Imine-Palladacycles as Phosphine-Free Precatalysts for Low-Temperature Suzuki-Miyaura Synthesis of Nucleoside Analogues in Aqueous Media

Article abstract of DOI:10.1021/acs.organomet.0c00580

The synthesis and characterization of new water-soluble dinuclear palladacycles of the general formula [{Pd(R-C^N-SO3Na)(μ-AcO)}2] (R = H (1), OMe (2), Cl (3)) incorporating an ortho-metalated sodium 4-(N-benzylideneamino)benzenesulfonate moiety is reported. These complexes have been revealed to be excellent phosphine-free catalysts for the synthesis of functionalized nucleoside analogues involving a low-temperature Suzuki-Miyaura coupling of 5-iodo-2′-deoxyuridine with different arylboronic acids in neat water. The potential of 1-3 as synthetic precursors was also tested, and bridging acetates were cleaved by reaction with neutral PPh3, yielding the corresponding mononuclear derivatives [Pd(R-C^N-SO3Na)(AcO)(PPh3)] (R = H (4), MeO (5), Cl (6)). Analytical and spectroscopic techniques confirmed the proposed formulas and reactivities reported for complexes 1-6. Structural characterization by X-ray diffraction of single crystals grown from samples of 4 and 6 produced the unexpected but valuable crystallization-mediated compounds 4cm and 6cm that also supported the results presented here.

Full text of DOI:10.1021/acs.organomet.0c00580

pubs.acs.org/Organometallics
Article
Imine-Palladacycles as Phosphine-Free Precatalysts for Low-
Temperature Suzuki−Miyaura Synthesis of Nucleoside Analogues in
Aqueous Media
́
́
́
Jose Luis Serrano,* Luis García, Jose Perez, Pedro Lozano, Jevy Correia, Santosh Kori, Anant R. Kapdi,*
and Yogesh S. Sanghvi
Cite This: https://dx.doi.org/10.1021/acs.organomet.0c00580
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: The synthesis and characterization of new water-
soluble dinuclear palladacycles of the general formula [{Pd(R-C^N-
SO3Na)(μ-AcO)}2] (R = H (1), OMe (2), Cl (3)) incorporating an
ortho-metalated sodium 4-(N-benzylideneamino)benzenesulfonate
moiety is reported. These complexes have been revealed to be
excellent phosphine-free catalysts for the synthesis of functionalized
nucleoside analogues involving a low-temperature Suzuki−Miyaura
coupling of 5-iodo-2′-deoxyuridine with different arylboronic acids in
neat water. The potential of 1−3 as synthetic precursors was also
tested, and bridging acetates were cleaved by reaction with neutral
PPh3, yielding the corresponding mononuclear derivatives [Pd(R-
C^N-SO3Na)(AcO)(PPh3)] (R = H (4), MeO (5), Cl (6)).
Analytical and spectroscopic techniques confirmed the proposed formulas and reactivities reported for complexes 1−6. Structural
characterization by X-ray diffraction of single crystals grown from samples of 4 and 6 produced the unexpected but valuable
crystallization-mediated compounds 4cm and 6cm that also supported the results presented here.
benzylideneamino)benzenesulfonate) has generated a partic-
ularly labile complex.8a In previous studies we found that the
availability of both halide- and acetate-bridged dinuclear
palladacycles, having not only different properties such as
solubility and robustness but also dissimilar reactivities, is a
powerful synthetic tool in order to prepare new derivatives.13
Clearly those different properties would also affect the catalytic
performance of the complexes. With regard to mono- and
dinuclear palladacycles catalyzing Suzuki coupling, we also
disclosed a nonspectator role for halide, acetate, and
pseudohalide imidate ligands.14 In addition, mechanistic
studies were developed with nonsulfonated N-phenylbenzaldi-
mine palladacycles.15 These results with analogous water-
insoluble complexes encouraged us to explore the synthesis
and catalytic properties of the bridging acetate complexes
reported in this article. The usefulness of the new complexes as
synthetic precursors has also been incipiently explored, with
the report of three new mononuclear PPh3 derivatives.
INTRODUCTION
■
It has been almost three decades since a natural and
unstoppable approach between metal catalysis and the use of
water as reaction solvent has taken place.1 The development of
hydrophilic ligands able to improve both the solubility and
stability of organometallic complexes has definitely set the pace
of such an approach.1,2 To accomplish this, the incorporation
of hydrophilic anionic functionalities, such as sulfonate and
carboxylate, in common ligands has been a successful strategy.3
Thus, sulfonated triphenylphosphine ligands were the focus of
the first studies4 and, from the initial work of Casalnuovo on
the TPPMS/Pd(OAc)2 system5 to more recent examples,6 still
have a prominent role in palladium-catalyzed reactions carried
out in water.7 In the case of palladacycles the inclusion of such
functionalities has provided promising results.7,8 Those and
other different approaches to introduce water solubility in
palladacycles, such as the significant results on oxime
complexes with a hydroxy substituent9 or initial work by
Ryabov including a crown ether fragment,10 have been recently
reviewed by Shaughnessy.11 Given the fact that the identity of
the palladacycle precursor has been claimed to affect both the
activity and lifetime of the catalysts,8a it is surprising that just
one example of a dinuclear acetate-bridged water-soluble
palladacycle has been described to date.12 Most examples have
a chloride-bridged moiety, which in the case of Shaughnessy’s
palladacycle [{Pd(C^N)(μ-Cl)}2] (C^N = sodium 4-(N-
Received: September 1, 2020
https://dx.doi.org/10.1021/acs.organomet.0c00580
© XXXX American Chemical Society
Organometallics XXXX, XXX, XXX−XXX
A

Organometallics
pubs.acs.org/Organometallics
Article
Scheme 1. Synthesis of the Dinuclear Complexes and Their PPh3 Derivatives
On the other hand, nucleosides are important molecules of
biological relevance due to their occurrence as the building
blocks of DNA (deoxyribose nucleic acid) and RNA (ribose
nucleic acid). Functionalization of nucleosides via a large
number of catalytic processes, including Suzuki−Miyaura
cross-coupling, C−H bond functionalization, Sonogashira
coupling, and many others,16 has been carried out over the
years. Application of the functionalized nucleosides has varied
over time from biological to fluorescent probes,17 while more
recently, antiviral or anticancer applications of nucleosides18
have also grown.
Among the various catalytic processes employed in the
literature for the modification of nucleosides, Suzuki−Miyaura
cross-coupling is the one that has found the most applications
due to its simplicity and ease of implementation.19 With regard
to uridine, several research groups have been involved in the
development of efficient protocols for the Suzuki−Miyaura
modification of 5-iodo-2′-deoxyuridine with boronic acids.20
Our research group has also been active in the development of
efficient catalytic processes for the modification of nucleosides,
including Suzuki−Miyaura cross-coupling.21
Problems associated with these catalytic protocols include
the use of phosphine ligands for the activation of the palladium
center that could eventually lead to the formation of a
phosphine oxide byproduct. The relatively higher temperature
of the catalytic system also is a hindrance for further
applications to the modification of thermally labile nucleoside
structural features as well as nucleotides. In the literature, these
issues have been addressed to a certain extent, although
separately. Len and co-workers recently reported the Suzuki−
Miyaura cross-coupling of 6-iodouridine at ambient temper-
ature in aqueous media.22 A few other examples for the
modification of 6-iodouridine at low temperature are also
known;23 however, to the best of our knowledge there have
been no reports of the functionalization of 5-iodo-2′-
deoxyuridine without any added phosphine/N-heterocyclic
carbene ligand. We present here the application of the
developed phosphine-free palladacyclic complexes in the first
low-temperature Suzuki−Miyaura coupling of 5-iodo-2′-
deoxyuridine as well as 5-iodo-2′-deoxycytidine with different
arylboronic acids reported in the literature, performed in water
as the sole reaction solvent.
RESULTS AND DISCUSSION
■
Synthesis and Characterization. Ligand Synthesis. The
three hydrophilic imine-based ligands L1−L3 were prepared
by condensation of the sodium salt of sulfanilic acid with
benzaldehyde, p-anisaldehyde, or p-Cl-benzaldehyde, respec-
tively, by adaptation of a reported procedure.24 Synthetic
details and characterization by analytical and spectroscopic
techniques are collected in the Experimental Section.
Dinuclear Palladacycles. As displayed in Scheme 1,
solvated orange acetato-bridged cyclometalated dimers con-
taining L1−L3 ligands [{Pd(R-C^N-SO3Na)(μ-AcO)}2]·
nCH3COOH were easily prepared by following a classical
method that involves reacting Pd(AcO)2 with Schiff base
ligands in boiling acetic acid. The infrared spectra of the new
complexes showed iminic absorptions and a strong, broad
band of carbonyl stretching close to 1600 cm−1, together with
characteristic absorptions of para substitution around 1045 and
840 cm−1 and those at ca. 1200 cm−1 featuring −SO3 groups,
which have been reported in analogous chloride-bridged
complexes.8b In addition, a strong band at around 1720
cm−1 was also observed in the spectra of the three complexes,
pointing out the likely presence of solvated acetic acid
1
molecules. This was supported by H NMR spectroscopy, as
B
https://dx.doi.org/10.1021/acs.organomet.0c00580
Organometallics XXXX, XXX, XXX−XXX

