Bridging of bipyridine units by phenylphosphine links: Linear and cyclic oligomers and some acid derivatives

Article abstract of DOI:10.1021/jo051586g

Reaction of 6,6′-dibromo-2,2′-bipyridine with phenylphosphine under palladium-promoted cross-coupling conditions provides a variety of linear oligomers bearing two reactive bromo substituents as well as a cyclic dimer, characterized by X-ray crystallograp

Full text of DOI:10.1021/jo051586g

Bridging of Bipyridine Units by Phenylphosphine Links: Linear
and Cyclic Oligomers and Some Acid Derivatives
Raymond F. Ziessel,* Lo¨ıc J. Charbonnie`re,* Samir Mameri, and Franck Camerel
Laboratoire de Chimie Mole´culaire, UMR CNRS 7509, ECPM-ULP, 25 rue Becquerel,
67087 Strasbourg Cedex, France
ziessel@chimie.u-strasbg.fr
Received July 29, 2005
Reaction of 6,6′-dibromo-2,2′-bipyridine with phenylphosphine under palladium-promoted cross-
coupling conditions provides a variety of linear oligomers bearing two reactive bromo substituents
as well as a cyclic dimer, characterized by X-ray crystallography, in which the bipyridine units are
constrained to a cis configuration by two phenylphosphine oxide bridges. Derivatives of the linear
species containing both carboxylate and phosphonate substituents are readily obtained.
Introduction
have demonstrated attracting water solubilizing capabili-
ties for hydrophobic CdSe semiconducting nanocrystals
and Pd or Au nanoparticles.7 Recently, the use of poly-
merizable functionalized phosphine oxide precursors, in
particular those possessing activable C-Br functions,
were adequately used to prevent aggregation of nano-
particles by the formation of polymer-nanoparticle com-
posites ensuring a better dispersion of the nanoparticles
in solid-state devices.8 The synthesis of such oligomers
combining coordinating phosphine oxide moieties associ-
ated to chromophoric bipyridyl units are very promising
targets as capping layers for the photosensitization of
lanthanide-based nanoparticles.9 The definitive request
for oligomeric bipyridine-based phosphine oxides prompted
us to consider sustainable methods for large-scale pro-
duction of such derivatives.
Segmented multidentate ligands capable of producing
linear chains or more complex arrays of metal centers
are of considerable interest, both topologically and from
the point of view of possible applications in the fields of
molecular recognition and catalysis.1,2 One of their
characteristics is the formation of metallamacrocycles,
some of which can bind selectively to further metal ions
and which commonly show strong electronic absorption
and photoluminescence.3 An avenue to the synthesis of
polynucleating ligands is the combination of phosphino
units with a chelating framework based on nitrogen
donor groups.4 Phosphine oxide based ligands are ef-
ficient for the complexation and extraction of lanthanide
cations in nuclear waste management.5 When associated
to chromophoric bipyridyl units, they ensure both strong
coordination to the metal cations and good ability to
generate highly luminescent complexes with ionophoric
properties.6 Furthermore, polymeric phosphine oxide
The synthetic value of P-C coupling reactions has been
widely demonstrated with aryliodides,10 alkenyl or aryl
triflates,11 1,3-dienes,12 vinyl bromide13 or triflates,14
(7) Kim, S.-W.; Kim, S.; Tracy, J. B.; Jasanoff, A.; Bawendi, M. G.
J. Am. Chem. Soc. 2005, 127, 4556.
(1) Lai, S.-Y.; Lin, T.-W.; Chen, Y.-H.; Wang, C.-C.; Lee, G.-H.; Yang,
M.-H.; Leung, M.-K.; Peng, S.-M. J. Am. Chem. Soc. 1999, 121, 250
and references therein.
(8) Skaff, H.; Sill, K.; Emrick, T. J. Am. Chem. Soc. 2004, 126, 11322.
(9) (a) Louis, C.; Bazzi, R.; Marquette, C. A.; Bridot, J.-L.; Roux, S.;
Ledoux, G.; Mercier, B.; Blum, L.; Perriat, P.; Tillement, O. Chem.
Mater. 2005, 17, 1673. (b) Meiser, F.; Cortez, C.; Caruso, F. Angew.
Chem., Int. Ed. 2004, 43, 5954.
(2) (a) Newkome, G. R. Chem. Rev. 1993, 93, 2067. (b) Kaes, C.; Katz,
A.; Hosseini, M. W. Chem. Rev. 2000, 100, 3553.
(3) Balch, A. L.; Catalano, V. J.; Chatfield, M. A.; Nagle, J. K.;
Olmstead, M. M.; Jr. Reddy, P. E. J. Am. Chem. Soc. 1991, 113, 1252.
(4) Grassi, M.; De Munno, G.; Nicolo, F.; Lo Schiavo, S. J. Chem.
