First synthesis of etidronate partial amides starting from PCl3.

Article abstract of DOI:10.1039/b305979k

Methods for the preparation of mixed tetra-amide esters 1 and 2, the partial amide ester 3, and tri- and P,P-diamides 4 and 5 from monophosphorus spieces 12, 8 and 9, respectively, were developed. Compounds 8 and 9 were obtained from phosphorus trichloride via MeOPCl2, which was treated with 2 eq. and 4 eq. of piperidine, followed by water or acetyl chloride, respectively. Tetrasubstituted amide bisphosphonates 1 and 2 were selectively dealkylated with lithium or silyl halide to achieve target compounds 3-5. Piperidine was found to be a good desilylation reagent. Quantum mechanical calculations illustrate why derivative 2 was produced in low yield. The usefulness of compounds 1, 3 and 4 as prodrugs of etidronate was determined in aqueous buffer and human serum.

Full text of DOI:10.1039/b305979k

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First synthesis of etidronate partial amides starting from PCl3
Petri A. Turhanen,*a Riku Niemi,b Mikael Peräkylä,a Tomi Järvinenb and
Jouko J. Vepsäläinena
a University of Kuopio, Department of Chemistry, P.O. Box 1627, FIN-70211, Kuopio, Finland.
E-mail: Petri.Turhanen@uku.fi; Fax: ϩ358 17 163259
b University of Kuopio, Department of Pharmaceutical Chemistry, P.O. Box 1627, FIN-70211,
Kuopio, Finland
Received 28th May 2003, Accepted 5th August 2003
First published as an Advance Article on the web 15th August 2003
Methods for the preparation of mixed tetra-amide esters 1 and 2, the partial amide ester 3, and tri- and P,P-diamides
4 and 5 from monophosphorus spieces 12, 8 and 9, respectively, were developed. Compounds 8 and 9 were obtained
from phosphorus trichloride via MeOPCl2, which was treated with 2 eq. and 4 eq. of piperidine, followed by water or
acetyl chloride, respectively. Tetrasubstituted amide bisphosphonates 1 and 2 were selectively dealkylated with lithium
or silyl halide to achieve target compounds 3–5. Piperidine was found to be a good desilylation reagent. Quantum
mechanical calculations illustrate why derivative 2 was produced in low yield. The usefulness of compounds 1, 3 and
4 as prodrugs of etidronate was determined in aqueous buffer and human serum.
Introduction
Results and discussion
Chemically and enzymatically stable bisphosphonates, charac-
terized by a P–C–P bridge, are analogues of pyrophosphate.1
These compounds bind strongly to calcium phosphate and
inhibit its formation, aggregation and dissolution. Their affinity
to bone mineral is the basis for their use as skeletal markers and
inhibitors of bone resorption. Bisphosphonates are the most
effective inhibitors of osteoclastic bone resorption, and are
therefore useful drugs in both the treatment and prevention of
osteoporosis.3 Etidronate, clodronate, alendronate and pami-
dronate are examples of these drugs which are used in various
bone diseases.1,3
Etidronate, (1-hydroxyethylidene)-1,1-bisphosphonic acid
(HEBPA) disodium salt, is highly hydrophilic and like other
tetraacidic bisphosphonates, its oral bioavailability is poor;
only 3–7% of the dose is absorbed.4 One way to increase the
lipophilicity and oral absorption is to prepare more lipophilic
compounds, such as the amide derivatives 1–5 shown in Fig. 1,
which might function as prodrugs of etidronate. A prodrug is a
drug derivative that requires a chemical or enzymatic biotrans-
formation to release the parent drug.5 Recently, pivaloyloxy-
methyl derivatives of HEBPA were reported as potential
prodrugs of HEBPA.6
New amide derivatives of etidronate were prepared from
monophosphorus starting materials 8 and 9 according to pre-
viously described procedures.7 However, these two compounds
were previously unknown derivatives of H–P(O)– and AcP(O)-
structures. Both 8 and 9 were obtained via MeOPCl2, which
was prepared from PCl3 and methanol. Preparation of the
piperidine derivatives in the next step was more problematic
than expected due to rearrangement of P() to P() and easy
cleavage of the P–N bond.8,9
The yield and purity of compound 7 was dependent on both
the reaction temperature and formation of the P–N bond from
the P–Cl, as reaction of the first two clorine atoms of PCl3 with
piperidine and subsequent treatment of the Cl–P(NR2)2-deriv-
ative with MeOH lead to a mixture of compounds, due to an
addition–elimination reaction between MeOH and trivalent
phosphorus amide.8 This results in the elimination of the amine
from phosphorus amide and addition of MeOH to the trivalent
phosphorus. In preparing compound 9 at room temperature or
at 0 ЊC, N-acetylpiperidine and compound 6 were observed to
be the main products (see Scheme 1).