Organometallics
pubs.acs.org/Organometallics
Article
resonances with variable integrals at ca. 1.90 ppm accompanied
the expected signals of bridging CH3COO− groups when
spectra were recorded in D2O or CD3OD. This extra
resonance was not observed when the spectrum was taken in
a 2/1 D2O/CD3CN mixture (solvents used in the preliminary
catalytic experiments, as explained later). The stability in both
D2O and D2O/CD3CN solutions of the complex containing
L1 was investigated over time and temperature (80 °C) as a
Thus, PPh3 adducts 4−6 were synthesized in good yields by
reaction of the dinuclear acetate complexes 1−3 with this
phosphine ligand in methanol (Scheme 1). Both solvated and
unsolvated precursors yielded identical PPh3 derivatives, as
confirmed by parallel experiments.
The IR spectra of the new phosphine complexes exhibit the
expected bands for the imine-cyclometalated backbone and
those attributed to the incoming PPh3 ligand. A strong
carbonyl band at around 1570 cm−1 supports the presence of a
1
model by H NMR. Variable extension of cis/trans isomer-
1
terminal acetate ligand. In the Experimental Section the H
ization was observed depending on the solvent, as has been
reported for related complexes.8a The absence of imine
hydrolysis suggests that the new complexes are stable in
these solvents and at the higher temperature used in the
catalytic experiments. Representative spectra of these experi-
ments are presented in the Supporting Information. 13C{1H}
NMR also confirmed the proposed formulas, displaying the
expected signals of iminic ligands and bridging acetate.
Additional support for their dinuclearity also arose from
negative ESI mass spectrometry. The addition of an aqueous
solution of ammonium formate/formic acid in the mobile
phase produced significant fragmentation of 1−3 and a
common fragmentation path, which included signals generated
from acetate/formate substitution. The solubilities of the new
complexes in water lie in the range S20 °C = 10.5−20.6 mg/mL
and compare well with the scarce data reported for related
complexes (see Catalytic Studies and the Supporting
Information for experimental details).3b
Initial attempts to remove solvated molecules and obtain
unsolvated samples were performed by 2 h of heating at 125
°C, slightly above the boiling point of acetic acid (118 °C). A
drastic color change from orange to yellow was then observed,
and both IR and 1H NMR revealed partial or complete
disappearance of acetic-related signals, depending on the
particular complex. A thorough thermal study including TG,
DTG, DSC, and coupled TG/MS (see Supporting Informa-
tion), which clearly displayed acetic mass loss (60 amu)
associated with several thermal events, allowed an individual
diagnosis to prepare the corresponding yellow complexes
[{Pd(R-C^N-SO3Na)(μ-AcO)}2] (R = H (1), OMe (2), Cl
(3)) free of solvated molecules by a simple oven treatment.
Before complex decomposition, which begins at ca. 240 °C and
implies the loss of bridging acetate, there are two other events
that take place with acetic loss. This means that there are
different types of acetic acid with different degrees of
interaction between the solvated molecules and the complexes.
The color change associated with the heating of the samples is
an interesting field to explore but is beyond the scope of the
present work. It is worth noting that the behaviors of dinuclear
solvated/unsolvated complexes were indistinguishable for both
synthetic and catalytic purposes.
and 31P{1H} NMR spectroscopic data of the mononuclear Pd
complexes are also collected. Good solubility in CD3OD
provided well-defined 1H NMR spectra of the new complexes,
which display an aromatic region with both the phosphine and
palladacyclic ligand. The iminic proton experiences a
noticeable coupling to phosphorus, appearing as a low-field
doublet signal, thus reproducing a behavior previously found in
related complexes.15a The characteristic singlet resonances
observed in the 31P{1H} NMR spectra of the new derivatives
are also in the expected chemical shift range. ESI-MS
spectrometry, which showed a common fragmentation pattern
for complexes 4−6, also confirmed the proposed formulas. The
solubilities of these PPh3 derivatives in water are in the range
S
20 °C = 2.7−6.2 mg/mL and are lower than those obtained for
the parent dinuclear precursors. Suitable crystals were grown
from samples of 4 and 6 by slow evaporation of their methanol
solutions, enabling a study by X-ray single-crystal diffraction.
Due to further transformations during the crystallization, none
of the single crystals reproduced the expected structures
proposed for 4 and 6 in Scheme 1, which in any event have
been thoroughly characterized in the bulk, as shown in the
Experimental Section. Nevertheless, the obtained crystalliza-
tion-mediated structures 4cm and 6cm still support the results
presented in our work. With regard to the crystal structure of
4cm, an unexpected neutral dimeric structure was observed in
which both AcO groups and two Na+ cations accompanying
sulfonate anions had been removed. Coordination to Pd was
then completed by oxygen atoms from two −SO3 groups, as
displayed in Figure 1. This process turned out to be not so
Unfortunately, crystals suitable for an X-ray diffraction study
could not be prepared, and powder difractograms obtained
with a synchrotron source were of poor quality, thus
preventing structural characterization of the dinuclear com-
plexes by this technique. It is worth mentioning that, to date,
there have been no reports of crystal structures containing
sulfonated imine palladacycles,8a,b the first examples being the
crystallization-mediated compounds 4cm and 6cm described
below.
Phosphine Derivatives. As mentioned above, we were
interested in the synthetic application of the new complexes,
both as a support of the characterization of parent dinuclear
precursors and as a route to new water-soluble derivatives.
Figure 1. Thermal ellipsoid plot of the crystal structure of 4cm, drawn
at the 50% probability level. The hydrogen atoms have been omitted
for clarity.
unusual, since a similar unexpected structure of palladacycle-
containing carboxylated Schiff bases has been reported by
Granell and co-workers in the course of their studies on water-
soluble metallacycles.25 This type of structure has also been
described by Shaughnessy in related carboxylated palladacy-
cles,8a although our report is the first one that involves the
more weakly coordinating sulfonate anion. The poor catalytic
performance of PPh3 derivatives in comparison with the parent
C
https://dx.doi.org/10.1021/acs.organomet.0c00580
Organometallics XXXX, XXX, XXX−XXX

Organometallics
pubs.acs.org/Organometallics
Article
phosphine-free precursors can be tentatively attributed to the
formation of such neutral species, although more evidence
should be obtained in future work. On the other hand, 6cm
presented a MeO group bound to Pd instead of terminal AcO,
which probably interchanged with the solvent during the
crystallization process in MeOH (Figure 2; selected data for
−16.90°, respectively), on the basis of the M−P−Cipso−C
torsion angle.
Catalytic Studies. Phosphine-Free Suzuki−Miyaura
Coupling of 5-Iodo-2′-deoxyuridine with Boronic Acids at
Low Temperature. The synthesized palladium complexes were
the next to be employed as catalysts for the Suzuki−Miyaura
cross-coupling of nucleosides in neat water. To investigate the
applicability of the complexes, it was necessary to first analyze
the extent of water solubility exhibited by them. The solubility
of the complexes 1−6 in water was therefore determined, and
the results are summarized in Table 2.
Table 2. Water-Solubility Study for Complexes 1−6
a
complex
solubility in water at 298 K (mg/mL)
1
2
3
4
5
6
10.47(0.05)
12.73(0.12)
20.57(0.05)
3.13(0.12)
2.73(0.17)
6.23(0.12)
Figure 2. Thermal ellipsoid plot of the crystal structure of 6cm, drawn
at the 50% probability level. The hydrogen atoms have been omitted
for clarity.
a
Mean value. Standard deviations (σ) are given in parentheses; see
the Supporting Information for details.
Table 1. Selected Bond Distances and Angles for 4cm and
6cm
Appreciable water solubility could be observed for
complexes 1−3, as the dimeric complexes with sulfonate
groups have a higher affinity for water, while complexes 4−6
are less soluble, perhaps due to the presence of hydrophobic
aryl groups of the PPh3 or the evolution to neutral species in
solution. The stage, therefore, is set to test these complexes for
Suzuki−Miyaura cross-coupling of nucleosides. Before we
initiate these studies, it is important to understand the lacunae
in the literature for the modification of nucleosides that
accordingly decided the applicability of the synthesized
complexes.
4cm
6cm
Pd(1)−C(1)
Pd(1)−N(1)
Pd(1)−O(1)
Pd(1)−P(1)
1.999(9)
2.122(7)
2.155(6)
2.247(2)
1.995(6)
2.107(5)
2.136(4)
2.2585(16)
C(1)−Pd(1)−N(1)
C(1)−Pd(1)−O(1)
C(1)−Pd(1)−P(1)
N(1)−Pd(1)−O(1)
N(1)−Pd(1)−P(1)
O(1)−Pd(1)−P(1)
81.3(4)
173.4(3)
92.6(3)
93.7(3)
171.4(2)
92.77(16)
81.7(2)
171.2(2)
94.62(19)
90.94(19)
175.38(15)
92.48(13)
(a) Our research group has recently published a catalytic
protocol involving the Pd/PTABS system for carrying
out nucleoside modification in neat water.21b,c However,
despite the reactivity of the highly water soluble system,
reactions were performed at an elevated temperature of
80 °C. This would restrict the future application of the
catalytic system to nucleosides with temperature-labile
functional groups as well as the modification of
nucleotides. The lability of the glycosidic bond also
complicates the situation, as lower temperatures favor
better product formation.
both crystal structures are collated in Table 1). 1H NMR of the
bulk solid 6 reported in the Experimental Section displayed a
methyl resonance from the acetate group at 0.923 ppm, which
1
disappeared in the H NMR spectrum of the crystal 6cm.
Here, a singlet in the typical methoxo range (4.5 ppm) was
observed instead.
The deviation from a planar coordination has been
quantified by measurement of the improper torsion angles.26
The values in the crystal of 4cm, dimeric with symmetry, are
w1 = −4.87° and w2 = −2.56°, while in the crystal of 6cm the
values found were w1 = −2.19° and w2 = −3.50°. Thus, the
ligand coordination around the Pd center is essentially planar
in the two Pd complexes, with a slight tetrahedral distortion in
the former and a square-pyramidal distortion in the latter. The
Pd−Pd distance in 4cm is 9.412 Å, and the bite angle involving
the C^N ligand is also close to 81°, similar to that found in
analogous complexes.15a
(b) The catalyst concentration has always been a cause of
concern, as the high concentration employed in most
literature protocols could be due to the possible
coordination of the heteroatom-rich backbone of the
nucleosides. This was addressed to a certain extent by
the Pd/PTABS system, but any further reduction would
be desirable.
(c) The requirement of an activating phosphine ligand for
catalytic modification generates phosphine oxide as the
byproduct and in many processes would be an
undesirable result. Difficulty in the removal of the
generated byproduct could also complicate the isolation
process of the modified nucleosides. A phosphine-free
catalytic system for promoting these transformations
would be an attractive alternative to the existing options.
Following the classification put forward by Dance and
Scudder,27 the conformation of the Pd−PPh3 group can be
described as a no rotor for both structures (T1 = 5.44, T2 =
41.26, T3 = 56.35° and T1 = −76.11, T2 = −34.60, T3 =
D
https://dx.doi.org/10.1021/acs.organomet.0c00580
Organometallics XXXX, XXX, XXX−XXX