Soc., Dalton Trans. 1992, 2367.
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Schultz, W. W. Solvent Extr. Ion Exch. 1985, 3, 75. (b) Martin, K. A.;
Horwitz, E. P.; Ferraro, J. R. Solvent Extr. Ion Exch. 1986, 4, 1149.
(6) Charbonnie`re, L. J.; Ziessel, R.; Montalti, M.; Prodi, L.; Zac-
cheroni, N.; Boehme, C.; Wipff, G. J. Am. Chem. Soc. 2002, 124, 7779.
(10) Herd, O.; Hessler, A.; Hingst, M.; Machnitzki, P.; Tepper, M.;
Stelzer, O. Catal. Today 1998, 42, 413.
(11) (a) Holt, D. A.; Erb, J. M. Tetrahedron Lett. 1989, 30, 5393. (b)
Uozumi, Y.; Tanahashi, A.; Lee, S.-Y.; Hayashi, T. J. Org. Chem. 1993,
58, 1945. (c) Kurz, L.; Lee, G.; Jr Morgans, D.; Waldyke, M. J.; Ward,
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297.
10.1021/jo051586g CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/01/2005
J. Org. Chem. 2005, 70, 9835-9840
9835

Ziessel et al.
SCHEME 1a
i
a Key: (i) PhPH2 (0.5 equiv), [Pd(PPh3)4] (10 mol %), Pr2EtN,
CH3CN, reflux; (ii) CH2Cl2, H2O, NaIO4, rt.
dinucleosides,15 and tyrosine-containing peptides.16 These
preparations are commonly based on the use of trimeth-
ylstannyl- or trimethylsilyl-diphenylphosphine17 or, more
conveniently, primary or secondary phosphines.18 The
synthesis of 2-pyridylphosphane is achieved by metala-
tion of pyridine at low temperature followed by reaction
with chlorophosphane or dichlorophosphane. The recent
use of pyridine-halogeno derivatives in metal catalyzed
P-C cross-coupling reaction has enabled the preparation
of mono-,19 di-,20 and tripyridinephosphane ligands.21 In
contrast, few examples of the P functionalization of
bipyridine22,23 or terpyridine24 skeletons are known. By
extension of our interest in the preparation and sensing
properties of lanthanide-based compounds built from a
bipyridine-based phosphine oxide,6 we have turned our
attention to the use of a palladium-promoted P-C cross-
coupling reaction using phenylphosphine.
FIGURE 1. 31P NMR at 162 MHz spectra for compounds: (a)
6 (in CDCl3); (b) 7 (in CDCl3); (c) 8 (in d6-DMSO); (d) 9 (in
CDCl3); and (e) 13 (in CD3OD).
X-ray structure (Figure 2a) confirm the presence of the
PO fragment.
After some experimentation, it was found that, when
6,6′-dibromo-2,2′-bipyridine 227 was allowed to react
under similar conditions with half an equivalent of
PhPH2, the monomer 4 was isolated in 47% yield. The
phosphorus chemical shift (δ ) 18.9 ppm) is in keeping
with structure 3. As would be expected by the presence
of two reactive bromine functions in 2, the macrocycle 5,
the dimer 6, the trimer 11, the tetramer 14, and the
pentamer 15 could be isolated, and these were purified
by careful chromatography and crystallization procedures
(Chart 1).
Results and Discussion
As a result of the presence of chiral tetrahedral
phosphorus atoms, the 31P NMR spectra of compounds
became increasingly complicated along the series. The
spectra of the dimers are particularly informative re-
garding the number of isomers and their relative propor-
tions. For the bromo derivative 6, ethylcarboxylic ester
7, and diethylphosphonic ester 9, two distinct peaks of
nearly equal intensity around 19 ppm are assigned to
the bridging phenylphosphine oxide phosphorus atoms
(Figure 1), the phosphonic ester phosphorus in 9 giving
rise to a singlet at 11.4 ppm (Figure 1d). Surprisingly,
for the diacid 8, the diastereomer ratio was found to be
70:30, possibly reflecting the stabilization of one dias-
teromer by hydrogen bonding interactions (Figure 1c).
Further increase in the number of bipyridyl-phenyl-
phosphine oxide units led to more complicated spectra.
For the trimeric diacid 13, where three diastereomers are
possible and seven separate 31P resonances should be
observed, five signals can in fact be resolved (Figure 1e).
The cyclic dimer 5 was also isolated in low yield in its
cis form and unambiguously characterized by an X-ray
structure determination (Figure 3). Attempts to develop
methodologies for a chemioselective synthesis of the
macrocyclic dimer failed up to now, despite the use of
templating matrixes and high dilution environment.
