Site-selective direct arylation of unprotected adenine nucleosides mediated by palladium and copper: insights into the reaction mechanism

Article abstract of DOI:10.1016/j.tet.2008.01.062

Reaction conditions facilitating the site-selective direct aryl functionalisation at the C-8 position of adenine nucleosides have been identified. Many different aromatic components may be effectively cross-coupled to provide a diverse array of arylated adenine nucleoside products without the need for ribose or adenine protecting groups. The optimal palladium catalyst loading lies between 0.5 and 5 mol %. Addition of excess mercury to the reaction had a negligible affect on catalysis, suggesting the involvement of a homogeneous catalytic species. A study by transmission electron microscopy (TEM) shows that metal containing nanoparticles, ca. 3 nm with good uniformity, are formed during the latter stages of the reaction. Stabilised PVP palladium colloids (PVP=N-polyvinylpyrrolidone) are catalytically active in the direct arylation process, releasing homogenous palladium into solution. The effect of various substituted 2-pyridine ligand additives has been investigated. A mechanism for the site-selective arylation of adenosine is proposed.

Full text of DOI:10.1016/j.tet.2008.01.062

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 6125e6137
www.elsevier.com/locate/tet
Site-selective direct arylation of unprotected adenine nucleosides
mediated by palladium and copper: insights into
the reaction mechanism
Thomas E. Storr a,b, Andrew G. Firth a,b, Karen Wilson a, Kate Darley c,
Christoph G. Baumann b, Ian J.S. Fairlamb a,
*
a Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
b Department of Biology, Area 10, University of York, Heslington, York YO10 5YW, UK
c Replizyme Ltd, Genesis 2 Building, York Science Park, Heslington, York Y010 5DQ, UK
Received 30 October 2007; received in revised form 30 November 2007; accepted 30 November 2007
Available online 18 January 2008
Abstract
Reaction conditions facilitating the site-selective direct aryl functionalisation at the C-8 position of adenine nucleosides have been identified.
Many different aromatic components may be effectively cross-coupled to provide a diverse array of arylated adenine nucleoside products with-
out the need for ribose or adenine protecting groups. The optimal palladium catalyst loading lies between 0.5 and 5 mol %. Addition of excess
mercury to the reaction had a negligible affect on catalysis, suggesting the involvement of a homogeneous catalytic species. A study by trans-
mission electron microscopy (TEM) shows that metal containing nanoparticles, ca. 3 nm with good uniformity, are formed during the latter
stages of the reaction. Stabilised PVP palladium colloids (PVP¼N-polyvinylpyrrolidone) are catalytically active in the direct arylation process,
releasing homogenous palladium into solution. The effect of various substituted 2-pyridine ligand additives has been investigated. A mechanism
for the site-selective arylation of adenosine is proposed.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Direct arylation; Purines; CeC Bond formation; Palladium; Copper(I) salts
1. Introduction
and the reactive heteroaromatic substituents was required
for successful couplings. However, recent studies have demon-
strated that unprotected halogenated nucleosides may be
effectively cross-coupled with various nucleophilic compo-
nents.5 Arguably more remarkable are the findings that Su-
zukieMiyaura cross-couplings are possible on halogenated
triphosphate purine bases,6,7 this despite the thermal and
base sensitivity of the phosphoester bonds in the triphosphate
moiety.
C-Modified nucleosides are widely used as pH sensors,
fluorescent markers, therapeutic agents and supramolecular
building blocks.1 Studies that probe biomolecular structure
and biochemical mechanisms2 are of fundamental importance,
driving the need for the development of efficient synthetic
methods to access structurally diverse non-natural nucleosides,
particularly purines.
There are several ways to functionalise purine compounds.
Sonogashira, Suzuki and Stille cross-coupling (hereafter cou-
pling) processes, catalysed by palladium(0),3 are routinely
used to access arylated purine nucleosides (Scheme 1).4 His-
torically the protection of both the sugar hydroxyl groups
Toxic reagents, e.g., organostannanes, limit the use of
Stille couplings in industrial scale-up processes, and whilst
organoboronic acids are versatile coupling components for
SuzukieMiyaura couplings, in some cases their stability (pro-
todeborylation) can be problematic, particularly in certain het-
eroaromatic components. Furthermore, these reactions cannot
generally be viewed as atom economic transformations. For
example, only the phenyl group (77 mu) is transferred from
* Corresponding author. Tel.: þ44 01904 434091; fax: þ44 01904 432516.
E-mail address: ijsf1@york.ac.uk (I.J.S. Fairlamb).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.062

6126
T.E. Storr et al. / Tetrahedron 64 (2008) 6125e6137
NH2
NH2
N
N
N
N
N
N
Br
R
N
H
HO
N
H
[Pd], base, additives
[Cu]
HO
O
O
R
OH OH
OH OH
NH2
NH2
N
N
N
N
Br
R'
N
N
N
H
N
H
R''O
R''O
[Pd], base, additives
O
O
B(OH)2
R'
OH OH
OH OH
O
P
O
P
O
P
R = aryl etc.
R' = aryl, amino acids etc.
O
P
R'' = H,
O
P
O
P
O
O
O
O
O
O
O
,
,
O
O
O
O
O
Scheme 1. Representative cross-couplings of unprotected purines with various nucleophilic components.
PhSnBu3 and the rest is waste (290 mu), a problem derived
from the need for prefunctionalisation in the ‘nucleophilic’
component. To combat these key issues, greener and more
efficient methods for aryl functionalisation continue to be
identified. Generally, protocols for direct arylation of organic
compounds,8 by CeH functionalisation, including the site-
selective modification9 of electron-rich heteroaromatics,10
have reached a point where they may be applied to more chal-
lenging molecular architecture.11
9-methyl-9H-purine (in DMSO, H2¼40.3; H8¼29.3)16 we
predict that preferential CeH activation should occur at site
1. N-arylation is further possibleda recent report details that
a PdeXantphos catalytic system can promote selective N-
arylation of protected 20-deoxyadenosines and 20-deoxyguano-
sines with aryl bromides.17
Initially, reaction conditions reported in the literature for
direct arylation of various heteroaromatic compounds were
screened to assess whether reactions of adenosine with aryl
iodides were possible. Using standard arylation conditions
{Pd(OAc)2, P(t-Bu)3$HBF4, PhCl or PhBr, K3PO4, DMA,
100 ꢀC, 24 h}, or {Pd(OAc)2, PhBr, NaOAc, 120 ꢀC, 20 h}
negligible direct arylation was seen. More success was had us-
ing the conditions described by Bellina and Rossi,18 which are
similar to those reported by Hocek and co-workers.12 How-
ever, deglycosylation was found to be an issue at high temper-
atures over prolonged reaction times. On monitoring a reaction
at 160 ꢀC by HPLC it was revealed that direct arylation had
occurred within minutes! On consumption and through exten-
sive deglycosylation of adenosine, any remaining PhI rapidly
homocoupled to give biphenyl. Deglycosylation of the cross-
coupled product then occurred steadily over the course of
several hours. Running the reaction at 120 ꢀC improved the
reaction efficacy considerably; the product profile is shown
in Scheme 2. Note: homocoupling of adenosine was not
observed under these conditions.19
With the primary aim of adding to the contemporary portfolio
of modified molecular probes for practical use in bioapplica-
tions, we wished to investigate whether catalytic direct arylation
methods can be employed for the synthesis of unprotected
purine nucleosides. In unison with our studies, Hocek and co-
workers recently disclosed that protected purines can be ary-
lated at the 8-position using catalytic palladium in the presence
of excess CuI in DMF at 160 ꢀC for 60 h.12 However, no sugar
variants were given. Our studies on the site-selective direct
arylation of purine nucleosides are reported in this paper.13
On consideration of the structures of the nucleosides a prob-
lem that emerges is the potential instability of the glycosyl
bond at high temperatures, e.g., 160 ꢀC (for adenosine the
t
1/2>8000 h at 90e100 ꢀC in water or formamide).14 Site se-
lectivity9,15 further needs to be considered; C-arylation can
potentially occur at C2 or C8 (Fig. 1). Whilst accurate exper-
imental pKa values for the CeH bonds in adenosine are not
known, based on the theoretical pKa values determined for
Rapid colour changes are observed in reaction mixtures of
adenosine and iodobenzene (Fig. 2). After 5 min of heating
a yellow/orange colour was evident (plate A), which changed
to a green/brown colour after 25 min (w30% conversion,
plate B). After 1.5 h the formation of metal containing nano-
particles was observed in the reaction mixture (w65% conver-
sion, plate C).
site 3
NH2
site 1
N
N
N
H
N
H
HO
site 2
O
The pH upon work-up should be w6.5, which allows the
product to be extracted with an ethyl acetate/isopropanol
solvent mixture (9:1). Subjecting the crude product to
OH OH
Figure 1. Potential sites of reaction for CeH and NeH bonds in adenosine.

