Purinyl N1-directed aromatic C-H oxidation in 6-arylpurines and 6-arylpurine nucleosides

Article abstract of DOI:10.1021/jo4008282

Palladium-catalyzed C-H bond activation and oxidation of C6 arylpurines as well as C6 arylpurine nucleosides can be accomplished using Pd(OAc) ₂/PhI(OAc)₂ in CH₃CN. Despite the presence of four nitrogen atoms in the purine moiety as well as the polyoxygenated saccharide and a labile glycosidic bond in the nucleosides, these reactions can be effectively conducted. Notably, the generally more labile 2′-deoxyribonucleosides also undergo reaction. The reaction conditions can be tuned to yield either monoacetoxylated or diacetoxylated products predominantly. In the course of these investigations, a dimeric Pd ^II-containing cyclopalladated C6 naphthylpurine derivative has been obtained and crystallographically characterized. This compound is competent in catalyzing the oxidization with PhI(OAc)₂, indicating its plausible intermediacy in the chemistry. The X-ray structure of a monoacetoxylated product from this reaction has also been obtained.

Full text of DOI:10.1021/jo4008282

Article
pubs.acs.org/joc
Purinyl N1-Directed Aromatic C−H Oxidation in 6‑Arylpurines and
6‑Arylpurine Nucleosides
Raghu Ram Chamala,† Damon Parrish,‡ Padmanava Pradhan,† and Mahesh K. Lakshman*,†
†Department of Chemistry, The City College and The City University of New York, 160 Convent Avenue, New York, New York
10031, United States
‡Naval Research Laboratory, Code 6030, 4555 Overlook Avenue, Washington, D.C. 20375, United States
S
* Supporting Information
ABSTRACT: Palladium-catalyzed C−H bond activation and
oxidation of C6 arylpurines as well as C6 arylpurine
nucleosides can be accomplished using Pd(OAc)2/PhI(OAc)2
in CH3CN. Despite the presence of four nitrogen atoms in the
purine moiety as well as the polyoxygenated saccharide and a
labile glycosidic bond in the nucleosides, these reactions can be
effectively conducted. Notably, the generally more labile 2′-deoxyribonucleosides also undergo reaction. The reaction conditions
can be tuned to yield either monoacetoxylated or diacetoxylated products predominantly. In the course of these investigations, a
dimeric PdII-containing cyclopalladated C6 naphthylpurine derivative has been obtained and crystallographically characterized.
This compound is competent in catalyzing the oxidization with PhI(OAc)2, indicating its plausible intermediacy in the chemistry.
The X-ray structure of a monoacetoxylated product from this reaction has also been obtained.
substrates in C−H bond activation studies, leading to C-8
arylated products.11−13 Particularly notable is the ability to
conduct this type of chemistry on 2′-deoxyadenosine, which is
quite a sensitive substrate.13
INTRODUCTION
■
Purines and purine nucleosides are highly important bio-
molecules that have found wide applications in biology, in
biochemistry, and as pharmaceutical agents.1 Therefore, the
ability to functionalize and, in particular, conduct otherwise
difficult transformations on these entities has important
consequences. Purines and purine nucleosides are generally
challenging substrates for metal-catalyzed reactions, due to the
presence of the polynitrogenated heterocycles, which can
sequester metals and thereby hinder catalytic pathways. With
nucleosides, this is additionally complicated by the presence of
multiple oxygen atoms as well as a labile glycosidic bond.
Furthermore, purine 2′-deoxyribonucleosides are more labile in
comparison to their ribo analogues.
In contemporary organic synthesis, a simple but powerful
approach to diverse modification of organic molecules involves
transition-metal-mediated C−H bond activation and function-
alization. Although a wide range of such transformations are
catalyzed by Pd, the use of other metals such as Cu, Fe, and Rh
is documented as well.2−4 Of relevance to this communication,
a recent review has focused on Pd-catalyzed C−O bond
formation.5
Despite the potential difficulties posed by purines and purine
nucleosides, these substrates have become increasingly
interesting for C−H bond activation and functionalization.
For example, C8 arylation reactions of xanthines with aryl
halides have been conducted using CuI6 or Pd(acac)2/CuI,7
and C−H/C−H cross-coupling of xanthines has been
accomplished using Pd(OAc)2/Cu(OAc)2.8 N9-alkyl adenine
derivatives have been subjected to C8 arylation reactions with
aryl halides using Pd(OH)2/CuI.9,10 More importantly,
adenosine and 2′-deoxyadenosine have also been used as
There is sparse literature on N-directed C−H bond
activation of purines and purine nucleosides and fewer studies
still on the highly labile 2′-deoxyribonucleosides.14−17 We have
recently reported Ru-catalyzed C−H bond activation and
arylation of 6-arylpurine 2′-deoxyribonucleosides under non-
acidic conditions.15 Acidic reaction media, which can be used in
reactions of purines and ribonucleosides, are precluded due to
the acid sensitivity of the glycosidic bond in the 2′-
deoxyribonucleosides. More recently, C−H bond activation
has been applied to the synthesis of polycycles containing fused
purines and purine ribonucleosides,16 and N-directed sulfona-
midation of two purines as well as two purine ribonucleosides
has been accomplished.17 Herein, we discuss our results on the
purinyl N1-directed Pd-catalyzed C−H bond activation and
monohydroxylation of 6-arylpurines, 6-arylpurine ribonucleo-
sides, and 2′-deoxy derivatives, under broadly applicable
nonacidic conditions. We also demonstrate that these
substrates can be subjected to bis oxidation by slight
modification of the conditions. Importantly, we have isolated
and characterized, for the first time, a palladated dimer from a
C6 arylpurine and investigated its plausible role in the catalytic
process.
Received: April 17, 2013
© XXXX American Chemical Society
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Table 1. Optimization of Reaction Conditions for C−H Bond Activation and Oxidation
a
entry
substrate
conditions
solvent
R
result
b
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
3a
3a
3a
5 mol % Pd(OAc)2 1.2 molar equiv PhI(OAc)2
10 mol % Pd(OAc)2 1.2 molar equiv PhI(OAc)2
5 mol % Pd(OAc)2 1.5 molar equiv PhI(OAc)2
5 mol % Pd(OAc)2 1.5 molar equiv PhI(OAc)2
5 mol % Pd(OAc)2 1.5 molar equiv PhI(OAc)2
5 mol % Pd(OAc)2 1.5 molar equiv PhI(OAc)2
5 mol % Pd(OAc)2 1.2 molar equiv PhI(OAc)2
MeCN
MeCN
MeCN
PhH
H
H
H
H
63% yield
63% yield
78% yield
73% yield
b
b
b
MeOH
AcOH
MeCN
MeCN
Me
H
66% yield of 2aMe (31% recovered 1a)
c
no discernible product
b
H
incomplete
57% yield
b
10 mol % Pd(OAc)2 1.5 molar equiv PhI(OAc)2
H
a
b
c
Where reported, yield is of isolated and purified product. After deacetylation with NaOMe/MeOH. Under conditions reported in ref 18 (5 mol %
of Pd(OAc)2, 1.5 mol equiv of PhI(OAc)2, Ac2O, AcOH, 120 °C, 5 h).
after acetate cleavage. These results indicate that (a) C6
arylpurines and C6 arylpurine nucleosides can be subjected to
C−H bond activation and oxidation, (b) the catalyst loading for
reactions of the nucleosides is likely to be higher than that for
the purine (we have observed differences in the Ru-catalyzed
arylation reactions of C6 phenylpurines and C6 arylpurine
nucleosides15), (c) the lower yield with the 2′-deoxyribonucleo-
side is possibly due to its higher lability, but the reaction is
satisfactory, (d) under the conditions tested no discernible bis
oxidation of the purine or the nucleoside was observed, in
contrast to the prior result,18 and (e) acid additive/solvent is
not necessary, which broadens the scope of the method to acid-
sensitive compounds.
Next, the general utility of these conditions for the C−H
bond activation and oxidation of a range of C6 arylpurines and
purine nucleosides was considered (Scheme 1). The four N9-
benzyl C6-arylpurines 1a−d were tested, and each gave
monohydroxylated products (after deacetylation) uneventfully
and in generally good yields. Interestingly, the C6 naphthyl
derivative 1d underwent regioselective oxidation at C3 and not
at C1, as evidenced by the presence of three well-resolved
singlets in the 1H NMR spectrum (two purinyl and one
naphthyl at δ 10.00, 8.97, and 8.20 ppm).
The four C6 arylpurine 2′-deoxyribonucleosides 3a−d also
underwent acetoxylation readily, yielding the monooxidation
products 4a−d. Oxidation of 3b had to be conducted with 0.85
molar equiv of PhI(OAc)2 because uncharacterized side
products were observed when 1.5 molar equiv was used.
Here 22% of 3b was recovered for a 53% isolated yield of 4b
(not based on recovered 3b). As was the case with 1d, the C6
naphthyl derivative 3d again yielded 4d as the only regioisomer.
