Synthesis of dinucleoside pyridylphosphonates involving palladium(0)-catalysed phosphorus-carbon bond formation as a key step

Article abstract of DOI:10.1039/b108857m

Dinucleoside 3-pyridylphosphates, as well as their 2- and 4-pyridyl positional isomers, have been synthesised using a palladium(0)-catalysed cross coupling strategy.

Full text of DOI:10.1039/b108857m

Synthesis of dinucleoside pyridylphosphonates involving
palladium(0)-catalysed phosphorus–carbon bond formation as a key
step
Tommy Johanssona and Jacek Stawinski*ab
a Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm,
Sweden. E-mail: js@organ.su.se
b Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan,
Poland
Received (in Cambridge, UK) 28th September 2001, Accepted 30th October 2001
First published as an Advance Article on the web 23rd November 2001
Dinucleoside 3-pyridylphosphonates, as well as their 2- and
4-pyridyl positional isomers, have been synthesised using a
palladium(0)-catalysed cross coupling strategy.
A palladium(0) catalytic cycle6 expected for this type of
reaction and supported by 31P NMR experiments, is depicted in
Scheme 1. It seemed that the most energy demanding step in this
cycle was the ligand substitution, i.e. the formation of a trans-
adduct B via nucleophilic attack of a phosphorus nucleophile on
the initial intermediate, trans-adduct A. Since the only inter-
mediate observed by 31P NMR spectroscopy during the course
of the reaction was that of trans-adduct A [dP = 24.2 ppm], the
two consecutive steps in which B collapsed to the pyr-
idylphosphonate products (see Scheme 1), both had to be
fast.‡
A pyridine ring is found in many natural products, e.g. in
pyridine alkaloids, vitamins (niacin, pyridoxal), nicotinamide
adenine dinucleotide phosphate (NADP), and constitutes a
functionality often present in drugs (e.g. isoniazid—anti-
tubercular activity; sulfapyridine—antibacterial and antiviral
properties; pyrilamine—antihistaminic drug).1
These prompted us to develop a synthetic method for
incorporation of a pyridine moiety in the form of pyr-
idylphosphonate functionality (Chart 1) into natural product
derivatives. Since the position of the phosphonyl group on the
pyridine ring may be important for biological activity, all three
isomeric compounds of type 1, 2, and 3 should be accessible for
chemical and biological studies.
To investigate the stereochemical outcome of this palla-
dium(0)-catalysed cross coupling, separate diastereomers of
dinucleoside H-phosphonate 4 were subjected to the reaction
with 3-bromopyridine 5a (Scheme 2). We found that the P–C
bond formation was completely stereospecific as the RP
diastereomer 4a, (dP = 6.9 ppm) afforded exclusively the
diastereomer 6a, (dP = 16.3 ppm), while the SP diastereomer 4b
(dP = 8.6 ppm) produced the other diastereomer of 3-pyr-
idylphosphonate 6b (dP = 17.2 ppm).
To find out if the formation of the P–C bond in this reaction
occurred with retention or with inversion of configuration at the
phosphorus center in 4, we decided to synthesise separate
diastereomers of dinucleoside 2-pyridylphosphonates 7 and
4-pyridylphosphonates 8 using palladium(0) chemistry and
compare them with the same compounds obtained in another
way.2,3
Chart 1
Dinucleoside 4-pyridylphosphonates 8 were prepared using
the protocol developed for 3-pyridylphosphonate 6, by reacting
separate diastereomers of dinucleoside H-phosphonate 4 with
Recently, we have developed efficient and general protocols
for the preparation of dinucleoside 2-pyridyl-2 and 4-pyr-
idylphosphonates3 but, unfortunately, 3-pyridylphosphonates
of type 3 cannot be prepared by these methods.
Introduction of a phosphonyl group into the 3-position of a
pyridine ring is rather difficult and the few methods available
for this purpose are usually low yielding.4 Encouraged by the
promising results of Hirao et al.5 in the synthesis of diethyl
3-pyridylphosphonate 3, we have embarked on a more detailed
investigation of chemistry and stereochemistry of this palla-
dium(0)-catalysed reaction, as a viable way for preparing
dinucleoside pyridylphosphonates 6–8.
We set out to prepare dinucleoside 3-pyridylphosphonates 6,
for which there was no synthetic method available. This
required considerable experimentation to develop the best
conditions of solvents and reagents, as well as the nature and
quantity of the catalyst. Eventually, the use of equimolar
amounts of dinucleoside H-phosphonate 4 and 3-bromopyridine
5a in the presence of 0.2 equiv. of Pd(PPh3)4, and 1.2 equiv. of
triethylamine (TEA) under reflux in THF, was found to serve
most needs.† Using these conditions, a cross coupling of
dinucleoside H-phosphonate 4 with 3-bromopyridine 5a
(Scheme 2) in the presence of a base (TEA) catalysed by the
added Pd(PPh3)4 proceeded quantitatively (31P NMR) and
afforded the desired 3-pyridylphosphonate derivatives 6 in ca.
85% yield.
Scheme 1
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Chem. Commun., 2001, 2564–2565
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b108857m