T.E. Storr et al. / Tetrahedron 64 (2008) 6125e6137
6127
Table 1
Evaluation of different palladium sources for direct arylation of adenosinea
NH2
N
NH2
N
N
N
N
N
Pd(OAc)2 (5 mol%),
CuI (3 equiv),
Yieldb/%
H
Entry
Pd source (5 mol %)/CuI (mol %)
N
H
N
H
Cs2CO3 (2.5 equiv), DMF,
120 °C, 13 h
65c,d
<5
4e
HO
HO
1
2
3
4
5
a
Pd(OAc)2/Cu (300)
Pd(OAc)2/Cu (5)
d/Cu (300)
Pd2(dba-H)3 /Cu (300)
Pd2(dm-dba)2$dm-dbag/Cu (300)
O
O
I
f
OH OH
OH OH
29
59
(2 equiv)
Reaction conditions: as for Scheme 2, changing the Pd source.
Yield obtained after chromatography on silica gel.
A yield of 4% was obtained for the N-arylated product (8-phenyl-N6-
b
c
phenyl-adenosine, see Fig. 3).
d
Under identical conditions using NMP as the solvent a yield of 63% was
obtained.
e
Significant deglycosylation observed.
dba-H¼dibenzylidene acetone (1,5-bis-phenyl-penta-1E,4E-dien-3-one).
f
g
dm-dba¼1,5-bis-(30,50-dimethoxyphenyl)penta-1E,4E-dien-3-one.
afforded the 8-arylated purine products in good yields (entries
1e4). Remarkably, ionisable substituents, e.g., OH and NH2
groups are also tolerated (entries 5 and 6, respectively). Sub-
strates possessing electron-deficient ortho-substituents are
not accepted for C-arylation (entries 7 and 10). Catellani
and co-workers reported that the ortho-trifluoromethyl group
can interact with Pd(II), reducing its subsequent reactivity, in
norbornene-assisted arylation processes.22 On switching this
substituent to the meta position the coupled product was
formed in good yield (entry 8). In the presence of a meta-nitro
substituent, the cross-coupled product was obtained in modest
yield (entry 11). The p-nitro substituent gave the best yield
from the most strongly ‘electron-deficient substituent series’
(entry 12). Iodonapthalene couples in near quantitative yield
(entry 13). Quite remarkably the chemoselectivity was re-
versed when an ortho-nitro substituent is presentdN-arylation
emerged as the exclusive reaction pathway (Fig. 3).
We have established that 1,4-diiodobenzene can also be
used as an arylation substrate (Scheme 3). Despite using fewer
equivalents of 1,4-diiodobenzene (0.5 rather than 2 equiv with
respect to the adenosine), both 1,4-di-(80-adenosinyl)benzene
and 8-(p-iodophenyl)adenosine were formed in this reaction,
albeit in low yield (non-optimised). These compounds could
be useful in supramolecular assembly or ligand design.
20-Deoxyadenosine can also be arylated under the standard
conditions by slight modification to the reaction conditions; at
120 ꢀC substantial deglycosylation was observed, giving 8-
phenyladenine (Scheme 4), reflecting the lower stability of
20-deoxyribose. However, arylation worked well at 80 ꢀC
giving the coupled product in 84% yield.
Scheme 2. Product evolution profile for direct arylation of adenosine with
iodobenzene monitored by HPLC (open circles¼8-phenyladenosine).
chromatography on silica gel gave the direct arylation product
in 65% yield (Table 1, entry 1). A similar yield was obtained
using N-methylpyrrolidone (NMP) as the solvent (63%). The
reproducibility of these reactions is ꢁ5%. In the presence of
catalytic quantities of CuI negligible turnover was observed
(entry 2). Omission of Pd(OAc)2 from the reaction resulted
in poor turnover (4%), significant decomposition and deglyco-
sylation (entry 3). The Pd(0) source, Pd2(dba)3 (dba¼E,E-di-
benzylidene acetone) acted as a catalyst (29% yield, entry
4), but was not as effective as Pd(OAc)2. The more activated
Pd2(dm-dba)3$dm-dba20 complex gave an improved yield
(59%, entry 5), showing that the dibenzylidene acetone ligand
is non-innocent in this direct arylation reaction, in accord with
other cross-coupling processes.21 Finally, microwave heating
is ineffective for direct arylation of adenosine due to signifi-
cant decomposition (mainly deglycosylation).
Having identified the key reaction/work-up parameters a li-
brary of aryl halides were evaluated for direct arylation of
adenosine (Table 2). A series of para-substituted aryl iodides
Figure 2. Colour changes during direct arylation of adenosine with iodobenzene (A: at 5 min; B: at 25 min; C: at 1.5 h).

6128
T.E. Storr et al. / Tetrahedron 64 (2008) 6125e6137
Table 2
Direct arylation of adenosines with aryl halides
their impact on the benchmark reaction (Scheme 2) with
a view to gaining additional insight into the reaction
mechanism.
NH2
N
NH2
R
N
N
N
N
Pd(OAc)2 (5 mol%),
CuI (3 equiv),
N
H
Cs2CO3 (2.5 equiv), DMF,
120 °C, 13 h
N
H
N
H
2.1. On the involvement of amine
HO
HO
O
O
R
Most of the direct arylation reactions produced a strong
amine odour, most likely due to degradation of DMF to give
Me2NH (and CO[). To test the importance of the degradation
process a standard reaction was performed in the presence of
2.5 equiv of Et2NH. In this case the additive slowed down the
catalytic turnover (38% yield). By contrast the reaction does
proceed in the presence of 2.5 equiv of Et2NH in the absence
of Cs2CO3, albeit slowly and in low yield (18%).
I
OH OH
OH OH
(2 equiv)
Entry
R
Yielda/%
1
4-Me
85
70
2
4-MeO
4-C(O)Me
4-F
3
48
44
4
5
4-CH2OH
4-NH2
2-CF3
53
42
6
7
0
66
2.2. On the involvement of carbon monoxide
8
3-CF3
4-CF3
9
75
To establish whether trace quantities of CO vide supra could
be influencing these reactions, CO was generated in situ by em-
ploying Co2(CO)8, a reagent, which rapidly decomposes under
thermal heating in polar solvents such as DMF and DMSO.
Thus Co2(CO)8 (10 mol %) was added to the benchmark reac-
tion at t¼0. Upon heating rapid CO evolution was evident; after
10
11
12
13
a
2-NO2
3-NO2
4-NO2
1-Napthyl
0 (51)b
34
43
>95
Yield obtained after chromatography on silica gel.
The number in brackets refers to selective N6-mono-arylation.
b
NO2
NH
NH
NH
N
N
N
N
N
N
N
N
N
N
H
N
H
N
H
HO
HO
HO
O
O
O
OH OH
OH OH
OH OH
Figure 3. N-arylation products of adenosine.
ribose
NH2
N
H
N
N
N
N
N
NH2
N
Pd(OAc)2 (5 mol%),
CuI (3 equiv),
Cs2CO3 (2.5 equiv), DMF,
120 °C, 13 h
N
N
N
H
NH2
ribose
N
O
N
H
(9%)
HO
+
I
NH2
I
N
N
N
OH OH
(0.5 equiv)
HO
I
N
H
ribose
(14%)
O
ribose =
OH OH
Scheme 3. Reaction of adenosine with 1,4-diiodobenzene.
2. Mechanistic studies
ca. 5 min a palladium black precipitate was produced. This
‘palladium black’ was catalytically inactive, inferred by the
finding that negligible direct arylation was seen over a period
of 13 h; adenosine degradation accounts for the majority of
the consumed material. Furthermore, a trace quantity of the
N-arylation product was obtained in 3% yield (see Fig. 3).
Having developed a generic set of conditions for the direct
arylation of adenosine and 20-deoxyadenosine we felt that
some of the observations made in the study warranted further
investigation. Several parameters have been probed to assess

T.E. Storr et al. / Tetrahedron 64 (2008) 6125e6137
6129
NH2
NH2
N
N
N
N
N
N
Pd(OAc)2 (5 mol%),
CuI (3 equiv),
Cs2CO3 (2.5 equiv), DMF,
80 °C, 13 h
H
N
H
N
H
HO
HO
O
O
I
OH
OH
(2 equiv)
(84%)
NH2
N
N
N
H
N
Scheme 4. Arylation of 20-deoxyadenosine.
2.3. On the involvement of heterogeneous and/or radical
species
homocoupling of iodobenzene at higher Pd loadings.29 For
the direct arylation reactions described herein (at 120 ꢀC),
this was not an issue. Furthermore, on lowering the Pd(OAc)2
loading to 0.5 mol %, a 51% yield of the arylated product was
obtained. Lowering the loading further by an order of magni-
tude {0.05 mol % Pd(OAc)2)} gave only a 9% yield.
It has been noted that all the reactions from this study pro-
duced black heterogeneous mixtures after 13 h. Fagnou and
Campeau reported similar observations in palladium-catalysed
direct arylation reactions.11b Generally, it is well established
that addition of Hg(0) poisons metal(0) heterogeneous cata-
lysts,23 through amalgamation of the metal catalyst or through
surface adsorption. This is perhaps the most popular test for
the homogeneous versus heterogeneous catalysis question.24
The suppression of catalysis by a large excess of Hg(0), in
a well-stirred solution, is seen as evidence for a heterogeneous
catalyst. Where catalysis continues it is inferred that the reac-
tion is homogeneous. It should be noted that the Hg(0) poison
test is not a universal test for all metal catalysts; some caution
is necessary as Hg(0) can react with certain mononuclear tran-
sition metal complexes.25 General rules for the use of this test,
and other means for addressing the homogeneous versus het-
erogeneous question in transition metal catalysed processes,
have been clearly defined by Finke and co-workers.26 The
Hg(0) poison test has also been used to test for heterogeneous
behaviour in related CeH activation processes mediated by
Pd(OAc)2, where no catalyst inhibition was observed.27
Hg(0) (ca. 325 equiv) was added to the benchmark reaction af-
ter 25 min at 120 ꢀC (w30% conversion to product by HPLC).
Further conversion to product was recorded up to 45 min
(w65e70%), thus Hg(0) does not quench the reaction
{note: a deleterious secondary reaction of either Hg(0) or
Hg(II) with 8-phenyladenosine was noticeable after 45 min
(deglycosylation)}. The fact that the reaction continues in
the presence of Hg(0) points to homogeneous species playing
a key role in the reaction.
2.5. Study by transmission electron microscopy (TEM) and
X-ray photoelectron spectroscopy (XPS)
TEM has been widely used to characterise metal containing
nanoparticles in a variety of different reactions.30 Two 1 ml
samples were removed from the benchmark reaction after
1.5 h for analysis by TEM. The first sample was concentrated
under high vacuum at 40 ꢀC to remove the DMF. The crude
black solid was resuspended in ethanol and subjected to anal-
ysis by TEM. One concern was that in removing the DMF
(a potential metal colloid stabiliser) we would be artificially
favouring the formation of aggregated metal species. Thus to
the second sample we added N-polyvinylpyrrolidone (PVP)
(Mw¼29,000; 20 monomer equivalents with respect to Pd) to
stabilise any metal nanoparticles that were formed. A compar-
ison of the TEM micrographs for each sample revealed similar
sized metal containing nanoparticles (Fig. 4).
The nanoparticles contained within the unstabilised reaction
sample were analysed further by X-ray photoelectron spectros-
copy (XPS) to identify whether both Cu and Pd are present and
to determine their oxidation states. Figure 5 shows the Pd 3d
and Cu 2p regions, which revealed the presence of both
Pd(0) and Pd(II) species with characteristic 3d5/2 binding ener-
gies of 335.9 and 337.8 eV, respectively, and a significant
amount of Cu(I) with a 2p3/2 binding energy of 932.7 eV. Quan-
tification of the Cu 2p and Pd 3d regions revealed that the Cu/
Pd atomic ratio is w19:1 (theoretical ratio¼60:1). XPS is a sur-
face technique, thus this difference can be explained by the
presence of larger particles containing bulk Cu(I). The pres-
ence of mixed PdeCu species cannot be confirmed from
XPS alone; however, the high Pd content might be attributed
to Pd segregation to form a capped PdeCu particle. The pres-
ence of other higher oxidation state Cu species, such as those
derived from Cu(II), can be ruled out due to the absence of
any characteristic Cu 2p satellite peaks approximately 8 eV
above the main photoelectron peak.31
It is worthy of note that galvinoxyl radical,28 a common test
for the participation of radical mechanisms where addition of
an exogenous radical is assumed to slow or stop a radical-
mediated reaction, had no affect on the global efficacy of the
benchmark reaction giving 8-phenyladenosine in 65% yield.
2.4. Effect of Pd loading
Sames and Lane reported that the arylation reactions of
N-substituted indoles were accompanied by significant