Rather good results were obtained by adding acetyl chloride
to compound 7 in ether at Ϫ30 ЊC giving 9 as the main product
over N-acetylpiperidine and 6. Similar problems were met in
Scheme 1 Reagents and conditions: i) MeOH; ii) 4 eq. piperidine;
iii) acetyl chloride, Ϫ30 ЊC; iv) 2 eq. piperidine; v) 1.05 eq. H2O in 1.1
eq. triethyl amine, 0 ЊC; vi) H2O.
Fig. 1 Prepared etidronate derivatives.
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 2 2 3 – 3 2 2 6
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preparing 8 from 7 by adding water, which is a common pro-
cedure to obtain H–P(O)-compounds from trivalent phos-
phites.7a,10 In the case of 7, both of the P–N bonds were cleaved,
resulting in the methyl phosphite 10, and only trace amounts of
8 were observed. Starting from 6, which was prepared from
MeOPCl2 and 2 eq. of piperidine, the production of 8 was more
successful as the more reactive chlorine atom was replaced by
OH and after rearrangement 8 was observed at reasonable yield
(see Scheme 1).
Recently, we have developed a method to selectively prepare
partial esters of HEBPA,12 and the same approach was also
successful for synthesizing compound 3, the first partial amide
ester of HEBPA. This derivative was prepared from 1 using
lithium iodide as a demethylation agent, affording 3 as the only
product (Scheme 2) without any degradation of the phos-
phonamide bond. Surprisingly, the same procedure gave 5 from
2, but the yield was rather low due to subsequent purification
problems (Scheme 2).
The bisphosphonate starting materials 1 and 2 were obtained
by a known method7 from the compounds above with dibutyl-
amine as catalyst (Scheme 2). Compound 1 was obtained in 55%
yield while only about 9% of derivative 2 was isolated. Instabil-
ity or lower reactivity of 8 may be reasons for the low yield of 2.
The lower reactivity of 8 offers possibilities for side-reactions,
which were actually observed in the 31P NMR spectrum
when preparing compound 2. This reaction was expected to
If both of the methyl groups need to be removed, the
silylation method12–14 was found to be useful for dealkyl-
ation over piperidine groups, but hydrolysis of silyl groups by
MeOH did not lead to 4 as a free acid, since P–N bonds
tended to hydrolyse as well. In contrast, when piperidine was
used as the desilylating reagent for the compound 11, the piper-
idinium salt of 4 was the only product (see Scheme 4 and
Experimental).
follow
a
mechanism reported earlier,7a,11 and quantum
mechanical calculations were made to examine some reasons
why derivative 2 was obtained only in 9% yield under these
conditions.
Scheme 4 Reagents and conditions: i) trimethylsilyl bromide, rt;
ii) piperidine.
31P NMR spectroscopy was used to follow the formation of
HEBPA amides and the purity of the compounds was analysed
by 1H and 31P NMR spectra. Some characteristic features
were found in the proton spectra; namely the unequal chemical
shifts of the P–N–CH2–R methylene protons due to pro-
chirality, which gives rise to a complex splitting pattern, as
previously reported for tetra-amide esters and partial amides
of methylene- and (dichloromethylene)bisphoshonates.15 The
triplet observed at 3.47 ppm for the tetra-amide ester 1 belong-
ing to the OH-proton indicates a strong hydrogen bond from
the OH-proton to the phosphorous double bonded oxygen, as
some tetra-esters we have recently published.7a
By definition, prodrugs are pharmacologically inactive com-
pounds that are able to release the active parent drug (in this
case etidronic acid) via a chemical or enzymatic reaction. To
evaluate the usefulness of compounds 1, 3 and 4 as prodrugs of
etidronate, we studied their hydrolysis kinetics and ability to
release etidronic acid in aqueous buffer and in 80% human
serum. Compounds 1 and 3 had half-lives of 4.2 h and 7.3 h
in 50 mM phosphate buffer (pH 7.4, 37 ЊC). However,
etidronic acid was not released, nor was it in the hydrolysis
experiments in 80% human serum. Hydrolysis in both experi-
ments apparently resulted in the formation of the corre-
sponding mono- or dimethyl esters. These products were chem-
ically and enzymatically stable, which was previously observed
with simple esters of clodronic acid.16 Therefore, compounds 1
and 3 are not prodrugs of etidronate. Compound 4 degraded
totally to etidronic acid in 50 mM phosphate buffer (pH 7.4;
37 ЊC) in 5 minutes, and can be considered as an etidronate
prodrug. However, its usefulness is questionable, due to its low
chemical stability.
