Reactions of Pd(PPh3)4 with 3′,5′-Di-O- acetylthymidine: Oxidative addition of Pd(PPh3)4 on thymidine N3 and C4 atoms

Article abstract of DOI:10.1021/om050058s

Oxidative addition reactions of Pd(PPh₃)₄ on the pyrimidine nucleosides 3′,5′-di-O-acetylthymidine and 3′,5′-di-O-acetyl-4-chlorothymidine and on the nucleobase 1-methylthymine have been investigated. N3 and C4 metal coordinated comp

Full text of DOI:10.1021/om050058s

Organometallics 2005, 24, 3401-3406
3401
Reactions of Pd(PPh3)4 with 3′,5′-Di-O-acetylthymidine:
Oxidative Addition of Pd(PPh3)4 on Thymidine N3 and
C4 Atoms
Alessandra Romanelli,† Rosa Iacovino,‡ Gennaro Piccialli,§ Francesco Ruffo,
Lorenzo De Napoli,| Carlo Pedone,† Benedetto Di Blasio,‡ and Anna Messere*,‡
Dipartimento di Scienze Biologiche Universita` di Napoli “Federico II”, Via Mezzocannone 16,
80134 Napoli, Italy, Dipartimento di Scienze Ambientali, Seconda Universita` di Napoli, Via
Vivaldi 43, 81100 Caserta, Italy, Dipartimento di Chimica delle Sostanze Naturali, Universita`
di Napoli “Federico II”, Via Montesano 49, 80131 Napoli, Italy, Dipartimento di Chimica,
Complesso Universitario di Monte S. Angelo, Via Cintia, 80126 Napoli, Italy, and
Dipartimento di Chimica Organica e Biochimica, Complesso Universitario di Monte S. Angelo,
Via Cintia, 80126 Napoli, Italy
Received January 28, 2005
Oxidative addition reactions of Pd(PPh3)4 on the pyrimidine nucleosides 3′,5′-di-O-
acetylthymidine and 3′,5′-di-O-acetyl-4-chlorothymidine and on the nucleobase 1-methylthy-
mine have been investigated. N3 and C4 metal coordinated complexes 3 and 7 were isolated
and characterized by spectroscopic techniques. Moreover, the crystal structure of the trans-
[PdCl(1-methyl thymine)(PPh3)2]‚H2O (4) is reported.
Introduction
selectively recognize DNA GC boxes, inhibiting the
binding of transcriptional factors, such as Sp1, with its
target DNA.3 Furthermore, phosphine complexes of
Ag(I), Au(I), and Sn(IV) and phosphine ligands by
In the past few years numerous chemical modifica-
tions to nucleic acid constituents have been investigated.
Modified bases and backbone DNA analogues have been
synthesized with the aim of creating new structures and
imparting new functions to oligonucleotides. Introduc-
tion of metals into oligonucleotide fragments by inser-
tion of ligandosides, in which the heterocyclic base is
substituted by a strong chelator, allowed the develop-
ment of new energy and electron-transfer systems, such
as semiconductors and molecular magnets.1 Hydroxy-
pyridone-based ligandosides complexed to Cu2+ ions
have been employed to build artificial DNA strands,
giving rise to self-assembled metal arrays.2 In the
medicinal chemistry field metal-complexed oligonucleo-
tides can be used to obtain more stable and biologically
active compounds.
The biological activity of some transition-metal com-
plexes is now well established. Pt, Ag, Zn, and Au
complexes have been widely investigated, and some of
those complexes are used for therapeutic purposes. The
most well known of these compounds is the anticancer
therapeutic cis-PtCl2, a compound that forms complexes
with DNA and is a highly effective treatment for growth
of certain types of cancers. Zn complexes, for example,
themselves have been shown to be anticancer, anti-HIV,
4-6
or antimitochondrial agents.
The study of metal
complex based drugs is still very challenging. In this
frame a better understanding of the role of the metal
ligands and the nature of the metal in the interaction
with biological systems will help in the development of
new drugs. In investigations aimed at understanding
the binding sites of antitumor Pt(II) compounds to
nucleic bases, Pd(II) compounds have been also em-
ployed. The interest arises from the similarity in the
chemical properties of palladium(II) and platinum(II);
in fact, both metal ions possess similar ionic radii, prefer
nitrogen rather than oxygen donor atoms, and form
strongly tetragonal complexes, but those with Pd(II)
react faster. The advantage of the much faster (105
times) ligand substitution reactions that the Pd(II)
presents in vitro makes it a good model for studies of
reactions in vivo with biological molecules.7-9
The aim of this work is the synthesis of new Pd-
nucleoside complexes having the metal covalently bonded
to the nucleobase which can be used in biological
experiments as potential anticancer drugs or as meta-
lated nucleoside building blocks that can be incorporated
into synthetic oligonucleotides. Oligonucleotides meta-
* To whom correspondence should be addressed. E-mail:
anna.messere@unina2.it. Tel: +39-0823-274602. Fax: +39-0823-
274605.