Some differences were noted in the reactions of the
ribonucleosides 5a−c. With methoxyl precursor 5b, both
mono- and diacetoxylation was observed (ratio of mono- to
diacetate ∼3.6:1). On the other hand, with fluoro precursor 5c,
although product 6c was isolated in a good yield, the reaction
remained incomplete and some starting material was isolated
along with an uncharacterized impurity. The overoxidation of
5b and the incomplete reaction of 5c could be attributable to
the electron densities of the two systems. Interestingly, in
RESULTS AND DISCUSSION
■
Although C−H bond activation and oxidation of N9-alkyl C6-
arylpurines were reported in a previous communication, only a
single nucleoside was evaluated.18 There, oxidation of 6-phenyl-
9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine gave mono- as
well as diacetoxylated products in a ∼2.1:1 ratio (combined
77% yield).18 This substrate, being a ribonucleoside and bearing
electron-withdrawing acetate protecting groups on the
saccharide, proved to be relatively stable in acetic acid at 120
°C. These conditions, however, are likely to be incompatible
with more sensitive substrates. Thus, we undertook an
evaluation of reaction conditions that would be broadly
applicable to purines, to purine ribonucleosides, and
importantly to the 2′-deoxy derivatives. In fact, the last species
are expected to be limiting cases. Table 1 shows the results
from this screening.
Using 5 mol % of Pd(OAc)2/1.2 molar equiv of PhI(OAc)2
in MeCN, complete consumption of 1a was observed.
However, in addition to the desired monoacetoxy product,
the phenol arising by hydrolysis was also observed. In order to
eliminate the need for separation, product yields were assessed
after deacetylation with NaOMe/MeOH. This first reaction
(entry 1) gave a respectable 63% product yield, and this
remained unaltered upon only increasing the amount of
Pd(OAc)2 to 10 mol % (entry 2). However, the product
yield improved to 78% when the amount of PhI(OAc)2 was
increased to 1.5 molar equiv while retaining 5 mol % Pd(OAc)2
(entry 3). Changing the solvent to PhH did not change the
outcome significantly (entry 4), although the reaction in MeCN
appeared a little cleaner by TLC (UV visualization). Use of
MeOH as solvent led to the clean formation of the
monomethyl ether 2aMe (66% yield), although 1a was not
fully consumed (entry 5).
Not unexpectedly, a reaction of deoxyribonucleoside 3a
conducted in AcOH led to no discernible product formation
(entry 6). However, in MeCN and with 5 mol % of Pd(OAc)2/
1.2 molar equiv of PhI(OAc)2 the reaction proceeded but was
incomplete. When the Pd(OAc)2 loading was increased to 10
mol % with 1.5 mol molar equiv of PhI(OAc)2, complete
consumption of 3a occurred and 4a was obtained in 57% yield
B
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a
Scheme 1. Monooxidation of Purines and Purine Nucleosides
a
In the case of the purine and most of the 2′-deoxyribonucleoside derivatives, because partial hydrolysis of the acetoxy group was observed, products
b
c
were isolated after deacetylation with NaOMe/MeOH. The reaction leading to 4b was conducted with 0.85 molar equiv of PhI(OAc)2. Product
was isolated and characterized as the monoacetate because no significant hydrolysis of the ester was observed at the end of the reaction.
reactions of the ribonucleoside precursors, hydrolysis of the
acetate group was not observed, and the products were isolated
as the esters.
Interestingly, the fluorophenyl substrate 5c gave 39% of the
diacetoxylated product 9c and 32% of monoacetoxylated 6c. As
stated earlier, this result may be attributable to the electron
deficiency of the ring undergoing oxidation. Nevertheless, the
relatively facile bis oxidation of these complex substrates is
feasible under slightly modified conditions.
Having completed these synthetic experiments, attention was
focused on the identification of potential reactive intermedi-
ate(s) in these transformations, so as to gain an understanding
of the plausible mechanism of these oxidations. Heating 9-
benzyl-6-(2-naphthyl)-9H-purine (1d) with stoichiometric
Pd(OAc)2 in PhH at 60 °C (2 h) led to the isolation of the
dimeric cyclopalladated species 10 (Figure 2) in 40% yield after
crystallization.
The unexplored bis oxidation of these substrates was then
evaluated. In order to ensure effective conversions, 3 molar
equiv of PhI(OAc)2 was used for reactions of both the purines
and the nucleosides. The amount of Pd(OAc)2 was increased to
10 mol % for the purine reactions and to 15 mol % for reactions
of the nucleosides. The substrates selected for these reactions
were 1a−c, 3a−c, and 5a−c. The C6 naphthyl substrates 1d
and 3d were not included, since it seemed unlikely that they
would yield the bis oxidation products on the basis of the
results described above: i.e., the regioselective oxidation
observed. The results from these experiments are shown in
Figure 1.
In prior work we had computationally determined the
distances between the ortho C−H bond, which undergoes bond
activation, and the N1 and N7 atoms in 9-benzyl-6-phenyl-9H-
As can be seen from Figure 1, all substrates underwent
reaction and the products could be isolated as the diacetates.
C
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Figure 1. Structures of the bis oxidation products of purines and purine nucleosides.
Figure 2. Crystals and crystal structure of dimeric cyclopalladated compound 10 obtained from 9-benzyl-6-(2-naphthyl)-9H-purine (1d).
1
Figure 3. H NMR spectrum of palladated complex 10 in CD2Cl2.
D
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purine. In this analysis, the N1···H distance was calculated to be
2.41 Å and the N7···H distance as 2.29 Å.15 By comparison, in
2-phenylpyridine the corresponding N...H distance is 2.49 Å.15
Thus, the N1···H distance in the purine derivative is similar to
that in 2-phenylpyridine. However, in 9-benzyl-6-phenyl-9H-
purine the phenyl ring and purine are coplanar,15 consistent
with crystallographic data in the literature.19 On this basis, we
had proposed the involvement of the purinyl N1 atom in the
Ru-catalyzed C−H bond activation and arylation.15
As seen from Figure 2, despite the presence of four purinyl
nitrogen atoms, complex 1020 involves the N1 atom. This is the
first such structure of a dimeric palladated species resulting
from purinyl N-directed C−H bond activation. The crystal
structure of a monomeric IrIII complex derived from N9-THP-
protected 6-phenylpurine, involving N-directed C−H bond
activation, has been recently obtained.21 Interestingly, the
absence of the THP substituent at N9 led to the formation of a
dimeric complex involving this nitrogen atom, and no C−H
bond activation was observed.21 This result also demonstrates
the precarious reactivity balance in the chemistry of these
heterocycles.
In CD2Cl2, the proton NMR spectrum of 10 (Figure 3)
shows the presence of four one-proton singlets at δ 8.58, 8.39,
7.75, and 7.04 ppm, corresponding to two purinyl resonances as
well as two aromatic resonances from the naphthyl moiety, in
addition to the remaining naphthyl resonances and the acetate
resonance. Here again, these data provide evidence for N-
directed palladation at the C3 position of the naphthalene
moiety rather than at the C2 position. More interesting,
however, is the presence of two doublets at δ 4.97 and 4.55
ppm (Jgem = 15.3 Hz) corresponding to the geminal protons of
the benzyl group.
Studies have recently been conducted into the mechanism of
N-directed C−H bond activation and oxidation. Whereas PdII/
PdIV redox cycles have been proposed in C−H bond activation
processes,22−27 dinuclear PdIII species have recently emerged as
plausible intermediates in these catalytic cycles.28−31 Such
dinuclear complexes would also account for the overall second-
order dependence on the Pd concentration, observed in the C−
H bond activation−arylation chemistry.27 Dinuclear complexes
are important to the formation and stabilities of high-valent
Pd−Pd bonds. In fact, modulation of bridging versus chelating
properties of ligands between two Pd centers has been shown
to influence the separation of the metal centers in dinuclear Pd
complexes, a factor that then influences the ease of one-electron
oxidation.32
We also evaluated comparatively the oxidation reactions
catalyzed by Pd(OAc)2 as well as the palladated dimer 10, and
the results of this analysis are shown in Table 2. Dimer 10
Table 2. Comparison of the Oxidation Reactions Catalyzed
a
by Pd(OAc)2 and Complex 10
time
b
entry substrate
catalyst
(h)
product: yield (%)
12: 86
1
2
1d
1d
5 mol % Pd(OAc)2
1
1
c
2.5 mol % 10
12: 91, incomplete
d
reaction
3
4
5
6
1d
1d
1d
3a
5 mol % Pd(OAc)2
5
12: 82
12: 91
12: 93
4aAc: 61
c
2.5 mol % 10
5
c
2.5 mol % 10
24
5
10 mol %
Pd(OAc)2
c
7
8
3a
3a
2.5 mol % 10
5
5
4aAc: 55, incomplete
e
reaction
c
5 mol % of 10
4aAc: 59, incomplete
f
reaction
a
b
1.5 molar equiv of PhI(OAc)2 was used in each reaction. Where
c
reported, the yield is of isolated and purified product. Based upon the
molecular weight of the dimer. About 5% of 1d was recovered,
contaminated with an impurity. About 27% of 3a was recovered,
contaminated with a trace amount of an impurity. A trace of 3a was
d
e
f
recovered, contaminated with an impurity.
produced cleaner reactions (TLC analysis) of 9-benzyl-6-(2-
naphthyl)-9H-purine (1d), with generally slightly better
product yields (entries 1 versus 2, and 3 versus 4). In the
reactions of nucleoside 3a, use of Pd(OAc)2 led to a completed
reaction and gave a 61% yield of monoacetoxy product 4aAc
(entry 6). This is comparable to the result in Scheme 1, where a
57% yield of 4a was obtained over two steps. On the other
hand, use of 2.5 mol % of 10 led to an incomplete reaction,
with a significant amount of residual 3a and 55% yield of 4aAc
(entry 7). Interestingly, increasing the loading of 10 to 5 mol %
produced a marginally better 59% yield of 4aAc and a trace
amount of 3a was left unconverted. As we have observed in Ru-
catalyzed arylation chemistry,15 and as seen in these results,
there are subtle reactivity differences between closely related
purines and the corresponding nucleosides.