Scheme 2 Preparation of the compounds 3 and 5. Reagents and
conditions: i) Bu2NH; ii) LiI–acetone.
The quantum mechanical calculations were carried out to
estimate relative stabilities of the P() and P() tautomers of
12 and 8 (Scheme 3). The P() tautomers are thought to be the
reactive species in the mechanism leading to 1 and 2. As
expected, the P() tautomers of both 12 and 8 are more stable
than their P() tautomers. For 12, the energy difference in the
gas phase was 32.6 kJ molϪ1 at the MP2/6-311G**//HF/6-31G*
level and 16.9 kJ molϪ1 at the B3LYP/6-311G**//B3LYP/6-
31G* level. Solvation by diethyl ether was estimated to stabilise
the P() tautomer of 12 by 2.5 kJ molϪ1 (at the HF/6-31G*
level) compared to P(). The P() tautomer of 8 was calculated
to be less stable than that of 12. In the gas phase the energy
difference was 0.8 kJ molϪ1 (MP2/6-311G**//HF/6-31G*) and
4.7 kJ molϪ1 (B3LYP/6-311G**//B3LYP/6-31G*). Inclusion of
solvation energies increased this difference to 5.3 kJ molϪ1 and
9.2 kJ molϪ1, respectively. On the basis of these calculations, the
lower population of reactive P() tautomer for 8, relative to 12,
leads to 1–2 orders of magnitude lower reactivity for 8 in the
reaction, which partly explains the lower yield of 2 when com-
pared to 1. The steric bulk of the  substituent is likely to play a
role in the sterically crowded transition state leading to com-
pound 2.
Conclusions
Two methods for the first synthesis of partial amides (4 and 5)
and a partial amide ester (3) of HEBPA have been developed.
Lithium iodide and trimethylsilyl bromide were used as
demethylation reagents, and piperidine was noticed to be very
useful agent for desilylation in these reactions. Quantum mech-
anical calculations and observed side-reactions in the reaction
mixture at least partly explains the low yield of 2 under these
reaction conditions.
Scheme 3 Tautomers of the dimethyl phosphite (12) and piperidin-
1-yl phosphinic acid methyl ester (8).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 2 2 3 – 3 2 2 6
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(30 ml) for 15 minutes and then placed into the freezer (Ϫ20 ЊC)
Experimental
for 2 hours. The hexane layer was separated, evaporated in
vacuo and distilled under reduced pressure to give 8 [1.07 g, 24%
(calculated from MeOPCl2), bp 51 ЊC/4.6Ϫ1 mbar] as a colour-
less liquid. 1H NMR (CDCl3) δ 6.72 (1H, d, 1JHP = 638.9), 3.65
(3H, d, 3JHP = 12.1), 3.09 (4H, m), 1.62 (2H, m), 1.53 (4H, m);
31P NMR (CDCl3) δ 15.45; 13C NMR (CDCl3) δ 50.10 qd
(2JCP = 6.2), 43.46 td (2JCP = 3.7), 26.15 td (3JCP = 4.2), 24.57 t.
