Efficient sonogashira coupling of unprotected halonucleosides in aqueous solvents using water-soluble palladium catalysts

Article abstract of DOI:10.1002/ejoc.201000313

A variety of applications of C-alkynylated nucleosides has prompted the continuing development of efficient synthetic methods for their preparation. We report an efficient and environmentally benign Sonogashira coupling reaction for alkynylation of unprotected halonucleosides in an aqueoussolvent. The combination of Pd(OAc)₂, CuI, and TXPTS [trisodium tri(2,4-dimethyl-5-sulfonatophenyl)phosphane] provided an effective catalyst for the alkynylation of 8-bromo-purines and 5-iodouridine in H₂O/CH ₃CN (1:1) in yields ranging from 42 to 98%.

Full text of DOI:10.1002/ejoc.201000313

FULL PAPER
DOI: 10.1002/ejoc.201000313
Efficient Sonogashira Coupling of Unprotected Halonucleosides in Aqueous
Solvents Using Water-Soluble Palladium Catalysts
Joon Hyung Cho,[a] Caitlin D. Prickett,[a] and Kevin H. Shaughnessy*[a]
Keywords: Nucleosides / Cross-coupling / Palladium / Nitrogen heterocycles
A variety of applications of C-alkynylated nucleosides has
prompted the continuing development of efficient synthetic
methods for their preparation. We report an efficient and
environmentally benign Sonogashira coupling reaction for
alkynylation of unprotected halonucleosides in an aqueous
solvent. The combination of Pd(OAc)2, CuI, and TXPTS [tri-
sodium tri(2,4-dimethyl-5-sulfonatophenyl)phosphane] pro-
vided an effective catalyst for the alkynylation of 8-bromo-
purines and 5-iodouridine in H2O/CH3CN (1:1) in yields
ranging from 42 to 98%.
examples often requiring either harsh conditions
(110 °C),[8f] long reaction times,[8g] or high copper (50 mol-
%) and alkyne (4 equiv.) loadings.[8i]
Introduction
Synthesis of non-natural nucleosides has attracted sig-
nificant interest due to their crucial roles in biochemical
systems.[1] Modified nucleosides containing alkynyl groups
on the purine or pyrimidine base have received interest as
potential anticancer and antiviral drugs,[2] as fluorescent[3]
or spin-active[4] labels, and as methods to stabilize DNA
duplex and triplex structures.[5] 5-Alkynyl-substituted urid-
ine derivatives have received particular attention because
this substitution does not impart any significant conforma-
tional changes in oligonucleotides incorporating the modi-
fied uridine base.[6] The importance of C-alkynylated nu-
cleosides and nucleotides has prompted continuing efforts
to develop efficient synthetic methods for alkynylation of
nucleosides.
Palladium-catalyzed coupling reactions have provided
powerful synthetic methods for the C-modification of nu-
cleosides.[7] Because nucleosides are insoluble in typical or-
ganic solvents, the hydroxy groups are often protected to
make the nucleoside more lipophilic prior to the coupling
reaction. The protecting groups must then be removed after
the coupling reaction, which results in a lower overall yield
and increased waste production. Direct couplings of unpro-
tected nucleosides in high polarity solvents in which they
are soluble would provide a more atom-economical meth-
odology. Alkynylations of unprotected pyrimidines, such as
5-iodouridine (5-IdU), are well precedented using DMF as
the solvent.[7a] Examples of alkynylation of unprotected 8-
halopurine nucleosides are less common, however.[8] 8-Bro-
moguanosine (8-BrG) and 8-bromo-2Ј-deoxyguanosine (8-
BrdG) have proven particularly challenging with reported
Water-soluble palladium catalysts have received signifi-
cant interest due to the potential environmental and econ-
omic benefits of doing catalysis in aqueous-organic biphasic
systems.[9] Although there is a significant body of literature
on the use of hydrophilic catalyst systems for cross-coupling
of hydrophobic substrates, the use of aqueous solvents for
homogeneous cross-coupling reactions of biomolecules has
received less attention. Casalnuovo[10] initially reported the
Suzuki and Sonogashira couplings of unprotected nucleo-
sides, nucleotides, and amino acids using Pd(TPPMS)3
[TPPMS = sodium diphenyl(3-sulfonatophenyl)phosphane]
as the catalyst. Moderate to good yields were obtained for
Sonogashira couplings of 5-iodopyrimidine nucleosides
with alkynes, but no examples of purine alkynylations were
reported. This methodology received limited attention until
recently, however.
