Michael addition of Grignard reagents to tetraethyl ethenylidenebisphosphonate

Article abstract of DOI:10.1016/S0022-328X(02)01179-8

Tetraethyl ethenylidenebisphosphonate can undergo facile Michael type adition reaction with simple Grignard reagents to give alkyl, arylalkyl, aryl C-substituted methylene bishopshonates. This addition easily occurs even if functionalised Grignard reagent

Full text of DOI:10.1016/S0022-328X(02)01179-8

Journal of Organometallic Chemistry 650 (2002) 77–83
www.elsevier.com/locate/jorganchem
Michael addition of Grignard reagents to tetraethyl
ethenylidenebisphosphonate
Marco L. Lolli, Loretta Lazzarato, Antonella Di Stilo, Roberta Fruttero,
Alberto Gasco *
Dipartimento di Scienza e Tecnologia del Farmaco, Uni6ersita degli Studi di Torino, Facolta di Farmacia, Via Pietro Giuria 9,
10125 Torino, Italy
Received 22 October 2001; accepted 9 January 2002
Abstract
Tetraethyl ethenylidenebisphosphonate can undergo facile Michael type addition reaction with simple Grignard reagents to give
alkyl, arylalkyl, aryl C-substituted methylene bisphosphonates. This addition easily occurs even if funtionalised Grignard reagents
are used. © 2002 Elsevier Science B.V. All rights reserved.
Keywords: Tetraethyl ethenylidenebisphosphonate; Grignard reagents; Michael addition; Bisphosphonates
and polyfunctional carbanions with tetraethyl ethenyli-
denebisphosphonate (1) was explored [4b,6]. By con-
trast, to our knowledge, only scattered examples of
addition of a Grignard reagent are described [4]. In this
note we show that Grignard reagents can be used to
prepare, by reaction with 1, a wide range of simple and
functionalised tetraethyl gem-bisphosphonates.
1. Introduction
gem-Bisphosphonic acids are taken up by the skele-
ton and inhibit osteoclast mediated bone resorption [1].
They are currently used in the management of bone
diseases including postmenopausal osteoporosis,
Paget’s disease, tumour- and nontumour-induced hy-
percalcemia. In addition they can be useful in con-
trolling bone resorption and soft time inflammation
associated with rheumatoid arthritis and osteoarthritis
[1]. Recently, antiprotozoal activity was reported for
these compounds [2].
One of the synthetic routes to these compounds goes
through the corresponding alkyl esters which can be
easily hydrolysed to the related acids [3]. Interestingly,
some of them show anti-inflammatory and -arthritic
activities unrelated to direct effect on calcium
metabolism [4a]. Access to tetraalkyl gem-bisphospho-
nic esters utilizing the electrophilic character of te-
traalkyl ethenylidenebisphosphonates was proposed.
These ethenylidene derivatives are able to react under
mild conditions with nitrogen, phosphorous or sulphur
nucleophiles to give the corresponding 1,4-addition
products in high yields [5]. Also the addition of simple
2. Results and discussion
In a first series of experiments we studied the reaction
between 1 and straight and branched alkyl, phenyl and
alkylphenylmagnesium halogenides (Scheme 1). The re-
action was run by slow addition of a THF solution of
the appropriate Grignard reagent to a dry and stirred
THF solution of 1 kept under argon at −15 °C. The
expected 1,4 addition occurred and products 2–6 were
isolated in good yield (64–72%). No compound derived
from 1,2-addition was produced in
manner.
a significant
Under the same reaction conditions, in a second
series of experiments (see Scheme 1), we studied the
reaction between functionalised Grignard reagents and
1. In order to introduce into the final bisphosphonate a
hydroxy function, the possibility of the addition to 1 of
the ‘Normant’ reagents [7] was explored. As an example
of this type of reagent the compound 7a was selected.
* Corresponding author. Tel.: +39-011-670-7670; fax: +39-011-
670-7687.
E-mail address: a.gasco@unito.it (A. Gasco).
0022-328X/02/$ - see front matter © 2002 Elsevier Science B.V. All rights reserved.
PII: S0022-328X(02)01179-8

78
M.L. Lolli et al. / Journal of Organometallic Chemistry 650 (2002) 77–83
Slow addition of a THF solution of this reagent to a
mechanically stirred dry THF solution of 1 resulted in
the formation of a precipitate, presumably the insoluble
magnesium 1,4 Michael adduct. The reaction mixture
was treated by standard procedure to give in high
yield (92%) the expected bisphosphonate 7, bearing a
hydroxy group in the lateral chain. The dihydroxybis-
phosphonate 14 was similarly realized by using 2-(2,2-
the reaction of 4-chlorobutylmagnesium bromide (10a)
with 1. The yield in the final product 10 was 70%.