In conclusion, we have developed a new method for the
preparation of dinucleoside pyridylphosphonates 6–8 based on
a palladium(0)-catalysed cross coupling of the corresponding H-
phosphonate diesters 4 and halopyridines 5. The reaction is
stereospecific, occurring most likely with retention of config-
uration and can be considered as a general entry to isomeric
pyridylphosphonate derivatives.
We are indebted to Professor P. J. Garegg for his interest in
this work. Financial support from the Swedish Natural Science
Research Council and the Swedish Foundation for Strategic
Research is gratefully acknowledged
Notes and references
† Typical protocol for the preparation of dinucleoside 3-pyridylphospho-
nates 6. Dry, degassed (argon) THF was used throughout and the reactions
were carried out under an atmosphere of argon. A separate diastereomer 4a
or 4b, (0.529 mmol), Pd(PPh3)4 (0.20 equiv.), triethylamine (1.2 equiv.) and
3-bromopyridine (1.0–1.2 equiv.) in freshly distilled and degassed THF (10
mL) was refluxed for 4–5 h. After concentration and partition of the reaction
mixture between sat. aq. NaHCO3 and CH2Cl2, the product was purified by
silica gel column chromatography using a stepwise gradient of methanol
(0.5–5%) in CH2Cl2 containing 0.1% TEA. White solids, purity > 98% (1H
NMR). 6a (85% from 4a, probably RP diastereomer). HRMS [M + H]+,
found 1212.4376. C67H67N5O15P requires 1212.4371. 6b (80% from 4b,
Scheme 2
4-bromopyridine 5c in the presence of Pd(PPh3)4. The reactions
were stereospecific and afforded products 8§ with the same
stereochemistry as those formed in the reaction of H-phospho-
nates 4 with the pyridine–trityl chloride–DBU reagent system.3
Since the latter provided products 8 most likely with retention of
configuration at the phosphorus center,3 we could tentatively
conclude that the palladium(0)-catalysed cross coupling of H-
phosphonate 4 with 4-bromopyridine 5c, and probably also that
with 3-bromopyridine 5a, occurred with the same ster-
eochemistry, i.e. with retention of configuration of the phospho-
rus center of 4.
Attempted preparation of dinucleoside 2-pyridylphosphonate
7 by a palladium(0)-catalysed coupling of H-phosphonate 4 with
2-bromopyridine 5b, turned out to be a more difficult task as the
protocol developed for the 3-pyridyl isomer 6 afforded the
desired product in less than 30% (31P NMR analysis).
Inspired by the recent findings of Hartwig et al.7 that
chelating, sterically hindered phosphines are superior (in terms
of yields and kinetics) ligands in palladium(0)-catalysed N-
arylation of amines, we replaced in our catalytic system
triphenylphosphine by 1,1A-bis(diphenylphosphino)ferrocene
(DPPF). With this modification, the efficiency of 2-pyr-
idylphosphonates 7 formation increased to ca 80% (31P NMR
analysis) and 7a and 7b were isolated in > 50% yield.¶∑ By
