Optimization, continuation and lack of the one-step diphosphorylation reaction. Assay of modification of the tetraethyl-(pyrrolidine-2,2-diyl)bisphosphonate

Article abstract of DOI:10.1080/10426500307821

The optimization of the one-step diphosphorylation reaction is reported. The synthesis of new α-aminobisphosphonates with four- and six-membered rings and acyclic species with several substituents on the nitrogen atom and on the carbon atom bearing the two phosphorus atoms is described.

Full text of DOI:10.1080/10426500307821

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Optimization, Continuation and Lack of the One-Step
Diphosphorylation Reaction. Assay of Modification of
the Tetraethyl(pyrrolidine-2,2-diyl)bisphosphonate
a
b
Gilles Olive & Alain Jacques
a
Laboratoire OPEP , Belgium
b
Laboratoire CSTR , Belgium
Published online: 27 Oct 2010.
To cite this article: Gilles Olive & Alain Jacques (2003) Optimization, Continuation and Lack of the One-Step
Diphosphorylation Reaction. Assay of Modification of the Tetraethyl(pyrrolidine-2,2-diyl)bisphosphonate, Phosphorus, Sulfur,
and Silicon and the Related Elements, 178:1, 33-46, DOI: 10.1080/10426500307821
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Phosphorus, Sulfur and Silicon, 2003, Vol. 178:33–46
Copyright �C 2003 Taylor & Francis
1
042-6507/03 $12.00 + .00
DOI: 10.1080/10426500390170138
OPTIMIZATION, CONTINUATION AND LACK OF
THE ONE-STEP DIPHOSPHORYLATION REACTION.
ASSAY OF MODIFICATION OF THE TETRAETHYL-
(
PYRROLIDINE-2,2-DIYL)BISPHOSPHONATE
a
b
Gilles Olive and Alain Jacques
a
b
Laboratoire OPEP, Belgium and Laboratoire CSTR, Belgium
(Received July 9, 2002; accepted July 9, 2002)
The optimization of the one-step diphosphorylation reaction is reported.
The synthesis of new �-aminobisphosphonates with four- and six-
membered rings and acyclic species with several substituents on the
nitrogen atom and on the carbon atom bearing the two phosphorus
atoms is described.
Keywords: Amide; bisphosphonates; diphosphorylation; lactam;
trialkylphosphite
INTRODUCTION
The gem-bisphosphonates show a structural analogy with py-
1
rophosphoric acid. They are known for their various uses: den-
2
–4
tal (toothpastes and mouthwashes)
and medical applications
5,6
(
against rheumatoid arthritis,
for the inhibition of bone resorp-
tive processes such osteoporosis and Paget’s disease,
scintigraphy when combined with Tc,
and antirheumatismal agents,
pain-easing activities, antimoebic ), antibacterial agents, plant
2
,7–9
skeletal
9
9
10–12
13
breast cancer therapy,
antiviral,1
4,15
antiinflammatory
16,17
18
1
6
15
21–23
19
2
0
19
growth regulators,
herbicides,
pesticides,
in the nuclear
industry,2
4–26
flame retardants, and chelators in water treatment,
21
21
as well as many others. Gem-bisphosphonates and gem-bisphosphonic
acids can readily form complexes with calcium and magnesium and this
behavior is one of the principles sustaining their use as drugs.3
Recently, amino-gem-bisphosphonates have been involved in the con-
,15
2
7
formational study of pyrrolinoxyl radicals and they also work as spin
2
8
trapping agents relevant to biology.
Address correspondence to Gilles Olive, Laboratoire OPEP, Rue Maison d’Orbais,
3/14, B-5032 Corroy-le Chateau, Belgium. E-mail: gilles.olive@excite.com
2
3
3