We[11] and others[12] have shown that palladium catalysts
derived from water-soluble phosphanes are active catalysts
for Suzuki couplings of 8-halopurine and 5-iodopyrimidine
nucleosides under mild conditions. Sonogashira alk-
ynylations of 5-IdU,[3d,12g] 6-chloropurine nucleosides,[12c]
7-iodo-7-deazapurine nucleosides and nucleotides[12e] and
8-bromo-2Ј-deoxyadenosine (8-BrdA)[12f] using catalysts de-
rived from Pd/TPPTS [TPPTS = trisodium tri(3-sulfonato-
phenyl)phosphane, Figure 1] have been reported. To the
best of our knowledge, there are no examples of alk-
ynylation of 8-bromoguanosine derivatives under these con-
ditions, however. The 8-bromopurines are less reactive in
Pd-catalyzed cross-coupling reactions than 6-halopurines or
5-halopyrimidines due to the halogen being attached to the
electron rich azole ring. 8-Bromoguanosines have proven to
be particularly challenging substrates in our experience.[11b]
The Pd/TXPTS catalyst system showed high activity for
Suzuki couplings of halonucleosides in aqueous solvent sys-
[a] Department of Chemistry, The University of Alabama,
Tuscaloosa, AL 35487-0336, USA
Fax: +1-205-348-9104
E-mail: kshaughn@bama.ua.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000313.
3678
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3678–3683

Efficient Sonogashira Coupling of Unprotected Halonucleosides
after 6 h). At longer reaction times, slow loss of 2a was
observed in some cases due to the formation of small
amounts of uncharacterized side products.
Figure 1. Water-soluble phosphanes screened for coupling of 5-IdU
and phenylacetylene.
tems.[11a] We have also shown that this catalyst system gives
higher activity in the Sonogashira coupling of simple aryl
bromides than catalysts derived from TPPTS.[13] Based on
these results, we have applied the Pd/TXPTS catalyst system
to the aqueous-phase Sonogashira coupling of unprotected
halonucleosides. We report an efficient and environmentally
benign methodology for alkynylation of nucleosides using
water-soluble palladium catalysts.
Figure 2. The variation of relative peak areas (%) of the products
of Sonogashira couplings of 5-IdU and phenylacetylene with
TPPTS(᭹), TXPTS (᭿), DCPES (᭡), and tBu–Amphos (o); see
also Equation (1).
The superior performance of TXPTS is consistent with
our previous results in the Suzuki coupling of halonucleos-
ides.[11a] Although tBu–Amphos provides superior catalysts
to TPPTS and TXPTS for the Suzuki and Sonogashira cou-
plings of simple aryl bromides,[14] it was found to give lower
activity catalysts in the Suzuki coupling of halonucleos-
ides.[11a] In our previous studies, increased ligand cone angle
correlated well with improved catalyst efficiency.[13–15]
Therefore increased steric demand of TXPTS (cone angle:
206°) compared to TPPTS (165°) may account for the in-
creased catalyst activity by promoting formation of the low-
coordinate LPd0 active species. The more electron rich tBu–
Amphos apparently gives a catalyst system that leads to
undesired side products with 5-IdU. The tBu–Amphos li-
gand may also be more easily displaced by the nucleoside
base leading to inactive catalyst species.[11b]
Results and Discussion
A series of water-soluble phosphanes (Figure 1) were
screened for their ability to provide active palladium cata-
lysts in a model Sonogashira coupling of unprotected 5-
iodouridine (5-IdU) and phenylacetylene [1a, Equation (1)].
The TPPTS and TXPTS ligands had both provided effec-
tive catalysts for the Suzuki coupling of halonucleosides,[11a]
while tBu–Amphos provided effective catalysts for the
Sonogashira coupling of simple aryl bromides.[14] Reactions
were carried out in 2:1 H2O/CH3CN at 50 °C using a cata-
lyst system derived from Pd(OAc)2 (5 mol-%), CuI (10 mol-
%), and the phosphane ligand (15 mol-%) in the presence
of triethylamine (2 equiv.).
In the course of these studies, slow decomposition of 5-
IdU was observed under the reaction conditions. For exam-
ple, heating a mixture of 5-IdU, Pd(OAc)2, TPPTS, and
Et3N at 80 °C resulted in a loss of 34 and 77% of the initial
5-IdU after 5 and 14 hours, respectively. Therefore, the cata-
lyst loading was raised to 10 mol-% Pd to ensure that the
coupling reaction occurred at a faster rate than the decom-
position. 5-IdU was coupled with alkynes 1a–d using
10 mol-% Pd(OAc)2, 10 mol-% CuI, 30 mol-% TXPTS,
1 equiv. of triethylamine at 65 °C in 1:1 H2O/CH3CN
[Equation (2)]. Optimal yields were obtained when the al-
(1)
The tBu–Amphos/Pd catalyst system showed the fastest
initial formation of product. An aliquot taken immediately
after addition of the alkyne showed 30% conversion (Fig-
ure 2). Complete consumption of 5-IdU occurred within
30 min, but the product selectivity was low as only approxi-
mately 60% conversion to product occurred. The TXPTS/
Pd system gave approximately 90% conversion of 5-IdU to
the desired product 2a within 1.5 hours. The TPPTS cata-
lyst system gave slow conversion to product with approxi-
mately 75% conversion after 6 hours. The catalyst derived
from DCPES gave very slow conversion to product (13%
(2)
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J. H. Cho, C. D. Prickett, K. H. Shaughnessy
FULL PAPER
kyne was added in 3 portions during the course of the reac- gests that one equivalent of TXPTS is required for each
tion, which limited loss of alkyne to homocoupling. The metal center (5 mol-% Pd + 10 mol-% Cu). At least one
reactions reached completion within 30 min. Product 2a de- equivalent of triethylamine was required (entries 8–11), but
rived from phenylacetylene was isolated in 71% yield under higher concentrations of base did not affect the catalyst per-
these conditions (Table 1). In comparison, repeating this re- formance.
action with tBu–Amphos as the ligand gave 2a in 43%
yield.