General
Solvents were HPLC-grade and were used without further
purification. The dimethyl phosphite (12) which was used to
prepare compound 1 is commercially available. Tubes filled with
anhydrous CaCl2 were used to protect reactions from outside
humidity if not stated otherwise. 1H, 31P and 13C NMR spectra
were recorded on a Bruker Avance 500 spectrometer operating
at 500.1, 202.5 and 125.8 MHz, respectively. TMS was used as
1-(Dipiperidin-1-yl-phosphinyl)ethanone (9). Compound 7
(3.95 g, 0.017 mol) was dissolved in ether (25 ml), and acetyl
chloride (1.33 g, 0.017 mol) was added slowly at Ϫ30 ЊC. The
reaction mixture was allowed to warm to room temperature
and the ether was removed in vacuo. Ethyl acetate was added
and the resulting precipitate was filtered; this step was repeated
three times. N-acetylpiperidine was removed in vacuo by stirring
at 40 ЊC for 24 hours. The residue was dissolved in hexane and
the solution was separated over formed solids and evaporated
in vacuo to give 9 (2.8 g, 63%) as a orange oil at 92% purity. 1H
NMR (CDCl3) δ 3.03 (8H, m), 2.49 (3H, d, 3JHP = 4.2) 1.59 (4H,
m), 1.51 (8H, m); 31P NMR (CDCl3) δ 12.17; 13C NMR (CDCl3)
δ 215.86 d (1JCP = 137.5), 44.60 t, 31.50 td (2JCP = 52.0), 26.09 td
(3JCP = 4.3), 24.59 t.
an internal standard for H and 13C measurements, and 85%
1
H3PO4 was used as an external standard for 31P measurements.
3
The JHH couplings are indicated by the letter “J” and all
J values are given in Hz. The number of protons on each carb-
on were detected from DEPT-135 experiments and marked
after each carbon by the letters d (doublet), t (triplet) or q
n
(quartet). The JCP couplings were calculated from carbon
spectra and the coupling constants are given in parenthesis as
hertz. The purity of products was determined from 1H and 31
P
NMR spectra and was ≥95% unless stated otherwise. Elemental
analyses were determined for compounds 1 and 3. Synthesis
yields were not optimised. The methods used in prodrug
evaluation are described elsewhere.6
All the quantum mechanical calculations were done with the
Gaussian 98 (Rev. A.7) program.17 The geometries of the mole-
cules were energy-minimised at the HF/6-31G* and B3LYP/
6-31G* levels followed by single-point energy calculations at
the MP2/6-311G** and B3LYP/6-311G** levels, respectively.
Several conformations of all the molecules were considered
and the reported results are calculated from lowest energy con-
formations. To estimate the effect of solvation on energies,
single-point calculations were made for the gas-phase optimised
structures using the polarisable continuum model (PCM) of
Tomasi and co-workers.18,19 The dieletric constant for diethyl
ether (ε = 4.335) was used in the solvation energy calculations.
[1-(Dipiperidin-1-yl-phosphinyl)-1-hydroxyethyl]-1-phos-
phonic acid dimethyl ester (1). Dimethyl phosphite (290 mg, 2.64
mmol) and dibutylamine (38.4 mg, 0.30 mmol) in ether (3 ml)
were cooled to 0 ЊC. Compound 9 (568 mg, 2.20 mmol) in ether
(2 ml) was slowly introduced at this temperature with stirring
and the mixture was allowed to warm to the room temperature
and refluxed for 2 hours. The resulting precipitate was filtered,
washed with ether and dried in vacuo to give 1 (445 mg, 55%) as
a slightly beige powder. 1H NMR (CDCl3) δ 3.88 (3H, d, 3JHP
=
3
3
10.4), 3.85 (3H, d, JHP = 10.4) 3.47 (–OH, t, JHP = 7.5), 3.28
(2H, m), 3.21 (4H, m), 3.10 (2H, m), 1.65 (3H, dd, 3JHP = 14.4,
3JHP, = 16.5), 1.60 (4H, m), 1.55 (8H, m); 31P NMR (CDCl3)
δ 29.17 d (2JPP = 36.4), 24.36 d; 13C NMR (CDCl3) δ 74.51 dd
Methyl(piperidin-1-yl)phosphinous chloride (6). Prepared
from 1 eq. of MeOPCl2 and 2 eq. of piperidine, giving 6 as a
colourless liquid (see preparation of 8). 31P NMR (CDCl3)
δ 174.32.
1
(1JCP = 116.6, JCP, = 150.3), 54.24 qd (2JCP = 7.2), 53.80 qd
(2JCP = 7.6), 45.93 t, 45.57 t, 26.17 td (3JCP = 5.4), 26.03 td
(3JCP = 4.6) 24.76 t, 24.56 t, 20.70 q. Anal. calcd for
C14H30N2O5P2: C, 45.65; H, 8.21; N, 7.61%. Found: C, 45.77; H,
8.20; N, 7.64%.