6130
T.E. Storr et al. / Tetrahedron 64 (2008) 6125e6137
A
Pd(II)
Pd(0)
349
347
345
343
Binding energy / eV
341
339
337
335
333
B
Cu(I)
958
953
948
Binding energy / eV
943
938
933
928
Figure 5. A: Pd 3d spectrum of post-reaction sample. B: Cu 2p spectrum of
post-reaction sample.
2.6. Benchmark test using PVP stabilised palladium colloids
Palladium colloids stabilised by PVP were synthesised
according to the method described by El-Sayed and Nar-
ayanan.32 A characterised PdePVP colloid (average particle
size¼2 nm) was tested as a substitute for Pd(OAc)2. The
amount of PdePVP colloid added corresponds to 0.5 mol %
Pd. Remarkably, PdePVP was an efficient mediator of the re-
action producing the direct arylation product in 51% yield
Figure 4. A: TEM micrograph of unstabilised metal containing nanoparticles.
B: PVP stabilised metal containing nanoparticles. C: Percentage distribution of
metal containing nanoparticles (by ImageJ; shown using KaleidaGraph).

T.E. Storr et al. / Tetrahedron 64 (2008) 6125e6137
6131
NH2
NH2
N
(after 13 h). It is interesting to note that a larger PdePVP col-
loid (average particle size¼3.4 nm) performed less well in the
reaction (18% yield after 13 h), indicating that there is a parti-
cle size dependence on catalytic activity. Further studies are in
progress to elucidate the origin of this phenomenon.
N
N
N
N
N
acetone-d ,
H
D0.88
O
6
Cs2CO3 (2.5 equiv.),
DMF, 120 °C, 10 h
N
H
N
H
HO
HO
O
then H2O
(neutralise with
dil. aq. HCl)
OH OH
OH OH
Scheme 5. Deprotonation at the C8 position of adenosine.
O
N
this temperature and there was no evidence for deuterium
incorporation at C2.
n
PVP (MW = 29,000)
3. Mechanistic discussion
2.7. Additive effects: substituted pyridines
Adenosine, as a substrate, is a complicated ligand with sev-
eral possible coordination modes to palladium.35 Monomers
such as I are known (Fig. 6), as are dimeric and higher order
complexes, where N7 is the dominant ligating atom. Similar
copper complexes can also be formed (e.g., II).
The addition of sub-stoichiometric amounts of electron-de-
ficient pyridines has been shown to be beneficial for certain
direct arylation processes.33 It can be postulated that this addi-
tive stabilises catalytically active Pd(0) species34 and may also
increase the reactivity (electrophilicity) of Pd(II) species.33a
We have investigated a range of substituted pyridines to assess
their effect on the reaction of adenosine and iodobenzene un-
der the optimised reaction conditions (Table 3). Addition of 3-
nitropyridine to the generic reaction gave the arylated product
in >95% yield (entry 1). The other pyridines lowered the yield
of the C-arylated product as compared to the benchmark reac-
tion (entries 2e5); the electron-releasing substituents on the
pyridine appeared to reduce the global efficacy of the reaction
(entries 4 and 5). More critical was the observation that despite
the effectiveness of 3-nitropyridine as an additive in the bench-
mark reaction other aryl halide reactions did not benefit
from its addition. For example, 4-acetylphenyl iodide and 3-
trifluoromethylphenyl iodide reacted with adenosine in yields
of 23 and 47%, respectively, which are markedly lower than
the yields observed in the absence of this additive {compare
entries 3 and 8 (Table 1)}. The beneficial effect of the 3-
nitropyridine on direct arylation appears to be substrate
dependent.
In terms of the reaction mechanism an electrophilic substitu-
tion, via intermediate III, can be proposed, in accord with the
proposals made by Miura (in the arylation of thiazoles and
imidazoles),36 Gevorgyan (in the arylation of indolizines),37
and Daugulis (for arylations of caffeine and other electron-
rich heterocycles).10 However, counting against this is the sus-
ceptibility of intermediate III towards deglycosylation. Amine
coordination38 (from the adenine ring system) to Cu(I) aids ac-
tivation of the CeH bond (as in structure II). The stoichiometric
requirement for Cu(I) is key to the direct arylation of adenosine,
which mirrors the observations made by Bellina, Rossi and
co-workers18 for the direct arylation of imidazoles. These re-
searchers proposed that the imidazole exists in equilibrium
with the corresponding organocuprate derivative (not directly
observed). The in situ generation of such species is supported
by literature precedent,39 which shows that Cu(I) salts can met-
allate acidic CeH bonds, specifically the C-2 position of imid-
azoles, which are expected to possess similar acidity to the
C-8 position in adenosine. Whilst CuI would be expected to
act as a co-catalyst in this reaction it is likely that higher concen-
trations are necessary to increase the concentration of the
2.8. Deprotonation of adenosine at C8
N
H2N
Deprotonation at C8 of adenosine occurs under ‘arylation
conditions’ in the absence of metal. This was confirmed by
a control experiment using acetone-d6 as a source of deuterium
in the presence of Cs2CO3 in DMF at 120 ꢀC for 10 h (Scheme
5). A near complete exchange occurred at C8 within 10 h at
2 X
R
N
N
R
N
N
N
[Cu]n+
N
H2N
N
N
H2N
N
x
R
N
N
R
N
Pd2+
N
N
II
N
Table 3
Effect of substituted pyridines on the direct arylation of adenosine with
iodobenzenea
NH2
R
NH2
N
HO
N
N
O
N
= R
Entry
Additive (40 mol %)
Yieldb/%
OH OH
I
X = Cl, Br, OAc
1
2
3
4
5
6
a
3-Nitropyridine
3-Methoxypyridine
Pyridine
95
44
50
42
30
48
NH2
N
S
S
4-Dimethylaminopyridine
4-Methoxypyridine
Nitrobenzene
N
Pd
Ar
H
N
N
H
III
R
Reaction conditions as for Scheme 2.
Yield obtained after chromatography on silica gel.
b
Figure 6. Possible intermediates in the direct arylation of purines.