Table 2. Optimization of the conditions for the coupling of 8-bro-
mopurines and phenylacetylene.[a]
Table 1. Sonogashira coupling of 5-IdU.
Entry Substrate
CuI
TXPTS
Et3N
T
Time S/P[b]
Entry
Alkyne
Product
Yield [%][a]
[mol-%] [mol-%] [equiv.] [°C] [h]
1
2
3
4
5
6
7
8
8-BrdA
8-BrdA
8-BrdA
8-BrdA
8-BrdA
8-BrdA
8-BrdA
8-BrdG
8-BrdG
8-BrdG
8-BrdG
2
5
25
25
25
10
15
20
25
30
30
30
30
2
2
2
2
2
2
2
0
1
2
3
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
65
10
10
10
14
14
14
14
1
68:32
59:41
52:48
71:29
49:51
44:56
48:52
99:1
1
2
3
4
5
1a
1a
1b
1c
1d
2a
2a
2b
2c
2d
71
43[b]
42
10
10
10
10
10
10
10
10
10
55[c]
84
[a] Average isolated yield from two or more trials. Reactions carried
out under conditions in Equation (2). [b] tBu–Amphos used as the
ligand. [c] Product coeluted with residual 5-IdU (18 wt.-%) as de-
termined by H NMR spectroscopy. Reported yield of 2c obtained
after subtracting mass of 5-IdU contaminant.
9
10
11
65
65
65
1
1
1
9:91
10:90
14:86
1
[a] Reactions were run under the conditions above using 5 mol-%
Pd(OAc)2 for 8-BrdA and 10 mol-% for 8-BrdG. [b] Substrate/prod-
uct ratios based on HPLC peak areas. Peak areas were not adjusted
for molar absorptivity of the substrates and products.
In contrast to the high yields achieved with phenylacetyl-
ene, reactions of 5-IdU with simple alkyl-substituted al-
kynes (1b and 1c) gave lower yields (42 and 55%, respec-
tively) of isolated products (entries 3–4). The more sterically
hindered alkyne 1d gave an 84% yield of 2d, though. With
the unhindered alkynes (1b and 1c), formation of a cyclized
byproduct was observed. In the case of 1-hexyne, the de-
sired product 2b and byproduct 3 were isolated in 42 and
15% yield, respectively [Equation (3)]. The formation of
this cyclized byproduct is commonly observed in alk-
ynylation of 5-IdU.[16] The rearrangement is catalyzed by
metal ions, such as CuI and PdII. This rearrangement pro-
cess appears to be competitive in the case of the sterically
undemanding alkynes 1b and 1c, while the more hindered
1a and 1d do not undergo rearrangement to a significant
extent over the course of the reaction.
Using the optimized conditions [10 mol-% Pd(OAc)2,
10 mol-% CuI, 30 mol-% TXPTS, and 1 equiv. of triethyl-
amine in 1:1 H2O/CH3CN], 8-BrdA and 8-BrdG were cou-
pled with alkynes 1a–d [Table 3, Equations (4) and (5)].
These reactions were run at 80 °C to ensure complete con-
version to product. Sonogashira couplings of 8-BrdA were
completed in 1–2 hours to give the desired product (4a–d)
in excellent yields (entries 1–4). Both phenylacetylene and
alkyl-substituted alkynes gave excellent yields of product
with no formation of side products. 8-Bromoadenosine (8-
BrA) gave somewhat lower yields when coupled with 1a and
1b (entries 5–6) than were obtained with the deoxy analog
(8-BrdA). Sonogashira couplings of 8-BrdG were com-
pleted under similar conditions to generate the desired
products (6a–d) in excellent yields (entries 7–10). In the Su-
zuki coupling at room temperature, 8-BrdG significantly in-
hibits the Pd/TXPTS catalyst system,[11b] but there was little
difference in the reactivity of 8-BrdA and 8-BrdG at the
higher temperatures used in these reactions.
(3)
The alkynylation conditions were further optimized for
the 8-bromopurines (Table 2). Reactions of 8-BrdA and
phenylacetylene were performed with varying CuI loadings
ranging from 2–10 mol-% (entries 1–3) at room tempera-
ture. The conversion to product increased when the CuI
loading was increased from 2 to 10 mol-%. This result is
opposite to that seen in the Sonogashira coupling of simple
aryl bromides using TXPTS/Pd(OAc)2 where the reaction
was most efficient when no copper cocatalyst was used.[13]
An increase in conversion was observed when the TXPTS
loading was increased from 10 mol-% to 15 mol-%, but fur-
ther increases in the ligand loading had no significant effect
Table 3. Sonogashira couplings of 8-bromopurine nucleosides.