Interestingly, a single peak, strongly upfield shifted, was
observed in the 31P NMR spectrum at δ ) 10.2 ppm,
pointing to a single isomer. As previously observed for
To the best of our knowledge, the use of dihalogeno-
substituted bipyridine synthons has not yet been applied
in reactions with arylphosphanes to produce oligomers
or macrocycles. Inspired by the protocol described by
Stelzer and co-workers for the one-step preparation of
water soluble phosphines,25 we found that reacting
6-bromo-6′-methyl-2,2′-bipyridine 126 with PhPH2, fol-
lowed by subsequent phase transfer oxidation with
sodium periodate, afforded 3 in 75% yield (Scheme 1).
The phosphorus chemical shift (δ ) 18.4 ppm) and the
(13) Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T. Tetrahedron
Lett. 1980, 21, 3595.
(14) (a) Kowalski, M. H.; Hinkle, R. J.; Stang, P. J. J. Org. Chem.
1989, 54, 2783. (b) Kowalski, M. H. J. Org. Chem. 1990, 55, 5033.
(15) Johansson, T.; Stawinski, J. Chem. Commun. 2001, 2564.
(16) Petrakis, K.; Nagabhushan, T. L. J. Am. Chem. Soc. 1987, 109,
2831.
(17) Tunney, S. E.; Stille, J. K. J. Org. Chem. 1987, 52, 748.
(18) Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T. Synthesis 1981,
56.
(19) Cheng, H.; Zhang, Z. Z. Coord. Chem. Rev. 1996, 147, 1.
(20) Driess, M.; Franke, F.; Merz, K. Eur. J. Inorg. Chem. 2001,
2661.
(21) Astley, T.; Hitchman, M. A.; Keene, F. R.; Tielink, E. R. T. J.
Chem. Soc., Dalton Trans. 1996, 1845.
(22) Penicaud, V.; Odobel, F.; Bujoli, B. Tetrahedron Lett. 1998, 39,
3689.
(23) Montalti, M.; Wadhwa, S.; Kim, W. Y.; Kipp, R. A.; Schmehl,
R. H. Inorg. Chem. 2000, 39, 76.
(24) Zakeeruddin, S. M.; Nazeeruddin, M. K.; Pechy, P.; Rotzinger,
F. P.; Humhry-Baker, R.; Kalyanasundaram, K.; Gra¨tzel, M. Inorg.
Chem. 1997, 36, 5937.
(25) Herd, O.; Hessler, A.; Hingst, M.; Tepper, M.; Stelzer, O. J.
Organomet. Chem. 1996, 522, 69.
(26) Houghton, M. A.; Bilyk, A.; Harding, M. M.; Turner, P.;
Hambley, T. W. J. Chem. Soc., Dalton Trans. 1997, 2725.
(27) Parks, J. E.; Wagner, B. E.; Holm, R. H. J. Organomet. Chem.
1973, 56, 53.
9836 J. Org. Chem., Vol. 70, No. 24, 2005

Bridging of Bipyridine Units by Phenylphosphine Links
FIGURE 2. ORTEP drawing of the molecular unit of the lattice of compound 3 (left) and 19 (right) showing the principal numbering
scheme (thermal ellipsoids drawn at 50% probability level).
CHART 1
related compounds,28 the enforced cis configuration of the
bipyridine fragments observed in the structure (vide
infra) is mainly responsible for such an upfield shift.
We and others have previously shown that modifying
chelating frameworks with deprotonatable functions such
-COOH,29 P(O)(OEt)(OH),30 and P(O)(OH)228 can provide
various highly luminescent complexes of great promise
in the fields of sensors and biomaterial labeling. To test
this option here, we decided to transform the dibromo
compound 2 to the diethylphosphonate 16 with diethyl
phosphite in the presence of the Hu¨nig base and catalytic
amounts of tetrakis[triphenylphoshine]palladium.18 This
cross-coupling reaction is efficient (73% isolated yield for
16) when excess triphenylphosphine is present. Selective
hydrolysis is feasible with aqueous sodium hydroxide,
providing 17 in 97% yield. The phosphonic ester group
in 17 was converted into its acid form under mild
conditions using excess bromotrimethylsilane.31 Direct
and quantitative conversion of 16 to 18 was also possible
by the use of HCl (12 N) at reflux. Transformation of
derivative 2 to the corresponding carboxylic esters and
carboxylic acids was made possible by the use of a
carboalkoxylation reaction promoted by Pd(0),32 followed
by a saponification of the ester.With these convenient
(28) Comby, S.; Imbert, D.; Chauvin, A.-S.; Bu¨nzli, J.-C. G.; Char-
bonnie`re, L. J.; Ziessel, R. F. Inorg. Chem. 2004, 43, 7369.
(29) (a) Bu¨nzli, J.-C. G.; Charbonnie`re, L. J.; Ziessel, R. F. J. Chem.