† Dipartimento di Scienze Biologiche Universita` di Napoli “Federico
II”.
(3) Aoki, S.; Kimura, E. Chem. Rev. 2004, 104, 769-787.
(4) Inouye, Y.; Kanamori, T.; Yoshida, T.; Bu, X.; Shionoya, M.;
Koike, T.; Kimura, E. Biol. Pharm. Bull. 1994, 17, 243-250.
(5) Mitsuya, H.; Broder, S. Nature 1987, 325, 773-778
(6) Berners-Price, S. J.; Sadler, P. J. Coord. Chem. Rev. 1996, 151,
1-40
(7) Pettit, L. D.; Bezer, M. Coord. Chem. Rev. 1985, 61, 97
(8) Nelson, D. J.; Yeagle, P. L.; Miller T. L.; Martin, R. B. Bioinorg.
Chem. 1976, 5, 353-358.
(9) Lim, M. C.; Martin, R. B. J. Inorg. Nucl. Chem. 1976, 38, 1915-
1918.
‡ Dipartimento di Scienze Ambientali, Seconda Universita` di Napoli.
§ Dipartimento di Chimica delle Sostanze Naturali, Universita` di
Napoli “Federico II”.
Dipartimento di Chimica, Complesso Universitario di Monte S.
Angelo.
| Dipartimento di Chimica Organica e Biochimica, Complesso Uni-
versitario di Monte S. Angelo.
(1) Wizman, H.; Tor, Y. J. Am. Chem. Soc. 2001, 123, 3375-3376.
(2) Tanaka, K.; Tengeiji, A.; Kato, T.; Toyama, M.; Shionoya, M.
Science 2003, 299, 1212-1213.
10.1021/om050058s CCC: $30.25 © 2005 American Chemical Society
Publication on Web 06/03/2005

3402 Organometallics, Vol. 24, No. 14, 2005
Romanelli et al.
Scheme 1
lated at fixed positions could possess improved and site-
specific biological activity. Nephrotoxic side effects
associated with therapies based on metal complexes,
caused by the excess of metal used and by their
uncontrolled biodistribution, can be reduced by linking
the metal to specific biological targets such as oligonu-
cleotides.10-13 Therefore, even today, the synthesis of
metallonucleosides is still very interesting.
In a previous paper we reacted Pt(PPh3)4 with meth-
ylthymine (2) and observed the formation of cis Pt
phosphine complexes in which the Pt atom was coordi-
nated to the N3 of the thymine base.14 We also inves-
tigated the reaction of Pt(PPh3)4 with 3′,5′-di-O-acetylthy-
midine (1) in the presence of KCl. This reaction resulted
in a mixture of two diastereoisomeric products, due to
the restricted rotation around the Pt-N3 bond, which
rapidly interconverted in solution. Here we report
studies on the reactions of the Pd(PPh3)4 complex with
3′,5′-di-O-acetylthymidine (1), its C4 chlorine-activated
derivative, 3′,5′-di-O-acetyl-4-chlorothymidine (6), and
1-methylthymine (2). The synthesis and NMR charac-
terization of the N3 and C4 3′,5′-di-O-acetylthymidine
oxidative addition complexes 3 and 7, together with the
X-ray structure of the Pd complex with 1-methylthy-
mine, 4, are described.
1
and mass measurements. The H NMR and FAB-MS
analyses indicated the presence of a complex in which
a single 3′,5′-di-O-acetylthymidine coordinated with a
single Pd(PPh3)2 unit and one chloride atom. In the 1H
NMR spectrum signals relative to CH3-C5, H6, and H1′
were all subjected to upfield shifts of respectively 0.7,
1.1, and 0.5 ppm as compared to the uncomplexed
nucleoside. The N3 proton signal was absent, suggesting
the involvement of this nitrogen in the metal coordina-
tion. The sugar protons, other than the H1′, were not
significantly influenced by the complexation. Comparing
13C spectra of 1 and 3 we found a downfield shift for C2
and C4 of 3.5 and 5.5 ppm, respectively, and an upfield
shift of 1.2 ppm for C5. On the basis of these data we
hypothesised that the coordination of the metal occurred
on the N3 atom of the nucleobase as observed in most
of the Pd(II)-thymidine complexes reported in the
literature.20 The 31P NMR spectrum at 25 °C showed
just one signal at 23.5 ppm, suggesting the presence of
two equivalent phosphines and a trans Pd configuration
for complex 3. Further, in the 31P NMR spectra mea-
sured at a lower temperature (-15 °C) we did not
observe changes in the spectrum appearance, thus
confirming at that temperature the presence of trans
magnetically equivalent phosphines.
Results and Discussion
Reactivity of the thymidine ring and its activated
4-chloro derivative with a zerovalent palladium complex
Pd(PPh3)4 was investigated. It is well known that the
metal-binding sites on the thymidine consist primarily
of the nitrogen atom N3 and the oxygen positions 2 and
4, depending on the coordinating metal.15-18 The aim
of this work was to investigate whether activation of
position 4 of the nucleoside could create a new coordina-
tion site for the metal and generate a new stable metal-
bound nucleoside derivative.