Entry
Nucleoside
1
Product
Yield [%][a]
1
2
3
4
5
6
7
8
9
8-BrdA
8-BrdA
8-BrdA
8-BrdA
8-BrA
1a
1b
1c
1d
1a
1b
1a
1b
1c
1d
4a
4b
4c
4d
5a
5b
6a
6b
6c
6d
88
89
98
98
53
74
86
85
85
84
8-BrA
8-BrdG
8-BrdG
8-BrdG
8-BrdG
10
[a] Average isolated yield from two or more trials. Reactions were
(entries 4–7). The optimal 15 mol-% loading of TXPTS sug- run under conditions in Equations (4) and (5).
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Efficient Sonogashira Coupling of Unprotected Halonucleosides
6.5 Hz, 1 H), 5.27 (d, J = 4.5 Hz, 1 H), 5.17 (t, J = 4.8 Hz, 1 H),
4.29–4.25 (m, 1 H), 3.69–3.65 (m, 1 H), 3.62–3.58 (m, 1 H), 2.19–
2.16 (m, 2 H) ppm. 13C NMR (126 MHz, [D6]DMSO): δ = 161.3,
149.3, 143.8, 131.0, 128.6, 128.5, 122.3, 98.1, 91.7, 87.5, 84.8, 82.4,
69.8, 60.7, 48.5, 40.1 ppm.
5-(1-Hexyn-1-yl)-2Ј-deoxyuridine (2b):[18] Using the general pro-
cedure, 5-IdU (108.4 mg, 0.306 mmol) was coupled with 1-hexyne
(50.8 mg, 0.60 mmol). The product 2b (39.6 mg, 42.0%) along with
3 was obtained after elution of the crude product through RP-
silica gel eluting with a gradient ranging from water to 40:60 water/
methanol. 1H NMR (500 MHz, [D6]DMSO): δ = 11.54 (br. s, 1 H),
8.11 (s, 1 H), 6.12 (dd, J = 6.8, 6.8 Hz, 1 H), 5.23 (d, J = 4.5 Hz,
1 H), 5.08 (t, J = 5.0 Hz, 1 H), 4.24–4.22 (m, 1 H), 3.80–3.78 (m,
1 H), 3.63–3.59 (m, 1 H), 3.58–3.54 (m, 1 H), 2.36 (t, J = 7.0 Hz,
2 H), 2.13–2.10 (m, 2 H), 1.51–1.45 (m, 2 H), 1.42–1.36 (m, 2 H),
0.89 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (126 MHz, [D6]DMSO):
δ = 161.7, 149.4, 142.5, 99.0, 93.1, 87.5, 84.5, 72.7, 70.1, 60.9, 48.5,
30.2, 21.3, 18.4, 13.4 ppm, one was obscured by solvent.
(4)
(5)
Conclusions
6-Butyl-3-(2-deoxy-β-D-erythro-pentofuranosyl)furano[2,3-d]-
pyrimidin-2-one (3):[16a] (14.5 mg, 15.4%) isolated as byproduct
The catalyst derived from TXPTS and Pd(OAc)2 pro-
vides an effective catalyst for the Sonogashira coupling of
8-halopurine nucleosides and 5-IdU under mild conditions
in aqueous solvents from which the product nucleoside ad-
ducts can easily be recovered. The TXPTS ligand was found
to give superior results to the more commonly used TPPTS
as well as hydrophilic trialkylphosphanes, such as tBu–
Amphos. The TXPTS catalyst system showed good general-
ity with 8-halopurine nucleosides for both aryl- and alkyl-
substituted alkyne substrates. In the coupling with 5-IdU,
the competitive cyclization of the alkyne adduct led to
lower yields of product with sterically undemanding al-
kynes. This methodology represents the first example of
Sonogashira coupling of unprotected 8-bromopurine nu-
cleosides in an aqueous solvent system.
1
with 2b. H NMR (360 MHz, [D6]DMSO): δ = 8.67 (s, 1 H), 6.43
(s, 1 H), 6.16 (dd, J = 6.1, 6.1 Hz, 1 H), 5.28 (d, J = 4.3 Hz, 1 H),
5.12 (t, J = 5.4 Hz, 1 H), 4.25–4.20 (m, 1 H), 3.92–3.89 (m, 1 H),
3.70–3.57 (m, 2 H), 2.65 (t, J = 7.4 Hz, 2 H), 2.40–2.34 (m, 1 H),
2.08–2.00 (m, 1 H), 1.64–1.55 (m, 2 H), 1.39–1.29 (m, 2 H), 0.90
(t, J = 7.38 Hz, 3 H) ppm. 13C NMR (126 MHz, [D6]DMSO): δ =
171.1, 158.2, 153.7, 136.6, 106.2, 99.6, 88.0, 87.3, 69.6, 60.7, 41.1,
28.4, 26.9, 21.4, 13.5 ppm.