Bromoalkylbisphosphonate 16 cannot be easily pre-
pared from the corresponding 4-bromobutylmagnesium
bromide since this reagent is not known and is very
difficult to prepare [8]. By contrast, the bromoalkylbis-
phosphonate 16 can be easily obtained from the alcohol
7 by treatment with triphenylphosphine and N-bromo-
succinimide (NBS).
dimethyl-1,3-dioxolan-4-yl)ethylmagnesium
bromide
(8a). In this case, the instable dioxolane intermediate 8
was immediately hydrolysed by dilute acetic acid in
THF to the final dihydroxy derivative 14 (overall yield
42%). If 2-(1,3-dioxolan-2-yl)ethylmagnesium bromide
(9a) is used in the reaction, the obtained dioxolane
bisphosphonate 9 is stable and can be isolated and
characterized (yield 75%). Hydrolysis of 9 in 80% acetic
acid at 65 °C provides the corresponding aldehyde 15.
Also bisphosphonates bearing a chlorine atom in the
lateral chain can be easily obtained by using
chloroalkylmagnesium bromides as demonstrated by
Finally, the amino bisphosphonates 11 and 13 were
obtained by using the appropriate Grignard reagents.
3-Dimethylaminopropylmagnesium chloride (11a) [15]
lead to the addition product 11 in 79% yield. The
Grignard derivative 12a, bearing an amino group pro-
tected as bis(trimethylsilyl)amide, was successfully ob-
tained by direct addition of 3-(bistrimethylsilyl-
amino)-1-bromopropane [16] to a stirred suspension of
an excess of highly active magnesium (Mg*, Rieke
magnesium [9]) kept below −12 °C. Immediate reac-
tion of 12a with 1 gave the expected product 12 which
Scheme 1.

M.L. Lolli et al. / Journal of Organometallic Chemistry 650 (2002) 77–83
79
was, without any further purification, directly trans-
formed by treatment with acetic acid in THF in the
final derivative 13 (overall yield 42%).
[11]) and functionalised Grignard reagents (7a [7], 8a
[12], 9a [13], 10a [14], 11a [15]) were synthesized in
accord with literature methods. 3-(Bistrimethylsily-
lamino)-1-bromopropane was prepared in according
with the Gomes method [16]. It was purified by double
distillation under reduced pressure and stored under Ar
atmosphere at low temperature. All the Grignard
reagents were titrated immediately before use [17]. Te-
trahydrofuran (THF) was distilled immediately before
use from Na and benzophenone under a positive atmo-
sphere of N2. All reaction were performed in flame- or
over-dried glassware under a positive pressure of dry
N2 or Ar. All the reactions were carried three times
without any attempts to optimize the yields.
All the final bisphosphonates were characterized by
1H-, 13C-, 31P-NMR spectra, data of which are listed in
Section 3. Spectral assignments were given on the basis
of chemical shifts, signal multiplicity and coupling con-
1
stant values [10a,10b]. H-NMR and proton decoupled
13C-NMR spectra show rather complex patterns due to
coupling with the two phosphorous nuclei, often result-
ing in second order multiplets, and/or to diastereotopic
effects. The protonic pattern of the ꢀCH group bearing
the two phosphonic groups is peculiar in all the spectra.
It occurs in the region 2.5–2.8 ppm and appears as a
triplet of triplets due to coupling with the two chemi-
cally equivalent phosphorous atoms (2JHP about 24 Hz)
and with vicinal CH2 protons (3JHH about 6 Hz). By
contrast, the chemical shift and the multiplicity of the
3.1. Michael reactions: general procedure
A titrated solution containing 1.66 mmol of the
Grignard reactant (0.062–2.44 M) in Et2O (compounds
2, 3) or THF (compounds 4–12) was slowly added to a
magnetically stirred solution of tetraethyl ethenyli-
denebisphosphonate (500 mg; 1.66 mmol) in dry THF
(10 ml) kept at −15 °C under Ar. The reaction pro-
gress was followed by TLC. Usually, at the end of the
addition the reaction was completed. The mixture was
allowed to reach room temperature (r.t.) and then it
was slowly poured into a saturated solution of NH4Cl
(20 ml). The mixture was extracted with Et2O (2×20
ml) and the combined dried organic layers were concen-
trated under reduced pressure. The crude residue so
obtained was purified by flash chromatography using
the appropriate eluent system to give the pure product
as an oil.
1
latter, vary according to the chemical environment. H-
and 13C-NMR signals of the tetraethyl moiety also
appear as complex patterns due to coupling interactions
with the two nonmagnetically equivalent phosphorous
nuclei. Nevertheless, the appearance of such multiplets
was characteristic and diagnostic to our purposes. For
this reason, the values of the virtual coupling constants
are also reported in spectral characterization [10b].
Proton decoupled 31P-NMR spectra display only one
signal indicating that the two nuclei are isochronous.
They appear in the range 24.1–24.6 ppm with respect
to external phosphoric acid. Only in the case of com-
pound 14 are observed two peaks (24.6 and 24.5 ppm,
respectively), due to diastereotopicity.