6132
T.E. Storr et al. / Tetrahedron 64 (2008) 6125e6137
organocuprate in solution. From our study it is pertinent to point
out that the XPS data indicates the presence of Cu(I) species
only.
conditions. Based on the assumption that ring-opening46 of the
purine heterocycle is unlikely, we propose that Cu(I) is able to
assist deprotonation at C8 in adenosine. A base-assisted depro-
tonation reaction leads to the in situ generation of an organo-
cuprate (path A, Scheme 6), which then participates in
transmetallation with the Pd(II) intermediate species in the
catalytic cycle. Isomerisation and reductive elimination reveal
the arylated adenosine, regenerating Pd(0) in the process. Ag-
gregation of Pd(0) species (and potential Cu species) emerges
as an issue during the latter stages of the reaction, where the
concentration of iodobenzene is low, a point supported by
the formation of metal containing nanoparticles vide supra.
The negative Hg(0) poison test strongly supports the involve-
ment of homogeneous catalytic species in the direct arylations
of adenosine. However, metal containing nanoparticles are
formed under the reaction conditions. In classical cross-cou-
pling reactions an inverse correlation, e.g., higher turnover fre-
quencies at lower palladium catalyst loadings {for Pd(OAc)2
and various palladacycles in Heck, Sonogashira and Suzuki
cross-couplings}, has been used as circumstantial evidence im-
plicating palladium clusters/nanoparticles in catalytic turn-
over.40 Moreover at lower ‘global’ palladium concentrations
there is a higher concentration of mononuclear species capable
of promoting the ‘homogenous’ cross-coupling reaction. Whilst
the palladium/substrate ratio is important, the observations
made in our study indicate that relatively high palladium load-
ings are necessary for optimum conversions. In a Heck reac-
tion41 of bromobenzene and n-butyl acrylate {mediated by
Pd(OAc)2 in NMP at 135 ꢀC} negligible catalytic turnover
was observed at a concentration of palladium similar to that
used in the direct arylations of adenosine. Oxidative addition
is proposed to be rate limiting in the case of bromobenzene, lead-
ing to aggregation of Pd(0), a particular problem at >1 mol %
Pd(OAc)2 catalyst loadings. In the case of iodobenzene, oxida-
tive addition is fast and gives a higher concentration of ‘Phe
PdeI’. Moreover,adenosineiscapableofstabilisingsuchacom-
plex (via N7 coordination to Pd), as is the solvent DMF (and
a pyridine additive). Such N-coordination will increase aryla-
tion efficacy; the Ullmann-type homocoupling of iodobenzene,
formed via halide bridged Pd(II) dimers/disproportionation42 or
via ‘Ar2L2PdXꢂ’ species,43 would be slowed down in that case.
The beneficial effect of in situ generated Me2NH {formed
by degradation of DMF, also producing CO(g)} remains
unclear at this stage. Sames and co-workers44 reported that ad-
dition of (iPr)2NH dramatically improved the yields obtained
in the Pd-catalysed C2-arylation of indoles by increasing the
rate of oxidative addition of the aryl halide to Pd(0). A higher
concentration of the ‘PhePdeX’ species also led to increased
amounts of biphenyl (for PhBr). It remains a possibility that
a sub-stoichiometric amount of Me2NH could assist the direct
arylations of adenosine. Addition of 10 mol % Co2(CO)8 to the
benchmark reaction led to rapid CO evolution and rapid palla-
dium black formation, which was catalytically inactive (for C-
arylation). CO is an excellent p-acceptor ligand, which will
reduce the reactivity of Pd(0) species. The study on PVPe
Pd stabilised colloids revealed that such species are catalyti-
cally active under the benchmark conditions. These heteroge-
nised sources release catalytically active Pd(0) into solution
(either monomeric or small clusters) allowing the homoge-
neous reaction to take place.45 In the direct arylations medi-
ated by Pd(OAc)2, the TEM micrographs reveal that metal
containing nanoparticles are formed, which are ca. 3e4 nm
(after 1.5 h; w65% conversion); a key question remaining un-
answered is what is their role in the reaction?
4. Conclusion
In summary, valuable reaction conditions for the direct aryl
functionalisation of unprotected adenosines have been devel-
oped. Deglycosylation has been identified as a major issue
using similar conditions to those described previously for
protected adenines and other direct arylation processes. The
above synthetic protocol allows C8-arylated adenosines to be
obtained in one step. In SuzukieMiyaura cross-couplings
there is an absolute requirement for the prefunctionalisation
of adenosine (bromination), which subsequently requires the
use of an organoboronic acid. A pragmatic point to consider
is that stoichiometric quantities of CuI are required for direct
arylation of adenosine. Thus, one has to remain open-minded
about what type of C8-aryl functionalisation might be required
for a given target and/or applicationdSuzukieMiyaura cross-
coupling will be a competitive alternative for certain struc-
tures. The direct arylation protocol is not intended to replace
SuzukieMiyaura cross-coupling procedures, rather it serves
to complement this key synthetic methodology.
Further mechanistic studies to confirm links between clas-
sical cross-coupling and direct arylation coupling processes
are ongoing in our laboratories. Perhaps more generally,
some of the observations reported in this study highlight the
challenges faced in the palladium catalysis field, particularly
in developing practical synthetic methodologies for the pro-
duction of more challenging molecular architectures, pharma-
ceutical compounds and other types of fine chemicals.
5. Experimental
5.1. General details
Proton (1H, 400 MHz) NMR spectra were recorded on an
Oxford AS400 spectrometer. Samples were prepared using
approximately 10 mg of compound dissolved in 0.7 ml of
DMSO-d6. Chemical shifts were referenced to residual undeu-
terated DMSO in DMSO-d6 at d¼2.5 ppm. All spectra were
reprocessed using MestRec version 4.9.9.6 on a PC (SineBell
apodization was used to obtain detailed proton spinespin cou-
pling patterns and constants). Carbon (13C, 100.6 MHz) NMR
spectra were recorded on the same NMR spectrometer. MS
(mass spectrometry) spectra were recorded on a Bruker
Daltronics micrOTOF machine with electrospray ionisation
The deprotonation experiment, performed in the absence of
metal, indicates that H/D exchange takes place under arylation

T.E. Storr et al. / Tetrahedron 64 (2008) 6125e6137
6133
eventually palladium
black precipitate
(mixed Pd/Cu?)
NH2
N
NH2
N
N
N
Ar
N
N
I
Ar
N
H
Pd0L
R
+ CuI
n
N
- CuI
R
Reductive
eliminatio
Oxidative
addition
n
I
Cu
NH2
N
NH2
NH2
N
path A
L
N
N
N
L
N
N
N
Catalytic
cycle
Cu
H
I PdII Ar
L
L
PdII
Ar
N
R
N
N
N
R
CsCO3H + CsI
R
Transmetallation
Isomerisation
NH2
Cs2CO3
L
Ar PdII
L
CsI + CsCO3H
CuI
N
N
N
R
N
HO
O
L = solvent or
substrate
R =
OH OH
Scheme 6. Proposed mechanism for the direct arylation of adenosine mediated by Pd/Cu in the presence of Cs2CO3.
(ESI). The mass to charge ratio, m/z, of the protonated molec-
ular ion is reported with any major fragments formed. IR
(infrared) spectra were recorded on a PerkineElmer Paragon
1000PC FT-IR spectrometer. UVevis (ultravioletevisible)
spectroscopy was performed on a Jasco V-560 UVevis spec-
trophotometer and temperature controlled at 20 ꢀC using a wa-
ter bath; spectra were taken in DMSO as approximately 50 mM
solutions in a quartz cuvette (lmax is reported). Melting points
(mp) were recorded using a Stuart digital SMP3 machine.
Reaction progress was monitored by TLC (thin layer chroma-
tography) on a silica gel matrix on aluminium, or plastic sup-
ported plates, with a fluorescent indicator at 254 nm. High
Performance Liquid Chromatography (HPLC) was used to
monitor the progress of the direct arylation reactions using
an Agilent 1100 system with a DAD (diode array detector)
and a Zorbax Eclipse XDB-C18 5 mm reverse-phase column.
Samples for HPLC analysis (50 ml) were removed by gas-tight
syringe and added directly to MeOH (2 ml). An aliquot of this
solution (100 ml) was then added to water (2 ml), which had
been filtered through a MILLEXÒGP filter unit (0.22 mm,
Millipore Ltd.). An aliquot of the aqueous sample (50 ml)
was analysed directly by HPLC using mixtures of HPLC grade
water and methanol as the eluants, while monitoring the absor-
bance of the effluent at 254 nm. Common abbreviations used:
operated at 120 keV. Prior to imaging, the samples were resus-
pended in ethanol and pipetted onto a gold grid.
5.3. X-ray photoelectron spectrometry
XPS measurements were performed using a Kratos AXIS
HSi instrument equipped with a charge neutraliser and Mg
Ka X-ray source. Spectra were recorded at normal emission
using an analyser pass energy of 20 eV and a X-ray power
of 144 W. Spectra were energy referenced to the valence
band and adventitious carbon. Quantification was performed
using appropriate elemental relative sensitivity factors.
5.4. General procedure for direct arylation
Adenosine (1.0 equiv, 500 mg, 1.87 mmol), Cs2CO3
(2.5 equiv, 1.53 g, 4.68 mmol), CuI (3.0 equiv, 1.07 g,
5.61 mmol), Pd(OAc)2 (5 mol %, 21 mg, 94 mmol) and the
aryl iodide (2.0 equiv, 3.74 mmol) were added to a vacuum
dried Schlenk tube. The reaction vessel was evacuated under
high vacuum at 25 ꢀC with stirring and then flushed with N2
(three cycles). DMF (10 ml) was then added and the reaction
was heated in an oil bath at 120 ꢀC, and stirred continuously
for 13 h. The mixture was then allowed to cool to 25 ꢀC and
1 M HCl solution (10 ml) added. The pH was then adjusted
to 6.5 with 1 M NaOH and the aqueous solution extracted
EtOAc¼ethyl
acetate;
MeOH¼methanol). Commercial chemicals were purchased
from SigmaeAldrich or Alfa Aesar.
DMF¼N,N-dimethylformamide;
i
with PrOH/EtOAc (1:9, v/v, 5ꢃ50 ml) mixture. The organic
extracts were combined, dried (MgSO4), filtered and reduced
in vacuo to yield a thick gum, which was dried under high
vacuum to give a powder. This powder was re-dissolved/sus-
pended in MeOH (20 ml), reduced in vacuo and adsorbed
onto silica gel (approximately 0.5 g). A short silica gel column
5.2. Transmission electron microscopy (TEM)
Metal containing nanoparticles were characterised using
a FEI Tecnai 12 Biotwin High Contrast Electron Microscope