Soc., Dalton Trans. 2000, 1917. (b) Weibel, N.; Charbonnie`re, L. J.;
Guardigli, M.; Roda, A.; Ziessel, R. J. Am. Chem. Soc. 2004, 126, 4888.
(30) (a) Gan, X.-M.; Duesler, E. N.; Paine, R. T. Inorg. Chem. 2001,
40, 4420. (b) Bornhop, D.; Hubbard, D. S.; Houlne, M. P.; Adair, C.;
Kiefer, G. E.; Pence, B. C.; Morgan, D. L. Anal. Chem. 1999, 71, 2607.
(31) McKenna, C. E.; Higa, M. T.; Cheung, N. H.; McKenna, M. C.
Tetrahedron Lett. 1977, 155.
(32) El-ghayoury, A.; Ziessel, R. J. Org. Chem. 2000, 65, 7757.
J. Org. Chem, Vol. 70, No. 24, 2005 9837

Ziessel et al.
the corresponding C-P-C angles are all smaller. The
bipyridine fragments adopt a planar, transoid conforma-
tion, with dihedral angles of 177.8(3)° and 171.0(3)°.
Repulsions between the lone pairs on O and N are
presumably the reason for the trans conformation of both
O-P-C-N moieties. For 19, a symmetry plane contain-
ing the phenyl ring and the phosphorus atom bisects the
molecule (Figure 2). The bipyridines are almost planar
in a transoid conformation (N1-C11-C12-N2 ) 179.8-
(1)°). Detailed description of the crystal packing (Figure
S1 and S2) is given as Supporting Information.
The molecular structure of the macrocycle 5 is shown
in Figure 3. The asymmetric unit contains two molecules
of 5, only differing one from the other by a rotation of
one of the phenyl rings. The macrocycle has the cis
configuration, with the two almost planar bipyridine
entities in a cisoid conformation (dihedral angles of 0.4
and 2.7° between the pyridine groups), linked by the
phosphorus atoms, the oxygen atoms diverging from the
macrocyclic void. Interestingly, the macrocyclic architec-
ture appears to perturb slightly the pseudotetrahedral
environment around the P atoms (Table S1) when
compared to those in 3 and 19. Notice that the oxygen
atoms diverge from the macrocyclic void. The complete
description of the crystal structure of compound 5 and
its crystal packing (Figure S3) are provided in the
Supporting Information.
FIGURE 3. ORTEP representations of the two nonequivalent
molecules of 5 present in the unit cell.
SCHEME 2a
In summary, an efficient synthesis of bis[6-bromo-2,2′-
bipyridyl-6-yl]phenylphosphine oxide under mild condi-
tions has been developed. This methodology produces
interesting side products, including a macrocyclic dimer,
and linear trimer, tetramer, and pentamer species. The
resulting bromo-containing products can be readily elabo-
rated to carboxylic esters, carboxylic acids, phosphonic
esters, and phosphonic acids by using known organo-
palladium coupling chemistry. The monomeric methyl,
carboxylic ester, and macrocyclic dimer were character-
ized by X-ray diffraction, revealing interesting features
in the conformation of these molecules in the solid state.
These oligomeric species are now currently used as
photoactive capping layer in lanthanide based nanocrys-
tals, and particular attention is given to the bromo
derivatives as starting material in the synthesis of poly-
(paraphenylene-vinylene) quantum dots composite ma-
terials.
a Key: (i) HP(O)(OEt)2 (2 equiv), [Pd(PPh3)4] (10 mol %), PPh3
i
(1 equiv), Pr2EtN, toluene, reflux; (ii) CH3OH, H2O, NaOH (2
equiv), reflux; (iii) TMSBr, CH2Cl2, rt; (iv) HCl (concentrated) at
reflux.
CHART 2
protocols in hand, it was then possible to transform the
monomer 4, dimer 6, and trimer 11 to their corresponding
acids. We first chose to transform derivative 4 to the
biscarboxylic acid by a two-step procedure using a car-
boethoxylation reaction, leading to 19 in 91% yield,
followed by saponification, leading to 20 in 78% isolated
yield. This protocol has been extended to compounds 6
and 11, giving rise to the diesters 7 (95%) and 12 (80%),
respectively, and the carboxylic diacids 8 (83%) and 13
(91%) after hydrolysis (Chart 1).Phosphorylation of 4 is
Experimental Part
Typical Procedure for the P-C Coupling Reactions.