3. Experimental
3.1.1. Tetraethyl butylidenebisphosphonate (2)
Colorless oil; yield 64%; Rf 0.61 (TLC eluent:
CH2Cl2–MeOH, 95:5 v/v); flash chromatography elu-
ent: CH2Cl2–MeOH, 98:2 v/v; 1H-NMR (CDCl3) l
The compounds were routinely checked by IR spec-
troscopy (Shimadzu, FTIR 8101 M) and mass spec-
trometry (Finnigan-MatTSQ-700 spectrometer, 70 eV,
direct inlet). 1H-, proton decoupled 13C- and proton
decoupled 31P-NMR spectra, were recorded on a
Bruker AC-200 spectrometer. The following abbrevia-
tions are used to indicate peak multiplicity: s=singlet;
d=doublet; t=triplet; qt=quartet; qn=quintet; m=
multiplet. 31P-NMR chemical shifts are referred to 85%
H3PO4. Flash column chromatography was performed
on silica gel (Merck Kiesekgel 60, 230–400 mesh
ASTM) using the indicated eluents. Thin layer chro-
matography (TLC) was carried out on 5×20 cm plates
with a layer thickness of 0.25 mm. When necessary they
were developed with iodine and KMnO4. Anhydrous
MgSO4 was used as the drying agent of the organic
extracts. Elemental analysis of the new compounds is
within 90.4% of the theoretical values. Alkyl, phenyl
and alkylmagnesium alogenides 2a–6a are commercial
products. Tetraethyl ethenylidenebisphosphonate (1
3
0.89 (t, 3H, JHH 7.0 Hz, CH3CH2CH2CHꢀ), 1.31 (t,
3
12H, JHH 7.0 Hz, ꢀPO(OCH2CH3)2), 1.5–1.7 (m, 2H,
CH3CH2CH2CHꢀ), 1.7–2.0 (m, 2H, CH3CH2CH2-
3
2
CHꢀ), 2.25 (tt, 1H, JHH 6.0 Hz, JPH 24.0 Hz, ꢀCH-
(PO(OCH2CH3)2)2), 4.07–4.22 (m, 8H, ꢀPO(OCH2-
CH3)2); 13C-NMR (CDCl3) l 13.6 (s, CH3CH2CH2-
3
CHꢀ), 16.2 (d, JPC 5.5 Hz, ꢀPO(OCH2CH3)2), 22.2 (t,
2
3JPC 7.0 Hz, CH3CH2CH2CHꢀ), 27.4 (t, JPC=5.0 Hz,
1
CH3CH2CH2CHꢀ), 36.4 (t, JPC 132.0 Hz, ꢀCH(PO-
(OCH2CH3)2)2), 62.2 (t, virtual J=7.0 Hz, ꢀPO(OCH2-
CH3)2); 31P-NMR (CDCl3) l 24.6; MS (CI) 331 [M+
1]+; Anal. (drying conditions: 40 °C, 8 h, pressure B1
mmHg) Found: C, 40.69; H, 8.33. Calc. for
C12H28O6P2·1.2H2O: C, 40.96; H, 8.71%.
3.1.2. Tetraethyl pentylidenebisphosphonate (3)
Colorless oil; yield 67%; Rf 0.50 (TLC eluent:
CH2Cl2–MeOH, 95:5 v/v); flash chromatography elu-

80
M.L. Lolli et al. / Journal of Organometallic Chemistry 650 (2002) 77–83
ent: CH2Cl2–MeOH, 98:2 v/v; 1H-NMR (CDCl3) l
0.91 (t, 3H, 3JHH 7.0 Hz, CH3CH2ꢀ), 1.34 [(t, 12H, 3JHH
7.0 Hz, ꢀPO(OCH2CH3)2), (m, 2H, CH3CH2ꢀ)], 1.5–1.6
(m, 2H, ꢀCH2CH2CHꢀ), 1.8–2.1 (m, 2H, ꢀCH2CH2-
CH2Cl2–MeOH, 95:5 v/v); flash chromatography elu-
ent: CH2Cl2–IsopropylOH, 95:5 v/v; 1H-NMR (CDCl3)
3
4
l 1.33 (dt, 12H, JHH 7.0 Hz, JPH 3.8 Hz, ꢀPO(OCH2-
CH3)2), 2.09–2.47 (m, 3H, PhCH2CH2CH(PO(OCH2-
3
2
3
CHꢀ), 2.27 (tt, 1H, JHH 6.0 Hz, JHP 24.0 Hz,
ꢀCH(PO(OCH2CH3)2)2), 4.1–4.3 (m, 8H, ꢀPO(OCH2-
CH3)2); 13C-NMR (CDCl3) l 13.6 (s, CH3CH2ꢀ), 16.3
CH3)2)2), 2.90 (t, 2H, JHH 7.4 Hz, PhCH2CH2CHꢀ),
4.04–4.27 (m, 8H, ꢀPO(OCH2CH3)2), 7.19–7.32 (m,
3
5H, C6H5ꢀ); 13C-NMR (CDCl3) l 16.2 (d, JPC 6.7 Hz,
3
2
(d, JPC 6.5 Hz, ꢀPO(OCH2CH3)2), 22.3 (s, CH3CH2ꢀ),
ꢀPO(OCH2CH3)2), 27.1 (t, JPC 4.5 Hz, PhCH2CH2-
3
2
3
25.1 (t, JPC 5.0 Hz, ꢀCH2CH2CHꢀ), 31.2 (t, JPC 6.0
Hz, ꢀCH2CH2CHꢀ), 36.6 (t, 1JPC 132.0 Hz,
ꢀCH(PO(OCH2CH3)2)2), 62.3 (t, virtual J=7.0 Hz,
ꢀPO(OCH2CH3)2); 31P-NMR (CDCl3) l 24.7; MS (CI)
345 [M+1]+; Anal. (drying conditions: 40 °C, 48 h,
pressure B1 mmHg) Found: C, 43.62; H, 8.88. Calc.