Organometallics
pubs.acs.org/Organometallics
Article
a b
,
Table 3. Catalyst Screening Studies
c
b
catalyst
time (h)
yield (%)
1
2
3
4
5
3.0
3.0
3.0
3.0
3.0
3.0
86
81
90
78
72
6
83
a
b
c
Unless stated otherwise: 0.5 mmol of 7, 0.75 mmol of 8a, 1.0 mmol of Et3N, CH3CN/H2O (3.0 mL). Isolated yields. Catalysts 1−3 (0.5 mol %)
or catalysts 4−6 (1.0 mol %).
a b
,
Table 4. Screening of Complex 3 for Suzuki−Miyaura Coupling in Neat Water
entry
5-IDU (equiv)
boronic acid (equiv)
catalyst (mol %)
base (equiv)
solvent
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.1
0.01
NEt3 (2.0)
NEt3 (2.0)
NEt3 (2.0)
NEt3 (2.0)
NEt3 (2.0)
NEt3 (2.0)
K3PO4 (2.0)
K2CO3 (2.0)
Cs2CO3 (2.0)
DBU(2.0)
CH3CN/H2O
CH3CN/H2O
CH3CN
H2O
H2O
H2O
H2O
H2O
H2O
H2O
80
40
40
40
60
80
60
60
60
60
60
60
90
90
52
55
89
87
80
84
71
65
71
NR
9
10
11
12
NEt3 (2.0)
NEt3 (2.0)
H2O
H2O
a
b
Unless stated otherwise: 0.5 mmol of 7, 0.75 mmol of 8a, 1.0 mmol of Et3N, H2O (4.0 mL). Isolated yields.
The synthesized and well-characterized phosphine-free pallada-
cycles and their phosphine variants were the next to be tested
for the development of a low-temperature Suzuki−Miyaura
protocol for the nucleoside 5-iodo-2′-deoxyuridine.
It was observed that the phosphine-free palladacyclic
complex 3 performed better than other catalysts, including
the phosphine-based analogues, possibly due to the generation
of the catalytically active species at a faster rate in comparison
to the others. The presence of a chloro group in the catalyst
structural backbone could provide enhanced stability to the
catalytically active Pd species thus formed. Better solubilization
of complex 3 as evidenced from the solubility studies also
could be an important factor in providing better yields. A series
of screening parameters such as solvent, temperature, base, and
catalyst concentration was also investigated (Table 4). Initially,
CH3CN/H2O at 80 and 40 °C performed better (entries 1 and
2, Table 4) in comparison to the use of CH3N or H2O (entries
3 and 4, Table 4). However, an increase in temperature from
40 to 60 °C using H2O as the sole reaction solvent provided a
Screening Studies. We first investigated the coupling
reaction of 5-iodo-2′-deoxyuridine with benzofuran-2-boronic
acid using the various synthesized complexes.
Initial conditions for the screening of the complexes
involved the reaction to be performed at 80 °C in H2O/
CH3CN (2/1) (which is the most commonly used solvent
system employed in catalytic Suzuki−Miyaura coupling of
nucleosides) with triethylamine as the soluble base. All six
synthesized complexes were first employed to conduct the
catalyst screening (at 1.0 mol % Pd concentration, Table 3).
E
https://dx.doi.org/10.1021/acs.organomet.0c00580
Organometallics XXXX, XXX, XXX−XXX

Organometallics
pubs.acs.org/Organometallics
Article
a,b
Scheme 2. Substrate Scope for Phosphine-Free Suzuki−Miyaura Cross-Coupling of 5-Iodo-2′-deoxyuridine
a
b
Unless stated otherwise: 0.5 mmol of 7, 0.75 mmol of 8a−h, 1.0 mmol of Et3N, H2O (4.0 mL), complex 3 (0.5 mol %). Isolated yields.
a b
,
Scheme 3. Substrate Scope for Phosphine-Free Suzuki−Miyaura Cross-Coupling of 5-Iodo-2′-deoxycytidine in Water
a
b
Unless stated otherwise: 0.5 mmol of 10, 0.75 mmol of 8, 1.0 mmol of Et3N, H2O (4.0 mL), complex 3 (0.5 mol %). Isolated yields.
competitive yield of the coupled product (entry 5, Table 4).
An increase in temperature for H2O as the reaction solvent to
80 °C failed to provide any further improvement in yield
(entry 6, Table 4). It was therefore decided to continue the
screening study in H2O at 60 °C.
The base study was the next to be conducted, with Et3N
replaced by K3PO4, K2CO3, Cs2CO3, and DBU (entries 7−10,
Table 4). In all cases, the reactivity was found to be lower than
that obtained for Et3N. Finally, catalyst loading experiments
were also performed, but the best result still was obtained with
a 0.5 mol % catalyst concentration of complex 3. It should be
noted that 0.1 mol % of catalyst loading could also be possible
at a compromised reactivity in cases where the metal
concentration needs to be restricted.
With this catalytic system in hand, the substrate scope for
the modification of a nucleoside was next undertaken. 5-Iodo-
2′-deoxyuridine was subjected to Suzuki−Miyaura cross-
coupling conditions using complex 3 (0.5 mol %) in H2O as
the reaction solvent at 60 °C with differently substituted
arylboronic acids. Activating aryl- and heteroarylboronic acids
provided good to excellent yields of the desired cross-coupled
products. However, reduced yields were observed for bulky
arylboronic acids such as triphenylamine, phenylnaphthyl, and
phenanthrene, as displayed in Scheme 2.
F
https://dx.doi.org/10.1021/acs.organomet.0c00580
Organometallics XXXX, XXX, XXX−XXX

Organometallics
pubs.acs.org/Organometallics
Article
Scheme 4. Poisoning Tests and Crabtree Tests to Disclose the Mechanistic Pathway
Phosphine-Free Suzuki−Miyaura Coupling of 5-Iodo-
2′-deoxycytidine with Boronic Acids at Low Temper-
ature. Successful cross-coupling of 5-iodo-2′-deoxyuridine
with arylboronic acids allowed further exploration of the scope
to incorporate 5-iodo-2′-deoxycytidine as a coupling partner in
water as the solvent. Complex 3 furnished a good yield of the
cross-coupled 5-arylated 2′-deoxycytidine derivatives (two
examples provided, Scheme 3) at 0.5 mol % catalyst loading
in water as the sole reaction solvent.
Mechanistic Studies of the Suzuki−Miyaura Coupling
of Iodo Nucleosides in Water Using Complex 3. At the
start of the reaction, a clear yellow solution was observed, and
as it progressed the reaction mixture changed color to a dark
solution, while on completion of the reaction a black
particulate matter was found to be settled at the bottom of
the reaction vessel. These observations point toward the
possible involvement of a colloidal or nanoparticular catalytic
species, as the complex 3 as well as the related complex could
easily dissociate to provide such an outcome. To investigate
such a possibility, it was decided to subject the catalytic
reaction to catalyst poisoning experiments and deduce the
mechanistic pathway followed.
the cross-coupling process. Although it is a positive result
pointing out a nanoparticular catalytic pathway, it is only the
starting point and further experiments are needed to ascertain
these observations.
Next, the carbon disulfide test involving the excess addition
of carbon disulfide (CS2) was undertaken. Sulfides are effective
poisons for a variety of metal catalysts due to the strong and
preferential binding to the metal center in comparison to other
ligands.29 The catalytic activity of complex 3 was therefore
found to be completely arrested again, supporting the
involvement of a colloidal/nanoparticular pathway. On the
other hand, the addition of tetra-n-butylammonium bromide
(TBAB) is commonly employed in ligand-free catalytic
reactions, as TBAB is an excellent stabilizer of the nano-
particles. An enhancement in catalytic reactivity, as happened
in our case, would also suggest the presence of naked Pd
nanoparticles that could be effectively stabilized by TBAB.
(Scheme 4a).30
All of the above tests were directly related to the possible
presence of nanoparticles in the solution and typically occur by
coordination/interaction to the nanoparticular surface. On the
other hand, the Crabtree test31 involves the employment of the
bulky metal-coordinating ligand dibenzo[a,e]cyclooctatetraene
(DCT), which is capable of displacing the accompanying
ligands, leading to the formation of a strong and preferential
Pd-DCT complex (Scheme 4b). This acts as a specific
sterically demanding poison for homogeneous catalytic species,
bringing about a reduction in catalytic activity, while
heterogeneous or nanoparticular systems are not affected by
the DCT coordination. In our case, it was observed that the
Whitesides in the early 1980s had put forth the simple and
commonly applicable catalyst poisoning procedure known as
the mercury (Hg) drop experiment.28 The addition of a drop
of Hg at the start of the catalytic reaction would engulf any
colloid/nanoparticles present in the catalytic solution,
amalgamating the palladium species. As a result, complete
inhibition of the catalyst reactivity was observed in our case, as
the catalytically active species was not available for promoting
G
https://dx.doi.org/10.1021/acs.organomet.0c00580
Organometallics XXXX, XXX, XXX−XXX