Although a prior report speculated on the plausible
intermediacy of palladated purinyl dimers in these oxidations,
we provide direct evidence herein.18 Thus, palladated dimers
such as 10, which can potentially form in the reaction, are
competent in catalyzing the oxidation reaction. The plausible
involvement of 10 in the catalytic cycle is shown in Scheme 2.
The crystal structure of product 1235 obtained from the
reaction of 1d (Scheme 2) confirms the structure and addresses
the regiochemistry question associated with the oxidation of
this substrate.
One notable aspect of these reactions is the role of acetic
acid. Typically C−H bond activation processes are conducted
in acetic acid, and a linear correlation has been observed
between the concentration of acetic acid and the rate of
reductive elimination in C−Cl bond-forming processes.30,34
This has led to the proposal that protonation of one acetate
bridge in the PdIII−PdIII dimer occurs, leading to cleavage of
one Pd−O bond and formation of a binuclear species with one
pentacoordinate Pd. Computations indicate that reductive
elimination from such a species is more favorable than in the
absence of protonation.30 Thus, the role of acetic acid solvent
may be important in these reactions. However, because of
Crystallographic structures of palladium acetate dimers from
2-phenylpyridine, 2-p-tolylpyridine, and benzo[h]quinoline
have been obtained. When the Pd−Pd bond distance in 10 is
compared to those in these simpler analogues, it is similar to
those in palladated pyridyl dimers33 and identical with that
formed from benzo[h]quinoline.30 It is a reasonable antici-
pation then that the mechanism of oxidative addition and
reductive elimination involving 10 could be similar to that of
the less complex heterocycles: that is, a bimetallic process
involving PdIII−PdIII bond formation.29,34
In order to probe this question, oxidation of 9-benzyl-6-(2-
naphthyl)-9H-purine (1d) was performed using 2.5 mol % of
the Pd dimer 10 (based upon the molecular weight of the
dimer) as a precatalyst and 1.5 molar equiv of PhI(OAc)2. This
reaction gave a high 93% yield of product 12 after a reaction
time of 24 h at 100 °C.
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Scheme 2. Plausible Mechanism for the N-Directed Oxidation and Crystallographic Structure of the Acetoxylation Product 12
instability of the nucleoside and/or protecting groups in hot
acetic acid, the reactions herein were conducted in MeCN.
Thus, the reductive elimination step in the present cases either
proceeds via a (slower) acid-independent pathway30 or simply
by the small amounts of acetic acid produced in the
cyclopalladation step. Notably, the 24 h reaction times do
not appear to be detrimental to the nucleosides.
In order to decipher the electron density differences between
the four purinyl nitrogen atoms, natural bond order (NBO)
analysis was performed by the B3LYP density functional
method with the triple-ζ basis set 6-311++G(d,p). These
calculations show that the N1 and N3 atoms in both 9-benzyl-
6-phenyl-9H-purine and 6-phenyl-9-(2′-deoxy-β-D-ribofurano-
syl)-9H-purine carry greater electron densities than the N7 and
N9 atoms (Figure 4). Thus, on the basis of these computations,
CONCLUSIONS
■
In summary, we have demonstrated that purines as well as
purine nucleosides (ribo and 2′-deoxyribo derivatives) undergo
N-directed C−H bond activation and oxidation via the use of
Pd(OAc)2/PhI(OAc)2 in MeCN as solvent. This is despite the
four nitrogen atoms of the purine, which can all coordinate to
the metal, the labile glycosidic bond, and the multiple oxygen
atoms of the saccharide moiety. Use of AcOH as solvent is
precluded because 2′-deoxyribonucleosides are not stable to
acidic conditions at elevated temperature. Thus, any rate-
enhancing effect of acidic solvent or additive is limited to the
AcOH produced upon cyclometalation. Despite this, satisfac-
tory reactions are observed. A dimeric cyclopalladated species
has been obtained from 9-benzyl-6-(2-naphthyl)-9H-purine,
and its structure has been established by crystallographic as well
as NMR analyses. In this species among the four nitrogen
atoms of the purine, the N1 atom is coordinated to the metal
center. This appears to be consistent with prior computational
results, which implicate this nitrogen atom in Ru-catalyzed C−
H bond activation processes as well. The cyclopalladated
species catalyzes the oxidation of 9-benzyl-6-(2-naphthyl)-9H-
purine with PhI(OAc)2. This is the first case wherein a
cyclopalladated PdII dimer resulting from a purine has been
isolated, characterized, and implicated in C−H bond activation
processes. Other studies on metal-mediated C−H bond
activation are currently ongoing in our laboratories and will
be reported in due course.
Figure 4. NBO analyzed natural charges on the nitrogen and two aryl
hydrogen atoms in 9-benzyl-6-phenyl-9H-purine and 6-phenyl-9-(2′-
deoxy-β-D-ribofuranosyl)-9H-purine.
EXPERIMENTAL SECTION
■
General Experimental Considerations. Thin-layer chromatog-
raphy was performed on aluminum-foil-backed TLC plates of 200 μm
thickness, and column chromatographic purifications were performed
on 200−300 mesh silica gel. MeCN was distilled over CaH2, and
commercially available anhydrous MeOH was used. Pd(OAc)2 and all
other reagents were obtained from commercial sources and were used
without further purification. The 6-arylpurine and 6-arylpurine
nucleoside precursors were synthesized by minor modifications of
published procedures.36,37 1H NMR spectra were recorded at 500
greater interactions of the metal with the N1 and N3 atoms can
be postulated in comparison to the N7 and N9 atoms, with the
N1-metal interactions leading to the reaction cascade. However,
all of the nitrogen atoms can in principle interact with the metal
center. Despite this, as demonstrated herein, both mono- and
diacetoxylation reactions can be accomplished, conceivably with
the involvement of the purinyl N1 atom.
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MHz in deacidified CDCl3 (deacidification is done by percolating
through a bed of basic alumina and NaHCO3) and are referenced to
the residual solvent resonance. 13C NMR spectra were recorded at 125
MHz in CDCl3 and are referenced to the solvent resonance. 19F NMR
spectra were recorded at 282 MHz using CDCl3 as the lock solvent
and CFCl3 as the internal standard. Chemical shifts (δ) are reported in
parts per million (ppm), and coupling constants (J) are in hertz (Hz).
Proton assignments indicated were made on the basis of COSY spectra
of representative compounds and comparisons with the literature.
HRMS analyses were performed using a TOF analyzer; the ionization
methods are provided in the compound characterization.
General Procedure for the Mono C−H Bond Oxidation of 6-
Aryl-9-benzyl-9H-purine. In an oven-dried, nitrogen gas flushed vial
equipped with a stirring bar was placed the 6-aryl-9-benzyl-9H-purine
(0.10 mmol) in anhydrous MeCN (1.0 mL). To this solution was
added Pd(OAc)2 (5 mol %) followed by PhI(OAc)2 (1.5 molar equiv).
The reaction mixture was flushed with nitrogen gas, sealed with a
Teflon-lined cap, and heated at 100 °C for 24 h. The crude reaction
mixture was then filtered through a short plug of silica, and the filtrate
was evaporated. The residue was dissolved in anhydrous MeOH (2
mL), NaOMe (2 molar equiv) was added, and the mixture was stirred
for 3 h at room temperature. After the completion of the reaction
(monitored by TLC), the MeOH was evaporated, the residue was
redissolved in CH2Cl2, and this solution was washed with 5% aqueous
HCl (1 mL). The organic layer was washed with saturated aqueous
NaHCO3 and dried over Na2SO4, and the solvent was evaporated
under reduced pressure. The crude material was purified by column
chromatography.
solvent was evaporated under reduced pressure and the crude material
was purified by column chromatography.
2-(9-Benzyl-9H-purin-6-yl)phenol (2a).
Chromatography using CH2Cl2 followed by 0.5% acetone in CH2Cl2
gave 23.7 mg (78% yield) of a light yellow solid. Rf (SiO2/10% acetone
in CH2Cl2) = 0.60. 1H NMR (500 MHz, CDCl3): δ 9.37 (d, 1H, Ar-H,
J = 7.8 Hz), 8.95 (s, 1H, Ar-H), 8.18 (s, 1H, Ar-H), 7.44−7.33 (m, 6H,
Ar-H), 7.09 (d, 1H, Ar-H, J = 8.3 Hz), 7.04 (t, 1H, Ar-H, J = 7.8 Hz),
5.51 (s, 2H, CH2). 13C NMR (125 MHz, CDCl3): δ 161.6, 155.8,
151.9, 149.8, 143.9, 134.9, 133.5, 132.4, 129.2, 128.7, 127.8, 119.2,
118.2, 117.3, 47.3. HRMS (ESI): calcd for C18H15N4O [M + H]+
303.1240, found 303.1243.