for C13H30O6P2·0.9H2O: C, 43.09; H, 8.90%.
CHꢀ), 34.5 (t, JPC 6.0 Hz, PhCH2CH2CHꢀ), 35.6 (t,
1JPC 132.0 Hz, ꢀCH(PO(OCH2CH3)2)2), 62.3 (t, virtual
J=7.0 Hz, ꢀPO(OCH2CH3)2), 126.0 (s, Ph(C4)), 128.3/
128.5 (s/s, Ph(C2/C3)), 140.8 (s, Ph(C1)); 31P-NMR
(CDCl3) l 24.3; MS (EI) 392 [M+]; Anal. (drying
conditions: 42 °C, 8 h, pressure B1 mmHg) Found: C,
52.04; H, 7.84. Calc. for C17H30O6P2: C, 52.04; H,
7.71%.
3.1.3. Tetraethyl (3-methylbutylidene)bisphosphonate (4)
Colorless oil; yield 67%; Rf 0.66 (TLC eluent:
CH2Cl2–MeOH, 95:5 v/v); flash chromatography elu-
ent: CH2Cl2–MeOH, 98:2 v/v; 1H-NMR (CDCl3) l
3.1.6. Tetraethyl (5-hydroxypentylidene)bisphosphonate
(7)
Due to the precipitation of a white crystalline solid
(Mg 1,4 Michael adduct), the solution of tetraethyl
ethenylidene bisphosphonate was mechanically stirred
during the addition of the Normant reagent. Colorless
oil; yield 92%; Rf 0.59 (TLC eluent: CH2Cl2–MeOH,
3
0.87 (d, 6H, JHH 6.4 Hz, (CH3)2CHCH2ꢀ), 1.30 (t,
3
12H, JHH 7.0 Hz, ꢀPO(OCH2CH3)2), 1.6–1.9 (m, 3H,
(CH3)2CHCH2ꢀ), 2.32 (tt, 1H, 3JHH 6.0 Hz, 2JPH 24 Hz,
ꢀCH(PO(OCH2CH3)2)2), 4.1–4.2 (m, 8H, ꢀPO(OCH2-
3
CH3)2); 13C-NMR (CDCl3) l 16.2 (d, JPC 6.0 Hz,
3
9:1 v/v); 1H-NMR (CDCl3) l 1.34 (t, 12H, JHH 6.0 Hz,
ꢀPO(OCH2CH3)2), 21.8 (s, (CH3)2CHCH2ꢀ), 26.7 (t,
ꢀPO(OCH2CH3)2), 1.5–2.2 (m, 6H, ꢀCH2CH2CH2-
2
3JPC 6.0 Hz, (CH3)2CHCH2ꢀ), 34.0 (t, JPC 5.5 Hz,
3
2
CHꢀ), 2.25 (tt, 1H, JHH 6.0 Hz, JPH 24.0 Hz,
1
(CH3)2CHCH2ꢀ), 34.6 (t, JPC 132.0 Hz, ꢀCH(PO-
3
ꢀCH(PO(OCH2CH3)2)2), 3.64 (t, 2H, JHH 6.0 Hz,
(OCH2CH3)2)2), 62.2 (t, virtual J=8.0 Hz,
ꢀPO(OCH2CH3)2); 31P-NMR (CDCl3) l 24.7; MS (CI)
345 [M+1]+; Anal. (drying conditions: 40 °C, 20 h,
pressure B1 mmHg) Found: C, 45.40; H, 8.88. Calc.
for C13H30O6P2: C, 45.35; H, 8.78%.