To synthesize a Pd-thymidine complex that could be
functionalized on the sugar moiety and inserted into
oligonucleotides, we carried out reactions using nucleo-
tides in which the sugar moiety was protected on the 3′
and 5′ OH by acetyl groups.
Unlike analogous Pt complexes, no diastereoisomers
(rotaxamers) due to the chiral centers on the sugar were
isolated, very likely because of the low rotational barrier
around the Pd-N bond.
To explore the potential coordination of the Pd to N3
through the effect of the metal on the N3 chemical shift
by 15N NMR, we synthesized the 15N3-labeled 3′,5′-di-
O-acetylthymidine Pd complex 3a.21 The 15N chemical
shift of the N3 did not change after complexation.
Attempts to crystallize complex 3 in order to further
confirm the proposed structure by X-ray analysis were
unsuccessful. Instead, we repeated the same reaction
on 1-methylthymine, a molecule containing the same
coordination sites as 3′,5′-di-O-acetylthymidine.
Reaction of 3′,5′-di-O-acetylthymidine (1) with Pd-
(PPh3)4 in refluxing toluene in the presence of KCl
afforded compound 3 in high yields (80%) (Scheme 1).19
The stoichiometry of complex 3 was determined by NMR
(10) Navarro, J. A. R.; Romero, M. A.; Vilaplana, R.; Gonzalez-
Vylchez, F.; Faure, R. J. Med. Chem. 1988, 41, 332-338.
(11) Perez, J. M.; Lopez-Solera, I.; Montero, E. I.; Brana, M. F.;
Alonso, C.; Robinson, S. P.; Navarro-Ranninger C. J. Med. Chem. 1999,
42, 5482-5486.
The reaction between Pd(PPh3)4 and 1-methylthy-
mine22 in refluxing toluene in the presence of KCl
afforded complex 4 with a 59% yield (Scheme 1). A
(12) Bierbach, U.; Sabat, M.; Farrell, N. Inorg. Chem. 2000, 39,
1882-90.
(13) Ludwig, T.; Oberleithner, H. Cell Physiol. Biochem. 2004, 14,
431-40.
comparison between the H, 13C, and 31P NMR of the
1
(14) De Napoli, L.; Iacovino, R.; Messere, A.; Montesarchio, D.;
Piccialli, G.; Romanelli, A.; Ruffo, F.; Saviano, M. J. Chem. Soc., Dalton
Trans. 1999, 12, 1945-1949.
complexes 3 and 4 suggested the same coordination.
Suitable crystals of trans-[PdCl(1-methylthymine)-
(PPh3)2]‚H2O (4) for X-ray crystallographic analysis were
obtained by slow evaporation of its MeOH/CHCl3 solu-
(15) Aoki, S.; Kimura, E. J. Am. Chem. Soc. 2000, 122, 4542-4548.
(16) Shionoya, M.; Kimura, E.; Shiro, M. J. Am. Chem. Soc. 1993,
115, 6730-6737.
(17) Shionoya, M.; Ikeda, T.; Kimura, E.; Shiro, M. J. Am. Chem.
Soc. 1994, 116, 3848-3859.
(18) Chen, H.; Parkinson, J. A.; Morris, R. E.; Sadler, P. J. J. Am.
Chem. Soc. 2003, 125, 173-186.
(20) Khan, B. T.; Bhatt, J.; Najmuddin, K.; Shamsuddin, S. An-
napoorna, K. J. Inorg. Biochem. 1991, 44, 55-63.
(21) Ariza, X.; Bon, V.; Vilarrasa, J.; Tereshko, V.; Campos, J. L.
Angew. Chem., Int. Ed. Engl. 1994, 33, 2454-2455.
(22) Itahara, T.; Fujii, Y.; Tada, M. J. Org. Chem. 1988, 53, 3421-
3424.
(19) The co-presence of KCl and Pd(PPh3)4 is known to afford anionic
Pd(0) complexes, e.g., [PdCl(PPh3)2]-, with enhanced nucleophilicity:
Kozuch, S.; Shaik, S.; Jutand, A.; Amatore, C. Chem. Eur. J. 2004,
10, 3072-3080, and references therein.

Oxidative Addition of Pd(PPh3)4
Organometallics, Vol. 24, No. 14, 2005 3403
Scheme 2
tion. The X-ray crystallographic data revealed that Pd
coordinates N3 of thymine, the chloride atom is trans
to the nitrogen N3, and the two phosphines are respec-
tively trans. Pd(PPh3)4 behaves in an analogous way to
Pt(PPh3)4, except for the coordination of phosphines,
which are cis in the Pt complex and trans in the Pd one.