Organometallics
pubs.acs.org/Organometallics
Article
ESI-MS analyses were performed on an Agilent 6220 Accurate Mass
TOF LC/MS instrument. The ionization mechanism used was
electrospray in positive and negative ion full scan modes using
acetonitrile as the solvent and nitrogen gas for desolvation. Specific
conditions were a 350 °C source temperature using ESI (electro-
spray), 40 psi nebulizer pressure, and nitrogen gas for drying at 11 L/
min. Scan source parameters: fragmentor (175 V), skimmer (65 V),
and Vcap (3500 V). Mobile phase: H2O/MeOH 25/75 with 5 mM
HCOONH4 and 0.1% HCOOH. Flow rate: 0.4 mL/min. TG and
DTG curves were recorded on a Mettler TG-50 thermobalance using
an atmosphere of pure nitrogen (50 cm3 min−1; heating rate 5 °C
min−1). DSC curves were recorded on a DSC822e Mettler Toledo
instrument.
reactivity of the catalytic system remained intact, as no
reduction in catalytic activity was observed, providing
additional support for a nanoparticular pathway operating in
our system.
It is worth noting that it has been reported8b for closely
related phosphine-free Shaughnessy-type Pd complexes with
five-membered rings that the catalytic process for the Suzuki
couplings proceeds on Pd(0) nanoparticles (as proved by
TEM analysis and experiments with the nanoparticle stabilizers
TBAB and PVP). On the other hand, Shaughnessy suggested
that, in the presence of the phosphine ligand t-Bu-Amphos, the
chloride-bridged analogue of 1 would form (t-Bu-Am-
phos)2Pd0 as homogeneous catalytically active species,8a
although the displaced palladacycle ligand still had an effect
on the activity and lifetime of these species.
Materials and Methods. The commercially available chemicals
were purchased from Aldrich Chemical Co. and were used without
further purification, and all of the solvents were dried by standard
methods before use.
Synthesis of the Ligands: Sodium Salts of N-(R)-Benzyli-
dene p-Aminobenzenesulfonate (R = H (L1), OMe (L2), Cl
(L3)). Sulfanilic acid (2.50 g, 14.4 mmol) was suspended in 40 mL of
hot methanol and deprotonated by adding a previously prepared 10
mL solution of NaOH (0.57 g, 14.4 mmol, 1 equiv). After 15 min of
stirring, a stoichiometric amount of the corresponding aldehyde was
added to the clear solution and a white suspension was immediately
formed. The mixture was stirred for a further 30 min at room
temperature and then concentrated and filtered. The crystalline white
product was washed with methanol and acetone and dried under
vacuum.
Sodium Salt of N-Benzylidene p-Aminobenzenesulfonate (L1).
Yield: 2.85 g, 70%. Anal. Found: C, 55.3; H, 3.9; N, 4.0; S, 11.5. Calcd
for C13H10NNaO3S: C, 55.1; H, 3.6; N, 4.9; S, 11.3. IR (cm−1):
1625m, 1581m, 1473s, 1378m, 1242m, 1185m (SO3), 1141m (SO3),
1059m (SO3), 849m, 736s, 723s, 641m, 574m, 565m. 1H NMR (400
MHz, (CD3)2SO): δ (ppm) 8.62 (s, 1H, NCH), 7.94 (m, 2H, Ho-
ald), 7.67 (d, 2H, Hm-sulf, J = 8.4 Hz), 7.51 (m, 3H, Hm, p-ald), 7.22
(d, 2H, Ho-sulf, J = 8.4 Hz). 13C{1H} NMR (400 MHz, (CD3)2SO):
δ (ppm) 161.0 (NCH), 151.4, 146.0, 136.0, 131.6, 128.9, 128.7,
126.6, 120.2.
Sodium Salt of N-(4-Methoxy)benzylidene p-Aminobenzenesul-
fonate (L2). Yield: 2.19 g, 51%. Anal. Found: C, 53.9; H, 4.0; N, 4.7;
S, 10.3. Calcd for C14H12NNaO4S: C, 53.7; H, 3.9; N, 4.5; S, 10.2. IR
(cm−1): 1610m, 1575m, 1477s, 1381s, 1309m, 1239m, 1189 m
(SO3), 1166m, 1138m (SO3), 1055m, 1030m (SO3), 853m, 736s,
628m, 581m. 1H NMR (400 MHz, (CD3)2SO): δ (ppm) 8.53 (s, 1H,
NCH), 7.88 (d, 2H, Ho-ald, J = 8.8 Hz), 7.61 (d, 2H, Hm-sulf, J =
8.4 Hz), 7.16 (d, 2H, Ho-sulf, J = 8.4 Hz), 7.06 (d, 2H, Hm-ald, J =
8.8 Hz), 3.84 (m, 3H, OCH3). 13C{1H} NMR (400 MHz,
(CD3)2SO): δ (ppm) 161.9 (NCH), 159.9, 153.6, 133.3, 130.3,
128.6, 127.6, 113.4, 113.1, 54.3.
CONCLUSION
■
Water-soluble dinuclear palladacycles that contain the ortho-
metalated backbone sodium 4-(N-benzylideneamino)-
benzenesulfonate and bridging acetate groups can be prepared
by a straightforward classical route from palladium acetate.
Their potential as synthetic precursors was demonstrated by
bridge cleavage with neutral PPh3. In addition, dinuclear
complexes have been revealed to be excellent phosphine-free
catalysts for the synthesis of functionalized nucleoside
analogues involving a low-temperature Suzuki−Miyaura
coupling of 5-iodo-2′-deoxyuridine with different arylboronic
acids in neat water. Specifically, catalyst 3 has provided the
following advantages in comparison to literature reports:
phosphine-free complexes provide an excellent alternative to
the phosphine-based catalytic systems; the catalyst concen-
tration is lower than for most examples reported to date;
catalytic reactions were achieved at a lower temperature than
has been reported in the literature for either phosphine-based
or phosphine-free systems; with water as the sole reaction
solvent, very few protocols provide a combination of catalyst
properties as exhibited by the synthesized complexes. Several
catalyst poisoning experiments and a Crabtree test were
conducted to get insight into the mechanism of the catalytic
reaction, pointing out the likely nanoparticular nature of the
pathway operating in our system. This would be in accordance
with previously reported results for analogous phosphine-free
dinuclear palladacycles claimed to act as a source of highly
active palladium nanoparticles.
Sodium Salt of N-(4-Chloro)benzylidene p-Aminobenzenesulfo-
nate (L3). Yield: 2.96 g, 65%. Anal. Found: C, 49.3; H, 3.0; N, 4.6; S,
10.3. Calcd for C13H9ClNNaO3S: C, 49.1; H, 2.9; N, 4.4; S, 10.1. IR
(cm−1): 1625m, 1584m, 1375s, 1220m, 1185m (SO3), 1128m (SO3),
1100m, 1040m (SO3), 1011m, 888m, 843m, 737s, 688m, 577m,
EXPERIMENTAL SECTION
■
General Procedures. All catalytic reactions were conducted
under an inert atmosphere of N2 on a Schlenk line. Melting points
were recorded on an electrothermal IA9000 Digital Melting Point
Apparatus and are uncorrected. TLC analysis was performed on
Merck 5554 aluminum-backed silica gel plates, and compounds were
visualized by ultraviolet light (254 nm), phosphomolybdic acid
1
561m. H NMR (400 MHz, (CD3)2SO): δ (ppm) 8.64 (s, 1H, N
CH), 7.95 (d, 2H, Ho-ald, J = 8.8 Hz), 7.63 (d, 2H, Hm-sulf, J = 8.4
Hz), 7.58 (d, 2H, Hm-ald, J = 8.8 Hz), 7.21 (d, 2H, Ho-sulf, J = 8.4
Hz). 13C{1H} NMR (400 MHz, (CD3)2SO): δ (ppm) 159.8 (N
CH), 151.0, 146.2, 136.1, 134.8, 130.4, 129.0, 126.6, 120.3.
Synthesis of Precursors [Pd(μ-AcO)(R-C^N-SO3Na)]2 (R = H
(1), OMe (2), Cl (3)). Palladium acetate (500 mg (2.22 mmol) was
suspended in hot glacial acetic acid (60 mL), and the stoichiometric
amount of the corresponding Schiff base was added in one portion
with stirring. The dark orange suspension that formed was kept for 3
h at reflux temperature and then cooled in the refrigerator for 1 h. The
orange nCH3COOH-solvated product was then isolated by filtration,
washed with diethyl ether and acetone, and air-dried. It was then
placed on a watch glass and left overnight in the air in an oven (150
°C, 1; 125 °C, 2; 180 °C, 3), yielding the desired desolvated yellow
products.
1
solution (5% in EtOH), or 1% ninhydrin in EtOH. H NMR spectra
of organic compounds were recorded at 270 MHz using a JEOL
EX270 spectrometer or at 400 MHz using a JEOL ECX400
spectrometer; 13C{1H} NMR spectra were recorded at 67.9 or
100.5 MHz. Chemical shifts are reported in parts per million
downfield from an internal tetramethylsilane reference. Coupling
constants (J values) are reported in hertz (Hz).
C, H, and N analyses were carried out with a Leco CNHS-932
instrument. IR spectra were recorded on a PerkinElmer 16F PC FT-
IR spectrophotometer, using Nujol mulls between polyethylene
sheets. NMR spectroscopic data of the complexes (1H and 31P{1H})
were recorded on Bruker Avance 200, 300, and 400 spectrometers.
H
https://dx.doi.org/10.1021/acs.organomet.0c00580
Organometallics XXXX, XXX, XXX−XXX