6134
T.E. Storr et al. / Tetrahedron 64 (2008) 6125e6137
(approximately 10 g) was eluted using CH3OH/CH2Cl2 (2:98
v/v, moving in stepwise increments to 10:90 by gradient
elution). The fractions containing the product were combined
and the solvents removed in vacuo. The final pure product was
isolated and dried under high vacuum.
NMR (100.6 MHz, DMSO-d6) d 197.5, 156.3, 149.9, 149.8,
137.5, 133.4, 129.8, 128.4, 119.4, 89.1, 86.7, 71.2, 70.9,
62.1, 26.8 (15 of a possible 16 carbon resonances observed);
ESI-MS m/z 386 [100% (MH)þ], 254 [31.2% (Mꢂb-D-
riboseþ2H)þ]; HR (MHþ) 386.1450 (calcd for C18H20O5N5
386.1459).
5.4.1. 8-Phenyladenosine
Light yellow solid (410 mg, 65%), mp 142e143 ꢀC (de-
5.4.5. 8-p-Fluorophenyladenosine
1
comp.); UVevis lmax 289 nm; H NMR (400 MHz, DMSO-
Light brown solid (296 mg, 44%), mp 151e153 ꢀC (de-
1
comp.); UVevis lmax 288 nm; H NMR (400 MHz, DMSO-
d6) d 8.17 (br s, 1H), 7.76 (m, 2H), 7.60 (m, 3H), 7.54 (br s,
2H), 5.83 (dd, J¼3.4, 9.2, 1H), 5.76 (d, J¼7.0, 1H), 5.49 (d,
J¼6.5, 1H), 5.18 (ddd, J¼4.7, 7.0, 6.5, 1H), 5.15 (d, J¼4.4,
1H), 4.16 (ddd, J¼1.9, 4.7, 4.4, 1H), 3.94 (ddd, J¼1.9, 3.5,
3.5, 1H), 3.70 (ddd, J¼3.4, 3.5, 12.3, 1H), 3.56 (ddd, J¼3.5,
9.2, 12.3, 1H); 13C NMR (100.6 MHz, DMSO-d6) d 156.2,
152.0, 150.9, 149.7, 130.1, 129.6, 129.4, 128.7, 119.2, 89.0,
86.7, 71.2, 71.1, 62.3; ESI-MS m/z 344 [100% (MH)þ], 212
[5.6% (Mꢂb-D-riboseþ2H)þ]; HR (MHþ) 344.1354 (calcd
for C16H18O4N5 344.1353).
d6) d 8.29 (br s, 1H), 7.80 (m, 2H), 7.56 (br s, 2H), 7.45 (m,
2H), 5.78 (m, 1H), 5.71 (d, J¼7.2, 1H), 5.48 (d, J¼6.0, 1H),
5.15 (m, 2H), 4.17 (m, 1H), 3.95 (m, 1H), 3.70 (m, 1H),
3.55 (m, 1H); 13C NMR (100.6 MHz, DMSO-d6) d 163.1 (d,
JCF¼248), 155.5, 151.6, 150.3, 149.6, 132.0 (d, JCF¼9),
125.7, 119.0, 115.9 (d, JCF¼22), 89.1, 86.7, 71.2, 70.9, 62.1;
ESI-MS m/z 362 [100% (MH)þ], 230 [55.1% (Mꢂb-D-
riboseþ2H)þ];
HR
(MHþ)
362.1257
(calcd
for
C16H17O4N5F 362.1259).
5.4.2. 8-p-Tolyladenosine
Light pink solid (570 mg, 85%), mp 144e147 ꢀC (de-
5.4.6. 8-p-Hydroxybenzyladenosine
Extended elution from the silica gel column was required.
1
comp.); UVevis lmax 290 nm; H NMR (400 MHz, DMSO-
Light yellow solid (370 mg, 70%), mp 173e176 ꢀC (de-
1
comp.); UVevis lmax 290 nm; H NMR (400 MHz, DMSO-
d6) d 8.15 (br s, 1H), 7.64 (d, J¼8.1, 2H), 7.47 (br s, 2H),
7.40 (d, J¼8.1, 2H), 5.83 (dd, J¼3.5, 9.4, 1H), 5.74 (d,
J¼7.1, 1H), 5.47 (d, J¼6.7, 1H), 5.17 (ddd, J¼5.0, 6.7, 7.1,
1H), 5.14 (d, J¼4.7, 1H), 4.16 (ddd, J¼1.9, 4.7, 5.0, 1H),
3.93 (ddd, J¼1.9, 3.7, 3.6, 1H), 3.69 (ddd, J¼3.5, 3.6, 12.5,
1H), 3.54 (ddd, J¼3.7, 9.4, 12.5, 1H), 2.41 (s, 3H); 13C
NMR (100.6 MHz, DMSO-d6) d 156.1, 151.9, 151.1, 149.8,
139.9, 129.5, 129.3, 126.5, 119.5, 89.1, 86.6, 71.2, 71.1,
62.3, 21.0; ESI-MS m/z 358 [100% (MH)þ], 226 [31.2%
(Mꢂb-D-riboseþ2H)þ]; HR (MHþ) 358.1508 (calcd for
C17H20O4N5 358.1510).
d6) d 8.15 (br s, 1H), 7.71 (d, J¼8.4, 2H), 7.52 (dþbr s,
J¼8.4, 4H), 5.85 (dd, J¼3.4, 9.3, 1H), 5.75 (d, J¼7.0, 1H),
5.48 (d, J¼6.6, 1H), 5.38 (t, J¼5.7, 1H), 5.18 (ddd, J¼5.2,
6.6, 7.0, 1H), 5.16 (d, J¼4.2, 1H), 4.61 (d, J¼5.7, 2H), 4.17
(m, 1H), 3.94 (ddd, J¼1.8, 3.7, 3.6, 1H), 3.70 (ddd, J¼3.4,
3.6, 12.2, 1H), 3.55 (ddd, J¼3.7, 9.3, 12.2, 1H); 13C NMR
(100.6 MHz, DMSO-d6) d 156.1, 151.9, 151.0, 149.7, 144.7,
129.4, 127.6, 126.5, 119.0, 89.0, 86.6, 71.1, 71.1, 62.4, 62.3;
ESI-MS m/z 374 [100% (MH)þ], 242 [29.5% (Mꢂb-D-
riboseþ2H)þ]; HR (MHþ) 374.1471 (calcd for C17H20O5N5
374.1459).
5.4.3. 8-p-Methoxyphenyladenosine
Light grey solid (487 mg, 70%), mp 162e164 ꢀC (de-
5.4.7. 8-p-Aminophenyladenosine
1
comp.); UVevis lmax 291 nm; H NMR (400 MHz, DMSO-
The reaction mixture was extracted with the organic solvent
10 times; an extended elution from the silica gel column was
required. Brown solid (282 mg, 42%), mp 176e180 ꢀC (de-
d6) d 8.14 (br s, 1H), 7.60 (d, J¼8.9, 2H), 7.47 (br s, 2H),
7.14 (d, J¼8.9, 2H), 5.85 (dd, J¼3.4, 9.3, 1H), 5.75 (d,
J¼6.9, 1H), 5.47 (d, J¼6.6, 1H), 5.17 (ddd, J¼5.0, 6.9, 6.6,
1H), 5.15 (d, J¼4.6, 1H), 4.16 (ddd, J¼1.9, 5.0, 4.6, 1H),
3.94 (ddd, J¼1.9, 3.5, 3.5, 1H), 3.85 (s, 3H), 3.69 (ddd,
J¼3.4, 3.5, 12.3, 1H), 3.56 (ddd, J¼3.5, 9.3, 12.3, 1H); 13C
NMR (100.6 MHz, DMSO-d6) d 160.6, 156.0, 151.7, 150.9,
149.7, 131.1, 121.5, 119.0, 114.2, 89.0, 86.6, 71.2, 71.1,
62.3, 55.3; ESI-MS m/z 374 [100% (MH)þ], 242 [1.3%
(Mꢂb-D-riboseþ2H)þ]; HR (MHþ) 374.1461 (calcd for
C17H20O5N5 374.1459).
1
comp.); UVevis lmax 311 nm; H NMR (400 MHz, DMSO-
d6) d 8.09 (br s, 1H), 7.43 (d, J¼8.6, 2H), 7.36 (br s, 2H),
6.68 (d, J¼8.6, 2H), 5.89 (dd, J¼3.4, 9.5, 1H), 5.80 (d,
J¼7.2, 1H), 5.66 (br s, 2H), 5.46 (d, J¼6.5, 1H), 5.15
(mþd, J¼4.2, 2H), 4.17 (m, 1H), 3.93 (m, 1H), 3.70 (ddd,
J¼3.4, 3.4, 12.5, 1H), 3.55 (ddd, J¼3.5, 9.5, 12.5, 1H); 13C
NMR (100.6 MHz, DMSO-d6) d 155.7, 152.2, 151.2, 150.5,
149.7, 130.7, 119.0, 115.8, 113.3, 89.0, 86.5, 71.1, 71.1,
62.4; ESI-MS m/z 359 [100% (MH)þ], 227 [60.4% (Mꢂb-D-
riboseþ2H)þ]; HR (MHþ) 359.1454 (calcd for C16H19O4N6
359.1462).
5.4.4. 8-p-Acetophenyladenosine
Brown solid (348 mg, 48%), mp 154e156 ꢀC (decomp.);
UVevis lmax 316 nm; 1H NMR (400 MHz, DMSO-d6)
d 8.27 (br s, 1H), 8.16 (d, J¼8.2, 2H), 7.91 (d, J¼8.2, 2H),
7.65 (br s, 2H), 5.79 (1H, m, 1H), 5.75 (d, J¼7.1, 1H), 5.50
(d, J¼6.8, 1H), 5.21e5.16 (br m, 2H), 4.17 (m, 1H), 3.96
(m, 1H), 3.71 (m, 1H), 3.56 (m, 1H), 2.66 (s, 3H); 13C
5.4.8. 8-m-Trifluoromethylphenyladenosine
Light yellow solid (507 mg, 66%), mp 163e167 ꢀC (de-
1
comp.); UVevis lmax 296 nm; H NMR (400 MHz, DMSO-
d6) d 8.15 (br s, 1H), 8.09 (s, 1H), 8.04 (d, J¼7.8, 1H), 7.95
(d, J¼7.8, 1H), 7.86 (t, J¼7.8, 1H), 5.77 (dd, J¼3.6, 9.1,