comparing the stereochemistry of 2-pyridylphosphonates 7
formed in this and in a DBU-catalysed reaction,2 we conclude
that both of them provided products with the same ster-
eochemistry at the phosphorus centre. Thus, palladium(0)-
catalysed formation of the P–C bond in this instance also most
likely occurred with retention of configuration as was found for
3- and 4-pyridylphosphonates 6 and 8.
probably SP diastereomer). HRMS [M
+
H]+, found 1212.4373.
67H67N5O15P requires 1212.4371. Some diagnostic spectral data (in
C
CDCl3) [compound, dP; dH(H-2 py); dH1A; dC(C-3 py) (JCP)]: 6a, 16.3 ppm;
8.42–8.75 ppm (with pyr-H6, 2H); 6.38 (1H) & 6.26 (1H) ppm; 123.68 ppm
(190 Hz). 6b, 17.2 ppm; 8.86 ppm (1H); 6.39 (1H) & 6.20 (1H) ppm; 123.61
ppm (189 Hz).
‡ The same course of the reaction was observed when H-phosphonate 4 was
allowed to react with a separately prepared intermediate A8 in THF under
reflux in the presence of TEA.
§ Compounds 8a (from 4a, 66% yield) and 8b (from 4b, 69% yield) were
identical to those obtained in another way.3 White solids, purity > 98% (1H
NMR).
¶ The reaction was carried out as described above for 3-pyridylphospho-
nates 6, with the exception that Pd(PPh3)4 was replaced by 0.2 equiv. of
Pd(OAc)2 and 0.4 equiv. of DPPF. Compounds 7a (from 4a, 54% yield) and
7b (from 4b, 51% yield) were identical to those obtained in another
way.2
∑ The stereochemical course of the reaction was the same as that with
Pd(PPh3)4. In contradistinction to DPPF, conformationally more flexible
1,3-bis(diphenylphosphino)propane (DPPP) was found to be unreactive,
which may indicate the importance of rigidity of the ligand in this
reaction.
†† With chelating ligands such as DPPF, oxidative addition (Scheme 1)
results in the formation of cis- rather than trans-adducts (of type A). This
may change geometry and electron distribution in the adduct and facilitate
substitution of bromide by a phosphorus nucleophile, which was assumed to
be the rate-determining step for the catalytic cycle.
1 The Merck Index, Merck & Co, Inc., Rahway, NJ, 1989.
2 T. Johansson, A. Kers and J. Stawinski, Tetrahedron Lett., 2001, 42,
2217.
3 A. Kers and J. Stawinski, Tetrahedron Lett., 1999, 40, 4263.
4 R. D. Bennett, A. Burger and W. A. Volk, J. Org. Chem., 1958, 23,
940.
5 T. Hirao, T. Masunaga, Y. Ohshiro and T. Agawa, Synthesis, 1981, 56.
6 C. Amatore and A. Jutand, Acc. Chem. Res., 2000, 33, 314.
7 M. S. Driver and J. F. Hartwig, J. Am. Chem. Soc., 1996, 118, 7217.
8 P. Fitton and E. A. Rick, J. Organomet. Chem., 1971, 28, 287.
It is worth noting that using DPPF in the synthesis of
3-pyridylphosphonates 6 shortened the reaction time from 4 to
2 h.†† Unfortunately, due to separation problems, yields of the
isolated products 6 were lower (ca. 55%) than those where
triphenylphosphine acted as a ligand.
Chem. Commun., 2001, 2564–2565
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