9-Benzyl-6-(2-methoxyphenyl)-9H-purine (2aMe).
General Procedure for the Bis C−H Bond Oxidation of 6-
Aryl-9-benzyl-9H-purine. In an oven-dried, nitrogen gas flushed vial
equipped with a stirring bar was placed the 6-aryl-9-benzyl-9H-purine
(0.10 mmol) in anhydrous MeCN (1.0 mL). To this solution was
added Pd(OAc)2 (10 mol %) followed by PhI(OAc)2 (3 molar equiv).
The reaction mixture was flushed with nitrogen gas, sealed with a
Teflon-lined cap, and heated at 100 °C for 24 h. After the completion
of the reaction (monitored by TLC), the solvent was evaporated under
reduced pressure and the crude material was purified by column
chromatography.
General Procedure for the Mono C−H Bond Oxidation of 6-
Arylpurine 2′-Deoxyribonucleosides. In an oven-dried, nitrogen
gas flushed vial equipped with a stirring bar was placed the 6-
arylpurine 2′-deoxyribonucleoside (0.10 mmol) in anhydrous MeCN
(0.5 mL). To this solution was added Pd(OAc)2 (10 mol %) followed
by of PhI(OAc)2 (1.5 molar equiv). The reaction mixture was flushed
with nitrogen gas, sealed with a Teflon-lined cap, and heated at 100 °C
for 24 h. The crude reaction mixture was filtered through a short plug
of silica gel, and the filtrate was evaporated. The residue was dissolved
in anhydrous MeOH (2 mL), NaOMe (2 molar equiv) was added, and
the mixture was stirred for 3 h at room temperature. After the
completion of the reaction (monitored by TLC), the MeOH was
evaporated, the residue was redissolved in CH2Cl2, and this solution
was washed with 5% aqueous HCl (1 mL). The organic layer was
washed with saturated aqueous NaHCO3 and dried over Na2SO4, and
the solvent was evaporated under reduced pressure. The crude
material was purified by column chromatography.
In an oven-dried, nitrogen gas flushed vial equipped with stirring bar
was placed 9-benzyl-6-phenyl-9H-purine (28.6 mg, 0.10 mmol) in
anhydrous MeOH (1.0 mL). To this solution was added Pd(OAc)2
(1.12 mg, 5 μmol, 5 mol %) followed by PhI(OAc)2 (48.3 mg, 0.15
mmol, 1.5 molar equiv). The reaction mixture was flushed with
nitrogen gas, sealed with a Teflon-lined cap, and heated at 100 °C for
24 h. After 24 the solvent was evaporated under reduced pressure and
the crude material was purified by chromatography on a silica gel
column using 5% acetone in CH2Cl2 to afford 21.0 mg (66% yield) of
1
a light brown solid. Rf (SiO2/10% acetone in CH2Cl2) = 0.14. H
NMR (500 MHz, CDCl3): δ 9.12 (s, 1H, Ar-H), 8.05 (s, 1H, Ar-H),
7.69 (d, 1H, Ar-H, J = 6.8 Hz), 7.45 (t, 1H, Ar-H, J = 7.8), 7.39−7.33
(m, 5H, Ar-H), 7.13−7.08 (m, 2H, Ar-H), 5.48 (s, 2H, CH2), 3.85, (s,
3H, OMe). 13C NMR (125 MHz, CDCl3): δ 157.8, 156.5, 152.5,
152.0, 144.5, 135.3, 132.5, 132.0, 131.8, 129.4, 128.8, 128.4, 128.2,
124.6, 120.9, 112.2, 56.2, 47.6. HRMS (ESI): calcd for C19H17N4O [M
+ H]+ 317.1397, found 317.1396.
2-(9-Benzyl-9H-purin-6-yl)-5-methylphenol (2b).
Note: 0.85 molar equiv of PhI(OAc)2 was used for the oxidation
substrate 3b.
Note: in the mono C−H bond oxidation reactions of 6-arylpurine
ribonucleosides, the procedure is exactly the same as for the 2′-
deoxyribo analogues, except that deacetylation using NaOMe was not
necessary and the products were isolated as the monoacetates.
General Procedure for the Bis C−H Bond Oxidation of 6-
Arylpurine 2′-Deoxyribonucleosides and 6-Arylpurine Ribo-
nucleosides. In an oven-dried, nitrogen gas flushed vial equipped
with a stirring bar was placed the 6-arylpurine 2′-deoxyribonucleoside
or 6-arylpurine ribonucleoside (0.10 mmol) in anhydrous MeCN (1.0
mL). To this solution was added Pd(OAc)2 (15 mol %) followed by
PhI(OAc)2 (3 molar equiv). The reaction mixture was flushed with
nitrogen gas, sealed with a Teflon-lined cap, and heated at 100 °C for
24 h. After the completion of the reaction (monitored by TLC), the
Chromatography using CH2Cl2 followed by 1% acetone in CH2Cl2
gave 22.4 mg (71% yield) of a yellow solid. Rf (SiO2/10% acetone in
CH2Cl2) = 0.55. 1H NMR (500 MHz, CDCl3): δ 9.24 (d, 1H, Ar-H, J
= 7.8 Hz), 8.88 (s, 1H, Ar-H), 8.11 (s, 1H, Ar-H), 7.38−7.31 (m, 5H,
Ar-H), 6.89 (s, 1H, Ar-H), 6.85 (d, 1H, Ar-H, J = 8.3 Hz), 5.48 (s, 2H,
CH2), 2.38 (s, 3H, CH3). 13C NMR (125 MHz, CDCl3): δ 161.8,
156.0, 151.9, 149.9, 144.9, 143.9, 135.2, 132.4, 129.4, 129.1, 128.9,
128.1, 120.7, 118.7, 114.8, 47.5, 22.0. HRMS (ESI): calcd for
C19H17N4O [M + H]+ 317.1397, found 317.1420.
G
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2-(9-Benzyl-9H-purin-6-yl)-5-methoxyphenol (2c).
6-[2-Acetoxy-4-methylphenyl]-9-[2-deoxy-3,5-di-O-(tert-bu-
tyldimethylsilyl)-β-D-ribofuranosyl]-9H-purine (4b).
Chromatography using CH2Cl2 followed by 2% acetone in CH2Cl2
gave 23.0 mg (69% yield) of an off-white solid. Rf (SiO2/10% acetone
in CH2Cl2) = 0.54. 1H NMR (500 MHz, CDCl3): δ 9.30 (d, 1H, Ar-H,
J = 8.8 Hz), 8.80 (s, 1H, Ar-H), 8.25 (s, 1H, Ar-H), 7.38−7.30 (m, 5H,
Ar-H), 6.58 (dd, 1H, Ar-H, J = 2.4 Hz, 8.8 Hz), 6.54 (d, 1H, Ar-H, J =
2.9 Hz), 5.44 (s, 2H, CH2), 3.84 (s, 3H, OCH3). 13C NMR (125 MHz,
CDCl3): δ 164.3, 164.2, 155.7, 151.6, 149.8, 143.6, 135.2, 133.9, 129.4,
128.8, 128.6, 128.0, 110.7, 107.8, 101.7, 55.3, 47.3. HRMS (ESI): calcd
for C19H17N4O2 [M + H]+ 333.1346, found 333.1349.
Chromatography using CH2Cl2, followed by 1% and then 2% acetone
in CH2Cl2 gave 32.4 mg (53% yield) of a yellow gum. Rf (SiO2/5%
1
acetone in CH2Cl2) = 0.39. H NMR (500 MHz, CDCl3): δ 8.97 (s,
1H, Ar-H), 8.37 (s, 1H, Ar-H), 8.12 (d, 1H, Ar-H, J = 7.8 Hz), 7.23 (d,
1H, Ar-H, J = 7.8 Hz), 7.08 (s, 1H, Ar-H), 6.55 (t, 1H, H-1′, J = 6.6
Hz), 4.66−4.64 (m, 1H, H-3′), 4.05 (app q, 1H, H-4′, Japp = 3.4 Hz),
3.88 (dd, 1H, H-5′, J = 4.1, 11.2 Hz), 3.79 (dd, 1H, H-5′, J = 2.9, 11.2
Hz), 2.71 (app quint, 1H, H-2′, Japp = 6.5 Hz), 2.49−2.44 (ddd + s,
4H, H-2′, CH3, J = 3.6, 5.9, 12.7 Hz), 2.18 (s, 3H, OAc), 0.93 and 0.90
(2 s, 18H, t-Bu), 0.12, 0.08, and 0.07 (3 s, 12H, SiCH3). 13C NMR
(125 MHz, CDCl3): δ 169.9, 154.8, 152.1, 151.7, 148.9, 143.1, 142.3,
132.6, 132.5, 127.2, 125.3, 124.6, 88.2, 84.7, 72.3, 63.0, 41.3, 29.9, 26.2,
25.9, 21.6, 21.5, 18.6, 18.2, −4.4, −4.6, −5.1, −5.2. HRMS (ESI): calcd
for C31H49N4O5Si2 [M + H]+ 613.3236, found 613.3210.