The X-ray structure revealed a 2.035 Å Pd-N3 bond
distance, suggesting a very strong interaction between
the metal and the imidic nitrogen, similar to what was
previously found in other phosphine Pt, Zn, and Au
thymidine complexes in which the metal is bound to
N3.16,17,23
Further evidence for the coordination of the metal to
the deprotonated imidic N3 atom comes from the
lowered CdO stretching frequencies, from 1705 and
1685 cm-1 in N1-methylthymine to 1690 and 1640 cm-1
in complex 4, which reflects the longer carbonyl bonds
due to deprotonation of the N3-H group. Those data are
consistent with other literature reports of thymidine N3-
metal complexes.
either the base or the sugar protons were observed.
Analysis of the 13C NMR spectrum of complex 7 on
comparison with the 13C chemical shift of 6 allowed us
to determine the palladium coordination site. In fact we
observed a 52.9 ppm downfield shift of C4, a 4.5 ppm
upfield shift of C2, a 9.2 ppm downfield shift of C5, and
a 4.4 ppm downfield shift for CH3-C5. Complex 7 can
be considered as a palladium(II) carbene complex,
stabilized by two heteroatoms situated at the R and γ
positions of the metal-bonded carbon. In the literature
there are numerous examples of carbene complexes
stabilized by a heteroatom in R position with respect to
the metal-bound carbon atom; γ-stabilized palladium-
(II) and platinum(II) carbene complexes can be obtained
via oxidative addition by displacement reactions. Pd-
(II) complex synthesis is carried out by reacting Pd(0)
complexes with aryl carbon atoms activated as tosylates
or halides.25-28 The nature of the metal-C(aryl) bond
has been investigated by NMR.
In the 13C NMR spectra a large shift in metal-
coordinated carbon atoms has already been observed in
several other metal complexes containing a covalent
bond between the metal and a carbon atom. For example
in a dinuclear Pd-MOP (MOP ) (S)-2-diarylphosphino-
1,1′-binaphthyl) complex in which a σ bond between the
binaphthyl C4 and palladium is formed a 45 ppm
downfield shift with respect to the uncomplexed MOP
was observed.29 In complex 7 the 52.9 ppm downfield
shift of the metal-bound carbon atom can be explained
by virtue of the strong electron donor character of the
Pd. It is reported that the M(PR3)X moiety (M ) Pd or
Pt and X ) halide) are π donors in inductive and
resonance modes, interacting with the π framework of
the aryl substituent. Complex 7 is a resonance hybrid
between two forms: 7a, in which the metal is connected
to the C4 through a σ bond, and 7b, in which the
positively charged metal is bonded to the C4 through a
double bond, thus stabilizing the enolate form of the
nucleobase. The 13C chemical shift of the C4 atom, which
appears at 221.0 ppm, strongly suggests the presence
No hypothesis can be formulated on the mechanism
of this reaction, since no intermediate was isolated,
probably due to their lability. Reasonably, complexes 3
and 4 are the thermodynamically stable products: in
fact ligand exchange and temperature shift experiments,
followed by 1H and 31P NMR analysis, revealed no
modification of their structure. Oxidative addition of the
Pd complex occurs on the endocyclic nitrogen N3,
confirming the high affinity of the palladium(II) ion for
nitrogen ligands.
To explore the reactivity of Pd(PPh3)4 on the activated
thymidine ring, in which the N3 was in a different
electronic environment, we reacted Pd(PPh3)4 with 3′,5′-
di-O-acetyl-4-chlorothymidine.24 From the reaction, per-
formed in refluxing toluene, complex 3 and the new
complex 7 were isolated in 70% and 30% yield, respec-
tively (Scheme 2). 1H, 13C, and 31P NMR spectra,
together with the FAB-MS data, allowed the charac-
terization of complex 7. As for complex 3 the metal
coordinates two phosphines, one chloride, and a nucleo-
base. The FAB-MS spectrum of compound 7 showed a
molecular weight lower than 3 by 16 u, thus suggesting
the lack of the oxygen atom on the thymidine C4. In
the 31P NMR spectrum of compound 7 there was only
one signal detected at 23.5 ppm, indicating the presence
of two equivalent phosphines. In the 1H NMR spectrum
no significant proton shifts relative to compound 6 for
(25) Arduengo, A. J., III; Harlow, R. L.; Kline, M. J. Am. Chem. Soc.
1991, 113, 361-363.
(26) Meyer, W. H.; Deetlefs, M.; Pohlmann, M.; Scholz, R.; Ester-
huysen, M. W.; Julius, G. R.; Raubenheimer, H. G. Dalton Trans. 2004,
413-420.
(27) Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 8704-
8705.
(23) Pill, T.; Polborn, K.; Kleinshmidt, A.; Erfle, V.; Breu, W.;
Wagner, H.; Beck, W. Chem. Ber. 1991, 124, 1541-1548.
(24) Matsuda, A.; Itoh, H.; Takenuki, K.; Sasaki, T.; Ueda, T. Chem.
Pharma. Bull. 1988, 36, 945-53.
(28) Manna, J.; Kuehl, C. J.; Whiteford, J. A.; Stang, P. J. Organo-
metallics 1997, 16, 1897-1905.
