-phosphonic acid (17, C11H20N2O8P2)
Compound 16 (518 mg, 2.0 mmol) was allowed to react with 2.2 mmol 3b under the same conditions
described for 9. After refluxing for 20h, usual workup and crystallization afforded 17. Yellow leaflets
1
(481 mg, 65% based on 9), mp 287–289ꢅC (acetone); H NMR (D2O): ꢁ ¼ 1.36 (2dt, JHH ¼ 6.6,
JPH ¼ 3.8 Hz, 2OCCH3), 3.24 (s.br, 2NCH3), 3.85 (d, JPH ¼ 21.5 Hz, HC-P), 4.09, 4.13 (2dq,
JHH ¼ 6.6, JPH ¼ 4.2 Hz, 2,OCH2), 7.59 (s, 6-CH) ppm; 31P NMR (D2O): ꢁ ¼ 32.17, 33.45 (2d, each
þ
ꢀ
Jpp ¼ 6 Hz, P–C–P) ppm; MS (EI): m=z (%) ¼ 370 (48) [M ]; IR (KBr): u ¼ 3190, 2910 (P-OH), 2228
(CN), 1690 (C¼O), 1232 (P¼O), 1100 (P–O–C) cmꢁ1
.
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