T.E. Storr et al. / Tetrahedron 64 (2008) 6125e6137
6135
1H), 5.70 (d, J¼7.0, 1H), 5.50 (d, J¼6.5, 1H), 5.15 (d, J¼4.6,
1H), 5.14 (ddd, J¼5.0, 7.0, 6.5, 1H), 4.14 (ddd, J¼1.9, 4.6,
5.0, 1H), 3.93 (ddd, J¼1.9, 3.6, 3.6, 1H), 3.69 (ddd, J¼3.6,
3.6, 12.4, 1H), 3.53 (ddd, J¼3.6, 9.1, 12.4, 1H); 13C NMR
(100.6 MHz, DMSO-d6) d 156.3, 152.4, 149.9, 149.3, 133.4,
130.4, 130.1, 129.6 (q, JCF¼33), 126.7, 126.2, 123.8 (q,
JCF¼272), 119.2, 89.1, 86.9, 71.3, 71.0, 62.2; ESI-MS m/z
412 [100% (MH)þ]; HR (MHþ) 412.1234 (calcd for
C17H17O4N4F3 412.1227).
5.4.12. 8-p-Nitrophenyladenosine
Yellow solid (311 mg, 43%), mp 233e238 ꢀC (decomp.);
UVevis lmax 249 nm; 1H NMR (400 MHz, DMSO-d6)
d 8.45 (d, J¼8.9, 2H), 8.19 (s, 1H), 8.04 (d, J¼8.9, 2H),
7.66 (br s, 2H), 5.76 (dd, J¼3.7, 9.1, 1H), 5.74 (d, J¼7.0,
1H), 5.50 (d, J¼6.7, 1H), 5.21 (d, J¼4.6, 1H), 5.16 (ddd,
J¼5.1, 6.7, 7.0, 1H), 4.17 (ddd, J¼2.0, 4.6, 5.1, 1H), 3.97
(ddd, J¼2.0, 3.7, 3.7, 1H), 3.71 (ddd, J¼3.7, 3.7, 12.4, 1H),
3.57 (ddd, J¼3.7, 9.1, 12.4, 1H); 13C NMR (100.6 MHz,
DMSO-d6) d 156.4, 152.6, 150.0, 148.7, 148.1, 135.4, 130.9,
123.9, 119.4, 89.1, 86.9, 71.3, 70.8, 62.1; ESI-MS m/z 389
[100% (MH)þ], 257 [44.7% (Mꢂb-D-riboseþ2H)þ]; HR
(MHþ) 389.1191 (calcd for C16H17O6N5 389.1204).
5.4.9. 8-p-Trifluoromethylphenyladenosine
Brown solid (572 mg, 75%), mp 187e189 ꢀC (decomp.);
UVevis lmax 301 nm; 1H NMR (400 MHz, DMSO-d6)
d 8.23 (br s, 1H), 7.99 (br s, 4H), 7.63 (br s, 2H), 5.79 (dd,
J¼3.5, 9.1, 1H), 5.72 (d, J¼7.1, 1H), 5.49 (d, J¼6.8, 1H),
5.20 (d, J¼4.7, 1H), 5.17 (ddd, J¼5.0, 6.8, 7.1, 1H), 4.16
(ddd, J¼1.8, 4.7, 5.0, 1H), 3.96 (ddd, J¼1.8, 3.7, 3.7, 1H),
3.71 (ddd, J¼3.5, 3.7, 12.3, 1H), 3.53 (ddd, J¼3.7, 9.1,
12.3, 1H); 13C NMR (100.6 MHz, DMSO-d6) d 149.7,
149.3, 133.2, 130.4, 130.1 (q, JCF¼32), 129.91, 125.64,
125.60, 125.48, 123.8 (q, JCF¼273), 89.04, 86.81, 71.19,
70.87, 62.09; ESI-MS m/z 412 [100% (MH)þ], 280 [2.8%
(Mꢂb-D-riboseþ2H)þ]; HR (MHþ) 412.1236 (calcd for
C17H17O4N4F3 412.1227).
5.4.13. 8-1-Napthyladenosine
Light yellow solid (735 mg, 99%), mp 173e177 ꢀC (de-
1
comp.); UVevis lmax 286 nm; H NMR (400 MHz, DMSO-
d6) d 8.26 (br s, 1H), 8.17 (t, J¼5.0, 1H), 8.07 (dd, J¼1.5,
8.1, 1H), 7.73 (m, 1H), 7.69 (m, 2H), 7.61 (ddd, 1.3, 6.8,
8.1, 1H), 7.55 (ddd, J¼1.5, 6.8, 8.3, 1H, overlapping with br
s, 2H), 5.89 (br m, 1H), 5.36 (d, J¼7.3, 1H), 5.32 (br m,
1H), 5.06 (br m, 1H), 4.97 (d, J¼4.1, 1H), 4.05 (m, 1H),
3.83 (m, 1H), 3.67 (ddd, J¼3.5, 3.5, 12.3, 1H), 3.54 (ddd,
J¼3.2, 9.3, 12.3, 1H); 13C NMR (100.6 MHz, DMSO-d6)
d 156.3, 152.2, 149.4, 149.4, 133.1, 131.8, 130.5, 128.4,
127.3, 126.9, 126.7, 125.4, 125.2, 119.4, 89.5, 86.7, 71.1,
71.1, 62.3 (19 resonances of a possible 20 observed); ESI-
MS m/z 394 [100% (MH)þ], 262 [23.1% (Mꢂb-D-
riboseþ2H)þ]; HR (MHþ) 394.1512 (calcd for C20H20O4N5
394.1510).
5.4.10. N6-o-Nitrophenyladenosine
Orange solid (370 mg, 51%), mp 121e124 ꢀC (decomp.);
UVevis lmax 283 nm; 1H NMR (400 MHz, DMSO-d6)
d 10.70 (br s, 1H), 8.65 (s, 1H), 8.41 (s, 1H), 8.40 (dd,
J¼1.2, 8.4, 1H), 8.12 (dd, J¼1.5, 8.3, 1H), 7.78 (ddd,
J¼1.4, 7.2, 8.4, 1H), 7.33 (ddd, J¼1.2, 7.4, 8.4, 1H), 5.97
(d, J¼5.9, 1H), 5.54 (d, J¼6.1, 1H), 5.25 (d, J¼4.8, 1H),
5.22 (dd, J¼5.1, 6.1, 1H), 4.64 (dd, J¼5.9, 11.0, 1H), 4.18
(ddd, J¼3.4, 4.9, 4.9, 1H), 3.98 (ddd, J¼3.7, 3.7, 3.7, 1H),
3.69 (ddd, J¼4.5, 4.5, 12.0, 1H), 3.56 (ddd, J¼3.9, 6.6,
12.0, 1H); 13C NMR (100.6 MHz, DMSO-d6) d 151.6,
151.0, 149.8, 141.9, 140.0, 134.7, 133.6, 125.4, 124.5,
123.7, 121.0, 87.8, 85.8, 73.6, 70.4, 61.4; ESI-MS m/z 389
[100% (MH)þ], 344 [3.8% (MꢂNO2þ2H)þ], 257 [17.0%
(Mꢂb-D-riboseþ2H)þ]; HR (MHþ) 389.1196 (calcd for
C16H17O6N5 389.1204).
5.5. Reaction of adenosine with 1,4-diiodobenzene
The general direct arylation procedure was followed using
0.5 equiv of 1,4-diiodobenzene (308 mg, 0.94 mmol) with re-
spect to adenosine (0.5 g, 1.87 mmol, 1 equiv). The yields
are based on 1,4-diiodobenezene (limiting substrate).
5.5.1. Data for 1,4-di-(80-adenosinyl)benzene
Light brown solid (49 mg, 9%), mp 188e191 ꢀC (de-
1
comp.); H NMR (400 MHz, DMSO-d6) d 8.21 (br s, 2H),
5.4.11. 8-m-Nitrophenyladenosine
7.75 (m, 2H), 7.60 (m, 2H), 7.56 (br s, 4H), 5.82 (dd,
J¼3.5, 9.2, 2H), 5.76 (d, J¼7.2, 2H), 5.50 (d, J¼6.4, 2H),
5.18 (m, 2H), 5.17 (d, J¼4.4, 2H), 4.16 (m, 2H), 3.94 (ddd,
J¼1.9, 3.5, 3.5, 2H), 3.70 (ddd, J¼3.5, 3.5, 12.4, 2H), 3.55
(ddd, J¼3.5, 9.2, 12.4, 2H); 13C NMR (100.6 MHz, DMSO-
d6) d 156.2, 152.0, 150.9, 149.7, 130.1, 129.6, 129.3, 128.7,
89.0, 86.7, 71.2, 71.0, 62.2 (13 of a possible 14 carbon reso-
nances observed); ESI-MS m/z 631 [17.9% (MNa)þ], 609
[17.4% (MH)þ], 477 [94.9% (Mꢂb-D-riboseþ2H)þ], 345
[100% (Mꢂ2b-D-riboseþ3H)þ], 212 [68.5% (Mꢂb-D-ribose-
adenosineþ3H)þ]; HR (MHþ) 631.1982 (calcd for
C26H28O8N10Na 631.1984). A trace quantity of the N6-phenyl
derivative was detected by ESI-MS only at m/z 685 [9.8%
(MN6-PhH)þ] and 553 [19.1% (MN6-Phꢂb-D-riboseþ2H)þ]
(this is not visible by NMR spectroscopy).
Yellow solid (245 mg, 34%), mp 203e207 ꢀC (decomp.);
UVevis lmax 280 nm; 1H NMR (400 MHz, DMSO-d6)
d 8.60 (dd, J¼1.7, 2.2, 1H), 8.44 (ddd, J¼1.0, 2.2, 8.0, 1H),
8.21 (ddd, J¼1.0, 1.7, 8.0, and overlapping br s, 2H), 7.91
(t, J¼8.0, 1H), 7.65 (br s, 2H), 5.79 (dd, J¼3.7, 9.1, 1H),
5.74 (d, J¼7.0, 1H), 5.53 (d, J¼6.5, 1H), 5.20 (d, J¼4.9,
1H), 5.15 (ddd, J¼5.1, 6.5, 7.0, 1H), 4.17 (ddd, J¼2.0, 4.9,
5.1, 1H), 3.97 (ddd, J¼2.0, 3.7, 3.7, 1H), 3.70 (ddd, J¼3.7,
3.7, 12.4, 1H), 3.56 (ddd, J¼3.7, 9.1, 12.4, 1H); 13C NMR
(100.6 MHz, DMSO-d6) d 156.4, 152.5, 149.9, 148.6, 147.9,
135.6, 130.8, 130.6, 124.8, 124.3, 119.2, 89.1, 86.9, 71.4,
70.9, 62.1; ESI-MS m/z 389 [100% (MH)þ], 257 [94.3%
(Mꢂb-D-riboseþ2H)þ]; HR (MHþ) 389.1204 (calcd for
C16H17O6N5 389.1204).