3
4
G. Olive and A. Jacques
SCHEME 1 Yokomatsu and Qian procedures for bisphosphonates synthesis.
Several procedures for the synthesis of �-amino-bisphosphonates al-
ready have been reported in the literature.2
9,30
Unfortunately most of
them are quite awkward to perform and require several steps.1
In 1994, Yokomatsu et al. were the first to describe an easy sin-
gle step synthesis by a Beckmann rearrangement of oximes reagents
,11,31–33
1
5
(
Scheme 1, Equation (1)). However, we failed to extend this method to
a five-membered ring bisphosphonate and found at least seven prod-
ucts by 31P NMR in the crude reaction with only 10% of the tar-
2
8
get bisphosphonate. In 1997 and 1999, Qian et al. detailed a one-
pot but intricate two-step procedure involving Vilsmeier reagents and
organophosphorus compounds with P H bounds (Scheme 1, Equation
23,34
(
2)).
At the same time, we have designed an easy one-step method
also employing Vilsmeier reagents (amide or lactam/POCl3) with
2
8,35
trialkylphosphite.
Schematically the experimental procedure is as follows: At low tem-
perature, under nitrogen, POCl3 (0.22 mol) was slowly added to a mix-
ture of lactam or amide (0.11 mol) and trialkylphosphite (0.21 mol).
The reaction mixture was then stirred at room temperature and then
poured over a cold aqueous solution saturated with NH4OH (Scheme 2).
SCHEME 2 Our easy one pot procedure of bisphosphonates synthesis.
In this article, we describe our optimization studies for the latter
reaction parameters, new kinds of synthesis, and also our failures. Be-
cause any change of the bisphosphonate properties is of interest for

�
-Aminobisphosphonates
35
their use as a drug, we also report our attempts toward modifying the
tetraethyl(pyrrolidine-2,2-diyl)bisphosphonate.
RESULTS AND DISCUSSION
Optimization: All the optimizations were performed on the 2-pyrrol-
idinone.
Temperature: As elsewhere mentioned,36 when the temperature
�
raises above 40 C, the yield drops to about 5% due to the presence
of gaseous HCl; it is well known that hydrochloric acid can hydro-
8,16,37
lyze phosphonate (Scheme 3).
Similarly, when the initial temper-
ature is too low for the reaction to occur or when the amide is frozen,
the consequent removal of the cold source induces an exothermic reac-
tion and possibly brings it to boil. In these circumstances, the yield is
somewhat low and the presence of polymers can be encountered as it
was the case with N-benzylacetamide. For the 2-pyrrolidinone, an opti-
�
mum yield of 58% is obtained at � 7.5 C and the adverse effect starts at
�
�
10 C. It should be noted that a water bath at room temperature has
to be used after the removal of the cold source in order to calm down
the reaction.
SCHEME 3 Hydrolysis of bisphosphonate by HCl.
Equivalent of POCl3: According to Qian,23 only one equivalent of
POCl3 has to be used but more satisfactory results can be obtained by
incorporating two equivalents.2 Attempts with 1, 1.5, and 1.75 equiv-
alents of POCl3 on 2-pyrrolidinone provide a yield of 56–57%, close to
what is obtained with two equivalents but the purity is lower as em-
8
1
13
31
phasized by the H, C, and P spectra. Furthermore in these cases,
we observed a change of color and, after a few weeks, the presence of a
small quantity of crystals.
Timing at room temperature: During our preliminary attempts, the
crude mixture was hydrolyzed on ice and NH4OH just after the addition
of POCl3. The corresponding product was pure and obtained with a good
yield (58%). It is actually advisable to wait for 1 h at room temperature
in order to allow the less reactive amide to react.
Continuation: All the products were purified by normal work-up for
an amine (an acido-basic extraction) unless stated in the text.
Ring size: Most of our efforts were focused on the five-membered
rings. However we also investigated the synthesis from both

3
6
G. Olive and A. Jacques
TABLE I Influence of the Ring Size on
the Reaction
31P NMRb
�/ppm
a
Bisphosphonate
Yield /%
1
2
28
22.2
58
24.7
24.0
3
19c
a
b
c
With optimized condition.
In CDCl3.
4
3% from Yokomatsu.15
2
-azitidinone and 2-piperidone (or �-valerolactam). Table I summarizes
the results.
It has to be noticed that the synthesis of 3 by our procedure is less effi-
15
cient than the one propounded by Yokomatsu (19% yield versus 43%).
Linear compounds: The results for the acyclic series are displayed
on Table II; the yields have to be compared with those asserted in the
literature.
The yield of 4, the simplest bisphosphonate in the series, is higher
2
3
than the one reported by Qian. If a second methyl group is added on
the nitrogen (tertiary amine), the corresponding return is almost di-
vided by a factor of two, being reduced from 68% to 30%. This behavior
has been previously described for the cyclic series by comparing the
tetraethyl(pyrrolidine-2,2-diyl)bisphosphonate 2 and the tetraethyl(N-
methyl-pyrrolidine-2,2-diyl)bisphosphonate for which the yield drops
3
5
from 47% to 17%. Qian has obtained a better yield of 66% for com-
pound 5. As emphasized by entries 6 and 12, a methyl group addition on
the carbon atom bearing two phosphorus atoms significantly increases
the yield, at least up to 80%. If a phenyl group takes the place of the