3-(9-Benzyl-9H-purin-6-yl)naphthalen-2-ol (2d).
6-[2-Hydroxy-4-methoxyphenyl]-9-[2-deoxy-3,5-di-O-(tert-
butyldimethylsilyl)-β-D-ribofuranosyl]-9H-purine (4c).
Chromatography using CH2Cl2 followed by 0.5% acetone in CH2Cl2
gave 28.5 mg (81% yield) of a yellow solid. Rf (SiO2/10% acetone in
CH2Cl2) = 0.62. 1H NMR (500 MHz, CDCl3): δ 10.00 (s, 1H, Ar-H),
8.97 (s, 1H, Ar-H), 8.20 (s, 1H, Ar-H), 7.95 (d, 1H, Ar-H, J = 8.3 Hz),
7.68 (d, 1H, Ar-H, J = 8.3 Hz), 7.47 (t, 1H, Ar-H, J = 7.3 Hz) 7.41−
7.33 (m, 6H, Ar-H), 7.30 (t, 1H, Ar-H, J = 7.6 Hz), 5.49 (s, 2H, CH2).
13C NMR (125 MHz, CDCl3): δ 157.6, 155.7, 152.3, 150.0, 144.6,
136.8, 135.1, 130.1, 129.7, 129.5, 128.9, 128.6, 128.1, 127.9, 126.2,
123.5, 119.6, 112.1, 47.6. HRMS (ESI): calcd for C22H17N4O [M +
H]+ 353.1397, found 353.1395.
6-[2-Hydroxyphenyl]-9-[2-deoxy-3,5-di-O-(tert-butyldime-
thylsilyl)-β-D-ribofuranosyl]-9H-purine (4a).
Chromatography using 80% CH2Cl2 in hexanes gave 39.7 mg (68%
yield) of a light yellow oil. Rf (SiO2/5% EtOAc in CH2Cl2) = 0.60. 1H
NMR (500 MHz, CDCl3): δ 9.33 (d, 1H, Ar-H, J = 8.8 Hz), 8.79 (s,
1H, Ar-H), 8.42 (s, 1H, Ar-H), 6.62 (dd, 1H, Ar-H, J = 2.4, 8.8 Hz),
6.57−6.55 (m, 2H, Ar-H, H-1′), 4.66−4.63 (m, 1H, H-3′), 4.06 (app
q, 1H, H-4′, Japp = 3.4 Hz), 3.90−3.87 (m + s, 4H, H-5′, OMe), 3.79
(dd, 1H, H-5′, J = 3.4, 11.2 Hz), 2.66 (app quint, 1H, H-2′, Japp = 6.5
Hz), 2.49 (ddd, 1H, H-2′, J = 3.9, 5.9, 13.2 Hz), 0.93 and 0.91 (2 s,
18H, t-Bu), 0.12 and 0.10 (2 s, 12H, SiCH3). 13C NMR (125 MHz,
CDCl3): δ 164.1, 155.5, 150.9, 149.3, 142.0, 133.8, 129.1, 110.6, 107.5,
101.6, 88.1, 84.4, 71.9, 62.7, 55.3, 41.4, 25.9, 25.7, 18.4, 18.0, −4.7,
−4.8, −5.4, −5.5. HRMS (ESI): calcd for C29H47N4O5Si2 [M + H]+
587.3080, found 587.3079.
6-[3-Hydroxy-2-naphthenyl]-9-[2-deoxy-3,5-di-O-(tert-butyl-
dimethylsilyl)-β-D-ribofuranosyl]-9H-purine (4d).
Chromatography using 50% CH2Cl2 in hexanes followed by 80%
CH2Cl2 in hexanes gave 31.6 mg (57% yield) of a yellowish green oil.
Rf (SiO2/5% EtOAc in CH2Cl2) = 0.60. 1H NMR (500 MHz, CDCl3):
δ 9.41 (dd, 1H, Ar-H, J = 1.71, 8.0 Hz), 8.88 (s, 1H, Ar-H), 8.50 (s,
1H, Ar-H), 7.42 (ddd, 2H, Ar-H, J = 1.5, 6.8, 8.5 Hz), 7.07−7.03 (m,
2H, Ar-H), 6.58 (app t, 1H, H-1′, Japp = 6.3 Hz), 4.67−4.64 (m, 1H,
H-3′), 4.07 (app q, 1H, H-4′, Japp = 3.4 Hz), 3.89 (dd, 1H, H-5′, J =
4.4, 11.2 Hz), 3.80 (dd, 1H, H-5′, J = 2.9, 11.2 Hz), 2.67 (app quint,
1H, H-2′, Japp = 6.5 Hz), 2.52 (ddd, 1H, H-2′, J = 3.9, 5.9, 13.2 Hz),
0.93 and 0.92 (2 s, 18H, t-Bu), 0.12 and 0.10 (2 s, 12H, SiCH3). 13C
NMR (125 MHz, CDCl3): δ 161.5, 155.7, 151.3, 149.4, 142.6, 133.5,
132.5, 129.9, 119.2, 118.2, 117.3, 88.1, 84.5, 71.9, 62.7, 41.4, 25.9, 25.7,
18.4, 18.0, −4.7, −4.8, −5.4, −5.5. HRMS (ESI): calcd for
C28H45N4O4Si2 [M + H]+ 557.2974, found 557.2976.
Chromatography using 50% CH2Cl2 in hexanes, followed by 80%
CH2Cl2 in hexanes and finally CH2Cl2, gave 36.7 mg (60% yield) of a
golden yellow solid. Rf (SiO2/5% acetone in CH2Cl2) = 0.52. 1H NMR
(500 MHz, CDCl3): δ 10.06 (s, 1H, Ar-H), 8.93 (s, 1H, Ar-H), 8.57
(s, 1H, Ar-H), 7.98 (d, 1H, Ar-H, J = 8.2 Hz), 7.69 (d, 1H, Ar-H, J =
H
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8.2 Hz), 7.47 (t, 1H, Ar-H, J = 7.8 Hz), 7.37 (s, 1H, Ar-H), 7.31 (t,
1H, Ar-H, J = 7.8 Hz), 6.60 (t, 1H, H-1′, J = 6.3 Hz), 4.69−4.66 (m,
1H, H-3′), 4.08 (app q, 1H, H-4′, Japp = 3.4 Hz), 3.91 (dd, 1H, H-5′, J
= 4.4, 11.2 Hz), 3.82 (dd, 1H, H-5′, J = 3.4, 11.2 Hz), 2.69 (app quint,
1H, H-2′, Japp = 6.3 Hz), 2.54 (ddd, 1H, H-2′, J = 3.9, 6.3, 13.2 Hz),
0.94 and 0.93 (2 s, 18H, t-Bu), 0.13 and 0.12 (2 s, 12H, SiCH3). 13C
NMR (125 MHz, CDCl3): δ 157.1, 155.1, 151.5, 149.3, 143.3, 136.7,
135.1, 130.4, 129.6, 128.5, 127.8, 126.0, 123.1, 119.2, 112.0, 88.3, 84.7,
71.8, 62.7, 41.5, 25.9, 25.7, 18.4, 18.0, −4.6, −4.8, −5.4, −5.5. HRMS
(ESI): calcd for C32H47N4O4Si2 [M + H]+ 607.3130, found 607.3132.
6-[2-Acetoxyphenyl]-9-[2,3,5-tri-O-(tert-butyldimethylsilyl)-
β-D-ribofuranosyl]-9H-purine (6a).
6-[2-Acetoxy-4-fluorophenyl]-9-[2,3,5-tri-O-(tert-butyldime-
thylsilyl)-β-D-ribofuranosyl]-9H-purine (6c).
Chromatography using 7% EtOAc in hexanes gave 42.3 mg (57%
yield) of a light brown gum. Rf (SiO2/20% EtOAc in hexanes) = 0.49.
1H NMR (500 MHz, CDCl3): δ 8.98 (s, 1H, Ar-H), 8.45 (s, 1H, Ar-
H), 8.22 (dd, 1H, Ar-H, J = 6.3, 8.8 Hz), 7.15 (td, 1H, Ar-H, J = 2.4,
8.3 Hz), 7.05 (dd, 1H, Ar-H, J = 2.4, 9.3 Hz), 6.16 (d, 1H, H-1′, J = 4.9
Hz), 4.69 (t, 1H, H-2′, J = 4.9 Hz), 4.34 (t, 1H, H-3′, J = 3.9 Hz), 4.16
(app q, 1H, H-4′, Japp = 3.2 Hz), 4.04 (dd, 1H, H-5′, J = 3.9, 11.2 Hz),
3.82 (dd, 1H, H-5′, J = 2.4, 11.2 Hz), 2.12 (s, 3H, OAc), 0.96, 0.94,
and 0.79 (3 s, 27H, t-Bu), 0.15, 0.14, 0.11, −0.03, and −0.24 (5 s, 18H,
SiCH3). 13C NMR (125 MHz, CDCl3): δ 169.2, 165.0, 163.0, 153.7,
152.2 (d, J = 5.9 Hz), 152.0, 150.3 (d, J = 11 Hz), 143.9, 134.1 (d, J =
9.6 Hz), 132.5, 124.5, 113.6 (d, J = 21.5 Hz), 112.0 (d, J = 24.3 Hz),
88.5, 85.9, 76.1, 72.2, 62.7, 26.3, 26.0, 25.8, 21.5, 18.7, 18.3, 18.0, −4.2,
−4.4, −4.5, −4.8, −5.1. 19F NMR (282 MHz, CDCl3): δ = −108.38
(br). HRMS (ESI): calcd for C36H60FN4O6Si3 [M + H]+ 747.3799,
found 747.3825.