5-(4-Hydroxy-1-butyn-1-yl)-2Ј-deoxyuridine (2c):[16a] Using the ge-
neral procedure, 5-IdU (137.3 mg, 0.3877 mmol) was coupled with
3-butyn-1-ol (0.0578 mg, 0.800 mmol). Adduct 2c (77.0 mg, 67.0%)
was obtained from the crude product by column chromatography
using normal phase silica gel eluted with 95:5 acetone/MeOH. The
product co-eluted with 5-IdU (88:12 2c/5-IdU, mol/mol) as deter-
mined by NMR spectroscopy. Yield of 2c was 63.4 mg (55.2%). 1H
NMR (500 MHz, [D6]DMSO): δ = 11.56 (br. s, 1 H), 8.12 (s, 1 H),
6.12 (dd, J = 6.7, 6.7 Hz, 1 H), 5.22 (d, J = 4.3 Hz, 1 H), 5.07 (t,
J = 5.0 Hz, 1 H), 4.83 (t, J = 5.6 Hz, 1 H), 4.25–4.22 (m, 1 H),
3.81–3.78 (m, 1 H), 3.63–3.51 (m, 4 H), 2.50 (t, J = 7.0 Hz, 2 H),
2.12–2.08 (m, 2 H) ppm. 13C NMR (126 MHz, [D6]DMSO): δ =
161.7, 149.3, 142.8, 98.8, 90.9, 87.4, 84.5, 73.3, 70.1, 60.9, 59.6, 23.3
ppm, one carbon resonance obscured by solvent.
Experimental Section
General Procedure for Sonogashira Coupling of Halonucleosides and
Alkynes: Palladium acetate (6.9 mg, 0.03 mmol), TXPTS (58.7 mg,
0.09 mmol), CuI (5.7 mg, 0.03 mmol), and the halonucleoside
(0.3 mmol) were assembled in a round-bottomed flask sealed with
a seputm in a nitrogen-filled glove box. After removal of the flask
from the glove box, deoxygenated 1:1 water/acetonitrile (3 mL) was
added, followed by addition of triethylamine (30.5 mg, 0.3 mmol).
The reaction mixture was placed in an oil bath at 80 °C for 8-BrdA
and 8-BrdG or at 65 °C for 5-IdU. The alkyne (0.6 mmol) was then
added in three portions at 0, 15, and 25 min. The reaction mixture
was stirred at 80 or 65 °C until RP-TLC (1:2 water/methanol) or
RP-HPLC showed complete conversion (0.5–2 h). The reaction
mixture was diluted with 10 mL of a mixture of 1:1 water/methanol
and neutralized with 10% aqueous HCl solution. The solvent was
evaporated and the crude product purified using reverse- or nor-
mal-phase silica gel.
5-(3-Hydroxy-3-methyl-1-butyn-1-yl)-2Ј-deoxyuridine (2d): Using
the general procedure, 5-IdU (105.2 mg, 0.2971 mmol) was coupled
with 2-methyl-3-butyn-2-ol (0.0515 mg, 0.600 mmol). Adduct 2d
(77.1 mg, 83.6%) was obtained from the crude product by column
chromatography using normal phase silica eluted with 2:8 acetone/
1
ethyl acetate. H NMR (360 MHz, [D6]DMSO): δ = 11.49 (br. s, 1
H), 8.14 (s, 1 H), 6.12 (dd, J = 6.7, 6.7 Hz, 1 H), 5.40 (br. s, 1 H),
5.26 (br. s, 1 H), 5.12 (br. s, 1 H), 4.26–4.22 (m, 1 H), 3.81–3.78
(m, 1 H), 3.65–3.55 (m, 2 H), 2.14–2.11 (m, 2 H), 1.42 (s, 6 H)
ppm. 13C NMR (126 MHz, [D6]DMSO): δ = 161.4, 149.4, 143.1,
98.5, 98.3, 87.5, 84.6, 73.0, 70.0, 63.6, 60.9, 40.0, 31.5 ppm. HRMS-
EI (m/z): [M – H2O]+ calcd. for C14H15N2O5, 292.1059; found,
292.1059.