�
-Aminobisphosphonates
37
TABLE II Linear �-Aminobisphosphonate
3
1P NMRa
Yield from
R1
R2
R3
Yield/%
�/ppm
literature/%
Ref.
4
5
6
7
8
9
0
1
2
3
4
H
H
Me
Me
Me
Me
Ph
Ph
Ph
Bn
Bn
Bn
Bn
H
Me
H
H
H
H
H
H
H
H
H
68
30
85
15
b
b
0
78
88
0
20.7
20.3
23.8
20.5
18.6
22.4
50
66
23
23
Me
Ph
H
Me
Ph
H
Me
CF3
Et
80c
43, 60 or 68
47
38
15
31
32
1
1
1
1
1
c
20.9
23.3
71
23.7
57
35
a
In CDCl3.
b
c
Not isolated.
Several steps.
latter methyl, the corresponding yield is reduced to 15% (compound 7).
In order to consolidate these observations, the N-benzyl series were
synthesized (compounds 11, 12, 13, and 14). The best results were ob-
tained with a methyl group, followed by a hydrogen atom and finally by
an ethyl group. The synthesis of the trifluoromethyl compound failed,
as mentioned in the lack section.
Considering the influence of the N-substitution, it appears that, in
all the occurrences, the best yield is obtained with a benzyl group and
to a lesser extent with a methyl group (compounds 4 and 11, 6 and 12).
Unfortunately, the syntheses involving phenyl groups are hampered by
inherent difficulties. The reactions occur but, in many cases, are incom-
plete: For compound 8 some of the triethylphosphite reactant remains
and, for compound 9, some of the amide. Furthermore, these compounds
cannot be satisfactorily purified due to the large number of spots found
on the TLC.
As a general rule, it appears that the yields obtained by our procedure
are higher than those reported in the literature with some exceptions
regarding inefficient reactions as for tertiary amide and for N-phenyl
compounds.

3
8
G. Olive and A. Jacques
A NMR study of these linear bisphosphonates shows a dependable
behavior. The 31P chemical shift are around � 20.5 ppm and � 23.5 ppm,
respectively for the formamide and acetamide. Similar observations are
made on compound 10 in reference 35 and on compound 7 from Olive
3
9
and van Genderen. The presence of a phenyl group on the nitrogen
affects these 31P chemical shifts with a respective increase of 2 and
1
ppm.
The 13C NMR spectrum of compound 7 displays a distinctive up-
field shift at 67 ppm for the quaternary carbon bearing two phosphorus
atoms when compared to the 57 ppm shift measured on compounds 6
and 12. A small coupling of around 5 Hz between the quaternary phenyl
carbon and the two phosphorus atoms can be measured on compounds
8
and 9. This is in agreement with the value reported by Yokomatsu.15
Synthesis of non symmetrical bisphosphonates: In the existing
literature,3
3,40
there have been very few reports devoted to non sym-
metrical bisphosphonates as depicted in Scheme 4.
SCHEME 4 Asymmetric bisphosphonate.
By applying our procedure to 2-pyrrolidinone in the presence of one
equivalent of P(OEt)3 and one equivalent of P(OiPr)3, a mixture of three
products 2, 15, and 16 is obtained (Scheme 5). Unexpectedly, 25%–25%–
3
1
5
0% proportions have been measured by P NMR and HPLC analy-
sis instead of the expected 33%–33%–33% ratios. Considering that the
distillation treatment failed, a pure sample of compound 16 was only
achieved by a preparative HPLC.
In a previous publication, the study of the 13C NMR spectrum of
28
2
the methyl on the phosphono group led to the conclusion that the Jpp
SCHEME 5 Synthesized non symmetric bisphosphonates.