Organometallics
pubs.acs.org/Organometallics
Article
[Pd(μ-AcO)(H−C^N-SO3Na)]2 (1). Yield: 0.98 g, 95%. Anal. Found:
C, 40.6; H, 2.9; N, 3.1; S, 7.1. Calcd for C30H24N2Na2O10Pd2S2: C,
40.2; H, 2.7; N, 3.0; S, 7.0. IR (cm−1): 1586s, 1568vs, 1549s, 1197s
(SO3), 1137m (SO3), 1045m (SO3), 843s, 652s, 589m. ESI-MS
(negative mode): calcd for C14H10NO5SPd [PdL1(formate)] − Na
m/z 409.9320 (found 409.9319); calcd for C27H19N2O8S2Pd2
[Pd2L12(formate)] − 2Na m/z 776.8667 (found 776.8667). 1H
NMR (400 MHz, CD3OD): δ (ppm) 7.96 (s, 1H; NCH), 7.56 (d,
2H, Hm-sulf; J = 8.4 Hz), 7.34 (d, 1H; Ho-ald, J = 6.8 Hz), 7.07 (m,
1H; Hp-ald), 6.93 (m, 1H; Hm, ald), 6.80 (d, 2H; Ho-sulf, J = 8.4
Hz), 6.40 (d, 1H; Hm-ald, J = 8.0 Hz), 1.81 (s, 3H; AcO). 13C{1H}
NMR (300 MHz, CD3OD): δ (ppm) 181.8 (CO, AcO), 176.7
(NCH), 155.9, 150.3, 147.3, 145.1, 133.0, 132.4, 129.9, 127.2,
(SO3), 1100s (SO3), 1030m (SO3); ν(PPh3) 528, 512. ESI-MS
(positive mode): calcd for C32H27NO4PPdS [PdL2PPh3 + 1] − Na
1
m/z 658.0445 (found 658.0446). H NMR (300 MHz, CD3OD): δ
(ppm) 8.09 (d, 1H, NCH, J = 6.0 Hz), 7.66 (m, 6H, 4H PPh3 + 2H
Hm-sulf), 7.40 (m, 3H, PPh3), 7.30 (m, 7H, 6H, PPh3 + 1H, Ho-ald),
7.10 (dd, 2H, Ho-sulf, J1 = 2.0 Hz, J2 = 2.0 Hz), 6.34 (dd, 1H, Hm-
ald; J1 = 2,4 Hz, J2 = 2,4 Hz), 5.88 (dd, br; 1H, Hm-ald; J1 = 2,4 Hz
J2 = 2,4 Hz), 3.63 (s, 3H, OCH3), 0.88 (s, 3H, AcO). 31P{1H} NMR
(300 MHz, CD3OD): δ (ppm): 42.09. SH O,20 °C = 2.73 mg/mL.
̅
2
[Pd(Cl−C^N-SO3Na)(AcO)(PPh3)] (6). Yield: 0.069 g, 63%). Anal.
Found: C, 53.5; H, 3.6; N, 2.0; S, 4.5.Calc. for C33H26ClNNaO5PPdS:
C, 53.2; H, 3.5; N, 1.9; S, 4.3%. IR (cm−1):ν(C = O) 1572s br,
1540m, 1194s (SO3), 1127m (SO3), 1037m (SO3); ν(PPh3) 543,
509. ESI-MS (positive mode): calc. for C31H24ClNO3PPdS
125.7, 124.0, 24.2 (CH3, AcO). SH O,20 °C = 10.47 mg/mL.
̅
2
1
[PdL3PPh3 + 1] - Na m/z 663.9937 (found 663.9927). H NMR
[Pd(μ-AcO)(MeO-C^N-SO3Na)]2 (2). Yield: 0.86 g, 86%. Anal.
Found: C, 40.6; H, 3.1; N, 3.0; S, 6.9. Calcd for
C32H28N2Na2O12Pd2S2: C, 40.2; H, 2.9; N, 2.9; S, 6.7. IR (cm−1):
1587m, 1562s, 1542m, 1273m, 1200s (SO3), 1133m (SO3), 1045m
(SO3), 847m, 808m, 640s, 593m. ESI-MS (negative mode): calcd for
C15H12NO6PdS [PdL2(formate)] − Na m/z 439.9426 (found
439.9426), calcd for C29H23N2O101Pd2S2 [Pd2L22(formate)] − 2Na
m/z 836.8879 (found 836.8877). H NMR (300 MHz, CD3OD): δ
(ppm): 7.73 (s, 1H; NCH), 7.58 (d, 2H; Hm-sulf, J = 8.4 Hz), 7.28
(d, 1H; Ho-ald, J = 8.4 Hz), 6.71 (d, 2H; Ho-sulf, J = 8.4 Hz), 6.61
(d, 1H; Hm-ald, J = 8.4 Hz), 5.89 (s, 1H; Hm-ald), 3.55 (s, 3H;
OCH3), 1.80 (s, 3H; AcO). 13C{1H} NMR (300 MHz, CD3OD): δ
(ppm) 181.7 (CO, AcO), 175.0 (NCH), 162.3, 159.3, 150.2,
144.9, 139.9, 131.4, 126.9, 123.9, 117.2, 112.5, 56.0 (OCH3), 24.2
(300 MHz, CD3OD): δ (ppm) 8.37 (d, 1H, NCH, J = 6.1 Hz),
7.67 (m, 8H, 6H PPh3 + 2H Hm-sulf), 7.36 (m, 12H, 9H, PPh3 + 1H,
Ho-ald +2H, Ho-sulf), 6.88 (dd, 1H, Hm-ald, J1 = 2,1 Hz J2 = 1,8
Hz), 6.29 (dd, 1H, Ho-ald, J1 = 1,8 Hz J2 = 1,8 Hz), 0.87 (s, 3H,
CH3). 31P{1H} NMR (300 MHz, CD3OD): δ (ppm) 40.07. S
̅
H2O,20 °C
= 6.23 mg/mL.
Data Related to Nucleosides. General Procedure for Suzuki−
Miyaura Cross-Coupling of 5-Iodo-2′-deoxyuridine with Arylbor-
onic Acids. A solution of precatalyst 3 (0.5 mol %) in degassed H2O
(4 mL) was stirred for 5 min at ambient temperature under N2. Then,
́
5-iodo-2-deoxyuridine (177 mg, 0.5 mmol) was added and the
solution was stirred for 5 min at 60 °C. Thereafter, 2-
benzofuranylboronic acid (120 mg, 0.75 mmol) was added along
with Et3N (1.0 mmol). The resulting solution was then stirred at 60
°C for 3.0 h. After the completion of the reaction the solvent was
removed under vacuum and the resultant residue obtained was
purified using column chromatography in a CH2Cl2/MeOH solvent
system (96/4) to afford the desired product as a white solid in 89%
yield (153 mg).
(CH3, AcO). SH O,20 °C = 12.73 mg/mL.
̅
2
[Pd(μ-AcO)(Cl−C^N-SO3Na)]2 (3). Yield: 1.06 g, 97%. Anal.
Found: C, 37.6; H, 2.6; N, 3.2; S, 6.9. Calcd for
C30H22Cl2N2Na2O10Pd2S2: C, 37.3; H, 2.3; N, 2.9; S, 6.6. IR
(cm−1): 1582m, 1557s, 1536m, 1201s (SO3), 1137s (SO3), 1093m,
1049m (SO3), 840m, 814m, 751m, 664m, 623s 589m. ESI-MS
(negative mode): calcd for C14H9ClNO5SPd [PdL3(formate)] − Na
m/z 445.8921 (found 445.8931); calcd for C27H17Cl2N2O8S2Pd2
[Pd2L32(formate)] − Na m/z 844.7875 (found 844.7870). 1H
NMR (300 MHz, CD3OD): δ (ppm) 7.92 (s, 1H; NCH), 7.78 (d,
2H; Hm-sulf, J = 8.4 Hz), 7.28 (d, 1H; Ho-ald, J = 8.1 Hz), 7.13 (d,
1H; Hm-ald, J = 8.1 Hz), 6.90 (d, 2H; Ho-sulf, J = 8.4 Hz), 6.48 (s,
1H; Hm-ald), 1.69 (s, 3H; AcO). 13C{1H} NMR (300 MHz,
CD3OD): δ (ppm) 182.6 (CO), 176.0 (NCH), 157.3, 149.5,
145.9, 137.5, 132.9, 130.9, 128.3, 127.5, 126.1, 124.1, 24.1 (CH3,
General Procedure for Suzuki−Miyaura Cross-Coupling of 5-
Iodo-2′-deoxycytidine with Arylboronic Acids. A solution of
precatalyst 3 (0.5 mol %) in degassed H2O (4.0 mL) was stirred
́
for 5 min at ambient temperature under N2. Then, 5-iodo-2-
deoxycytidine (176 mg, 0.5 mmol) was added and the solution was
stirred for 5 min at 60 °C. Thereafter, 3-thiopheneboronic acid (0.75
mmol) was added along with Et3N (1.0 mmol). The resulting solution
was then stirred at 60 °C for 24.0 h. After the completion of the
reaction the solvent was removed under vacuum and the resultant
residue obtained was purified using column chromatography in a
CH2Cl2/MeOH solvent system (95/5) to afford the desired product
as a white solid in 72% yield (110 mg).
AcO). SH O,20 °C = 20.57 mg/mL.
̅
2
Preparation of the Complexes [Pd(R-C^N-SO3Na)(AcO)-
(PPh3)] (R = H (4), MeO (5), Cl (6)). The new complexes were
obtained by treating 0.07 g of the appropriate precursor [Pd(μ-
AcO)(R-C^N-SO3Na)]2 (R = H (1), OMe (2), Cl (3)) dissolved in
MeOH (10 mL) with the stoichiometric amount of triphenylphos-
phine (molar ratio 1:2) previously dissolved in 5 mL of MeOH. The
resulting solution was stirred for 30 min and then filtered through a
short Celite column and concentrated until ca. one-fifth of the initial
volume. Slow addition of diethyl ether completed the precipitation of
the title complexes, which were filtered off, washed with ether, and air-
dried.
General Procedure for Mercury (Hg) Poisoning Study. A solution
of precatalyst 3 (0.5 mol %) in degassed H2O (4.0 mL) was stirred for
́
5 min at ambient temperature under N2. Then, 5-iodo-2-deoxyuridine
(177 mg, 0.5 mmol) was added and the solution was stirred for 5 min
at 60 °C. Thereafter, 2-benzofuranylboronic acid (0.75 mmol) was
added along with Et3N (1.0 mmol). Mercury (Hg) (0.15 mmol, 30
mg) was then added (at the start of the reaction), and the reaction
mixture was stirred at 60 °C for 3 h. On completion of the stipulated
time, a TLC analysis of the reaction mixture revealed no progress in
the reaction, thus suggesting complete inhibition of the catalytic
reaction.
[Pd(C^N-SO3Na)(AcO)(PPh3)] (4). Yield: 0.055 g, 50%. Anal.
Found: C, 56.0; H, 4.0; N, 2.1; S, 4.6. Calcd for C33H27NNaO5PPdS:
C, 55.8; H, 3.8; N, 2.0; S, 4.5. IR (cm−1): ν(CO) 1585s br, 1197s
(SO3), 1129s (SO3), 1038m (SO3); ν(PPh3) 537, 518. ESI-MS
(positive mode): calcd for C31H25NO3PPdS [PdL1PPh3 + 1] − Na
General Procedure for Carbon Disulfide Poisoning Study. A
solution of precatalyst 3 (0.5 mol %) in degassed H2O (4.0 mL) was
́
stirred for 5 min at ambient temperature under N2. Then, 5-iodo-2-
deoxyuridine (177 mg, 0.5 mmol) was added and the solution was
stirred for 5 min at 60 °C. Thereafter, 2-benzofuranylboronic acid
(0.75 mmol) was added along with Et3N (1.0 mmol). Carbon
disulfide (CS2) (0.25 mL, 5 mmol) was then added (at the start of the
reaction), and the reaction mixture was stirred at 60 °C for 3 h. On
completion of the stipulated time, a TLC analysis of the reaction
mixture revealed no progress in the reaction, thus suggesting complete
inhibition of the catalytic reaction.
1
m/z 628.0338 (found 628.0323). H NMR (300 MHz, CD3OD): δ
(ppm) 8.34 (d, 1H, NCH, J = 6.9 Hz), 7.72 (d, 2H, Hm-sulf, J =
8,4 Hz), 7.65 (m, 6H, 5H, PPh3 + 1H, Ho-ald), 7.52 (m, 1H, Hp-ald),
7.39 (m, 5H, 4H, PPh3 + 1H, Ho-ald), 7.29 (m, 8H, 6H, PPh3 + 2H,
Ho-sulf), 6.86 (m, 1H, Hm-ald), 0.99·s, 3H, AcO).31P{1H} NMR
(300 MHz, CD3OD): δ(ppm): 42.40. SH O,20 °C = 3.13 mg/mL.
̅
2
[Pd(MeO-C^N-SO3Na)(AcO)(PPh3)] (5). Yield: 0.084 g, 77%. Anal.
Found: C, 55.5; H, 4.1; N, 2.0; S, 4.4. Calcd for C34H29NNaO6PPdS:
C, 55.2; H, 3.9; N, 1.9; S, 4.3. IR (cm−1): ν(CO) 1582s br, 1199s
General Procedure for Tetra-n-butylammonium Bromide (TBAB)
Study. A solution of precatalyst 3 (0.5 mol %) in degassed H2O (4.0
I
https://dx.doi.org/10.1021/acs.organomet.0c00580
Organometallics XXXX, XXX, XXX−XXX