(29) Dotta, P.; Anil Kumar P. G, Pregosin, P. S. Organometallics
2004, 23, 4247-4254.

3404 Organometallics, Vol. 24, No. 14, 2005
Romanelli et al.
of a covalent bond between the metal and the C4, thus
stabilizing the enol form of the pyrimidine base (Scheme
2).
Experiments carried out by Meyer et al.26 demon-
strated that on the neutral quinolin-2-one-4-yl and the
cationic quinolin-4-ylidene palladium and platinum
complexes the chemical shifts of the metal-bound carbon
atoms were different, depending on which of the forms
(M-C single bond or M-C double bond with positive
charge on the metal) was stabilized. In the neutral form
of the quinoline complex the metal-bound carbon atom
resonates at 176 ppm, 32 ppm downfield shifted with
respect to the uncomplexed molecule; in the cationic
form, stabilized through derivatization of the γ oxygen,
the metal-bound carbon atom resonates around 207
ppm.26
Complex 7 bears a Pd(PPh3)2Cl unit directly bound
to the pyrimidine ring through the C4 atom; phosphines
are trans positioned and chloride is therefore trans to
the C4 of thymidine. To the best of our knowledge, 7 is
the first complex in which the palladium is directly
bound to the C4 of the thymidine.
Some aspects of reactivity of the new compounds 3
and 7 were also explored. Complex 3 dissolved in
deuteriochloroform was treated with a stoichiometric
amount of gaseous HCl. The NMR spectrum of the fresh
reaction mixture disclosed rapid cleavage of the Pd-N
bond with formation of [PdCl2(PPh3)2] and free thymi-
dine. The organic compound could be separated from
the metal complex by usual workup.
Figure 1. ORTEP36 projection of two molecules of trans-
[PdCl(1-MeThy)(PPh3)2], 4. Thermal ellipsoids are drawn
at the 30% probability level.
Table 1. Intramolecular Bond Distances for
trans-[PdCl(1methylthymine)(PPh3)2] with
Estimated Standard Deviations in Parentheses
atoms
bond distance (Å)
Very interestingly the same treatment on 7 had a
different outcome. The NMR spectrum recorded im-
mediately after the addition of the protic acid showed
the presence of a new complex with the H6 signal
markedly shifted to higher frequency with respect to
that of the parent compound. Addition of an aqueous
solution of KOH in deuterium oxide instantaneously
restored the starting complex 7. These evidences indi-
cate that HCl does not cleave the Pd-C bond, leaving
the organic moiety linked to the metal center. Alterna-
tively, it is likely that the proton attacks the basic O
site of 7b with formation of a cationic product 8, having
the chloride as the counterion (Scheme 2). It should be
noted that preparing corresponding salts might be a
useful way to tune the physical properties of 7 without
substantially altering its structure.
The stability of the palladium-nucleobase linkage to
the basic conditions has been tested for 3 and 7.
Removal of the acetyl groups at the 3′ and 5′ sugar
positions of 3 was achieved by treatment with a solution
of 32% aqueous ammonia in methanol (1:1, v/v), giving
complex 5 (60%), whose structure was confirmed by
spectroscopic data (Scheme 1). Importantly the pal-
ladium-N3 nucleobase linkage is stable to the basic
conditions, making it a suitable compound for insertion
in oligonucleotide chains. On the other hand, compound
7 was not stable in these conditions nor in a solution of
Na2CO3 in H2O/methanol, affording a complex mixture
of products.
Pd(1)-N(1)
Pd(1)-P(1)
Pd(1)-P(2)
Pd(1)-Cl(1)
N(1)-C(6)
N(1)-C(1)
N(2)-C(4)
N(2)-C(6)
N(2)-C(5)
O(1)-C(1)
O(2)-C(6)
C(2)-C(1)
C(2)-C(4)
C(2)-C(3)
2.035(11)
2.303(4)
2.319(4)
2.297(4)
1.32(2)
1.37(2)
1.35(2)
1.38(2)
1.50(2)
1.24(2)
1.26(2)
1.39(2)
1.34(2)
1.46(3)
plex 3 was recovered unaltered and formation of the
expected dithiocarbamate was not observed.
Molecular Structure of trans-[PdCl(1-methylthy-
mine)(PPh3)2]‚H2O, 4. The crystal structure of trans-
[PdCl(1-methylthymine)(PPh3)2]‚H2O, 4, is illustrated
in Figure 1, which also gives the atom-numbering
scheme. Selected bond distances and angles are in Table
1. The palladium atom displays square planar coordina-
tion: two trans corners of the square plane are occupied
by the phosphorus atoms of two triphenylphosphines.
The chlorine atom and the amide nitrogen of the
1-methylthymine ligand are trans. The dihedral angles
P(1)-Pd-P(2) [172.8(11)°] and N(1)-Pd-Cl(1) [179.0-
(3)°] show a slight distortion from the planarity of the
square planar coordination mode of the Pd atom. The
plane of the 1-methylthymine ligand is approximately
perpendicular to the palladium coordination plane, as
seen by the torsion angles P(1)-Pd-N(1)-C(1) and
P(1)-Pd-N(1)-C(6) of -89.3(10)° and 91.7 (11)°, re-
spectively.