5-(2-Phenyl-1-ethyn-1-yl)-2Ј-deoxyuridine (2a):[17] Using the general
procedure, 5-IdU (102.6 mg, 0.290 mmol) was coupled with phenyl-
acetylene (62.5 mg, 0.60 mmol). Product 2a (67.7 mg, 71.2%) was
obtained after elution of the crude product through RP-silica gel
eluting with a gradient ranging from water to 40:60 water/meth-
anol. 1H NMR (360 MHz, [D6]DMSO): δ = 11.69 (br. s, 1 H), 8.40
(s, 1 H), 7.49–7.47 (m, 2 H), 7.42–7.40 (m, 3 H), 6.14 (dd, J = 6.5,
8-(2-Phenyl-1-ethyn-1-yl)-2Ј-deoxyadenosine (4a): Using the general
procedure, 8-BrdA (99.0 mg, 0.30 mmol) was coupled with phenyl-
acetylene (62.5 mg, 0.60 mmol). Adduct 4a (92.8 mg, 88.0%) was
obtained after elution of the crude product through RP-silica gel
eluting with a gradient ranging from water to 40:60 water/meth-
anol. 1H NMR (360 MHz, [D6]DMSO): δ = 8.18 (s, 1 H), 7.71–
7.50 (m, 5 H), 7.65 (br. s, 2 H), 6.54 (dd, J = 6.8, 7.6 Hz, 1 H),
Eur. J. Org. Chem. 2010, 3678–3683
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J. H. Cho, C. D. Prickett, K. H. Shaughnessy
FULL PAPER
5.37 (d, J = 4.7 Hz, 1 H), 5.34–5.31 (m, 1 H), 4.54–4.49 (m, 1 H), 8-(1-Hexyn-1-yl)adenosine (5b):[8c] Using the general procedure, 8-
3.93–3.90 (m, 1 H), 3.72–3.66 (m, 1 H), 3.55–3.48 (m, 1 H), 3.20– BrA (109.6 mg, 0.316 mmol) was coupled with1-hexyne (73.9 mg,
3.12 (m, 1 H), 2.31–2.25 (m, 1 H) ppm. 13C NMR (126 MHz, 0.90 mmol). Adduct 5b (82.0 mg, 74.5%) was obtained after elution
[D6]DMSO): δ = 156.0, 153.3, 148.5, 132.7, 131.8, 130.3, 129.0,
119.8, 119.5, 94.2, 88.2, 84.9, 78.5, 71.1, 62.1, 37.7 ppm. HRMS-
EI (m/z): [M]+ calcd. for C18H17N5O3, 351.1331; found, 351.1322.
of the crude product through RP-silica gel eluting with a gradient
ranging from water to 40:60 water/methanol. 1H NMR (500 MHz,
[D6]DMSO): δ = 8.13 (s, 1 H), 7.57 (br. s, 2 H), 5.93 (d, J = 6.8 Hz,
1 H), 5.56 (dd, J = 8.6, 3.9 Hz, 1 H), 5.41 (d, J = 6.1 Hz, 1 H),
5.18 (d, J = 4.5 Hz, 1 H), 5.00 (dd, J = 11.8, 6.6 Hz, 1 H), 4.18 (td,
J = 4.8, 2.3 Hz, 1 H), 3.96 (dd, J = 6.1, 3.9 Hz, 1 H), 3.67 (dt, J =
12.0, 3.9 Hz, 1 H), 3.52 (ddd, J = 12.3, 8.6, 4.1 Hz, 1 H), 2.58 (t,
J = 6.9 Hz, 2 H), 1.62–1.54 (m, 2 H), 1.50–1.40 (m, 2 H), 0.93 (t,
J = 7.3 Hz, 3 H) ppm. 13C NMR (126 MHz, [D6]DMSO): δ =
156.4, 153.5, 148.8, 134.5, 119.6, 97.9, 89.8, 87.0, 72.0, 71.5, 70.7,
62.7, 30.0, 21.8, 18.7, 13.8 ppm.
8-(1-Hexyn-1-yl)-2Ј-deoxyadenosine (4b): Using the general pro-
cedure, 8-BrdA (99.0 mg, 0.299 mmol) was coupled with 1-hexyne
(61.0 mg, 0.51 mmol). Adduct 4b (88.3 mg, 89.0%) was obtained
after elution of the crude product through RP-silica gel eluting with
1
a gradient ranging from water to 40:60 water/methanol. H NMR
(360 MHz, [D6]DMSO): δ = 8.13 (s, 1 H), 7.53 (br. s, 2 H), 6.41
(dd, J = 8.3, 6.5 Hz, 1 H), 5.41 (dd, J = 7.9, 4.3 Hz, 1 H), 5.32 (d,
J = 4.0 Hz, 1 H), 4.49–4.45 (m, 1 H), 3.91–3.88 (m, 1 H), 3.70–
3.64 (m, 1 H), 3.53–3.46 (m, 1 H), 3.16–3.09 (m, 1 H), 2.59 (t, J = 8-(2-Phenylethyn-1-yl)-2Ј-deoxyguanosine (6a):[8g] Using the general
14.0 Hz, 2 H), 2.20–2.14 (m, 1 H), 1.63–1.55 (m, 2 H), 1.51–1.41 procedure, 8-BrdG (105.5 mg, 0.305 mmol) was coupled with phen-
(m, 2 H), 0.93 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (90.6 MHz,
[D6]DMSO): δ = 155.8, 152.9, 148.2, 133.3, 119.0, 97.5, 88.2, 85.1,
71.2, 70.2, 62.1, 37.5, 29.4, 21.3, 18.1, 13.3 ppm. HRMS-EI (m/z):
[M]+ calcd. for C16H21N5O3, 331.1644; found, 331.1653.
ylacetylene (62.5 mg, 0.60 mmol). Adduct 6a (96.5 mg, 86.1%) was
obtained after elution of the crude product through RP-silica gel
eluting with a gradient ranging from water to 40:60 water/meth-
anol. 1H NMR (360 MHz, [D6]DMSO): δ = 10.86 (br. s, 1 H),
7.65–7.62 (m, 2 H), 7.51–7.49 (m, 3 H), 6.61 (br. s, 2 H), 6.34 (dd,
J = 7.2, 7.2 Hz, 1 H), 5.29 (d, J = 4.3 Hz, 1 H), 4.87 (t, J = 5.9 Hz,
1 H), 4.43–4.40 (m, 1 H), 3.83–3.79 (m, 1 H), 3.65–3.59 (m, 1 H),
3.54–3.48 (m, 1 H), 3.12–3.05 (m, 1 H), 2.21–2.15 (m, 1 H) ppm.