Organometallics
pubs.acs.org/Organometallics
Article
mL) was stirred for 5 min at ambient temperature under N2. Then, 5-
iodo-2-deoxyuridine (177 mg, 0.5 mmol) was added and the solution
and characterization of the reported complexes by ESI-
MS, and thermogravimetric curves of solvated samples
of 1−3 (PDF)
́
was stirred for 5 min at 60 °C. Thereafter, 2-benzofuranylboronic acid
(0.75 mmol) was added along with Et3N (1.0 mmol). TBAB (0.161 g,
0.5 mmol, 1.0 equiv) was added to the reaction mixture and the
resulting solution was then stirred at 60 °C for 3.0 h. After the
completion of the reaction the solvent was removed under vacuum
and the resultant residue obtained was purified using column
chromatography in a CH2Cl2/MeOH solvent system (96/4) to
afford the desired product as a white solid.
Accession Codes
CCDC 1973979−1973980 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Crabtree Test. A solution of precatalyst 3 (0.5 mol %) in degassed
H2O (4.0 mL) was stirred for 5 min at ambient temperature under
́
N2. Then, 5-iodo-2-deoxyuridine (177 mg, 0.5 mmol) was added and
the solution was stirred for 5 min at 60 °C. Thereafter, 2-
benzofuranylboronic acid (0.75 mmol) was added along with Et3N
(1.0 mmol). After 15 min, DCT (0.002 g, 1 × 10−2 mmol) was added
to the reaction mixture and the resulting solution was then stirred at
60 °C for 3.0 h. After the completion of the reaction the solvent was
removed under vacuum and the resultant residue obtained was
purified using column chromatography in a CH2Cl2/MeOH solvent
system (96/4) to afford the desired product as a white solid.
X-ray Data Collection, Structure Solution, and Refinement
for 4cm and 6cm. X-ray data were collected with a Bruker D8
QUEST diffractometer. Data were collected at 100(2) and 133(2) K
for 4cm and 6cm, respectively, using Mo Kα radiation (Kα = 0.71073
Å). The strategy for the data collection was evaluated using the
APEX2 (Bruker, 2013) software. The data were collected by the
standard “ω scan techniques” and were scaled and reduced using
SAINT (Bruker, 2013) software. The structures were solved by direct
methods using SHELXS-97 and refined by full-matrix least squares
with SHELXL-97, with refinement on F2 (Table 5).32
AUTHOR INFORMATION
■
Corresponding Authors
́
Jose Luis Serrano − Departamento de Ingeniería Química,
Área de Química Inorgánica, 30203 Regional Campus of
International Excellence, Universidad Politécnica de
Cartagena, 30203 Cartagena, Spain; orcid.org/0000-
0002-6545-9395; Email: jose.serrano@upct.es
Anant R. Kapdi − Institute of Chemical Technology, Mumbai,
Mumbai 400019, India; orcid.org/0000-0001-9710-
8146; Email: ar.kapdi@ictmumbai.edu.in
Authors
Luis García − Departamento de Ingeniería Química, Área de
Química Inorgánica, 30203 Regional Campus of
International Excellence, Universidad Politécnica de
Cartagena, 30203 Cartagena, Spain
Table 5. X-ray Data Collection Parameters for 4cm and 6cm
́
́
Jose Perez − Departamento de Ingeniería Química, Área de
Química Inorgánica, 30203 Regional Campus of
International Excellence, Universidad Politécnica de
Cartagena, 30203 Cartagena, Spain
4cm
6cm
formula
fw
C31H24NO3PPdS
627.94
C32H26NO4ClPPdSNa·2H2O
752.44
Pedro Lozano − Departamento de Bioquímica y Biología
Molecular B e Inmunología, Facultad de Química, Regional
Campus of International Excellence “Campus Mare
Nostrum”, Universidad de Murcia, 30071 Murcia, Spain;
orcid.org/0000-0001-6043-3893
Jevy Correia − Institute of Chemical Technology, Mumbai,
Mumbai 400019, India
Santosh Kori − Institute of Chemical Technology, Mumbai,
Mumbai 400019, India; Department of Chemistry, Institute
of Chemical Technology-Indian Oil Odisha Campus, IIT
Kharagpur Extension Centre, Bhubaneswar 751013, Odisha,
India
Yogesh S. Sanghvi − Rasayan Inc., Encinitas, California
92024-6615, United States
cryst color, habit
cryst size (mm)
cryst syst
space group
a (Å)
b (Å)
c (Å)
α (deg)
β (deg)
γ (deg)
V (Å3)
Z
Dcalcd (g/cm3)
F000
no. of rflns measd
no. of observns
no. of variables
R1
colorless, block
0.18 × 0.18 × 0.18
monoclinic
P21/c (No. 14)
9.7232(8)
28.575(2)
10.8223(9)
90
112.621(3)
90
2775.5(4)
4
1.503
1272
73077
2256
347
0.0515
0.1552
1.056
colorless, prism
0.16 × 0.14 × 0.09
triclinic
̅
P1 (No. 2)
9.2792(5)
10.9951(7)
18.4733(11)
77.442(2)
75.440(2)
88.903(2)
1779.32(18)
2
1.404
764
122745
6418
413
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.organomet.0c00580
0.0691
0.2086
1.107
Notes
wR2
goodness of fit
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.organomet.0c00580.
This work has been partially supported by RTI2018-098233-B-
C21 (FEDER/MICINN/Agencio Estatal de Investigacion)
■
sı
́
and 20790/PI/18 (Fundacion SENECA CARM) grants.
A.R.K. acknowledges the SERB for an EMR grant (EMR/
́
2016/005439). Professor Gregorio Sanchez, who recently
NMR characterization of the catalysis products and for
the organic compounds 9a−h and 11a−c detailed in
Schemes 2 and 3, representative NMR stability studies
passed away, is gratefully acknowledged for his contribution to
this work and his wise and continuous advice and support.
J
https://dx.doi.org/10.1021/acs.organomet.0c00580
Organometallics XXXX, XXX, XXX−XXX