�
-Aminobisphosphonates
39
coupling constant had to be larger than 15 Hz. In the view of the newly
synthesized bisphosphonates, this coupling constant has been resolved
to 58 Hz. It has to be noticed that all NMR spectra obtained from these
compounds are the sum of the data corresponding to 2 and 15 with the
3
1
exception of the P spectra.
Lacks: All the cases of deficiencies that we encountered fall into three
categories that are summarized on Table III: The reactants failed to
react, the reaction went wrong, the products were unstable or could not
be purified.
TABLE III Lack
No reaction
Wrong reaction
Unstable
1
7
2
0
21
22
1
8
1
9
8
9
1
0
1
3

4
0
G. Olive and A. Jacques
Surprisingly, primary amides as in 17 and 18 are not keen to react
and only the corresponding hydrolysis product of the triethylphosphite
has been found. Compound 19 only duplicates a lack that has been al-
3
5
ready described for succinimide and confirms that tetraphosphonates
cannot be obtained in this way. The failure of compound 10 probably
comes from steric hindrance. Nevertheless the latter can be attained by
3
1
the Kreutzkamp synthesis. It is likely that the high electronegativity
of the fluorine prevents the N-benzyltrifluoroactamide from reacting
(
compound 13).
Fortunately, compound 20 is the only case where the reaction goes
3
1
wrong. However a P NMR study on its products allows to rule out a
potential polymerization.
All the compounds reported in the third column of Table III have
been identified by their respective NMR spectra.
SCHEME 6 Aminolysis of bisphosphonate.
�
-Amino methoxyphosphonates are known to undergo aminolysis re-
4
1,42
actions (Scheme 6).
This probably happens while synthesizing com-
pound 21 which appears to be awkward to purify due to its instability.
However, its NMR spectrum has been quickly acquired after several
preparative TLC. The presence of an ester group apparently hinders a
proper build-up of compound 22. Its formation can be assumed by the
3
1
appearance of two peaks in the P NMR spectrum and of a character-
istic quaternary carbon triplet at 62.3 ppm with a coupling constant
1
3
of 129 Hz in the C NMR spectrum. Unfortunately, these spectra also
reveal several by-products as validated by a TLC (11 spots). As earlier
discussed, compounds 8 and 9 could not be purified; their TLC carry 16
and 12 spots respectively.
Assay of modification of the tetraethyl(pyrrolidine-2,2-diyl)bisphos-
phonate: Two different sites of the �-aminophosphonates can poten-
tially be modified; the phosphorus atoms and the nitrogen atom. How-
ever, most of our attempts led to failures. In order to enhance the
biodisponibility of the phosphonates, these alterations are usually re-
quired. It seems that the most problematic task is to enhance their
lipophilicity by lowering the polarity while maintaining their complex-
ing behavior.26

�
-Aminobisphosphonates
41
SCHEME 7 Modification on the phosphorus atoms.
Modifications on the phosphorus atoms: Our first efforts were devoted
to synthesize compound 23 (Scheme 7) by applying the second procedure
4
3
described by Veps a¨ l a¨ inen. Therefore compound 2 from Table I has
�
been heated at 110 C with 10 equivalents of piperidine for 20 min. The
resulting mixture still contains some of the starting reactants but its
3
1
P NMR study reveals the presence of two coupled phosphorus atoms
at 29 ppm and 18 ppm shifts with a 43 Hz coupling constant which is
incompatible with the structure of equivalent phosphorus atoms.
The aim of our second attempt was to synthesize compound 24. Noth-
ing arose from adding twenty equivalents of pyridine to molecule 2 and
�
warming the mixture to 120 C for 15 min. If it is left to stand for one
night, a complete degradation of compound 2 occurs.
Our conclusion is the same as Herlinger’s26 introduction: The prepa-
ration of a partial ester is difficult due to the poor selectivity of the
involved reactions.
SCHEME 8 Modification on the nitrogen atom.
Modifications on the nitrogen atom: At first, the synthesis of the qua-
ternary ammonium molecule 25 has been attempted (Scheme 8). The
objective was to open the five-membered ring by an Hofmann elimina-
tion. The resulting molecule would have provided a convenient build-
ing block for different kinds of pathways (Scheme 9). Unfortunately, no
reaction takes place when molecule 2 is mixed with iodomethane in
diethyl ether. However a complex mixture is obtained after 72 h in
3
1
pure CH3I; the corresponding P NMR spectrum shows 21 peaks and