6136
T.E. Storr et al. / Tetrahedron 64 (2008) 6125e6137
5.5.2. Data for 8-p-iodophenyladenosine
were added acetone-d6 and DMF (2 ml, 1:1, v/v). The mixture
was heated to 120 ꢀC for 10 h. The reaction was quenched by
addition of water (2 ml) and neutralised using dilute (1 M)
hydrochloric acid (2 ml), which was then extracted with ethyl
acetate/ethanol (9:1, v/v, 4ꢃ10 ml). The combined organic ex-
tracts were then dried (MgSO4), filtered and concentrated in
vacuo to give a beige solid (42 mg). 1H NMR (400 MHz,
DMSO-d6, selected peaks) d 8.35 (s, 0.12H, C8-H), 8.13 (s,
1H, C2-H); ESI-MS m/z 269 [72% (MH)þ], 132 [100%];
HR (MHþ) 269.1105 (calcd for C10H13D1O4N5 269.1103).
Light yellow solid (62 mg, 14%), mp 148e150 ꢀC (de-
comp.); 1H NMR (400 MHz, DMSO-d6, selected data)
d 8.16 (s, 1H), 7.75 (m, 2H), 7.60 (m, 2H), 7.53 (br s, 2H),
5.83 (dd, J¼3.4, 9.4, 1H), 5.75 (d, J¼6.6, 1H), 5.49 (d,
J¼6.4, 1H), 5.18 (m, 1H), 5.16 (d, J¼4.2, 1H), 4.16 (m,
1H), 3.94 (ddd, J¼1.8, 3.6, 3.6, 1H), 3.69 (ddd, J¼3.4, 3.6,
12.5, 1H), 3.54 (ddd, J¼3.6, 9.4, 12.5, 1H); 13C NMR
(100.6 MHz, DMSO-d6) d 156.2, 152.0, 150.9, 149.7, 130.1,
129.6, 129.3, 128.7, 119.0, 89.0, 86.7, 71.2, 71.0, 62.3; ESI-
MS m/z 366 [5.0% (MꢂIþHþNa)þ], 344 [9.2%
(MꢂIþ2H)þ], 212 [100% (Mꢂb-D-riboseꢂIþ3H)þ].
Acknowledgements
5.5.3. 8-Phenyl-20-deoxyadenosine
Light orange solid (514 mg, 84%); H NMR (400 MHz,
The authors wish to thank Dr. D.A. Ashford for a prelimi-
nary reaction analysis by reverse-phase liquid chromatography
and mass spectrometry, Ms. M. Stark for technical assistance
with the transmission electron microscopy, and Dr. R.G. Stur-
mey and Professor H.J. Leese for the use of an Agilent 1100
high performance liquid chromatography system. Mr. P. Ellis,
Dr. P. Sehnal and Dr. A.F. Lee (York) are thanked for provid-
ing characterised PdePVP colloids and for valuable discus-
sions. We are grateful to BBSRC (CASE award to A.G.F.),
ESPRC (DTA award to T.E.S.), the University of York and
Replizyme Ltd. for funding these studies. The Royal Society
is thanked for a generous equipment grant and funding for a re-
search fellowship (I.J.S.F.). Astra-Zeneca (Dr. D.M. Hollins-
head) is thanked for an unrestricted research grant (awarded
to I.J.S.F.).
1
DMSO-d6) d 8.15 (s, 1H), 7.70 (m, 2H), 7.59 (m, 3H), 7.46
(br s, 2H), 6.15 (dd, J¼6.2, 8.7, 1H), 5.58 (dd, J¼4.0, 8.3,
1H), 5.24 (d, J¼4.0, 1H), 4.45 (dddd, J¼1.9, 1.9, 4.0, 5.8,
1H), 3.87 (ddd, J¼1.9, 4.2, 4.2, 1H), 3.69 (ddd, J¼4.0, 4.2,
12.2, 1H), 3.53 (ddd, J¼4.2, 8.3, 12.2, 1H), 3.30 (ddd,
J¼5.8, 8.7, 13.2, 1H), 2.145 (ddd, J¼1.9, 6.2, 13.2, 1H); 13C
NMR (100.6 MHz, DMSO-d6) d 156.1, 152.0, 150.4, 149.8,
130.1, 129.6, 129.4, 128.8, 119.1, 88.4, 85.7, 71.4, 62.3,
37.2; ESI-MS m/z 328 [8.1% (MþH)þ], 212 [100% (Mꢂb-
D-riboseþ2H)þ]; HR (MHþ) 328.1394 (calcd for
C16H18O3N5 328.1404).
5.5.4. 8-Phenyl-(N6-phenyl)adenosine
Orange solid (32 mg, 4%;) 1H NMR (400 MHz, DMSO-d6)
d 10.09 (s, 1H), 8.43 (s, 1H), 7.96 (m, 2H), 7.82 (m, 2H), 7.63
(m, 3H), 7.35 (m, 2H), 7.06 (m, 1H), 5.80 (d, J¼6.9, 1H), 5.56
(dd, J¼4.0, 8.6, 1H), 5.51 (d, J¼6.5, 1H), 5.24 (ddd, J¼5.0,
6.9, 6.5, 1H), 5.19 (d, J¼4.4, 1H), 4.21 (ddd, J¼2.0, 5.0,
4.4, 1H), 3.96 (ddd, J¼2.0, 4.0, 4.0, 1H), 3.74 (ddd, J¼4.0,
4.0, 12.2, 1H), 3.58 (ddd, J¼4.0, 8.6, 12.2, 1H); 13C NMR
(100.6 MHz, DMSO-d6) d 152.1, 151.9, 151.5, 150.0, 139.3,
130.4, 129.8, 129.6, 129.4, 129.1, 128.8, 128.8, 128.4,
122.9, 121.0, 120.2, 115.4, 89.2, 86.6, 71.1, 70.9, 62.2; ESI-
MS m/z 420 [100% (MH)þ]; HR (MHþ) 420.1667 (calcd for
C22H22O4N5 420.1666).
References and notes
1. Burgess, K.; Cook, D. Chem. Rev. 2000, 100, 2047.
2. (a) De Clercq, E. Biochem. Pharmacol. 1984, 33, 2159; (b) Minakawa, N.;
Kojima, N.; Sasaki, T.; Matsuda, A. Nucleosides Nucleotides 1996, 15,
251; (c) De Clercq, E.; Descamps, J.; De Somer, P.; Barr, P. J.; Jones,
A. S.; Walker, R. T. Proc. Natl. Acad. Sci. U.S.A. 1979, 76, 2947; (d)
Manfredini, S.; Baraldi, P. G.; Bazzanini, R.; Marangoni, M.; Simoni,
D.; Balzarini, J.; De Clercq, E. J. Med. Chem. 1995, 38, 199; (e) Hocek,
´
´
M.; Holy, A.; Votruba, I.; Dvorakova, H. J. Med. Chem. 2000, 43, 1817.
3. Fairlamb, I. J. S. Tetrahedron 2005, 61, 9661.
4. (a) Agrofoglio, L. A.; Gillaizeau, I.; Saito, Y. Chem. Rev. 2003, 103, 1875;
(b) Hocek, M. Eur. J. Org. Chem. 2003, 245; (c) Lakshman, M. K. Curr.
Org. Synth. 2005, 2, 83.
5.5.5. N6-Phenyladenosine
5. (a) Firth, A. G.; Fairlamb, I. J. S.; Darley, K.; Baumann, C. G. Tetrahe-
dron Lett. 2006, 47, 3529; (b) Collier, A.; Wagner, G. Synth. Commun.
2006, 36, 3713; (c) Shaughnessy, K. H. Eur. J. Org. Chem. 2006, 1827.
6. Capek, P.; Pohl, R.; Hocek, M. Org. Biomol. Chem. 2006, 4, 2278.
7. (a) Collier, A.; Wagner, G. Org. Biomol. Chem. 2006, 4, 4526; (b) Collier,
A.; Wagner, G. Chem. Commun. 2008, doi:10.1039/b714379f
8. Catellani, M.; Motti, E.; Della Ca’, N.; Ferraccioli, R. Eur. J. Org. Chem.
2007, 4153.
Light yellow solid (17 mg, 3%); 1H NMR (400 MHz,
DMSO-d6) d 9.96 (br s, 1H), 8.55 (s, 1H), 8.41 (s, 1H), 7.94
(d, J¼8.0, 2H), 7.32 (dd, J¼7.4, 8.0, 2H), 7.05 (t, J¼7.4,
1H), 5.97 (d, J¼6.1, 1H), 5.51 (d, J¼6.4, 1H), 5.31 (dd,
J¼4.6, 6.4, 1H), 5.24 (d, J¼4.6, 1H), 4.65 (m, 1H), 4.18 (m,
1H), 3.96 (m, 1H), 3.70 (ddd, J¼4.0, 4.6, 12.0, 1H), 3.58
(ddd, J¼4.0, 6.4, 12.0, 1H); 13C NMR (100.6 MHz, DMSO-
d6) d 152.1, 151.9, 140.7, 139.5, 128.3, 122.7, 120.83, 87.8,
85.8, 73.5, 70.5, 61.5 (12 of possible 14 carbon resonances ob-
served); ESI-MS m/z 344 [100% (MH)þ]; HR (MHþ)
344.1360 (calcd for C16H18O4N5 344. 1353).
9. Fairlamb, I. J. S. Chem. Soc. Rev. 2007, 36, 1036.
10. Chiong, H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449; For an excellent
review, see: Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173.
11. For general reviews, see: (a) Godula, K.; Sames, D. Science 2006, 312, 67;
(b) Campeau, L.-C.; Fagnou, K. Chem. Commun. 2006, 1253; related: (c)
Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439; For a review on
s-Chelation-directed CeH functionalizations, see: (d) Yu, J.-Q.; Giri, R.;
Chen, X. Org. Biomol. Chem. 2006, 4, 4041.
5.5.6. Deuteration of adenosine at C8
To a reaction vessel containing adenosine (100 mg,
0.37 mmol) and Cs2CO3 (306 mg, 0.94 mmol, 2.5 equiv)
ꢀ
ˇ
´ˇ
´
12. Cerna, I.; Pohl, R.; Klepetarova, B.; Hocek, M. Org. Lett. 2006, 8, 5389.
13. During the 15th European Symposium of Organic Chemistry (Dublin, July
2007), we became aware of preliminary direct arylation studies on