Organometallics
pubs.acs.org/Organometallics
Article
Study of Pd-based catalysts within red algae-derived polysaccharide
supports in a Suzuki cross-coupling reaction. RSC Adv. 2018, 8,
37939−37948. (h) Ge, J.; Jiang, J.; Yuan, Ch.; Zhang, Ch.; Liu, M.
Palladium nanoparticles stabilized by phosphine ligand for aqueous
phase room temperature Suzuki−Miyaura coupling. Tetrahedron Lett.
2017, 58, 1142−1145. (i) Bouriazos, A.; Vasiliou, C.; Tsichla, A.;
Papadogianakis, G. Catalytic conversions in green aqueous media.
Part 8: Partial and full hydrogenation of renewable methyl esters of
vegetable oils. Catal. Today 2015, 247, 20−32. (j) Hikawa, H.; Koike,
T.; Izumi, K.; Kikkawa, S.; Azumaya, I. Borrowing hydrogen
methodology for N-benzylation using a π-benzylpalladium system in
water. Adv. Synth. Catal. 2016, 358, 784−791.
REFERENCES
■
(1) (a) Metal catalysed reactions in water; Dixneuf, P., Cadierno, V.,
Eds.; Wiley-VCH: Weinheim, Germany, 2013. (b) Zhou, F.; Li, Ch-J.
En route to metal-mediated and metal-catalysed reactions in water.
Chem. Sci. 2019, 10, 34−46. (c) Kitanosono, T.; Masuda, K.; Xu, P.;
Kobayashi, S. Catalytic Organic Reactions in Water toward
Sustainable Society. Chem. Rev. 2018, 118 (2), 679−746.
(2) (a) Shaughnessy, K. H. Hydrophilic ligands and their application
in aqueous-phase metal-catalyzed reactions. Chem. Rev. 2009, 109,
643−710. (b) Scalambra, F.; Lorenzo-Luis, P.; de los Rios, I.;
Romerosa, A. Isomerization of allylic alcohols in water catalyzed by
transition metal complexes. Coord. Chem. Rev. 2019, 393, 118−148.
(c) Guerriero, A.; Peruzzini, M.; Gonzalvi, L. Ruthenium(II)-Arene
Complexes of the Water-Soluble Ligand CAP as Catalysts for
Homogeneous Transfer Hydrogenations in Aqueous Phase. Catalysts
2018, 8, 88. (d) Sierra, D.; Contreras, C.; Francos, J.; Gomez, J.;
Cadierno, V. Novel ferrocenylphosphino sulfonates: Synthesis, crystal
structure and preliminary application as ligands in aqueous catalysis. J.
Organomet. Chem. 2018, 854, 106−112.
(7) Shaughnessy, K. H. In Metal catalysed reactions in water; Dixneuf,
P., Cadierno, V.; Eds.; Wiley-VCH: Weinheim, Germany, 2013; p 1
and references therein.
(8) (a) Huang, R.; Shaughnessy, K. H. water-soluble palladacycles as
precursors to highly recyclable catalysts for the Suzuki Coupling of
aryl bromides in aqueous solvents. Organometallics 2006, 25, 4105−
4112. (b) Zhou, J.; Li, X.; Sun, H. An efficient and recyclable water-
soluble cyclopalladated complex for aqueous Suzuki reactions under
aerial conditions. J. Organomet. Chem. 2010, 695, 297−303. (c) Li, Y.;
Fu, Z.; Rao, L.; Wang, L.; Li, R.; Li, T.; Wu, Y. Water-soluble and
recyclable cyclopalladated ferrocenylimine for Suzuki Coupling
reaction. J. Chin. Chem. Soc. 2014, 61, 397−403.
(3) (a) Shahnaz, N.; Puzari, A.; Paul, B.; Das, P. Activation of aryl
chlorides in water for Suzuki coupling with a hydrophilic salen-Pd(II)
catalyst. Catal. Commun. 2016, 86, 55−58 and references therein.
(b) Matsinha, L. C.; Mao, J.; Mapolie, S. F.; Smith, G. S. Water-
Soluble Palladium(II) Sulfonated thiosemicarbazone complexes: facile
synthesis and preliminary catalytic studies in the Suzuki−Miyaura
cross-coupling reaction in water. Eur. J. Inorg. Chem. 2015, 2015,
́
(9) (a) Botella, L.; Najera, C. J. Cross-coupling reactions with
boronic acids in water catalysed by oxime-derived palladacycles. J.
́
Organomet. Chem. 2002, 663, 46−57. (b) Botella, L.; Najera, C. A
́
4088−4094. (c) Garrido, R.; Hernandez-Montes, P. S.; Gordillo, A.;
convenient oxime carbapalladacycle-catalyzed Suzuki cross-coupling
́
́
́
Gomez-Sal, P.; Lopez-Mardomingo, C.; de Jesus, E. Water-soluble
palladium(II) complexes with sulfonated N-heterocyclic carbenes in
Suzuki cross-coupling and hydrodehalogenation reactions. Organo-
metallics 2015, 34, 1855−1863. (d) Zhou, J.; Guo, X.; Tu, Ch.; Li, X.;
Sun, H. Aqueous Suzuki coupling reaction catalyzed by water-soluble
diimine/Pd(II) systems. J. Organomet. Chem. 2009, 694, 697−702.
(e) Lihi, N.; Bunda, S.; Udvardy, A.; Joo, F. Coordination chemistry
and catalytic applications of Pd(II), and Ni(II)−sulfosalan complexes
in aqueous media. J. Inorg. Biochem. 2020, 203, 110945. (f) Francos,
of aryl chlorides in water. Angew. Chem., Int. Ed. 2002, 41, 179−181.
́
(c) Botella, L.; Najera, C. Controlled mono and double Heck
reactions in water catalyzed by an oxime-derived palladacycle.
́
Tetrahedron Lett. 2004, 45, 1833−1836. (d) Botella, L.; Najera, C.
Mono- and β,β-double-Heck reactions of α,β-unsaturated carbonyl
compounds in aqueous media. J. Org. Chem. 2005, 70, 4360−4369.
(e) Han, X.; Li, H.-M.; Xu, Ch.; Xiao, Z.-Q.; Wang, Z.-Q.; Fu, W.-J.;
Hao, X.-Q.; Song, M.-P. Water-soluble palladacycles containing
hydroxymethyl groups: synthesis, crystal structures and use as
catalysts for amination and Suzuki coupling of reactions. Transition
Met. Chem. 2016, 41, 403−411.
́
́
J.; Moreno-Narvaez, M. E.; Cadierno, V.; Sierra, D.; Ariz, K.; Gomez,
J. Gold(I) Complexes with Ferrocenylphosphino Sulfonate Ligands:
Synthesis and Application in the Catalytic Addition of Carboxylic
Acids to Internal Alkynes in Water. Catalysts 2019, 9, 955.
(4) Jagtap, S. A.; Bhanage, B. M. Semi-hydrogenation of alkynes
using Ru/TPPTS as a biphasic recyclable catalyst in ethylene glycol-
toluene solvent system. Mol. Catal 2018, 460, 1−6 and references
therein.
(10) Bezsoudnova, E. Y.; Ryabov, A. D. Water-soluble cyclo-
palladated aryl oxime: a potent ‘green’ catalyst. J. Organomet. Chem.
2001, 622, 38−42.
(11) Shaughnessy, K. H. In Palladacycles: Catalysis and Beyond, 1st
ed.; Kapdi, A., Maiti, D.; Eds.; Elsevier: 2019; p 225.
(12) Li, H.; Wu, Y. Water-soluble 2-arylnaphthoxazole derived
palladium(II) complexes as phosphine-free catalysts for the Suzuki
reaction in aqueous solvent. Appl. Organomet. Chem. 2008, 22, 233−
236.
(5) Casalnuovo, A. L.; Calabrese, J. C. Palladium-catalyzed
alkylations in aqueous media. J. Am. Chem. Soc. 1990, 112, 4324−
4330.
(6) (a) Shaughnessy, K. H. Beyond TPPTS: New approaches to the
development of efficient palladium catalyzed aqueous-phase cross-
coupling reactions. Eur. J. Org. Chem. 2006, 2006, 1827−1835.
(b) Moore, J. N.; Laskay, N. M.; Duque, K. S.; Kelley, S. P.; Rogers,
R. D.; Shaughnessy, K. H. Synthesis of 4-sulfonatobenzylphosphines
and their application in aqueous-phase palladium-catalyzed cross-
coupling. J. Organomet. Chem. 2015, 777, 16−24. (c) Anderson, K.
W.; Buchwald, S. L. General catalysts for the Suzuki−Miyaura and
Sonogashira coupling reactions of aryl chlorides and for the coupling
of challenging substrate combinations in water. Angew. Chem., Int. Ed.
́
́
(13) (a) Serrano, J. L.; García, L.; Perez, J.; Perez, E.; Galiana, J. M.;
́
García, J.; Martínez, M.; Sanchez, G.; da Silva, I. New cyclometallated
precursors of unsubstituted N-phenylpyrazole [{Pd(phpz)(μ-X)}2]
(X = AcO or OH) and study of their reactivity towards selected
́
ligands. Dalton Trans. 2011, 40, 156−168. (b) Sanchez, G.; García, J.;
́
́
Meseguer, D.; Serrano, J. L.; García, L.; Perez, J.; Lopez, G. Synthesis
and characterisation of cyclometallated palladium(II) complexes with
phosphine-carboxylate and phosphine-amide ligands. Dalton Trans.
2003, 4709−4717.
(14) (a) Fairlamb, I. J. S.; Taylor, R. J. K.; Serrano, J. L.; Sanchez, G.
Halide and pseudohalide effects in Pd-catalysed cross-coupling
reactions. New J. Chem. 2006, 30, 1695−1704. (b) Serrano, J. L.;
2005, 44, 6173−6177. (d) Turkmen, H.; Pelit, L.; Çetinkaya, B.
̈
Water-soluble cis-[(NHC)PdBr2(TPPTS)] catalysts and their appli-
cations in Suzuki−Miyaura coupling of aryl chlorides. J. Mol. Catal. A:
́
́
́
Fairlamb, I. J. S.; Sanchez, G.; García, L.; Perez, J.; Vives, J.; Lopez,
G.; Crawforth, C. M.; Taylor, R. J. K. Palladacyclopentadiene
complexes with mono- and didentate imidato ligands: synthesis,
hemilabile behaviour and catalytic application in the Stille reaction.
Eur. J. Inorg. Chem. 2004, 2004, 2706−2715. (c) Fairlamb, I. J. S.;
́
Chem. 2011, 348, 88−93. (e) Drelon, M.; Merel, D. S.; Mortreux, A.;
Suisse, I.; Sauthier, M. towards selective syntheses of octadienylethers
from the butadiene palladium-catalyzed telomerization with polyols in
aqueous biphasic medium. ChemCatChem 2019, 11, 1742−1746.
(f) Scattolin, T.; Canovese, L.; Visentin, F.; Paganelli, S.; Canton, P.;
Demitri, N. Synthesis of novel allyl palladium complexes bearing
purine based NHC and a water soluble phosphine and their catalytic
activity in the Suzuki−Miyaura coupling in water. Appl. Organomet.
Chem. 2018, 32, e4034. (g) Wolfson, A.; Biton, S.; Levy-Ontman, O.
́
́
Kapdi, A. R.; Lee, A. F.; Sanchez, G.; Lopez, G.; Serrano, J. L.; García,
́
́
L.; Perez, J.; Perez, E. Mono- and binuclear cyclometallated
palladium(II) complexes containing bridging (N,O-) and terminal
(N-) imidate ligands: air stable, thermally robust and recyclable
K
https://dx.doi.org/10.1021/acs.organomet.0c00580
Organometallics XXXX, XXX, XXX−XXX