In a Schlenk tube under Ar, the bromo-bipyridine derivatives
(1 equiv), phenylphosphine (0.5 equiv), [Pd(PPh3)4] (0.1 equiv),
and diisopropylethylamine were dissolved in dry acetonitrile
and heated at 80 °C for 19 h. The solvent was removed under
reduced pressure, and the resulting yellowish solid was
partitioned between water (30 mL) and CH2Cl2 (80 mL), and
NaIO4 (excess) was added. After it was stirred for 20 h, the
aqueous layer was extracted three times with 90 mL of CH2-
Cl2. The combined organic layers were dried (MgSO4), filtered
and evaporated to dryness, and the resulting solid was purified
by column chromatography.
Bis-[6′-bromo-2,2′-bipyridine-6-yl]phenylphosphine ox-
ide (4). Phenylphosphine (2 g, 18.2 mmol), anhydrous diiso-
propylethylamine (6.6 mL, 38 mmol), 2 (11.4 g, 36.3 mmol),
and Pd(PPh3)4 (2.1 g, 1.82 mmol) in CH3CN (150 mL).
Chromatography (Al2O3; CH2Cl2) gave compound 4 (5.01 g,
47%) as a white crystalline powder: Rf ) 0.50, Al2O3, CH2Cl2/
i
straightforward using HP(O)(OEt)2, Pr2EtN, and [Pd0-
(PPh3)4] as mediator and leads to 21 in 91% yield.
Hydrolysis with aqueous HCl (12 N) converts 21 to 23
in 81% yield and base hydrolysis provides 22 in 74%
yield. Similar procedures can be used to convert 6 to 9
in 76% yield, and hydrolysis of 9 in HCl gives 10 (66%).
The X-ray crystal structure of compounds 3 and 19
unambiguously confirmed the grafting of the two bipy-
ridine fragments on the phenylphosphine center (Figure
2). The phosphorus atom has a distorted tetrahedral
geometry, evidenced in small deviations of the bond
angles from the tetrahedral ideal (109° 28′). Whereas the
O-P-C angles are all larger than this value (Table S1),
9838 J. Org. Chem., Vol. 70, No. 24, 2005

Bridging of Bipyridine Units by Phenylphosphine Links
1
3
MeOH ) 99/1. H NMR (400 MHz, CDCl3): δ 7.45 (d, 2H, J
Bis-[6′-carboxy-2,2′-bipyridine-6-yl]phenylphosphine
oxide (20). Compound 19 (180 mg, 0.30 mmol), NaOH (50 mg,
1.25 mmol), EtOH (15 mL), and H2O (10 mL) are heated at 72
°C for 14 h to give 20‚2HCl‚H2O (147 mg, 78%) as a yellow
crystalline solid. 1H NMR (300 MHz, CD3OD): δ 7.59-7.70 (m,
3H), 7.97 (t, 2H, 3J ) 8.0 Hz), 8.13-8.21 (m, 8H), 8.42 (d, 2H,
3J ) 8.0 Hz), 8.79-8.83 (m, 2H). 13C{1H} NMR (75 MHz, CD3-
OD): δ 124.9, 125.5, 126.6, 129.5 (d, JPC ) 11 Hz), 129.8, 130.7
(d, JPC ) 104 Hz), 133.6 (JPC ) 9 Hz), 134.0, 139.1 (d, JPC ) 9
Hz), 139.8, 149.1, 156.4, 156.7, 156.8, 157.1, 167.9. 31P NMR
(CD3OD): δ 21.45. IR (KBr, cm-1): 2922 (w), 1763 (w), 1717
(s, νCO), 1577 (m, νCdC,νCdN), 1557 (w), 1430 (s, νCdC), 1379 (m),
1353 (m), 1238 (m, νPdO), 1135 (m), 1103 (m), 1077 (s), 766 (s).
MS (FAB+): m/z 523.3 ([M + H]+, 100%). Anal. Calcd for
C28H19N4PO5‚2HCl‚H2O: C 54.83, H 3.78, N 9.13. Found: C
54.64, H 3.65, N 8.96%.
Typical Procedure for the Phosphorylation Reac-
tions, Monohydrolysis, and Complete Hydrolysis. In a
Schlenk tube under Ar, the bromo-bipyridine derivatives (1
equiv), diethyl phosphite (varying amount), [Pd(PPh3)4] (0.1
equiv), PPh3 (1 equiv), and diisopropylethylamine were dis-
solved in dry toluene and heated at 110 °C for 12-20h. Toluene
was removed under reduced pressure, and the resulting
residue was oxidized by phase transfer using an aqueous
solution of NaIO4 (5 equiv) during one night. After extraction
with dichloromethane and evaporation to dryness the residue
was purified by column chromatography.
Monohydrolysis was performed with aqueous NaOH (1
equiv), H2O (10 mL), and MeOH (15 mL) heated at 80 °C for
15 h. After the mixture had cooled to rt, the solvents were
evaporated under reduced pressure. The solid was dissolved
in H2O/MeOH and precipitated with Et2O. Conversion of this
salt to the bisphosphonic acid is achieved using TMSBr in
anhydrous dichloromethane at rt.