Finally, as it is known that amides coordinated to
metals can undergo insertion of unsaturated molecules,
a functionalization of the nucleoside complex 3 was
attempted by reaction with an excess of CS2 in a
chloroform solution. After some days the starting com-

Oxidative Addition of Pd(PPh3)4
Organometallics, Vol. 24, No. 14, 2005 3405
Table 2. Selected Angles for
signal of the protonated solvent (CDCll3, δ 7.26 and 77.0;
DMSO-d6, δ 2.55 and 39.5). The 31P NMR spectra were run
on a Bruker WM-400 spectrometer at 161.98 MHz, with
external reference to 85% H3PO4 (δ 0.0). The FAB mass spectra
(positive) were recorded on a ZAB 2SE spectrometer. The
HPLC analyses and purifications were carried out on a
Beckman System Gold instrument equipped with a UV detec-
tor module 166 and a Shimadzu Chromatopac C-R6A integra-
tor. Pd(PPh3)4 was used as supplied by Sigma.
Synthesis of Complex 3. A 0.30 g sample of 3′,5′-di-O-
acetylthymidine (1) (0.92 mmol) was reacted with 1.06 g of
Pd(PPh3)4 (0.92 mmol) in refluxing dry toluene in the presence
of KCl (0.92 mmol). After stirring 5 h, toluene was evaporated.
The crude mixture was redissolved in chloroform and purified
by silica gel chromatography using chloroform as eluent. Pure
complex 3 (0.76 g) was obtained (87% yield of pure product).
Rf ) 0.7 (eluent CHCl3/CH3OH 98:2 v/v). 1H NMR (DMSO-
d6): δ 1.2 (3H, bs, CH3-C5); 2.0 (3H, s, CH3-CO); 2.1 (3H, s,
CH3-CO); 2.5 (2H, m, H2′); 4.1 (1H, m, H4′); 4.2 (2H, m, H5′);
5.1 (1H, m, H3′); 5.8 (1H, dd, H1′); 6.4 (1H, bs, H6); 7.7-7.5
(15H, m, C6H5-P). 13C NMR (CDCl3): δ 13.4 (CH3-C5); 20.4,
20.6 (CH3-CO); 36.7 (C2′); 63.4 (C5′); 73.8 (C4′); 80.7 (C3′);
84.2 (C1′); 108.9 (C5); 134.7-127.71 (C6H5-P); 153.7 (C2); 168.9
(C4); 169.8 and 170.1 (CH3-CO). 31P NMR (DMSO-d6): δ 23.5.
FAB-MS: (106Pd) 991 m/z; [M + H]+. Anal. Calcd for C43H38-
ClN2O5P2Pd: C, 59.60; H, 4.42; Cl, 4.09; N, 3.23; O, 9.23; P,
7.15; Pd, 12.28. Found: C, 59.69; H, 4.60; Cl, 3.92; N, 3.10; P,
7.03.
trans-[PdCl(1-methylthymine)(PPh3)2] with
Estimated Standard Deviations in Parentheses
atoms
bond angle (deg)
C(6)-N(1)-C(1)
Pd(1)-N(1)-C(6)
Pd(1)-N(1)-C(1)
C(6)-N(2)-C(4)
C(4)-N(2)-C(5)
C(6)-N(2)-C(5)
O(1)-C(1)-N(1)
O(1)-C(1)-C(2)
N(1)-C(1)-C(2)
C(1)-C(2)-C(4)
C(4)-C(2)-C(3)
C(1)-C(2)-C(3)
N(2)-C(4)-C(2)
O(2)-C(6)-N(1)
O(2)-C(6)-N(2)
N(1)-C(6)-N(2)
124.4(12)
118.7(10)
116.9(9)
117.8(14)
122.3(15)
119.9(14)
120.6(13)
123.3(14)
116.1(13)
119.4(15)
122.2(17)
118.4(15)
123.3(17)
120.2(14)
120.8(14)
119.0(14)
The analysis of the two triphenylphosphine moieties
in cis position with respect to the Cl(1) atom shows the
Cl(1) atom in a staggered conformation with respect to
the C(41), C(51), C(61) and C(11), C(21), C(31) atoms of
the phenyl rings: the dihedral angles Cl(1)-Pd-P(2)-
C(41), Cl(1)-Pd-P(2)-C(51), Cl(1)-Pd-P(2)-C(61), Cl-
(1)-Pd-P(1)-C(11), Cl(1)-Pd-P(1)-C(21), and Cl(1)-
Pd-P(1)-C(31) are 173.9(6)°, 55.7(5)°, -62.3(6)°,
-55.2(5)°, -171.7(6)°, and 67.4(6)°, respectively.