OHCH2CH2ꢀ), 4.1–4.2 (m, 8H, ꢀPO(OCH2CH3)2); 13C-
3
NMR (CDCl3) l 16.2 (d, JPC 5.8 Hz, ꢀPO(OCH2-
CH3)2), 24.7/24.9 (o6erlapping triplets, ꢀCH2CH2CHꢀ),
1
31.9 (s, ꢀCH2CH2OH), 36.5 (t, JPC 133.0 Hz,
ꢀCH(PO(OCH2CH3)2)2), 61.7 (s, ꢀCH2CH2OH), 62.2–
62.5 (m, ꢀPO(OCH2CH3)2); 31P-NMR (CDCl3) l 24.5;
MS (CI) 361 [M+1]+; Anal. (drying conditions:
40 °C, 24 h, pressure B1 mmHg) Found: C, 42.97; H,
8.50. Calc. for C13H30O7P2: C, 43.33; H, 8.39%.
3.1.4. Tetraethyl (2-phenylethylidene)bisphosphonate (5)
Pale yellow oil; yield 72%; Rf 0.65 (TLC eluent:
CH2Cl2–MeOH, 95:5 v/v); flash chromatography elu-
ent: CH2Cl2–MeOH, 98:2 v/v; 1H-NMR (CDCl3) l
3
4
1.23 (dt, 12H, JHH 7.0 Hz, virtual JPH 3.8 Hz,
3
2
3.1.7. Tetraethyl (6-chlorohexylidene)bisphosphonate
(10)
ꢀPO(OCH2CH3)2), 2.63 (tt, 1H, JHH 6.4 Hz, JPH 24.0
3
Hz, ꢀCH(PO(OCH2CH3)2)2), 3.22 (td, 2H, JHH 6.2 Hz,
3JPH 16.4 Hz, PhCH2CHꢀ), 4.0–4.2 (m, 8H,
ꢀPO(OCH2CH3)2), 7.2–7.3 (m, 5H, C6H5ꢀ); 13C-NMR
Colorless oil; yield 69%; Rf 0.48 (TLC eluent:
CH2Cl2–MeOH, 95:5 v/v); flash chromatography elu-
ent: CH2Cl2–MeOH, 98:2 v/v; 1H-NMR (CDCl3) l
3
(CDCl3) l 16.0 (d, JPC 5.7 Hz, ꢀPO(OCH2CH3)2), 31.0
3
2
1
1.34 (t, 12H, JHH 7.0 Hz, ꢀPO(OCH2CH3)2), 1.4–2.1
(t, JPC 5.0 Hz, PhCH2CHꢀ), 38.8 (t, JPC 131.0 Hz,
ꢀCH(PO(OCH2CH3)2)2), 62.2–62.5 (m, ꢀPO(OCH2-
CH3)2), 126.2 (s, Ph(C4)), 128.0/128.7 (s/s, Ph(C2)/
(m, 8H, ClCH2CH2CH2CH2CH2CHꢀ), 2.27 (tt, 1H,
2
3JHH 6.0 Hz, JPH 24.0 Hz, ꢀCH(PO(OCH2CH3)2)2),
3
Ph(C3)), 139.4 (t, JPC 7.0 Hz, Ph(C1)); 31P-NMR
3
3.53 (t, 2H, JHH 6.6 Hz, ClCH2CH2ꢀ), 4.1–4.3 (m, 8H,
3
ꢀPO(OCH2CH3)2); 13C-NMR (CDCl3) l 16.3 (d, JPC
(CDCl3) l 23.5; MS (EI) 378 [M+]; Anal. (drying
conditions: 40 °C, 16 h, pressure B1 mmHg) Found:
C, 49.10; H, 7.40. Calc. for C16H28O6P2·0.6H2O: C,
49.38; H, 7.56%.
3
6.0 Hz, ꢀPO(OCH2CH3)2), 25.3 (t, JPC 5.0 Hz,
ꢀCH2CH2CH2CHꢀ), 26.4 (s, ClCH2CH2CH2ꢀ), 28.2 (t,
2JPC 6.0 Hz, ꢀCH2CH2CH2CHꢀ), 32.0 (s, ClCH2-
1
CH2CH2ꢀ), 36.6 (t, JPC 132.0 Hz, ꢀCH(PO(OCH2-
CH3)2)2), 44.8 (s, ClCH2CH2ꢀ), 62.4 (t, virtual J=7.0
Hz, ꢀPO(OCH2CH3)2); 31P-NMR (CDCl3) l 24.5; MS
(CI) 393/395 [M+1]+; Anal. (drying conditions:
3.1.5. Tetraethyl (3-phenylpropylidene)bisphosphonate
(6)
Colorless oil; yield 66%; Rf 0.39 (TLC eluent:

M.L. Lolli et al. / Journal of Organometallic Chemistry 650 (2002) 77–83
81
40 °C, 72 h, pressure B1 mmHg) Found: C, 42.10; H,
8.06. Calc. for C14H31ClO6P2: C, 42.81; H, 7.95%.
3.1.10. Tetraethyl (4-(1,3-dioxolan-2-yl)butylidene)-
bisphosphonate (9)
Colorless oil; yield 75%; Rf 0.38 (TLC eluent:
CH2Cl2–MeOH, 95:5 v/v); flash chromatography elu-
ent: CH2Cl2–MeOH, 95:5 v/v; 1H-NMR (CDCl3) l
3.1.8. Tetraethyl (5-bromopentylidene)bisphosphonate
(16)
3
NBS (2.96 g; 16.64 mmol) was added over 1 h to a
magnetically stirred at −15 °C under Ar solution of
tetraethyl (5-hydroxypentylidene)bisphosphonate (5.00
g; 13.87 mmol) and triphenylphosphine (4.36 g; 16.64
mmol) in dry CH2Cl2 (50 ml). At the end of the
addition the mixture was allowed to reach r.t. and then
was washed with a saturated solution of NaCl (3×15
ml). The aq. layers were extracted with CH2Cl2 (15 ml).
The combined organic layers were dried and then con-
centrated under reduced pressure. The solid crude ma-
terial so obtained was extracted with hexane (5×20
ml). The organic extracts were concentrated under re-
duced pressure and the residue was purified by flash
chromatography (eluent CH2Cl2–MeOH, 98:2 v/v) to
give the title compound as a colorless oil. Yield 44%; Rf
1.33 (t, 12H, JHH 7.4 Hz, ꢀPO(OCH2CH3)2), 1.6–2.1
3
(m, 6H, ꢀCH2CH2CH2CHꢀ), 2.27 (tt, 1H, JHH 5.8 Hz,
2JPH 24.0 Hz, ꢀCH(PO(OCH2CH3)2)2), 3.8–4.0 (m, 4H,
ꢀOCH2CH2Oꢀ), 4.1–4.2 (m, 8H, ꢀPO(OCH2CH3)2),
3
4.84 (t, 1H, JHH 4.0, (O)CH(O));13C-NMR (CDCl3) l
16.2 (d, 3JPC 5.8 Hz, ꢀPO(OCH2CH3)2), 23.5 (t, 3JPC 7.0
2
Hz, ꢀCH2CH2CH2CHꢀ), 25.3 (t, JPC 4.2 Hz,
ꢀCH2CH2CH2CHꢀ), 34.0 (s, (O)CH(O)CH2ꢀ), 36.6 (t,
1JPC 132.0 Hz, ꢀCH(PO(OCH2CH3)2)2), 62.3 (t, virtual
J=7.0 Hz, ꢀPO(OCH2CH3)2), 64.70 (s, ꢀOCH2-
CH2Oꢀ), 104.0 (s, (O)CH(O)); 31P-NMR (CDCl3) l
24.4; MS (CI) 403 [M+1]+; Anal. (drying conditions:
40 °C, 8 h, pressure B1 mmHg) Found: C, 44.72; H,
8.07. Calc. for C15H32O8P2: C, 44.78; H, 8.02%.
1
0.67 (TLC eluent: CH2Cl2–MeOH, 9:1 v/v); H-NMR
3
(CDCl3) l 1.34 (t, 12H, JHH 7.0 Hz, ꢀPO(OCH2-
3.1.11. Tetraethyl (5-oxopentylidene)bisphosphonate (15)
A solution of tetraethyl (4-(1,3-dioxolan-2-yl)butyli-
dene)bisphosphonate (9) (487 mg; 1.21 mmol) in 80%
AcOH (10 ml) was heated at 65 °C for 1.5 h. The
progress of the reaction was followed by TLC
(CH2Cl2–MeOH, 95:5 v/v). The mixture was allowed to
reach r.t. and then was concentrated under reduced
pressure. The residue so obtained was dissolved in
CH2Cl2 (15 ml) and the resulting solution was washed
with a saturated solution of NaHCO3 (4×5 ml), dried
and then concentrated under reduced pressure. The
crude material so obtained was purified by flash chro-
matography (eluent CH2Cl2–MeOH from 98:2 to 95:5
v/v) to give the pure compound as a colorless oil. Yield
60%; Rf 0.54 (TLC eluent: CH2Cl2–MeOH, 9:1 v/v);
CH3)2), 1.6–2.2 (m, 6H, ꢀCH2CH2CH2CHꢀ), 2.26 (tt,
3
3
1H, JHH 6.0 Hz, JPH 24.0 Hz, ꢀCH(PO(OCH2-
3
CH3)2)2), 3.41 (t, 2H, JHH 6.0 Hz, BrCH2CH2ꢀ), 4.1–
4.2 (m, 8H, ꢀPO(OCH2CH3)2); 13C-NMR (CDCl3) l
16.2 (d, 3JPC 6.5 Hz, ꢀPO(OCH2CH3)2), 24.7 (t, 3JPC 5.2
2
Hz, ꢀCH2CH2CH2CHꢀ), 27.5 (t, JPC 6.0 Hz,
ꢀCH2CH2CH2CHꢀ), 32.25/33.05 (s/s, BrCH2CH2ꢀ),
1
36.5 (t, JPC 133.0 Hz, ꢀCH(PO(OCH2CH3)2)2), 62.4 (t,
virtual J=7.0 Hz, ꢀPO(OCH2CH3)2); 31P-NMR
(CDCl3) l 24.6; MS (CI) 423/425 [M+1]+; Anal.