Chromatography using 9% EtOAc in hexanes gave 47.5 mg (65%
yield) of a light brown solid. Rf (SiO2/40% EtOAc in hexanes) = 0.63.
1H NMR (500 MHz, CDCl3): δ 9.01 (s, 1H, Ar-H), 8.45 (s, 1H, Ar-
H), 8.15 (d, 1H, Ar-H, J = 7.8 Hz), 7.54 (t, 1H, Ar-H, J = 7.8 Hz), 7.43
(t, 1H, Ar-H, J = 7.6 Hz), 7.29 (d, 2H, Ar-H, J = 7.8 Hz), 6.16 (d, 1H,
H-1′, J = 5.4 Hz), 4.72 (t, 1H, H-2′, J = 4.6 Hz), 4.35 (t, 1H, H-3′, J =
3.9 Hz), 4.17 (app q, 1H, H-4′, Japp = 3.2 Hz), 4.04 (dd, 1H, H-5′, J =
3.5, 11.4 Hz), 3.82 (dd, 1H, H-5′, J = 2.7, 11.5 Hz), 2.16 (s, 3H, OAc),
0.96, 0.95, and 0.79 (3 s, 27H, t-Bu), 0.14, 0.13, 0.12, −0.03, and −0.24
(5 s, 18H, SiCH3). 13C NMR (125 MHz, CDCl3): δ 169.6, 154.5,
152.1, 152.0, 149.0, 143.8, 132.6, 131.5, 128.1, 126.2, 124.1, 88.5, 85.8,
76.0, 72.2, 62.7, 26.3, 26.0, 25.8, 21.5, 21.5, 18.7, 18.3, 18.0, −4.2, −4.4,
−4.5, −4.8, −5.2. HRMS (ESI): calcd for C36H61N4O6Si3 [M + H]+
729.3893, found 729.3880.
2-(9-Benzyl-9H-purin-6-yl)-1,3-phenylene Diacetate (7a).
Chromatography using CH2Cl2 followed by 4% acetone in CH2Cl2
6-[2-Acetoxy-4-methoxyphenyl]-9-[2,3,5-tri-O-(tert-butyldi-
methylsilyl)-β-D-ribofuranosyl]-9H-purine (6b).
gave 26.1 mg (65% yield) of a light brown solid. Rf (SiO2/5% acetone
1
in CH2Cl2) = 0.43. H NMR (500 MHz, CDCl3): δ 9.07 (s, 1H, Ar-
H), 8.06 (s, 1H, Ar-H), 7.54 (t, 1H, Ar-H, J = 8.3 Hz), 7.39−7.32 (m,
5H, Ar-H), 7.22 (d, 1H, Ar-H, J = 8.3 Hz), 5.48 (s, 2H, CH2), 1.96 (s,
6H, OAc). 13C NMR (125 MHz, CDCl3): δ 168.5, 152.2, 151.8, 151.5,
149.4, 144.8, 135.0, 132.8, 130.5, 129.2, 128.7, 127.8, 121.6, 120.9,
47.4, 20.9. HRMS (ESI): calcd for C22H19N4O4 [M + H]+ 403.1401,
found 403.1401.
2-(9-Benzyl-9H-purin-6-yl)-5-methyl-1,3-phenylene Diace-
tate (7b).
Chromatography using 10% EtOAc in hexanes gave 43.5 mg (57%
yield) as a light yellow gum. Rf (SiO2/20% EtOAc in hexanes) = 0.30.
1H NMR (500 MHz, CDCl3): δ 8.95 (s, 1H, Ar-H), 8.42 (s, 1H, Ar-
H), 8.28 (d, 1H, Ar-H, J = 8.8 Hz), 6.97 (dd, 1H, Ar-H, J = 2.2, 8.5
Hz), 6.80 (d, 1H, Ar-H, J = 2.4 Hz), 6.14 (d, 1H, H-1′, J = 5.4 Hz),
4.71 (t, 1H, H-2′, J = 4.6 Hz), 4.35 (t, 1H, H-3′, J = 3.7 Hz), 4.16 (app
q, 1H, H-4′, Japp = 3.2 Hz), 4.04 (dd, 1H, H-5′, J = 4.1, 11.5 Hz), 3.87
(s, 3H, OMe), 3.81 (dd, 1H, H-5′, J = 2.7, 11.5 Hz), 2.21 (s, 3H,
OAc), 0.95, 0.94, and 0.79 (3 s, 27H, t-Bu), 0.14, 0.13, 0.11, −0.03,
and −0.23 (5 s, 18H, SiCH3). 13C NMR (125 MHz, CDCl3): δ 169.7,
162.3, 154.3, 152.0, 150.5, 143.5, 133.9, 132.2, 120.5, 112.4, 109.8,
88.5, 85.9, 76.0, 72.2, 62.7, 55.8, 26.3, 26.1, 25.8, 21.5, 18.7, 18.3, 18.1,
−4.2, −4.4, −4.5, −4.8, −5.1. HRMS (ESI): calcd for C37H63N4O7Si3
[M + H]+ 759.3999, found 759.4014.
Chromatography using CH2Cl2 followed by 5% acetone in CH2Cl2
gave 28.5 mg (68% yield) of a light brown solid. Rf (SiO2/5% acetone
1
in CH2Cl2) = 0.33. H NMR (500 MHz, CDCl3): δ 9.05 (s, 1H, Ar-
H), 8.04 (s, 1H, Ar-H), 7.39−7.29 (m, 5H, Ar-H), 7.03 (s, 2H, Ar-H),
5.46 (s, 2H, CH2), 2.44 (s, 3H, CH3), 1.95 (s, 6H, OAc). 13C NMR
(125 MHz, CDCl3): δ 168.9, 152.4, 152.0, 151.9, 149.3, 144.7, 141.7,
135.3, 133.0, 129.4, 128.9, 128.0, 121.8, 119.0, 47.5, 21.7, 21.2. HRMS
(ESI): calcd for C23H21N4O4 [M + H]+ 417.1557, found 417.1539.
I
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2-(9-Benzyl-9H-purin-6-yl)-5-methoxy-1,3-phenylene Diace-
tate (7c).
6-[2,6-Diacetoxy-4-methoxyphenyl]-9-[2-deoxy-3,5-di-O-
(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-9H-purine (8c).
Chromatography using CH2Cl2 followed by 6% acetone in CH2Cl2
gave 23.4 mg (54% yield) of a fluffy, light brown solid. Rf (SiO2/10%
acetone in CH2Cl2) = 0.32. H NMR (500 MHz, CDCl3): δ 9.04 (s,
1
Chromatography using CH2Cl2 followed by 3% acetone in CH2Cl2
gave 42.0 mg (61% yield) of a pale yellow gum. Rf (SiO2/5% acetone
in CH2Cl2/) = 0.41. 1H NMR (500 MHz, CDCl3): δ 8.98 (s, 1H, Ar-
H), 8.35 (s, 1H, Ar-H), 6.77 (s, 2H, Ar-H), 6.55 (app t, 1H, H-1′, Japp
= 6.6 Hz), 4.64 (m, 1H, H-3′), 4.04 (app q, 1H, H-4′, Japp = 3.4 Hz),
3.89−3.84 (m + s, 4H, H-5′, OMe), 3.79 (dd, 1H, H-5′, J = 3.4, 11.2
Hz), 2.70 (app quint, 1H, H-2′, Japp = 6.5 Hz), 2.46 (ddd, 1H, H-2′, J =
3.7, 5.9, 13.2 Hz), 1.96 (s, 6H, OAc), 0.90 and 0.89 (2 s, 18H, t-Bu),
0.09, 0.06, and 0.05 (3 s, 12H, SiCH3). 13C NMR (125 MHz, CDCl3):
δ 168.6, 161.4, 152.0, 151.8, 151.4, 150.5, 143.2, 133.7, 114.5, 107.5,
88.2, 84.6, 72.3, 63.1, 55.9, 41.3, 26.1, 25.9, 21.2, 18.6, 18.2, −4.5, −4.6,
−5.3, −5.3. HRMS (ESI): calcd for C33H51N4O8Si2 [M + H]+
687.3240, found 687.3243.
1H, Ar-H), 8.02 (s, 1H, Ar-H), 7.39−7.31 (m, 5H, Ar-H), 6.77 (s, 2H,
Ar-H), 5.47 (s, 2H, CH2), 3.86 (s, 3H, OCH3), 1.96 (s, 6H, OAc). 13
C
NMR (125 MHz, CDCl3): δ 168.5, 161.3, 152.0, 151.5, 150.2, 144.5,
129.2, 128.7, 127.8, 107.2, 55.8, 47.4, 21.1. HRMS (ESI): calcd for
C23H21N4O5 [M + H]+ 433.1506, found 433.1509.