In the two phosphine ligands, all the C-C bond
lengths are typical for conjugated aromatic rings (1.32-
1.41 Å).30 In the crystal packing the molecules are
characterized by one intermolecular hydrogen bond
between the oxygen (O3) of the water molecule and O(2)
atom of the 1-methylthymine ligand [distance O3‚‚‚O(2)
2.75(1) Å; angle O3‚‚‚O(2)dC(6) 127.64(5)°]. The crystal
structure is further stabilized by van der Waals interac-
tions involving the phenyl and the methyl groups.
Synthesis of Complex 3a. Complex 3a was synthesized
following the same procedure described for 3, using 15N3-
labeled 3′,5′-di-O-acetyl thymidine. 15NMR (DMSO-d6):
δ
160.9.
Synthesis of Complex 4. See procedure described for 3,
using 1-methylthymine as substrate.
Complex 4 was purified by silica gel column chromatography
using 7:3 v/v C6H6/CH3COOCH2CH3 as eluent (59% yield of
pure product). Rf ) 0.4 (eluent C6H6/CH3COOCH2CH3 7/3 v/v).
1H NMR (DMSO-d6): δ 1.2 (3H, bs, CH3-C5); 2.6 (3H, s, CH3-
N1); 6.3 (1H, bs, H6); 7.8-7.4 (15H, m, C6H5-P). 13C NMR
(CDCl3): δ 13.1 (CH3-C5); 36.1 (CH3-N1); 107.9 (C5); 134.8-
127.7 (C6H5-P); 154.7 (C2); 170.1 (C4). 31P NMR (DMSO-d6):
δ 23.5. FAB-MS: (106 Pd) 771 m/z; [M + H]+.
Conclusions
Synthesis of Complex 5. Derivative 3 (0.1 g, 0.1 mmol)
was dissolved in 2 mL of CH3OH; then 2 mL of NH4OH (37%)
was added. The mixture was treated at 50 °C for 2 h; the
solvent was evaporated, and the product was purified by silica
gel column chromatography, eluting using increasing amounts
of CH3OH in CHCl3 (from 0 to 5%) to give 0.6 mmol of pure
complex 5 (60% yield of pure product).
Palladium oxidative addition reactions were carried
out on the pyrimidine nucleobase 1-methylthymine (2)
and the nucleosides 3′,5′-di-O-acetylthymidine (1) and
3′,5′-di-O-acetyl-4-chlorothymidine (6). Reactivity of the
pyrimidinic ring can be tuned by activating the ring,
and the oxidative addition reaction of the zerovalent Pd-
(PPh3)4 complex can be directed on either N3 or C4 of
thymidine. When the pyrimidine ring is not chlorinated,
the metal prefers coordinating the endocyclic nitrogen
in position 3, giving rise to the trans complex 5.
Activation of the nucleobase by halogenation on C4
directs the metal coordination on C4, to form the trans
carbene-Pd complex 7. The strong π-electron interaction
between Pd and thymidine is demonstrated in the 13C
spectra by the C4 resonance at 221.0 ppm, which is
diagnostic for the Pd(II) carbene complex. Complex 7 is
the first example of oxidative addition of palladium on
the C4 of a thymidine reported so far.
1
Rf ) 0.8 (eluent 85:15 CHCl3/CH3OH v/v). H NMR (CD3-
OD): δ 1.4 (3H, bs, CH3-C5); 1.7 (1H, m, H2′); 2.1 (1H, m, H2′);
3.7 (2H, m, H5′); 3.8 (1H, m, H4′); 4.2 (1H, m, H3′); 5.7 (1H,
dd, H1′); 6.9 (1H, bs, H6); 7.9-7.4 (15H, m, C6H5-P). 13C NMR
(CD3OD): δ 13.9 (CH3-C5); 41.7 (C2′); 63.1 (C5′); 71.9 (C3′);
88.5 (C4′); 87.1 (C1′); 110.2 (C5); 136.2-129.6 (C6H5-P); 156.1
(C2); 172.3 (C4).
Synthesis of Complex 7. See procedure described for 3,
using 3′,5′-di-O-acetyl-4-chlorothymidine as substrate. The
crude mixture was redissolved in chloroform and purified by
silica gel chromatography using chloroform as eluent (30%
yield of pure product).
Rf ) 0.3 (eluent 98:2 CHCl3/CH3OH v/v). 1H NMR (DMSO-
d6): δ 1.9 (3H, bs, CH3-C5); 2.1 (6H, s, CH3-CO); 2.5 (2H, m,
H2′); 4.2 (1H, m, H4′); 4.4 (2H, m, H5′); 5.1 (1H, m, H3′); 6.3
Experimental Section
(1H, dd, H1′); 6.5 (1H, bs, H6); 8.1-7.2 (15H, m, C6H5-P). 13
C
The 1H and 13C NMR spectra were recorded on a Bruker
WM-400 spectrometer at 400 and 100.13 MHz, respectively.