(drying conditions: 40 °C, 8 h, pressure B1 mmHg)
Found: C, 37.09; H, 7.01. Calc. for C13H29BrO6P2: C,
36.89; H, 6.91%.
3
1H-NMR (CDCl3) l 1.35 (t, 12H, JHH 7.1 Hz,
3.1.9. Tetraethyl (5-dimethylaminopentylidene)-
bisphosphonate (11)
Pale yellow oil; yield 79%; Rf 0.37 (TLC eluent:
ꢀPO(OCH2CH3)2), 1.8–2.5 (m, 7H, ꢀCH2CH2CH2-
CHꢀ), 4.1–4.3 (m, 8H, ꢀPO(OCH2CH3)2), 9.8 (m, 1H,
3JHH 1.5 Hz, CH(O)CH2ꢀ); 13C-NMR (CDCl3) l 16.3
3
3
CH2Cl2–MeOH, 9:1 v/v); flash chromatography eluent:
(d, JPC 5.5 Hz, ꢀPO(OCH2CH3)2), 21.5 (t, JPC 7.2 Hz,
1
2
CH2Cl2–MeOH, 9:1 v/v then pure MeOH; H-NMR
ꢀCH2CH2CH2CHꢀ), 25.0 (t, JPC 5.2 Hz, ꢀCH2CH2-
3
1
(CDCl3) l 1.31 (t, 12H, JHH 7.0 Hz, ꢀPO(OCH2-
CH2CHꢀ), 36.5 (t, JPC 132.0 Hz, ꢀCH(PO(OCH2-
CH3)2), 1.4–2.4 (m, 9H, (CH3)2NCH2CH2CH2CH2-
CHꢀ), 2.56 (s, 6H, (CH3)2NCH2ꢀ), 4.1–4.2 (m, 8H,
CH3)2)2), 43.3 (s, HC(O)CH2ꢀ), 62.5 (t, virtual J=7.2
Hz, ꢀPO(OCH2CH3)2), 201.8 (s, HC(O)CH2ꢀ); 31P-
NMR (CDCl3) l 24.1; MS (CI) 359 [M+1]+; Anal.
(drying conditions: 40 °C, 8 h, pressure B1 mmHg)
Found: C, 42.00; H, 7.99. Calc. for C13H28O7P2·
0.6H2O: C, 42.30; H, 7.97%.
3
ꢀPO(OCH2CH3)2); 13C-NMR (CDCl3) l 16.3 (d, JPC
2
6.1 Hz, ꢀPO(OCH2CH3)2), 25.4 (t, JPC 6.0 Hz, ꢀCH2-
3
CH2CH2CHꢀ), 26.6 (t, JPC 5.3 Hz, ꢀCH2CH2CH2-
1
CHꢀ), 26.9 (s, ꢀCH2CH2N(CH3)2), 36.6 (t, JPC 132.0
Hz, ꢀCH(PO(OCH2CH3)2)2), 45.0 (s, (CH3)2NCH2ꢀ),
59.1 (s, (CH3)2NCH2ꢀ), 62.36 (t, virtual J=7.2 Hz,
ꢀPO(OCH2CH3)2); 31P-NMR (CDCl3) l 24.6; MS (EI)
387 [M]+; Anal. (drying conditions: r.t., 3 weeks, pres-
sure B1 mmHg) Found: C, 44.13; H, 8.96; N, 3.42.
Calc. for C15H35NO6P2·H2O: C, 44.44; H, 9.20; N,
3.46%.
3.1.12. Tetraethyl (5,6-dihydroxyhexylidene)bisphos-
phonate (14)
A solution of 2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl-
magnesium bromide (0.062 M; 3.97 mmol; 64 ml) was
added over 2 h to a stirred at −15 °C solution of 1

82
M.L. Lolli et al. / Journal of Organometallic Chemistry 650 (2002) 77–83
(1.19 g; 3.97 mmol) in dry THF (40 ml) under inert
atmosphere (Ar). The progress of the reaction was
followed by TLC (eluent: CH2Cl2–MeOH, 9:1 v/v).