6-[2,6-Diacetoxyphenyl]-9-[2-deoxy-3,5-di-O-(tert-butyldi-
methylsilyl)-β-D-ribofuranosyl]-9H-purine (8a).
6-[2,6-Diacetoxyphenyl]-9-[2,3,5-tri-O-(tert-butyldimethyl-
silyl)-β-D-ribofuranosyl]-9H-purine (9a).
Chromatography using CH2Cl2 followed by 1%, 2%, and 3% acetone
in CH2Cl2 gave 36.1 mg (55% yield) of a pale yellow solid. Rf (SiO2/
1
5% acetone in CH2Cl2) = 0.36. H NMR (500 MHz, CDCl3): δ 9.02
(s, 1H, Ar-H), 8.38 (s, 1H, Ar-H), 7.53 (t, 1H, Ar-H, J = 8.3 Hz), 7.22
(d, 2H, Ar-H, J = 8.3 Hz), 6.56 (t, 1H, H-1′, J = 6.6 Hz), 4.66−4.64
(m, 1H, H-3′), 4.05 (app q, 1H, H-4′, Japp = 3.4 Hz), 3.87 (dd, 1H, H-
5′, J = 4.4, 11.2 Hz), 3.79 (dd, 1H, H-5′, J = 3.4, 11.2 Hz), 2.70 (app
quint, 1H, H-2′, Japp = 6.6 Hz), 2.47 (ddd, 1H, H-2′, J = 3.4, 5.8, 12.7
Hz), 1.97 (s, 6H, OAc), 0.93 and 0.90 (2 s, 18H, t-Bu), 0.12, 0.08, and
0.07 (3 s, 12H, SiCH3). 13C NMR (125 MHz, CDCl3): δ 168.5, 151.7,
151.3, 149.4, 143.6, 133.5, 130.6, 121.3, 120.9, 88.1, 84.4, 72.0, 62.8,
41.2, 25.9, 25.8, 21.0, 18.4, 18.0, −4.7, −4.8, −5.4, −5.5. HRMS (ESI):
calcd for C32H49N4O7Si2 [M + H]+ 657.3134, found 657.3137.
6-[2,6-Diacetoxy-4-methylphenyl]-9-[2-deoxy-3,5-di-O-(tert-
butyldimethylsilyl)-β-D-ribofuranosyl]-9H-purine (8b).
Chromatography using 70% EtOAc in hexanes gave 52.8 mg (67%
yield) of a light brown solid. Rf (SiO2/EtOAc) = 0.24. H NMR (500
1
MHz, CDCl3): δ 9.02 (s, 1H, Ar-H), 8.43 (s, 1H, Ar-H), 7.53 (t, 1H,
Ar-H, J = 8.3 Hz), 7.22 (d, 2H, Ar-H, J = 8.3 Hz), 6.16 (d, 1H, H-1′, J
= 5.9 Hz), 4.72 (t, 1H, H-2′, J = 5.1 Hz), 4.33 (t, 1H, H-3′, J = 3.7
Hz), 4.16 (app q, 1H, H-4′, Japp = 3.1 Hz), 4.03 (dd, 1H, H-5′, J = 4.4,
11.2 Hz), 3.82 (dd, 1H, H-5′, J = 2.7, 11.2 Hz), 2.97 (s, 6H, OAc),
0.96, 0.95, and 0.78 (3 s, 27H, t-Bu), 0.14, 0.13, 0.11, −0.04, and −0.29
(5 s, 18H, SiCH3). 13C NMR (125 MHz, CDCl3): δ 168.7, 152.0,
151.8, 151.6, 149.6, 144.1, 133.8, 130.7, 121.7, 121.0, 88.4, 86.1, 75.9,
72.4, 62.8, 26.3, 26.0, 25.8, 21.2, 18.7, 18.3, 18.0, −4.2, −4.3, −4.4,
−4.9, −5.2. HRMS (ESI): calcd for C38H63N4O8Si3 [M + H]+
787.3948, found 787.3944.
6-[2,6-Diacetoxy-4-methoxyphenyl]-9-[2,3,5-tri-O-(tert-bu-
tyldimethylsilyl)-β-D-ribofuranosyl]-9H-purine (9b).
Chromatography using CH2Cl2 followed by 3% acetone in CH2Cl2
gave 40.9 mg (61% yield) of a light yellow solid. Rf (SiO2/5% acetone
1
in CH2Cl2) = 0.45. H NMR (500 MHz, CDCl3): δ 9.00 (s, 1H, Ar-
H), 8.36 (s, 1H, Ar-H), 7.03 (s, 2H, Ar-H), 6.59 (app t, 1H, H-1′, Japp
= 6.6 Hz), 4.64 (m, 1H, H-3′), 4.05 (app q, 1H, H-4′, Japp = 3.4 Hz),
3.87 (dd, 1H, H-5′, J = 4.4, 11.2 Hz), 3.79 (dd, 1H, H-5′, J = 3.4, 11.2
Hz), 2.70 (app quint, 1H, H-2′, Japp = 6.6 Hz), 2.49−2.44 (m + s, 4H,
H-2′, CH3), 1.97 (s, 6H, OAc), 0.93 and 0.91 (2 s, 18H, t-Bu), 0.12,
0.08, and 0.07 (3 s, 12H, SiCH3). 13C NMR (125 MHz, CDCl3): δ
168.8, 151.9, 151.4, 149.3, 143.5, 141.8, 133.7, 121.7, 88.3, 84.6, 72.3,
63.1, 41.4, 26.2, 25.9, 21.7, 21.3, 18.6, 18.2, −4.4, −4.6, −5.1, −5.2.
HRMS (ESI): calcd for C33H51N4O7Si2 [M + H]+ 671.3291, found
671.3298.
Chromatography using 30% EtOAc in hexanes gave 52.8 mg (65%
yield) of a fluffy, yellow solid. Rf (SiO2/30% EtOAc in hexanes) = 0.28.
1H NMR (500 MHz, CDCl3): δ 8.99 (s, 1H, Ar-H), 8.40 (s, 1H, Ar-
H), 6.78 (s, 2H, Ar-H), 6.14 (d, 1H, H-1′, J = 5.9 Hz), 4.72 (t, 1H, H-
2′, J = 4.9 Hz), 4.33 (t, 1H, H-3′, J = 3.7 Hz), 4.16 (app q, 1H, H-4′,
Japp = 3.4 Hz), 4.03 (dd, 1H, H-5′, J = 4.1, 11.5 Hz), 3.85 (s, 3H,
OMe), 3.82 (dd, 1H, H-5′, J = 2.9, 11.2 Hz), 1.98 (s, 6H, OAc), 0.95,
J
dx.doi.org/10.1021/jo4008282 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
0.94, and 0.78 (3 s, 27H, t-Bu), 0.14, 0.13, 0.11, −0.04, and −0.28 (5 s,
18H, SiCH3). 13C NMR (125 MHz, CDCl3): δ 168.6, 161.5, 151.9,
151.7, 150.4, 143.9, 133.7, 107.5, 88.4, 86.0, 75.9, 72.4, 62.8, 56.0, 26.3,
26.0, 25.8, 21.3, 18.7, 18.3, 18.0, −4.2, −4.3, −4.4, −4.8, −5.1. HRMS
(ESI): calcd for C39H65N4O9Si3 [M + H]+ 817.4054, found 817.4078.
6-[2,6-Diacetoxy-4-fluorophenyl]-9-[2,3,5-tri-O-(tert-butyldi-
methylsilyl)-β-D-ribofuranosyl]-9H-purine (9c).
In an oven-dried, nitrogen gas flushed vial equipped with a stirring bar
was placed the 9-benzyl-6-(2-naphthyl)-9H-purine 1d (33.6 mg, 0.10
mmol) in CH3CN (1 mL). To this mixture was added the Pd catalyst
(see below and refer to Table 2) followed by PhI(OAc)2 (48.3 mg,
0.15 mmol). The mixture was flushed with nitrogen gas, sealed with a
Teflon-lined cap, and heated at 100 °C for an appropriate period of
time (see below and refer to Table 2). Evaporation of the solvent and
chromatography of the reaction mixture on a silica gel column eluted
with 1% acetone in CH2Cl2 followed by 7% acetone in CH2Cl2 gave
12 as a pale yellowish white solid.
Pd(OAc)2 (1.1 mg, 5 μmol) over 1 h gave 33.8 mg (86% yield) of
12.
Complex 10 (2.5 mg, 2.5 μmol) over 1 h gave 35.9 mg (91% yield)
of 12.
Pd(OAc)2 (1.1 mg, 5 μmol) over 5 h gave 32.5 mg (82% yield) of
12.
Complex 10 (2.5 mg, 2.5 μmol) over 5 h gave 36.0 mg (91% yield)
of 12.