4
2
G. Olive and A. Jacques
SCHEME 9 Hoffmann elimination.
some of the starting reactant remains. This result is compatible with
reference 44.
Our second attempt was to build compound 26 and, from it, a
tetraphosphorus molecule, whose direct synthesis appears not feasible.
The reaction yields an inseparable mixture of three components (the
expected end product, the related ammonium form and the starting
acylchloride). Unfortunately, it degrades after a few days.
The synthesis of compound 27 is our only successful alteration on the
nitrogen. It is readily obtained by dissolving 2 in hydrochloric acid and
by freely evaporating the remaining water. Its NMR study provides a
valuable insight into the reaction mechanism. Furthermore, it shows a
similar behavior as described by Pietri et al. in Krebs conditions: the
conversion from the acidic to the basic form comes with an NMR shift
4
5
from 24 to 17 ppm.
CONCLUSION
By optimizing the temperature during the addition of POCl3, the quan-
tity of POCl3 equivalents and the amount of time at room temperature,
we have significantly increased the yields as for example from 48% to
5
8% in the case of 2. The synthesis of new cyclic or acyclic compounds
and the modifications brought to some of the aminobisphosphonates
give a valuable insight into the reaction process. These are still un-
der investigation in our laboratory. Apart from the tertiary amides and
from the N-phenyl compounds, it appears that the yields obtained by
our procedure for linear compounds are higher than those reported in
the literature. Furthermore we hope that the description of our failures
provides some interesting information.
EXPERIMENTAL SECTION
Synthesis and Characterizations. General
1
NMR spectra were performed on a Varian Inova 400 ( H, 400.16 MHz,
1
3
31
1
C, 100.63 MHz, P, 162.00 MHz) or on a Varian Gemini 300 ( H,
1
3
31
3
00.046 MHz, C, 75.454 MHz, P, 121.460 MHz) spectrometer. �
1
13
are given in ppm and referred to internal TMS for H and C and

�
-Aminobisphosphonates
43
to external 85% H3PO4 for 31P. 15N-NMR spectra were recorded on a
Varian Inova 500 at 50.649 MHz (Inverse gated method) and the chemi-
cal shifts (�) in ppm referred to external CD3NO2. All J values are given
in Hz. Elemental analyses were determined in the Eindhoven Univer-
sity of Technology. Solvents were purchased from Biosolve. All starting
materials were Aldrich reagents and were used as purchased, unless
otherwise indicated.
General Optimized Procedure
In a double walled flask, under nitrogen, phosphorus oxichloride (20
�
ml, 0.22 mol) was added in 1 h time to a mixture at � 7.5 C of amide or
lactam (0.11 mol) and trialkylphosphite (0.21 mol). The reaction mix-
ture was stirred for 1 h at room temperature and then poured over a
mixture of ice (200 g) and ammonia 30% (400 ml). The aqueous layer
was extracted with methylene chloride (3 � 100 ml) and then the lat-
ter was removed to obtain an oil. The oil was dissolved in 100 ml of
methylene chloride. An aqueous solution of hydrochloric acid (10 ml of
3
2% HCl solution, 190 ml of water) was added (check that pH 1) and
the aqueous layer was washed with methylene chloride (3 � 100 ml). A
�
1
solution of sodium hydroxide (200 g�l ) was added up to pH 10 and the
aqueous layer was extracted with methylene chloride (4 � 100 ml). The
organic layer was dried over sodium sulfate, filtered and the removal
of the solvent afforded the desired bisphosphonates.
Tetraethyl(azetidine-2,2-diyl)bisphosphonate 1 (slightly yellow liq-
1
uid, 10.14 g, 28%). H-NMR (400 MHz, CDCl3) � 1.17 (12H, t, J = 7.2,
4
CH3CH2O), 2.23 (1H, s, NH ), 2.64 (2H, tt, JPH = 17.4, JHH = 8.0,
13
CH2CP2), 3.54 (2H, t, J = 7.8, CH2N), 4.06 (8H, m, 4 CH3CH2O). C-
NMR (100 MHz, CDCl3) � 16.1 (2 t, J = 3.1, 4 CH3CH2O), 25.2 (t, J = 6.1,
CH2CP2), 45.3 (t, J = 7.2, CH2N), 60.3 (t, J = 149.2, CP2), 62.6 (t, J = 3.0,
3
1
2
�
CH3CH2O), 63.1 (t, J = 3.5, 2 CH3CH2O). P-NMR (162 MHz, CDCl3)
22.2. Anal. Calcd for C11H25NO6P2: C, 40.13; H, 7.65; N, 4.25. Found:
C, 40.21; H, 7.55; N, 4.12.
Tetraethyl( N-methyl-1-aminoethan-1,1-diyl)bisphosphonate
slightly yellow liquid, 29.20 g, 84%). H-NMR (300 MHz, CDCl3) �
6
1
(
1
.36 (12H, t, J = 6.9, 4 CH3CH2O), 1.56 (3H, t, JPH = 17.0, CH3CP2),
.77 (1H, ls, NH), 2.55 (3H, s, CH3N), 4.23 (8H, m, 4 CH3CH2O).
C-NMR (75 MHz, CDCl3) � 14.8 (t, J = 3.8, CH3CP2), 15.8 (t,
1
1
3
J = 2.7, 4 CH3CH2O), 29.5 (t, J = 6.5, CH3N), 56.8 (t, J = 143.8, CP2)
31
6
(
2.0 (t, J = 3.8, 2 CH3CH2O), 62.3 (t, J = 3.2, 2 CH3CH2O). P-NMR
121 MHz, CDCl3) � 23.8. Anal. Calcd for C11H27NO6P2: C, 39.88;
H, 8.21; N, 4.23. Found: C, 40.02; H, 8.30; N, 4.20. Rf (EtOH/CH2Cl2
.5/9.5) = 0.52.
0