The mixture was allowed to reach r.t. and then poured-
into a saturated solution of NH4Cl (60 ml). The mix-
ture was extracted with Et2O (60 ml); the dried organic
layer was concentrated under reduced pressure to give
the crude tetraethyl (4-(2,2-dimethyl-1,3-dioxolan-4-
yl)butylidene)bisphosphonate (8). Due to its instability
the dioxolane intermediate 8 was immediately trans-
formed into the corresponding diol without any further
purification. A solution of crude 8 (119 mg; 0.28 mmol)
in 30% aq. AcOH (3 ml) was stirred at r.t. for 2 h. The
progress of the reaction was followed by TLC (eluent:
CH2Cl2–MeOH, 9:1 v/v). The mixture was concen-
trated under reduced pressure and the residue was
dissolved into CH2Cl2 (10 ml). The resulting solution
was washed with a saturated solution of NaHCO3
(2×5 ml). The aq. layers were extracted with CH2Cl2
(4×10 ml) and then the combined organic layers were
dried and concentrated under reduced pressure. The
crude product was purified by flash chromatography
(eluent: CH2Cl2–MeOH, 98:2 v/v) to give the desidered
compound as a colorless oil. Yield 42%; Rf 0.36 (TLC
3.1.14. Tetraethyl (5-aminopentylidene)bisphosphonate
(13)
A solution of 12 (823 mg; 1.63 mmol) in dry THF (20
ml) and AcOH (2 ml) was stirred at r.t. for 4 h. The
mixture was concentrated under reduced pressure and
the residue was dissolved in water (5 ml). The resulting
solution, maintained at pH 10 by addition of 2 M
NaOH, was extracted with CH2Cl2 (7×10 ml). The
combined organic layers were concentrated obtaining
the pure product as a colorless oil. Yield 42%; Rf 0.5
(TLC eluent: CH2Cl2–MeOH–NH4OH (30% v/v),
1
3
9:1:0.1 v/v/v); H-NMR (CDCl3) l 1.33 (t, 12H, JHH
7.2 Hz, ꢀPO(OCH2CH3)2), 1.4–2.0 (m, 8H, H2NCH2-
3
2
CH2CH2CH2ꢀ), 2.27 (t, 1H, JHH 6.0 Hz, JPH 24.0 Hz,
3
ꢀCH(PO(OCH2CH3)2)2), 2.69 (t, 2H, JHH 6.8 Hz,
H2NCH2ꢀ), 4.1–4.2 (m, 8H, ꢀPO(OCH2CH3)2); 13C-
3
NMR (CDCl3) l 16.3 (d, JPC 6.5 Hz, ꢀPO(OCH2-
3
CH3)2), 25.2 (t, JPC 5.2 Hz, ꢀCH2CH2CH2CHꢀ), 26.2
2
(t, JPC 7.0 Hz, ꢀCH2CH2CH2CHꢀ), 33.1 (s, ꢀCH2CH2-
1
CH2CHꢀ), 36.54 (t, JPC 132.0 Hz, ꢀCH(PO(OCH2-
CH3)2)2), 41.5 (s, H2NCH2ꢀ); 62.3 (t, virtual J=7.8 Hz,
ꢀPO(OCH2CH3)2), 31P-NMR (CDCl3) l 24.6; MS (CI)
360 [M+1]+; Anal. (drying conditions: 40 °C, 8 h,
pressure B1 mmHg) Found: C, 40.70; H, 8.56; N,
3.59. Calc. for C13H31NO6P2·1.25H2O: C, 40.89; H,
8.84; N, 3.67%.
1
eluent: CH2Cl2–MeOH, 9:1 v/v); H-NMR (CDCl3) l
3
1.34 (t, 12H, JHH 7.0 Hz, ꢀPO(OCH2CH3)2), 1.44 (q,
3
2H, JHH 6.8 Hz, HOCHCH2CH2ꢀ), 1.6–1.8 (m, 2H,
ꢀCH2CH2CH2CHꢀ), 1.8–2.1 (m, 2H, ꢀCH2CH2CH2-
3
2
CHꢀ), 2.31 (tt, 1H, JHH 5.6 Hz, JPH 24.0 Hz,
ꢀCH(PO(OCH2CH3)2)2), 3.4–3.7 (m, 3H, OHCH2-
(OHCH)CH2ꢀ), 4.1–4.2 (m, 8H, ꢀPO(OCH2CH3)2);
Acknowledgements
This work was supported by a grant from MURST
Studi e Ricerche Finalizzate 40% Roma.
13C-NMR (CDCl3)
l
16.2 (d, 3JPC 6.1 Hz,
ꢀPO(OCH2CH3)2), 24.6/24.9 (overlapping triplets,
ꢀCH2CH2CH2CHꢀ), 32.2 (s, ꢀCH2CH2CH2CHꢀ), 36.3
1
(t, JPC 133.0 Hz, ꢀCH(PO(OCH2CH3)2)2), 62.3–62.7
References
(m, ꢀPO(OCH2CH3)2), 66.6 (s, OHCH2ꢀ), 71.2 (s,
OHCHꢀ); 31P-NMR (CDCl3) l 24.5/24.6; MS (CI) 391
[M+1]+; Anal. (drying conditions: 40 °C, 8 h, pres-
sure B1 mmHg) Found: C, 42.49; H, 8.43. Calc. for
C14H32O8P2: C, 43.08; H, 8.26%.
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