13C NMR (126 MHz, [D6]DMSO): δ = 156.5, 154.4, 151.4, 132.1,
130.4, 129.5, 129.4, 121.0, 118.0, 93.1, 88.2, 84.0, 80.2, 71.5, 62.6,
37.8 ppm.
8-(4-Hydroxy-1-butyn-1-yl)-2Ј-deoxyadenosine (4c): Using the gene-
ral procedure, 8-BrdA (101.4 mg, 0.307 mmol) was coupled with 3-
butyn-1-ol (43.0 mg, 0.60 mmol). Adduct 4c (93.7 mg, 98.0%) was
obtained after elution of the crude product through RP-silica gel
eluting with a gradient ranging from water to 40:60 water/meth-
anol. 1H NMR (500 MHz, [D6]DMSO): δ = 8.15 (s, 1 H), 7.52 (br.
s, 2 H), 6.44 (dd, J = 8.0, 6.8 Hz, 1 H), 5.40 (dd, J = 8.0, 4.0 Hz,
1 H), 5.33 (d, J = 4.0 Hz, 1 H), 5.05 (t, J = 5.5 Hz, 1 H), 4.41–4.47
(m, 1 H), 3.92–3.89 (m, 1 H), 3.70–3.64 (m, 3 H), 3.54–3.49 (m, 1
8-(1-Hexyn-1-yl)-2Ј-deoxyguanosine (6b): Using the general pro-
cedure, 8-BrdG (104.2 mg, 0.301 mmol) was coupled with phenyl-
H), 3.15–3.10 (m, 1 H), 2.72–2.71 (t, J = 6.5 Hz, 2 H), 2.21–2.17 acetylene (50.8 mg, 0.60 mmol). Adduct 6b (89.0 mg, 85%) was ob-
(m, 1 H) ppm. 13C NMR (90.6 MHz, [D6]DMSO): δ = 156.4, 153.5,
148.8, 133.9, 119.6, 96.4, 88.8, 85.6, 71.8, 71.2, 62.8, 59.6, 38.2,
23.7 ppm. HRMS-EI (m/z): [M]+ calcd. for C14H17N5O4, 319.1281;
found, 319.1286.
tained after elution of the crude product through RP-silica gel elut-
ing with a gradient ranging from water to 40:60 water/methanol.
1H NMR (360 MHz, [D6]DMSO): δ = 10.76 (br. s, 1 H), 6.48 (br.
s, 2 H), 6.24 (dd, J = 7.9, 6.8 Hz, 1 H), 5.24 (d, J = 4.0 Hz, 1 H),
4.87 (t, J = 5.9 Hz, 1 H), 4.37–4.35 (m, 1 H), 3.80–3.77 (m, 1 H),
3.64–3.57 (m, 1 H), 3.52–3.45 (m, 1 H), 3.09–3.01 (m, 1 H), 2.52
(t, J = 6.8 Hz, 2 H), 2.22–2.05 (m, 1 H), 1.60–1.52 (m, 2 H), 1.48–
1.38 (m, 2 H), 0.92 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (126 MHz,
[D6]DMSO): δ = 156.2, 153.5, 150.4, 129.7, 116.7, 95.3, 71.1, 71.0,
62.1, 36.9, 29.5, 21.3, 18.2, 13.3 ppm. HRMS-EI (m/z): [M]+ calcd.
for C16H21N5O4, 347.1594; found, 347.1589.
8-(3-Hydroxy-3-methyl-1-butyn-1-yl)-2Ј-deoxyadenosine (4d): Using
the general procedure, 8-BrdA (102.0 mg, 0.3090 mmol) was cou-
pled with 2-methyl-3-butyn-2-ol (51.5 mg, 0.600 mmol). Adduct 4d
(101.1 mg, 98.2%) was purified by column chromatography using
normal phase silica gel eluted with a gradient of neat ethyl acetate
1
to 1:4 MeOH/ethyl acetate. H NMR (500 MHz, [D6]DMSO): δ =
8.15 (s, 1 H), 7.57 (br. s, 2 H), 6.41 (dd, J = 7.9, 6.8 Hz, 1 H), 5.85
(s, 1 H), 5.41 (dd, J = 7.9, 4.3 Hz, 1 H), 5.35 (d, J = 4.0 Hz, 1 H),
4.52–4.47 (m, 1 H), 3.92–3.89 (m, 1 H), 3.72–3.66 (m, 1 H), 3.55–
3.48 (m, 1 H), 3.14–3.07 (m, 1 H), 2.23–2.16 (m, 1 H), 1.52 (s, 6
H) ppm. 13C NMR (126 MHz, [D6]DMSO): δ = 155.9, 153.1,
148.3, 132.8, 119.2, 101.6, 88.3, 85.0, 71.2, 70.2, 63.7, 62.2, 37.7,
30.85, 30.83 ppm. HRMS-EI (m/z): [M]+ calcd. for C15H19N5O4,
333.1437; found, 333.1437.