Dihydrolysis for the bisphosphonate was performed with
concentrated aqueous HCl (12 mL) by heated at 75 °C for 35
h. After the mixture had cooled to rt, the solvent was
evaporated under reduced pressure. The solid was recrystal-
lized with MeOH-Et2O to provide the phosphonic acid as a
beige solid.
3
4
) 8.0 Hz), 7.48-7.64 (m, 5H), 7.94 (td, 2H, J ) 8.0 Hz, J )
4.0 Hz), 8.10-8.13 (m, 4H), 8.19 (dd, 2H, 3J ) 8.5 Hz, 4J ) 1.0
Hz), 8.50 (d, br, 2H, 3J ) 8.0 Hz). 13C{1H}-NMR (100 MHz,
CDCl3): δ 120.1, 123.1 (d, JCP ) 3 Hz), 128.2, 128.3, 128.4,
128.5, 128.7, 130.3 (d, JCP ) 103 Hz), 132.3, 132.8 (d, JCP ) 9
Hz), 137.3 (d, JCP ) 10 Hz), 139.3, 154.7, 154.9, 155.1, 156.4,
156.6. 31P NMR (162 MHz, CDCl3): δ 18.90. IR (CH2Cl2; cm-1):
2917 (w, νCH), 1600, 1575, 1545 (s, νCdC, νCdN), 1414 (s), 1207
(m, νPdO), 1119 (s), 785 (s, νCdC). MS (FAB+): m/z ) 357.2 ([M-
C10H6N2Br]•, 25%), 359.2 ([M-C10H6N2Br]•, 25%), 593.2 ([M
+ H]+, 100%). Anal. Calcd for C26H17N4Br2PO: C 52.73, H 2.89,
N 9.46. Found: C 52.54, H 2.71, N 9.14%.
Compound 5 was obtained as a byproduct in the purifica-
tion of 4: (40 mg, 0.4%) as a white crystalline powder. Rf )
0.52, Al2O3, CH2Cl2/MeOH ) 97/3. 1H NMR (300 MHz,
CDCl3): δ 7.30 (dt, 4H, 3J ) 7.5 Hz, JPH ) 3.5 Hz), 7.46 (t,
2H, 3J ) 7.5 Hz), 7.85-7.91 (m, 8H), 8.36-8.40 (t, br, 4H),
8.51 (dd, 4H, 3J ) 8.1 Hz, JPH ) 11 Hz). 13C{1H}-NMR (75
MHz, CDCl3): δ 122.7 (JPC ) 3 Hz), 127.3 (JPC ) 21 Hz), 128.3
(JPC ) 12 Hz), 131.5, 132.3 (JPC ) 101 Hz), 132.5 (JPC ) 9
Hz), 136.6 (JPC ) 10 Hz), 155.65, 155.70, 156.0, 157.4. 31P NMR
(162 MHz, CDCl3): δ 10.19; IR (CH2Cl2, cm-1): 2928 (w), 1573
(m), 1552 (m), 1432 (m), 1412 (m), 1184 (s), 1158 (s), 1142 (m),
1105 (m), 799 (m), 763 (m), 746 (s). MS (FAB+): m/z ) 557.2
([M + H]+, 100%). Anal. Calcd for C32H22N4P2O2: C 69.07, H
3.98, N 10.07. Found: C 68.81, H 3.64, N 9.76%.
Typical Procedure for the Carboethoxylation Reac-
tion and Hydrolysis Step. A solution of the bromobipyridine
(1 equiv) and [Pd(PPh3)2Cl2] (0.1 equiv) in a 1/1 mixture of
EtOH and Et3N was heated at 70 °C for 20 h under a
continuous flow of CO. The solvent was evaporated to dryness,
and the residue was dissolved in CH2Cl2, filtered, and washed
with water. The aqueous layer was extracted with CH2Cl2, and
the combined organic layers were dried (MgSO4), filtered, and
evaporated to dryness. The residue was finally purified by
column chromatography. The resulting ester were dissolved
in a mixture of EtOH and NaOH in water and heated at 70
°C during 14 h. After the mixture had cooled to room
temperature, the solvents were evaporated under reduced
pressure. The solid was dissolved in H2O, precipitated with
aqueous HCl (2 N) and centrifuged.