T.E. Storr et al. / Tetrahedron 64 (2008) 6125e6137
6137
´
´
´
a protected and unprotected adenosine by the Hocek group in Prague. This
group later reported these studies as a communication (available online
Serrano, J. L.; Garcıa, L.; Perez, J.; Perez, E. Dalton Trans. 2004, 3970;
(c) de Vries, J. G. Dalton Trans. 2006, 421; (d) Fairlamb, I. J. S.; Taylor,
R. J. K.; Serrano, J. L.; Sanchez, G. New J. Chem. 2006, 30, 1695.
31. Wagner, C.; Riggs, W.; Davis, L.; Moulder, J.; Muilenberg, G. Handbook
of X-ray Photoelectron Spectroscopy; PerkineElmer, Physical Electronics
Division: Eden Prairie, MN, 1979.
ꢀ
ˇ
25th October 2007), see: Cerna, I.; Pohl, R.; Hocek, M. Chem. Commun.
2007, 4729.
14. The t1/2 value is expected to fall dramatically in the presence of a base.
15. Schroter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245.
¨
16. Shen, K.; Fu, Y.; Li, J.-N.; Liu, L.; Guo, Q.-X. Tetrahedron 2007, 63, 1568.
17. Ngassa, F. N.; DeKorver, K. A.; Melistas, T. S.; Yeh, E. A.-H.; Lakshman,
M. K. Org. Lett. 2006, 8, 4613.
32. Narayanan, R.; El-Sayed, M. A. J. Am. Chem. Soc. 2003, 125, 8340; For
catalytic applications of PVP-stabilised palladium nanoparticles, see: (a)
´
´
Gniewek, A.; Trzeciak, A. M.; Zio1kowski, J. J.; Ke˛pinski, L.; Wrzyszcz,
´
J.; Tylus, W. J. Catal. 2005, 229, 332; (b) Trzeciak, A. M.; Wojtkow, W.;
18. (a) Bellina, F.; Cauteruccio, S.; Rossi, R. Eur. J. Org. Chem. 2006, 1379;
(b) Bellina, F.; Cauteruccio, S.; Mannina, L.; Rossi, R.; Viel, S. Eur. J.
Org. Chem. 2006, 693; (c) Bellina, F.; Calandri, C.; Cauteruccio, S.;
Rossi, R. Tetrahedron 2007, 63, 1970.
´
Zio1kowski, J. J.; Wrzyszcz, J.; Zawadzki, M. New J. Chem. 2004,
28, 859.
33. A subtle ligand substituent effect on pyridine has also been observed in
Pd(II) catalysed aerobic oxidative annulations of indoles. It is believed
that certain electron-deficient pyridines make the Pd(II) catalyst more
electrophilic and reactive, see: (a) Ferreira, E. M.; Stoltz, B. M. J. Am.
Chem. Soc. 2003, 125, 9578. It is likely that 3-nitropyridine could play
a similar role in the cross-coupling of N-acetylindoles and arenes {as
well as stabilising Pd(0)}, see: (b) Stuart, D. R.; Fagnou, K. Science
2007, 316, 1173.
19. It has been reported that there is a requirement for O2 in the oxidative
dimerisation of purine heterocycles, see Ref. 12.
20. This palladium(0) complex is available through SigmaeAldrich (Cat. No.
656933).
21. (a) Amatore, C.; Jutand, A.; Khalil, F.; M’Barki, M. A.; Mottier, L. Or-
ganometallics 1993, 12, 3168; (b) Amatore, C.; Jutand, A.; Meyer, G. In-
org. Chim. Acta 1998, 273, 76; (c) Fairlamb, I. J. S.; Kapdi, A. R.; Lee,
´
A. F. Org. Lett. 2004, 6, 4435; (d) Mace, Y.; Kapdi, A. R.; Fairlamb,
34. Private communication from Professor Keith Fagnou (University of
Toronto, Canada).
I. J. S.; Jutand, A. Organometallics 2006, 25, 1785; (e) Fairlamb, I. J. S.;
Kapdi, A. R.; Lee, A. F.; McGlacken, G. P.; Weissburger, F.; de Vries,
A. H. M.; Schmieder-van de Vondervoort, L. Chem.dEur. J. 2006,
12, 8750; (f) Fairlamb, I. J. S.; Lee, A. F. Organometallics 2007, 26, 4087;
For interesting effects of dibenzylidene acetone ligands, see: (g) Firmansjah,
L.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 11340; (h) Zhao, Y.; Wang, H.;
Hou, X.; Hu, Y.; Lei, A.; Zhang, H.; Zhu, L. J. Am. Chem. Soc. 2006, 128,
15048.
35. (a) Pneumatikakis, G. Inorg. Chim. Acta 1984, 93, 5; (b) Dehand, J.;
Jordanov, J. J. Chem. Soc., Chem. Commun. 1976, 594; (c) Dehand, J.;
Jordanov, J. J. Chem. Soc., Dalton Trans. 1977, 1588.
36. Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull.
Chem. Soc. Jpn. 1998, 71, 467.
37. Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan, V.
Org. Lett. 2004, 6, 1159.
22. Professor Marta Catellani commented on this phenomenon at the Euro-
pean Symposium of Organic Chemistry (Dublin, July 2007). For related
references, see: Catellani, M.; Motti, E.; Faccini, F.; Ferraccioli, R.
Pure Appl. Chem. 2005, 77, 1243.
38. Amine coordination is possible. For palladium(II) complexes containing
deoxyadenosine the interaction is weak, see: Camboli, D.; Besancon, J.;
Tirouflet, J.; Gautheron, B.; Meunier, P. Inorg. Chim. Acta 1983,
78, L51.
23. 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. Organometallics 1985, 4, 1819.
39. (a) Lewis, J. C.; Wiedermann, S. H.; Bergman, R. G.; Ellman, J. A. Org.
Lett. 2004, 6, 35; (b) Takeuchi, Y.; Yeh, H. J. C.; Kirk, K. L.; Cohen, L. A.
J. Org. Chem. 1978, 43, 3565.
24. Widegren, J. A.; Finke, R. G. J. Mol. Catal. A: Chem. 2003, 198, 317.
25. Representative examples, see: (a) Stein, J.; Lewis, L. N.; Gao, Y.; Scott,
R. A. J. Am. Chem. Soc. 1999, 121, 3693; (b) Jones, R. A.; Real, F. M.;
Wilkinson, G.; Galas, A. M. R.; Hursthouse, M. B. J. Chem. Soc., Dalton
Trans. 1981, 126.
40. For inverse correlations in Sonogashira cross-couplings, see: Ref. 30b; For
inverse correlations in carbonylation, see: Fairlamb, I. J. S.; Grant, S.;
McCormack, P.; Whittall, J. Dalton Trans. 2007, 859.
41. de Vries, A. H. M.; Mulders, J. M. C. A.; Mommers, J. H. M.; Henderickx,
H. J. W.; de Vries, J. G. Org. Lett. 2003, 5, 3285.
26. (a) Lin, Y.; Finke, R. G. Inorg. Chem. 1994, 33, 4891; (b) Widegren, J. A.;
Bennett, M. A.; Finke, R. G. J. Am. Chem. Soc. 2003, 125, 10301.
27. Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc.
2005, 127, 7330.
42. Stanforth, S. P. Tetrahedron 1998, 54, 263 and references cited therein.
43. Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314 and references
cited therein.
44. Wang, X.; Gribkov, D. V.; Sames, D. J. Org. Chem. 2007, 72, 1476.
28. Some caution is necessary when using radical trapping agents. For exam-
ple, galvinoxyl and 2,2-diphenyl-2-picrylhydrazyl hydrate (DPPH) radi-
cals are known to react with palladium(II) hydrido complexes, see:
45. Kohler, K.; Kleist, W.; Prockl, S. S. Inorg. Chem. 2007, 46, 1876; It has
¨ ¨
been shown that a heterogeneous source of palladium (Pd(OH)2/C, Pearl-
man’s catalyst) effectively mediates the direct arylation reactions, the
active catalyst being a homogeneous one, see: Parisien, M.; Valette, D.;
Fagnou, K. J. Org. Chem. 2005, 70, 7578.
´
´
´
Albeniz, A. C.; Espinet, P.; Lopez-Fernandez, R.; Sen, A. J. Am. Chem.
Soc. 2002, 124, 11278; It was noted in this work that [PdPhCl(PPh3)2]
did not react in a similar fashion with galvinoxyl radical under the
same conditions that produced decomposition for [PdHCl(PPh3)2].
29. Lane, B. S.; Sames, D. Org. Lett. 2004, 6, 2897.
46. Ring-opening has been proposed for the Pd-catalyzed direct arylation
of benzoxazoles; the benzoxazole proton is particularly acidic
(pKa<16), thus the conjugate base predominantly exists as 2-isocyano-
´
30. (a) Reetz, M. T.; de Vries, J. G. Chem. Commun. 2004, 1559; (b)
phenolate, see: Sanchez, R. S.; Zhuravlev, F. A. J. Am. Chem. Soc.
´
Fairlamb, I. J. S.; Kapdi, A. R.; Lee, A. F.; Sanchez, G.; Lopez, G.;
´
2007, 129, 5824.