All chemical shifts are expressed in ppm with respect to the
NMR (CDCl3): δ 20.2 (CH3-C5); 21.4, 21.5 (CH3-CO); 39.0 (C2′);
64.0 (C5′); 74.1 (C4′); 82.6 (C3′); 86.1 (C1′); 122.0 (C5); 136.5-
129.5 (C6H5-P, C6); 148.4 (C2); 221.0 (C4); 169.9 and 170.1
(CH3-CO). 31P NMR (DMSO-d6): δ 23.49. FAB-MS: (106 Pd)
974 m/z; [M + H]+. Anal. Calcd for C48H43ClN2O6P2Pd: C,
(30) Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen
A. G.; Taylor, R. J. Chem. Soc., Perkin Trans. 1987 2, S1-S19.

3406 Organometallics, Vol. 24, No. 14, 2005
Romanelli et al.
60.83; H, 4.57; Cl, 3.74; N, 2.96; O, 10.13; P, 6.54; Pd, 11.23.
Found: C, 61.19; H, 4.63; Cl, 3.90; N, 2.53; P, 6.46.
monitored periodically and showed no significant change
during data collection. A total of 7473 independent reflections
were measured with the ω-2θ scan mode. Using a prescan
speed of 4.12° min, reflections with a net intensity I < 0.5σ(I)
were flagged as “weak”; those with I g 0.5σ(I) were measured
at lower speed depending on the value of σ(I)/I. The structure
was solved by direct methods using the SIR 92 program.33 The
best E maps revealed all the non-H atoms and the water
solvent molecule.
Refinement by the full-matrix least-squares procedure on
F2 (all data) used the SHELXL 97 program with anisotropic
thermal factors for all non-hydrogen atoms.34 Hydrogen atom
positions were calculated and allowed to ride on their attached
atoms, with Uiso ) 1.2Ueq of the attached atom. The scattering
factors for all atomic species were calculated from Cromer and
Waber.35
Addition of HCl to complexes 3 and 7: a solution of the
appropriate complex (0.025 mmol) in 0.5 mL of deuteriochlo-
roform was treated with 0.6 mL of gaseous HCl (0.025 mmol).
The reaction mixture was analyzed by NMR spectroscopy (see
text). Addition of a KOH solution in D2O to the NMR tube
containing 8 restored complex 7 according to the 1H NMR
analysis.
1H NMR (8) (CDCl3): δ 1.9 (3H, bs, CH3-C5); 2.1 (6H, s, CH3-
CO); 2.4 (2H, m, H2′); 3.9 (1H, br s, OH-C2), 4.1 (1H, m, H4′);
4.2 (2H, m, H5′); 4.9 (1H, m, H3′); 5.6 (1H, dd, H1′); 6.9 (1H,
br s, H6); 8.1-7.2 (15H, m, C6H5-P).
Crystallography. Suitable crystals of trans-[PdCl(1-meth-
ylthymine)(PPh3)2]‚H2O (4) for X-ray analysis were obtained
by slow evaporation of MeOH/CHCl3 at 4 °C. Intensity data
collection was performed using graphite-monochromated Mo
KR radiation (λ ) 0.70930 Å) and a pulse-high discrimination
on an automated MACH3 Enraf-Nonius. Data analysis was
performed with the maXus program.31 Intensities for com-
plexes were corrected empirically for absorption effects with
the DIFABS program and corrected for absorption effects using
the package.32 The independent reflections were measured in
the θ range 2-25°. Unit cell parameters were determined by
least-squares refinement of the setting angles of 25 high-angle
reflections (5° < θ < 12°). Three standard reflections were
Crystal Data. C42H34ClN2O2P2Pd‚H2O, MW ) 822.01,
monoclinic, space group name P21/c (no. 14), a ) 17.780(10)
Å, b ) 12.955(6) Å, c ) 19.190(10) Å, â ) 117.08(5)°, V )
3936(4) Å3, T ) 298 K, Z ) 4, µ(Mo KR) ) 0.794 mm-1, 7473
unique reflections (Rint ) 0.0) used in all calculations. The final
Rw(F2) was 0.1908; R1 ) 0.0707.
OM050058S
(33) Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A. J.
Appl. Crystallogr. 1994, 27, 1045-1050.
(34) Sheldrick, G. M. SHELXL97, Program for the Refinement of
Crystal Structures. University of Go¨ttingen: Germany, 1997.
(35) Cromer, D. T.; Waber, J. T. International Tables for X-Ray
Crystallography; Kynoch Press: Birmingham, 1974; IV, Table 2.2 B.
(36) Johnson, C. K. ORTEP-II, A Fortran Thermal-Ellipsoid Plot
Program; Report ORNL-5138; Oak Ridge National Laboratory: Oak
Ridge, TN, 1976.
(31) Mackay, S.; Gilmore, C. J.; Edwards, C.; Stewart, N.; Shank-
land, K. maXus Computer Program for the Solution and Refinement
of Crystal Structures; Nonius: The Netherlands, MacScience: Japan,
and The University of Glasgow, 1999.
(32) Walker, N.; Stuart, D. DIFABS. Acta Crystallogr. 1983, A39,
158-166.