Bis-[6′-diethylphosphonate-2,2′-bipyridine-6-yl]phe-
nylphosphine Oxide (21). Starting from 4 (100 mg, 0.17
mmol) and diethyl phosphite (50 µL, 0.39 mmol) gave com-
pound 21 (109 mg, 91%) as a milky oil: Rf ) 0.44, Al2O3, CH2-
Cl2/ MeOH ) 97/3. 1H NMR (300 MHz, CDCl3): δ 1.28 (t, 12H,
3J ) 7 Hz), 4.14-4.32 (m, 8H), 7.44-7.56 (m, 3H), 7.74 (td,
2H, 3J ) 8.0 Hz, 4JPH ) 5.5 Hz), 7.88 (ddd, 2H, 3J ) 7.5 Hz, 4J
) 1.0 Hz, 3JPH ) 6.4 Hz), 7.93 (td, 2H, 3J ) 8.0 Hz, 4JPH ) 4.0
Bis-[6′-carboethoxy-2,2′-bipyridine-6-yl]phenylphos-
phine oxide (19). A solution of 4 (77 mg, 0.13 mmol) and [Pd-
(PPh3)2Cl2] (9.1 mg, 0.013 mmol) in a mixture of EtOH (20
mL) and Et3N (20 mL) was heated at 70 °C for 20 h under a
CO atmosphere. The solvent was evaporated, and the residue
was dissolved in CH2Cl2 (15 mL), filtered, and washed with
water (5 mL). After the aqueous layer was washed with CH2-
Cl2 (10 mL), the combined organic layers were dried (MgSO4),
filtrated, and evaporated to dryness. The yellowish residue was
purified by column chromatography (Al2O3 previously deacti-
vated with 10% H2O; CH2Cl2) to give compound 19 (69 mg,
91%) as a white crystalline solid. Rf ) 0.29, Al2O3, CH2Cl2/
MeOH ) 99/1. 1H NMR (400 MHz, CDCl3): δ 1.44 (t, 6H, 3J )
3
4
3
Hz), 8.11 (ddd, 2H, J ) 7.5 Hz, J ) 1.0 Hz, JCH ) 5.5 Hz),
3
4
8.12-8.23 (m, 2H), 8.30 (ddd, 2H, J ) 8.0 Hz, J ) 1.0 Hz,
JPH ) 2.0 Hz), 8.57 (ddd, 2H, J ) 7.5 Hz, 4J ) 1.0 Hz, JPH
2.0 Hz). 13C{1H} NMR (100 MHz, CDCl3): δ 16.4, 16.5, 63.09,
63.12, 63.16, 63.18, 123.0 (d, JPC ) 2.5 Hz), 123.4 (d, JPC
)
3
)
3.5 Hz), 128.1 (d, JPC ) 9.0 Hz), 128.2 (d, JPC ) 3.5 Hz), 128.4
(d, JPC ) 21 Hz), 129.7 (d, JPC ) 103 Hz), 132.2 (d, JPC ) 2.5
Hz), 132.7 (d, JPC ) 8.5 Hz), 137.0 (d, JPC ) 12.5 Hz), 137.2
(d, JPC ) 9.0 Hz), 150.5, 152.7, 154.9, 155.3, 155.5, 155.8, 156.0,
156.2. 31P NMR (162 MHz, CDCl3): δ 11.35, 18.67. IR (CH2-
Cl2, cm-1): 2981 (m, νCH), 2927 (m, νCH), 1571 (m, νCdC,νCdN),
1428 (s), 1257 (s, νPdO), 1203 (m, νPdO), 1050 (s, νCH2,CH3), 1025
(s, νCH2,CH3), 971 (m, νP-O), 797 (s, νCdC). MS (FAB+): m/z )
662.3 ([M-EtO + H]+., 28%), 707.2 ([M + H]+, 100%). Anal.
Calcd for C34H37N4O7P3: C 57.79, H 5.28, N 7.93. Found: C
57.55, H 5.04, N 7.74%.
3
7.0 Hz), 4.47 (q, 4H, J ) 7.0 Hz), 7.49-7.59 (m, 3H), 7.78 (t,
2H, 3J ) 8.0 Hz), 7.97 (td, 2H,3J ) 8.0 Hz, JPH ) 4.0 Hz),
4
8.07 (d, 2H, 3J ) 8.0 Hz), 8.13 (dd, 2H, 3J ) 7.5 Hz, 3JPH ) 5.5
3
Hz), 8.21 (dd, br, 2H), 8.34 (d, 2H, J ) 8.0 Hz), 8.67 (d, br,
2H, 3J ) 8.0 Hz). 13C{1H} NMR (100 MHz, CDCl3): δ 14.4,
62.0, 123.3 (JPC ) 3 Hz), 124.3, 125.3, 128.2, 128.3, 128.4,
128.6, 130.5 (2JPC ) 103 Hz), 132.3 (JPC ) 3 Hz), 132.8 (JPC
)
Bis-[6′-ethylphosphonate-2,2′-bipyridine-6-yl]phen-
ylphosphine Oxide Sodium Salt (22). Compound 21 (104
mg, 147 µmol), NaOH (28 mg, 0.70 mmol), MeOH (15 mL),
and H2O (10 mL) were heated at 76 °C for 15 h to give 22 (78
mg, 74%) as a beige crystalline solid. 1H NMR (400 MHz, CD3-
9 Hz), 137.3 (JPC ) 10 Hz), 137.9, 148.0, 155.5, 155.6, 155.7,
156.3, 165.2. 31P NMR (162 MHz, CDCl3): δ 19.14. IR (CH2-
Cl2; cm-1): 2918 (w, νCH), 1719 (m, νCO), 1594 (s, νCdC,νCdN),
1429 (m), 1384 (m), 1241 (m, νPdO), 1133 (s), 1046 (m), 767
(m). MS (FAB+): m/z ) 578.1 ([M + H]+, 100%). Anal. Calcd
for C32H27N4O5P: C 66.43, H 4.70, N 9.68. Found: C 66.32, H
4.59, N 9.50%.