Dipiperidin-1-yl methyl phosphite (7). PCl3 (16 g, 0.12 mol)
was dissolved in ether (100 ml) and cooled to 0 ЊC under a
nitrogen atmosphere. Methanol (4.3 g, 0.13 mol) was slowly
introduced with stirring. The reaction mixture was allowed to
warm to room temperature with continuous stirring for 2 hours.
Ether was first removed by distillation using a 15 cm fraction
column, and the residue was further distilled to give MeOPCl2
(8.0 g, 0.060 mol, 50% bp 91–93 ЊC), which was then dissolved
in ether (200 ml), treated with piperidine (21.3 g, 0.25 mol) and
stirred for 48 hours at room temperature. The resulting precipi-
tate was filtered, and ether was removed to give 7 (8.4 g, 60%) as
a slightly yellow oil at 91% purity. 1H NMR (CDCl3) δ 3.40 (3H,
[1-(Dipiperidin-1-yl-phosphinyl)-1-hydroxyethyl]-1-phos-
phonic acid piperidinyl methyl ester (2). Prepared similarly to 1
from 8 (500 mg, 3.06 mmol), 9 (712 mg, 2.76 mmol) and di-
butylamine (60 mg, 0.46 mmol), but without cooling, only 5 ml
of ether was used, and the reflux time was 40 h. The synthesis
was carried out under a nitrogen atmosphere. Ether was
removed in vacuo. The remaining mixture was dissolved in
chloroform (2 ml) and hexane (10 ml) was added with rapid
stirring. The solution was separated from a heavier syrup
and evaporated in vacuo. The residue was purified by column
chromatography using ethyl acetate–methanol (70 : 30) as an
eluent (TLC Rf = 0.6, visualized by iodine) to give 2 (91 mg, 9%)
as a slightly yellow syrup and still crude product (purity ca.
70%). Only one stereoisomer was observed. 1H NMR (CDCl3)
δ 3.67 (3H, d, 3JHP = 11.1), 3.35–3.05 (12H, m), 1.62–1.48 (18H,
m), 1.57 (3H, dd, 3JHP = 14.7, 3JHP, = 16.9); 31P NMR (CDCl3)
δ 30.52 d (2JPP = 35.9), 27.81 d.
3
d, JHP = 12.7), 2.95 (8H, m), 1.56 (4H, m), 1.45 (8H,m); 31P
NMR (CDCl3) δ 131.94; 13C NMR (CDCl3) δ 51.57 qd (2JCP
16.6), 45.59 td (2JCP = 16.8), 27.19 td (3JCP = 5.1), 25.53 t.
=
Piperidin-1-yl phosphinic acid methyl ester (8). MeOPCl2
(3.7 g, 0.028 mol) was dissolved in ether (100 ml) and cooled to
0 ЊC under a nitrogen atmosphere. Piperidine (4.7 g, 0.055 mol)
was slowly introduced with rapid stirring. The reaction mixture
was allowed to warm to room temperature and stirring was
continued for 1.5 hours. Ether (80 ml) was added and the reac-
tion mixture was cooled to 0 ЊC. Triethylamine (3.1 g, 0.031
mol) in water (0.53 g, 0.029 mol) was slowly introduced to the
mixture at this temperature with stirring and the resulting reac-
tion mixture was allowed to warm to room temperature. Stir-
ring was continued for 2.5 hours, then filtered and the filtrate
was evaporated in vacuo. The residue was stirred with hexane
[1-(Dipiperidin-1-yl-phosphinyl)-1-hydroxyethyl]-1-phos-
phonic acid monomethyl ester monolithium salt (3). Compound 1
(191 mg, 0.52 mmol) and LiI (74 mg, 0.55 mmol) were dissolved
in acetone (4 ml) and heated with stirring in an oil bath at 55 ЊC
for 2.5 hours. The formed precipitate was filtered, washed
with acetone and dried in vacuo to give 3 (145 mg, 78%) as a
1
3
white powder. H NMR (CD3OD) δ 3.70 (3H, d, JHP = 9.9),
3
3
3.26 (6H, m) 3.17 (2H, m), 1.60 (3H, dd, JHP = 14.3, JHP, =
15.6), 1.60 (4H, m) 1.54 (8H, m); 31P NMR (CD3OD) δ 34.13 d
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 2 2 3 – 3 2 2 6
3225

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(2JPP = 32.8), 18.81 d; 13C NMR (CD3OD) δ 76.49 dd (1JCP
=
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120.2, 1JCP, = 141.4), 53.71 qd (2JCP = 6.8), 47.13 t, 47.06 t, 27.48
td (3JCP = 5.3), 27.42 td (3JCP = 5.3), 26.03 td (3JCP = 4.5) 25.98 t,
25.84 t, 22.08 q. Anal. calcd for C13H27LiN2O5P2: C, 43.34; H,
7.55; N, 7.78%. Found: C, 43.04; H, 7.48; N, 7.64%.