Organometallics
pubs.acs.org/Organometallics
Article
catalysts for cross-coupling processes. Dalton Trans. 2004, 3970−
Ardhapure, A. V.; Kapdi, A. R.; Sanghvi, Y. S.; Serrano, J. L.; Schulzke,
C. C-C bond formation: synthesis of C5 substituted pyrimidine and
C8 substituted purine nucleosides using water soluble Pd-imidate
complex. Current Protocols in Nucleic Acid Chemistry 2016, 65, 1.37.1−
1.37.15. (e) Kapdi, A. R.; Ardhapure, A.; Sanghvi, Y. S. modulation of
the electronic properties of non-innocent (e,e)-dibenzylideneacetone
for palladium(0)-mediated Heck alkenylation of 5-Iodo-2′-deoxyur-
idine and scale-up studies. Synthesis 2015, 47, 1163−1169. (f) Bhilare,
S.; Bandaru, S.; Kapdi, A. R.; Sanghvi, Y. S.; Schulzke, C. Pd/PTABS:
An efficient water-soluble catalytic system for the amination of 6-
chloropurine ribonucleoside and synthesis of alogliptin. Curr. Protoc.
Nucleic Acids Chem. 2018, 74, e58. (g) Bhilare, S.; Murthy Bandaru, S.
S.; Shah, J.; Chrysochos, N.; Schulzke, C.; Sanghvi, Y. S.; Kapdi, A. R.
Pd/PTABS: Low temperature etherification of chloroheteroarenes. J.
Org. Chem. 2018, 83, 13088−13102. (h) Murthy Bandaru, S.; Bhilare,
S.; Chryosochos, N.; Gayakhe, V.; Trentin, I.; Schulzke, C.; Kapdi, A.
R. Pd/PTABS: catalyst for room temperature amination of
heteroarenes. Org. Lett. 2018, 20, 473−476. (i) Murthy Bandaru, S.
S.; Bhilare, S.; Cardozo, J.; Chrysochos, N.; Schulzke, C.; Sanghvi, Y.
S.; Gunturu, K. C.; Kapdi, A. R. Pd/PTABS: low-temperature
thioetherification of chloro(hetero)arenes. J. Org. Chem. 2019, 84,
8921−8940.
3981. (d) Crawforth, C. M.; Fairlamb, I. J. S.; Kapdi, A. R.; Serrano, J.
́
L.; Taylor, R. J. K.; Sanchez, G. Air-stable, phosphine-free anionic
palladacyclopentadienyl catalysts: remarkable halide and pseudohalide
effects in Stille coupling. Adv. Synth. Catal. 2006, 348, 405−412.
́
́
(15) (a) Serrano, J. L.; García, L.; Perez, J.; Perez, E.; García, J.;
́
Sanchez, G.; Sehnal, P.; De Ornellas, S.; Williams, T. J.; Fairlamb, I. J.
S. Synthesis and characterization of imine-palladacycles containing
imidate “pseudohalide” ligands: efficient Suzuki−Miyaura cross-
coupling precatalysts and their activation to give Pd0Ln species (L
= Phosphine). Organometallics 2011, 30, 5095−5109. (b) Kapdi, A.
́
R.; Dhangar, G.; Serrano, J. L.; Perez, J.; García, L.; Fairlamb, I. J. S.
[Pd(C∧N)(X)(PPh3)] palladacycles react with 2,4,6-trifluorophenyl
boronic acid to give stable transmetallation products of the type
[Pd(C∧N)(2,4,6-F3C6H2)(PPh3)]. Chem. Commun. 2014, 50, 9859−
9861.
(16) (a) Palladium-catalyzed modification of nucleosides, nucleotides,
and oligonucleotides; Kapdi, A. R., Maiti, D., Sanghvi, Y. S., Eds.;
Elsevier: Amsterdam, 2018. (b) Kapdi, A. R.; Gayakhe, V.; Sanghvi, Y.
S.; Fairlamb, I. J. S. Catalytic C−H bond functionalisation of purine
and pyrimidine nucleosides: a synthetic and mechanistic perspective.
Chem. Commun. 2015, 51, 11944−11960.
(17) Fluorescent Analogs of Biomolecular Building Blocks: Design and
Application; Wilhelmsson, M., Tor, Y., Eds.; Wiley: Hoboken, NJ,
2016.
́
(22) Sartori, G.; Enderlin, G.; Herve, G.; Len, C. highly effective
synthesis of C-5-substituted 2′-deoxyuridine using Suzuki−Miyaura
cross-coupling in water. Synthesis 2012, 44, 767−772.
(23) Mizuta, M.; Seio, K.; Miyata, K.; Sekine, M. Fluorescent
pyrimidopyrimidoindole nucleosides: control of photophysical
characterizations by substituent effects. J. Org. Chem. 2007, 72,
5046−5055.
(18) Herve, G.; Len, C. Heck and Sonogashira couplings in aqueous
media − application to unprotected nucleosides and nucleotides.
Sustainable Chem. Processes 2015, 3, 3.
(19) Biteau, N.; Hervin, V.; Roy, V.; Agrofoglio, L. A. Suzuki−
Miyaura cross-coupling as a synthetic tool for nucleosides and
nucleotide modification. In Palladium-catalyzed modification of
nucleosides, nucleotides, and oligonucleotides; Kapdi, A. R., Maiti, D.,
Sanghvi, Y. S.; Eds.; Elsevier: Amsterdam, 2018; pp 37−74.
(20) (a) Amann, N.; Pandurski, E.; Fiebig, T.; Wagenknecht, H.-A.
Electron injection into DNA: synthesis and spectroscopic properties
of pyrenyl-modified oligonucleotides. Chem. - Eur. J. 2002, 8, 4877−
4883. (b) Kohyama, N.; Katashima, T.; Yamamoto, Y. Synthesis of
novel 2-Aryl AICAR derivatives. Synthesis 2004, 2004, 2799−2804.
(c) Collier, A.; Wagner, G. K. Suzuki−Miyaura cross-coupling of
unprotected halopurine nucleosides in water-influence of catalyst and
cosolvent. Synth. Commun. 2006, 36, 3713−3721. (d) Kogler, M.;
Vanderhoydonck, B.; De Jonghe, S.; Rozenski, J.; Van Belle, K.;
Herman, J.; Louat, T.; Parchina, A.; Sibley, C.; Lescrinier, E.;
Herdewijn, P. Synthesis and evaluation of 5-substituted 2′-
deoxyuridine monophosphate analogues as inhibitors of flavin-
dependent thymidylate synthase in mycobacterium tuberculosis. J.
Med. Chem. 2011, 54, 4847−4862. (e) Ehrenschwender, T.;
Wagenknecht, H.-A. Synthesis and spectroscopic characterization of
BODIPY-modified uridines as potential fluorescent probes for nucleic
acids. Synthesis 2008, 2008, 3657−3662. (f) Western, E. C.; Daft, J.
R.; Johnson, E. M.; Gannett, P. M.; Shaughnessy, K. H. Efficient one-
step Suzuki arylation of unprotected halonucleosides, using water-
soluble palladium catalysts. J. Org. Chem. 2003, 68, 6767−6774.
(g) DeVasher, R. B.; Moore, L. R.; Shaughnessy, K. H. Aqueous-
phase, palladium-catalyzed cross-coupling of aryl bromides under mild
conditions, using water-soluble, sterically demanding alkylphosphines.
J. Org. Chem. 2004, 69, 7919−7927.
(24) Robert, F.; Naik, A. D.; Hidara, F.; Tinant, B.; Robiette, R.;
Wouters, J.; Garcia, Y. Engineering solid-state molecular switches: n-
salicylidene n-heterocycle derivatives. Eur. J. Org. Chem. 2010, 2010,
621−637.
(25) Albert, J.; D’Andrea, L.; Bautista, J.; Gonzalez, A.; Granell, J.;
Font-Bardia, M.; Calvet, T. Unexpected structure of palladacycles
containing carboxylated schiff bases. synthesis of some water-soluble
metallacycles. Organometallics 2008, 27, 5108−5117.
́
́
(26) Perez, J.; García, L.; Perez, E.; Serrano, J. L.; Martínez, J. F.;
́
́
Sanchez, G.; Lopez, G.; Espinosa, A.; Liu, M.; Sanz, F. Solid state
conformational and theoretical study of complexes containing the
(CxN)Pd moiety (CxN = 2-(phenylazo)phenyl-C,N and its
derivatives). New J. Chem. 2003, 27, 1490−1496.
(27) Dance, I.; Scudder, M. Intramolecular and supramolecular
geometry of coordinated PPh3. J. Chem. Soc., Dalton Trans. 2000,
1579−1585.
(28) Whitesides, G. M.; Hackett, M.; Brainard, R. L.; Lavalleye, J.-P.
P. M.; Sowinski, A. F.; Izumi, A. N.; Moore, S. S.; Brown, D. W.;
Staudt, E. M. Suppression of unwanted heterogeneous platinum(0)-
catalyzed reactions by poisoning with mercury(0) in systems involving
competing homogeneous reactions of soluble organoplatinum
compounds: thermal decomposition of bis(triethylphosphine)-
3,3,4,4-tetramethylplatinacyclopentane. Organometallics 1985, 4,
1819−1830.
(29) Crabtree, R. H. Resolving heterogeneity problems and impurity
artifacts in operationally homogeneous transition metal catalysts.
Chem. Rev. 2012, 112, 1536−1554.
(30) (a) Khake, S. M.; Soni, V.; Gonnade, R. G.; Punji, B. Design
and development of POCN-pincer palladium catalysts for C−H bond
arylation of azoles with aryl iodides. Dalton Trans. 2014, 43, 16084−
16096. (b) Prajapati, D.; Schulzke, C.; Kindermann, M. K.; Kapdi, A.
R. Selective palladium-catalysed arylation of 2,6-dibromopyridine
using N-heterocyclic carbene ligands. RSC Adv. 2015, 5, 53073−
53085.
(21) (a) Kapdi, A.; Gayakhe, V.; Sanghvi, Y. S.; García, J.; Lozano,
́
P.; da Silva, I.; Perez, J.; Serrano, J. L. New water soluble Pd-imidate
complexes as highly efficient catalysts for the synthesis of C5-arylated
pyrimidine nucleosides. RSC Adv. 2014, 4, 17567−17572. (b) Bhilare,
S.; Gayakhe, V.; Ardhapure, A. V.; Sanghvi, Y. S.; Schulzke, C.;
Borozdina, Y.; Kapdi, A. R. Novel water-soluble phosphatriazenes:
versatile ligands for Suzuki−Miyaura, Sonogashira and Heck reactions
of nucleosides. RSC Adv. 2016, 6, 83820−83830. (c) Gayakhe, V.;
Ardhapure, A.; Kapdi, A. R.; Sanghvi, Y. S.; Serrano, J. L.; et al. Water-
soluble Pd−imidate complexes: broadly applicable catalysts for the
synthesis of chemically modified nucleosides via Pd-catalyzed cross-
coupling. J. Org. Chem. 2016, 81, 2713−2729. (d) Gayakhe, V.;
(31) Anton, D. R.; Crabtree, R. H. Dibenzo[a,e]cyclooctatetraene in
a proposed test for heterogeneity in catalysts formed from soluble
platinum-group metal complexes. Organometallics 1983, 2, 855−859.
(32) Sheldrick, G. M. SHELX-97, Program for Crystal Structure
̈
̈
Refinement; University of Gottingen: Gottingen, Germany, 1997.
L
https://dx.doi.org/10.1021/acs.organomet.0c00580
Organometallics XXXX, XXX, XXX−XXX