3
3
OD): δ 1.24 (t, 6H, J ) 7.0 Hz), 4.09 (qt, 4H, J ) 7.0 Hz),
7.59-7.70 (m, 3H), 7.82-7.91 (m, 4H), 8.11-8.20 (m, 6H), 8.27
(d, br, 2H, 3J ) 8.0 Hz), 8.75-8.78 (m, 2H). 13C{1H} NMR (100
J. Org. Chem, Vol. 70, No. 24, 2005 9839

Ziessel et al.
MHz, CD3OD): δ 16.95, 17.01, 62.8, 62.9, 123.1 (br), 124.8 (br),
128.4 (JPC ) 22 Hz), 129.4 (JPC ) 21 Hz), 129.7 (JPC ) 12 Hz),
935 (m, νP-O), 800 (m), 741 (s). MS (FAB+): m/z ) 595.2 ([M
+ H]+, 100%). Anal. Calcd for C26H21N4O7P3.2HCl‚2.5H2O: C
43.84, H 3.97, N 7.87. Found: C 43.85, H 4.37, N 7.71%.
130.9 (JPC ) 104 Hz), 133.6 (JPC ) 9 Hz), 133.9, 138.2 (JPC
)
11 Hz), 138.9 (JPC ) 9 Hz), 155.0, 156.0, 156.2, 156.3, 157.1,
157.5, 157.7, 159.3. 31P NMR (162 MHz, CD3OD): δ 8.87,
21.27. IR (KBr, cm-1): 3055 (w, νCHali), 2977 (w, νCHaro), 1567
(m, νCdC,νCdN), 1438 (m), 1227 (s, br, νPdO), 1202 (m, νPdO), 1071
(s, νCH ,CH ), 1046 (s, νCH ,CH ), 941 (m, νP-O), 749 (m). MS
Acknowledgment. The Ministe`re de la Recherche
et des Nouvelles Technologies and the Centre National
de la Recherche Scientifique are gratefully acknowl-
edged for financial support of this work and Professor
Jack Harrowfield for careful reading of this manuscript
prior to publication.
2
3
2
3
(FAB-): m/z ) 324.3 ([M-2Na]2-, 25%), 625.1 ([M-Na]-,
100%). Anal. Calcd for C30H27N4Na2O7P3‚H2O: C 50.57, H 4.10,
N 7.86. Found: C 50.35, H 3.81, N 7.49%.
Bis-[6′-phosphonic acid-2,2′-bipyridine-6-yl]phenylphos-
phine Oxide (23). Compound 21 (107 mg, 150 µmol), con-
centrated HCl (12 mL) were heated at 75 °C for 35 h to give
23 (83 mg, 81%) as a beige solid. 1H NMR (300 MHz, CD3OD):
δ 7.65 (s, br, 3H), 8.0-8.10 (m, 3H), 8.10-8.32 (m, 5H), 8.40-
8.55 (m, 3H), 8.60-8.80 (m, 3H); 13C{1H}-NMR (75 MHz, CD3-
OD): δ 124.0, 124.9, 128.0, 128.3, 129.6, 129.8, 133.6, 134.0,
139.2, 154.1, 154.9, 156.1, 156.7, 157.0. 31P NMR (162 MHz,
CD3OD): δ 11.90, 23.72. IR (KBr, cm-1): 2923 (w, νCHaro), 1571
(m, νCdC,νCdN), 1429 (s), 1259 (m, br, νPdO), 1142 (m), 988 (s),
Supporting Information Available: Detailed X-ray crys-
tal structure determination of compounds 3, 19, and 5 with
their crystal packing (Figures S1-S3, pages S1-S6). Geo-
metrical parameters observed by X-ray crystal structure for
3, 19, and 5 (Table S1, page S7). Experimental details and
complete characterization of compounds 3 and 6-18 (pages
S7-S16). This material is available free of charge via the
Internet at http://pubs.acs.org.
JO051586G
9840 J. Org. Chem., Vol. 70, No. 24, 2005