4
4
G. Olive and A. Jacques
Tetraethyl( N-methyl-1-amino-1-phenylmethane-1,1-diyl)bisphos-
1
phonate 7 (colorless liquid, 6.00 g, 15%). H-NMR (300 MHz, CDCl3)
�
1.20 (6H, t, J = 6.9, 2 CH3CH2O), 1.29 (6H, t, J = 7.1, 2 CH3CH2O),
2
.48 (3H, s, CH3N), 4.11 (8H, m, 4 CH3CH2O), 7.35 (3H, m, Aromatics
13
ortho and para), 7.82 (2H, m, Aromatics meta). C-NMR (75 MHz,
CDCl3) � 15.8 (t, J = 3.2, 2 CH3CH2O), 15.9 (t, J = 3.2, 2 CH3CH2O),
3
2
0.6 (t, J = 9.1, CH3N), 62.9 (t, J = 3.8, 2 CH3CH2O), 63.0 (t, J = 3.2,
CH3CH2O), 67.4 (t, J = 136.8 CP2), 126.8 (t not resolved, Aromatics
para), 127.0 (t not resolved, Aromatics meta), 128.4 (t, J = 5.4, Aromat-
31
ics ortho), 131.8 (t, J = 3.8, quaternary aromatic). P-NMR (121 MHz,
CDCl3) � 20.5 Anal. Calcd for C16H29NO6P2: C, 48.86; H, 7.43; N, 3.56.
Found: C, 49.32; H, 7.03; N, 3.76. Rf (EtOH/CH2Cl2 0.5/9.5) = 0.60.
Tetraethyl(N-benzyl-1-aminoethan-1,1-diyl)bisphosphonate 12 (or-
1
ange liquid, 33.48 g, 88%). H-NMR (300 MHz, CDCl3) � 1.38 (12H,
m, 4 CH3CH2O), 1.67 (3H, t, JPH = 16.8 CH3CP2), 4.06 (2H, s, CH2N),
13
4
.38 (8H, m, 4 CH3CH2O), 7.36 (5H, m, Aromatics). C-NMR (75 MHz,
CDCl3) � 16.1 (t, J = 3.2, 4 CH3CH2O) and CH3CP2), 47.4 (t, J = 5.9,
CH2N), 57.4 (t, J = 142.7, CP2), 62.4 (t, J = 3.8, 2 CH3CH2O), 62.9 (t,
J = 3.2, 2 CH3CH2O), 126.3 (Aromatic para), 127.6 and 127.7 (Aromat-
ics ortho and meta), 139.8 (quaternary aromatic). 31P-NMR (121 MHz,
CDCl3) � 23.3 Anal. Calcd for C17H31NO6P2: C, 50.12; H, 7.67; N, 3.44.
Found: C, 49.88; H, 7.41; N, 3.04.
0
0
P,P-Diethyl-P ,P -diisopropyl(pyrrolidine-2,2-diyl)bisphosphonate
6 (colorless liquid, 9.85 g, 25%). 16 was purified by preparative
1
HPLC on a Kromasil column (10 �m, 8 int = 50 mm, L = 25 cm) with
�
1
CH3CN/H2O 60/40 as eluent. Rate: 50 ml�mn . 70 mg by injection. UV
detector at 204 nm. TR (Kromasil column 10 �m, CH3CN/H2O 60/40,
�
1
rate: 0.5 ml�mn , UV detector at 204 nm) = 7.57 mn.
1
H-NMR (300 MHz, CDCl3) � 1.35 (6H, t, J = 7.8, 2 CH3CH2O), 1.37
(
2
12H, d, J = 6.6, 2 (CH3)2CHO), 1.88 (2H, t, J = 6.7, CH2CH2CH2),
.30 (2H, m, CH2CP2), 3.07 (2H, t, J = 6.5, CH2N), 4.21 (4H, m, 2
13
CH3CH2O), 4.82 (2H, m, 2 (CH3)2CHO). C-NMR (75 MHz, CDCl3)
16.2 (t, J = 4.9, 2 CH3CH2O), 23.5 (t, J = 5.4, 2 (CH3)2CHO), 24.0
�
(
d, J = 3.2, (CH3)2CHO), 24.1 (d, J = 3.2, (CH3)2CHO), 25.8 (t, J = 3.2,
CH2CH2CH2), 30.2 (t, J = 2.7, CH2P2), 47.1 (t, J = 4.3, CH2N), 61.5 (t,
J = 152.9, CP2), 62.4 (d, J = 7.5, CH3CH2O), 62.9 (d, J = 7.5, CH3CH2O),
31
7
(
1.0 (d, J = 7.5, (CH3)2CHO), 71.6 (d, J = 7.5, (CH3)2CHO). P-NMR
162 MHz, CDCl3) � 22.7 (d, JPP = 59, P(OiPr)2, 24.9 (d, JPP = 58,
15
P(OEt)2. N-NMR (C6D6) � � 340.4 (t, JN--P = 9.3). Anal. Calcd for
C14H31NO6P2: C, 45.28; H, 8.41; N, 3.77. Found: C, 45; 21; H, 8.55;
N, 4.02.