Complex 10 (2.5 mg, 2.5 μmol) over 24 h gave 36.7 mg (93% yield)
Chromatography using 60% EtOAc in hexanes gave 31.7 mg (39%
yield) gave a light brown gum. Rf (SiO2/70% EtOAc in hexanes) =
0.21. 1H NMR (500 MHz, CDCl3): δ 9.00 (s, 1H, Ar-H), 8.43 (s, 1H,
Ar-H), 7.01 (d, 2H, Ar-H), 6.16 (d, 1H, H-1′, J = 5.9 Hz), 4.70 (t, 1H,
H-2′, J = 5.1 Hz), 4.32 (t, 1H, H-3′, J = 3.4 Hz), 4.16 (app q, 1H, H-4′,
Japp = 3.1 Hz), 4.03 (dd, 1H, H-5′, J = 4.1, 11.5 Hz), 3.82 (dd, 1H, H-
5′, J = 2.7, 11.5 Hz), 1.97 (s, 6H, OAc), 0.96, 0.94, and 0.78 (3 s, 27H,
t-Bu), 0.14, 0.13, 0.11, −0.04, and −0.29 (5 s, 18H, SiCH3). 13C NMR
(125 MHz, CDCl3): δ 168.2, 163.9, 161.9, 152.2, 151.8, 151.1, 150.3
(d, J = 13.3 Hz), 144.1, 133.8, 118.3, 109.4 (d, J = 24.7 Hz), 88.4, 86.1,
76.0, 72.4, 62.9, 60.6, 26.3, 26.0, 25.8, 21.1, 18.7, 18.3, 18.0, −4.2, −4.3,
−4.4, −4.8, −5.2. 19F NMR (282 MHz, CDCl3): δ −107.87 (t, J = 7.6
Hz). HRMS (ESI): calcd for C38H62FN4O8Si3 [M + H]+ 805.3854,
found 805.3851.
of 12.
1
Rf (SiO2/10% acetone in CH2Cl2) = 0.40. H NMR (500 MHz,
CDCl3): δ 9.09 (s, 1H, Ar-H), 8.80 (s, 1H, Ar-H), 8.11 (s, 1H, Ar-H),
7.98 (d, 1H, Ar-H, J = 7.8 Hz), 7.86 (d, 1H, Ar-H, J = 7.8 Hz), 7.73 (s,
1H, Ar-H), 7.56 (t, 1H, Ar-H, J = 7.6 Hz), 7.51 (t, 1H, Ar-H, J = 7.6
Hz), 7.41−7.35 (m, 5H, Ar-H), 5.51 (s, 2H, CH2), 2.23 (s, 3H, OAc).
13C NMR (125 MHz, CDCl3): δ 170.0, 154.7, 152.4, 152.3, 146.2,
144.8, 135.3, 134.6, 133.9, 132.0, 131.4, 129.3, 129.0, 128.8, 128.0,
127.5, 127.2, 126.3, 121.4, 47.5, 21.5. HRMS (ESI): calcd for
C24H19N4O2 [M + H]+ 395.1503, found 395.1506.
6-[2-Acetoxyphenyl]-9-[2-deoxy-3,5-di-O-(tert-butyldime-
thylsilyl)-β-D-ribofuranosyl]-9H-purine (4aAc).
Procedure for the Synthesis of Palladated Complex 10.
In an oven-dried, nitrogen gas flushed vial equipped with a stirring bar
was placed the 6-phenylpurine 2′-deoxyribonucleoside 3a (54.1 mg,
0.10 mmol) in CH3CN (0.5 mL). To this mixture was added the Pd
catalyst (see below and refer to Table 2) followed by PhI(OAc)2 (48.3
mg, 0.15 mmol). The mixture was flushed with nitrogen gas, sealed
with a Teflon-lined cap and heated at 100 °C for an appropriate period
of time (see below and refer to Table 2). Evaporation of the solvent
and chromatography on a silica gel column using CH2Cl2, followed by
1%, 2%, and 3% acetone in CH2Cl2, gave 4aAc as a yellowish, gummy
oil.
In an oven-dried, nitrogen gas flushed vial equipped with a stirring bar
was placed 9-benzyl-6-naphthyl-9H-purine (33.6 mg, 0.10 mmol) in
anhydrous benzene (1.0 mL). To this solution was added Pd(OAc)2
(23.0 mg, 0.10 mmol), and the mixture was heated at 60 °C for 2 h.
After all the starting material was consumed (monitored by TLC), the
solvent was evaporated and the crude product was dissolved in a
minimum amount of CH2Cl2. The solution was layered with heptane
and kept in the freezer overnight to provide 39.9 mg (40% yield) of
1
Pd(OAc)2 (2.2 mg, 10 μmol) over 5 h gave 36.6 mg (61% yield) of
the palladated complex as yellowish orange crystals. H NMR (500
4aAc.
MHz, CDCl3): δ 8.58 (s, 1H, Ar-H), 8.39 (s, 1H, Ar-H), 7.75 (s, 1H,
Ar-H), 7.60 (d, 1H, Ar-H, J = 8.3 Hz), 7.53−7.49 (m, 2H, Ar-H),
7.34−7.30 (m, 4H, Ar-H), 7.15−7.14 (m, 2H, Ar-H), 7.04 (s, 1H, Ar-
H), 4.97 (d, 1H, benzylic CH, J = 15.3 Hz), 4.55 (d, 1H, benzylic CH,
J = 15.3 Hz). 13C NMR (125 MHz, CDCl3): δ 182.2, 161.0, 152.5,
151.3, 147.9, 146.1, 142.7, 135.3, 134.0, 130.8, 130.4, 129.8, 129.7,
129.6, 129.1, 128.8, 128.4, 128.2, 128.1, 127.7, 124.6, 47.6, 25.3 (one
resonance at 128−129 ppm is from PhH).
Complex 10 (2.5 mg, 2.5 μmol) over 5 h gave 33.0 mg (55% yield)
of 4aAc.
Complex 10 (5 mg, 5 μmol) over 5 h gave 35.2 mg (59% yield) of
4aAc.
1
Rf (SiO2/5% acetone in CH2Cl2) = 0.42. H NMR (500 MHz,
CDCl3): δ 9.00 (s, 1H, Ar-H), 8.40 (s, 1H, Ar-H), 8.16 (d, 1H, Ar-H, J
= 7.8 Hz), 7.53 (t, 1H, Ar-H, J = 7.6 Hz), 7.42 (t, 1H, Ar-H, J = 7.3
Hz), 7.27 (d, 1H, Ar-H, J = 7.8 Hz), 6.56 (t, 1H, H-1′, J = 6.3 Hz),
3-(9-Benzyl-9H-purin-6-yl)-2-naphthyl Acetate (12).
4.65 (app quint, 1H, H-3′, Japp = 2.9 Hz), 4.05 (app q, 1H, H-4′, Japp
=
3.4 Hz), 3.88 (dd, 1H, H-5′, J = 4.1, 11.0 Hz), 3.79 (dd, 1H, H-5′, J =
2.9, 11.2 Hz), 2.71 (app quint, 1H, H-2′, Japp = 6.5 Hz), 2.48 (ddd, 1H,
H-2′, J = 3.9, 5.9, 13.2 Hz), 2.17 (s, 3H, OAc), 0.93 and 0.90 (2 s,
18H, t-Bu), 0.12, 0.08, and 0.07 (3 s, 12H, SiCH3). 13C NMR (125
MHz, CDCl3): δ 169.7, 154.4, 151.9, 149.1, 143.6, 132.7, 131.6, 127.8,
126.3, 124.1, 88.3, 84.7, 72.2, 63.0, 41.4, 26.2, 25.9, 21.5, 18.6, 18.2,
−4.4, −4.6, −5.2, −5.3. HRMS (ESI): calcd for C30H47N4O5Si2 [M +
H]+ 599.3080, found 599.3080.
K
dx.doi.org/10.1021/jo4008282 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
24, 85−116. (t) Yu, J.-Q.; Giri, R.; Chen, X. Org. Biomol. Chem. 2006,
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ASSOCIATED CONTENT
* Supporting Information
NMR spectra of all products, representative COSY spectra, and
X-ray crystallographic data and CIF files for compounds 10 and
12. This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
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AUTHOR INFORMATION
Corresponding Author
*E-mail for M.K.L.: lakshman@sci.ccny.cuny.edu.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Infrastructural support at CCNY was provided by National
Institutes of Health Grant 2G12RR03060-26A1 from the
National Center for Research Resources and by
8G12MD007603-27 from the National Institute on Minority
Health and Health Disparities. This work was partially
supported by NSF Grant CHE-1265687. We thank Ms.
Nonka Sevova and Dr. Bill Boggess (University of Notre
Dame Mass Spectrometry and Proteomics Facility) for some of
the HRMS analyses reported herein, the acquisition of which
was supported by NSF Grant CHE-0741793. Dr. R. Pratap, Dr.
A. Deb, and Ms. O. Liu are thanked for some preliminary
experiments.
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(35) Compound 12: C24H18N4O2; Mw = 394.42; T = 296(2) K; λ =
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̅
c = 12.154(3) Å; α = 84.335(5)°, β = 84.569(5)°, γ = 70.466(5)°; V =
977.5(5) Å3; Z = 2; calculated density 1.340 Mg/m3; crystal size 0.41
× 0.23 × 0.05 mm3; R1 = 0.0706, wR2 = 0.1363 (all data).
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