8-(4-Hydroxy-1-butyn-1-yl)-2Ј-deoxyguanosine (6c): Using the gene-
ral procedure, 8-BrdG (100.0 mg, 0.289 mmol) was coupled with 3-
butyn-1-ol (43.4 mg, 0.60 mmol). Adduct 6c (82.6 mg, 85.2%) was
purified by column chromatography using normal phase silica gel
eluted with 1:1 MeOH/ethyl acetate. 1H NMR (360 MHz, [D6]-
DMSO): δ = 11.05 (br. s, 1 H), 6.61 (br. s, 2 H), 6.26 (dd, J = 7.4,
7.4 Hz, 1 H), 5.26 (br. s, 1 H), 5.02 (br. s, 2 H), 4.40–4.38 (m, 1 H),
3.82–3.78 (m, 1 H), 3.64–3.61 (m, 3 H), 3.53–3.49 (m, 1 H), 3.10–
3.02 (m, 1 H), 2.66 (t, J = 6.84 Hz, 2 H), 2.12–2.06 (m, 1 H) ppm.
13C NMR (90.6 MHz, [D6]DMSO): δ = 157.1, 154.6, 151.1, 130.1,
117.3, 94.0, 88.3, 84.2, 72.1, 71.6, 62.7, 59.6, 37.6, 23.8 ppm.
HRMS-ESI (m/z): [M + H]+ calcd. for C14H17N5O5, 336.1308;
found, 336.1312.
8-(2-Phenylethyn-1-yl)adenosine (5a):[8c] Using the general pro-
cedure, 8-BrA (103.9 mg, 0.299 mmol) was coupled with phenyl-
acetylene (62.5 mg, 0.60 mmol). Adduct 5a (58.1 mg, 53.1%) was
obtained after elution of the crude product through RP-silica gel
eluting with a gradient ranging from water to 40:60 water/meth-
anol. 1H NMR (500 MHz, [D6]DMSO): δ = 8.18 (s, 1 H), 7.70–
7.68 (m, 4 H), 7.56–7.52 (m, 3 H), 6.05 (d, J = 6.8 Hz, 1 H), 5.57 8-(3-Hydroxy-3-methyl-1-butyn-1-yl)-2Ј-deoxyguanosine (6d): Using
(dd, J = 8.4, 3.6 Hz, 1 H), 5.49 (d, J = 6.6 Hz, 1 H), 5.26 (d, J = the general procedure, 8-BrdG (104.0 mg, 0.300 mmol) was coupled
4.8 Hz, 1 H), 5.02 (dd, J = 12.2, 6.5 Hz), 4.21 (td, J = 5.1, 2.5 Hz,
with 2-methyl-3-butyn-2-ol (51.5 mg, 0.60 mmol). Adduct 6d
1 H), 4.01 (dd, J = 5.7, 3.4 Hz, 1 H), 3.70 (dt, J = 12.2, 3.9 Hz, 1 (88.5 mg, 84.4%) was purified by column chromatography using
H), 3.55 (ddd, J = 12.3, 8.4, 3.9 Hz, 1 H) ppm. 13C NMR
(126 MHz, [D6]DMSO): δ = 156.0, 153.3, 148.5, 133.2, 131.8,
normal phase silica gel eluted with a solvent gradient ranging from
CH2Cl2 to 25:75 MeOH/CH2Cl2. 1H NMR (360 MHz, [D6]-
130.3, 129.0, 119.8, 119.5, 94.2, 89.3, 86.6, 78.4, 71.6, 70.9, 62.1 DMSO): δ = 10.91 (br. s, 1 H), 6.64 (br. s, 2 H), 6.24 (dd, J = 7.2,
ppm.
7.2 Hz, 1 H), 5.74 (s, 1 H), 5.27 (d, J = 4.3 Hz, 1 H), 4.91 (t, J =
3682
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Eur. J. Org. Chem. 2010, 3678–3683

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Supporting Information (see also the footnote on the first page of
1
this article): H and 13C NMR spectra of compounds in Tables S1
and S3.
Acknowledgments
Partial support of this work by the National Science Foundation
(NSF) (CHE-0124255) is acknowledged. C. D. P. thanks the Uni-
versity of Alabama (Howard Hughes Medical Internship program)
for a summer fellowship.
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Received: March 5, 2010
Published Online: May 19, 2010
Eur. J. Org. Chem. 2010, 3678–3683
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3683