�
-Aminobisphosphonates
45
Tetraethyl(pyrrolidine-2,2-diyl)bisphosphonate hydrochloride 27
1.08 g, 98%). In a 10 ml flask, tetraethyl(pyrrolidine-2,2-diyl)bi-
(
sphosphonate 2 (1.00 g, 2.9 mmol) and an hydrochloric acid solution
10 ml HCl 32% and 90 ml H2O) was kept at room temperature for
days and then the water was removed under reduced pressure to
(
3
give 1.08 g (yield = 98%) of dark yellow oil.
1
H-NMR (400 MHz, CDCl3) � 1.30 (12H, t, J = 7.2, 4 CH3CH2O),
2
.11 (2H, quint., J = 7.0, CH2CH2CH2), 2.49 (2H, m, CH2CP2), 3.55
(
2H, t, J = 7.0, CH2N), 4.22 (8H, m, 4 CH3CH2O), 8.30 (2H, s, 2 NH2).
1
3
C-NMR (100 MHz, CDCl3) � 15.9 (4 CH3CH2O), 24.1 (CH2CH2CH2),
1.0 (CH2P2), 49.0 (CH2N), 62.9 (t, J = 146.0, CP2), 65.3 (4 CH3CH2O).
P-NMR (162 MHz, CDCl3) � 16.9. Anal. Calcd for C12H28ClNO6P2: C,
7.95; H, 7.43; N, 3.69. Found: C, 38.12; H, 7.64; N, 3.37.
3
3
1
3
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