[1-(Dipiperidin-1-yl-phosphinyl)-1-hydroxyethyl]-1-phos-
phonic acid dipiperidinium salt (4). Compound 1 (100 mg, 0.27
mmol) was dissolved in trimethylsilyl bromide (1.0 ml) and
stirred for 2 hours at room temperature. The mixture was evap-
orated in vacuo and the residue was dissolved in toluene with a
few drops of piperidine added and then stirred 1 minute before
evaporation to dryness. The residue was dissolved in dry acet-
one. Any solids were filtered and the filtrate was evaporated to
dryness, then piperidine (1.5 ml) was added and the mixture was
stirred for 30 minutes at room temperature. The piperidine was
removed in vacuo, ether was added and the precipitate was fil-
tered, washed with ether and dried in vacuo to give 4 (70 mg,
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51%) as a slightly yellow solid. H NMR (CDCl3) δ 3.23 (6H,
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m), 3.17 (2H, m) 3.00 (8H, t, J = 5.4), 1.71 (8H, m), 1.59 (3H,
3
3
dd, JHP = 13.7, JHP, = 15.5) 1.57 (8H, m), 1.51 (8H, m); 31P
NMR (CDCl3) δ 34.00 d (2JPP = 24.3), 18.42 d; 13C NMR
(CDCl3) δ 74.31 dd (1JCP = 121.3, 1JCP, = 127.2), 46.02 t, 45.80 t,
45.04 t, 26.44 td (3JCP = 5.0), 26.35 td (3JCP = 4.5), 24.96 t, 24.86
t, 24.04 t, 23.48 t, 22.86 q.
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C. Adamo, S. Clifford, J. Ochterski, G. A. Petersson, P. Y. Ayala,
Q. Cui, K. Morokuma, D. K. Malick, A. D. Rabuck,
K. Raghavachari, J. B. Foresman, J. Cioslowski, J. V. Ortiz, B. B.
Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi,
R. Gomperts, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham,
C. Y. Peng, A. Nanayakkara, C. Gonzalez, M. Challacombe,
P. M. W. Gill, B. G. Johnson, W. Chen, M. W. Wong, J. L. Andres,
M. Head-Gordon, E. S. Replogle and J. A. Pople, GAUSSIAN 98
(Revision A.7), Gaussian, Inc., Pittsburgh, PA, 1998.
18 S. Miertus, E. Scrocco and J. Tomasi, Chem. Phys., 1981, 55,
117.
[1-(Dipiperidin-1-yl-phosphinyl)-1-hydroxyethyl]-1-phos-
phonic acid monopiperidinyl ester monolithium salt (5). Prepared
similarly to 3, from 2 [(60 mg, 0.14 mmol (calculated as the pure
compound)] and lithium iodide (20 mg, 0.15 mmol), but the
reaction time was 25 h. 5 [(12 mg, 21% (calculated from pure 2)]
was obtained as a beige solid. 1H NMR (CD3OD): δH 3.29 (6H,
m), 3.20 (6H, m) 1.60 (6H, m), 1.53 (12H, m), 1.49 (3H, dd,
3JHP = 14.6, 3JHP, = 15.9); 31P NMR (CD3OD) δ 37.15 d (2JPP
=
32.9), 20.32 d;13C NMR (CD3OD) δ 78.17 dd (1JCP = 111.2,
1JCP, = 124.9), 47.09 t, 46.86 t, 30.51 t, 27.48 td (3JCP = 5.1),
27.40 td (3JCP = 4.1), 26.33 t, 26.04 t, 25.84 t, 23.48 t, 20.70 q.
Acknowledgements
This study was financially supported by the Academy of
Finland and the National Technology Agency of Finland.
The authors thank Mrs Maritta Salminkoski and Mr Pekka
Savolainen for their skilful technical assistance and Mrs Tiina
Koivunen for elemental analyses.
References
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19 M. Cossi, V. Barone, R. Cammi and J. Tomasi, Chem. Phys. Lett.,
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O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 2 2 3 – 3 2 2 6
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