Aqueous-phase heck coupling of 5-iodouridine and alkenes under phosphine-free conditions

Article abstract of DOI:10.1055/s-0031-1289886

Palladium-catalyzed Heck couplings between 5-iodouridine and alkenes were carried out in aqueous media in the presence of triethylamine under phosphine-free conditions to give the desired products in high yields. In the absence of phosphine ligand, trieth

Full text of DOI:10.1055/s-0031-1289886

LETTER
2963
Aqueous-Phase Heck Coupling of 5-Iodouridine and Alkenes under
Phosphine-Free Conditions
A
queous-P
o
hase
H
eck
C
o
oupling of
5
n
-
Iodouridine and
A
H
lkenes yung Cho, Kevin H. Shaughnessy*
Department of Chemistry, The University of Alabama, Tuscaloosa, AL 35487-0336, USA
Fax +1(205)3489104; E-mail: kshaughn@bama.ua.edu
Received 10 August 2011
varicella-zoster viruses.2 5-Vinyluridine derivatives, such
as 5-carboxyvinyl-2¢-deoxyuridine (CVU), have also re-
ceived significant interest as biochemical probes. CVU
and related compounds are effective tools for photoliga-
Abstract: Palladium-catalyzed Heck couplings between 5-iodouri-
dine and alkenes were carried out in aqueous media in the presence
of triethylamine under phosphine-free conditions to give the desired
products in high yields. In the absence of phosphine ligand, triethyl-
amine appears to play a critical role in both generating the active tion in DNA and RNA.3 The 5-vinyluridines undergo se-
catalyst species and serving as the base in the reaction.
lective [2+2] photocyclization with the C5–C6 double
bond of thymine. Alkene-modified purine nucleosides
have received less attention, but have shown useful cyto-
kinin, cytotoxic (1), and antimycobacterial activity.4
Key words: aqueous phase, cross-coupling, Heck reaction, nucleo-
sides, palladium
The Heck coupling is the most common method to intro-
duce alkene substituents on the base of nucleosides. Early
examples involved the palladium-catalyzed reaction of
alkenes with mercuriated nucleosides.5 The more accessi-
ble halonucleosides, such as 5-iodo-2¢-deoxyuridine (5-
IdU), are more widely used, however. The first practical
large-scale preparation of BVDU used the Pd(OAc)2/
PPh3-catalyzed coupling of 5-IdU and methyl acrylate in
dioxane.6 This methodology has been used in the synthe-
sis of a variety of 5-alkenylated 2¢-deoxyuridine deriva-
tives.7 DMF is often used as a solvent to provide improved
solubility for the nucleoside.8 Heck coupling of 6-halo-
purine nucleosides have been reported using Pd2(dba)3
under ligand-free conditions.9 Lakshman has reported
coupling of aryl iodides and 8-vinyladenosine using Pd/
P(o-tol)3.10 Heck couplings are also used in the synthesis
of C-nucleosides.11
Nucleosides are central building blocks of all living sys-
tems. Because of this central role, there is extensive inter-
est in methods to prepare modified nucleosides for use as
pharmaceuticals and biochemical probes. Palladium-cata-
lyzed reactions have proven to be effective ways to mod-
ify nucleosides through C–C or C–heteroatom bond-
forming reactions.1 All major classes of palladium-cata-
lyzed coupling reactions have been used in nucleoside
synthesis, including couplings with organometallic re-
agents (Suzuki, Stille, Hiyama), alkynylations (Sonoga-
shira), alkenylations (Heck), and C–N bond formation
(Buchwald–Hartwig).
Alkene-modified nucleosides have found important appli-
cations in medicine and biochemistry. 5-(E)-2-Bromo-
ethenyl-2¢-deoxyuridine (BVDU, Figure 1) is a highly
potent and selective inhibitor of the herpes simplex and
Water is an attractive solvent for organic synthesis due to
its low toxicity, flammability, and environmental impact.
In addition, aqueous biphasic catalysis offers the opportu-
nity to separate water-soluble catalyst systems from or-
ganic product streams and recycle the aqueous-phase
catalyst.12 Hydrophilic catalysts offer the opportunity for
homogeneous-phase coupling of water-soluble substrates,
such as nucleosides. In this way, issues with low solubility
of biomolecules in organic solvents can be avoided. The
use of water-soluble catalysts based on monosulfonated
triphenylphosphine (TPPMS) for cross-coupling of halo-
nucleosides was first demonstrated by Casalnuovo.13 Our
group and others have extended this work to develop effi-
cient methods for Suzuki14 and Sonogashira15 couplings
of halonucleosides using palladium complexes of water-
soluble ligands. These coupling reactions can be carried
out on the unprotected nucleosides or nucleotides, thus
avoiding wasteful protection/deprotection steps.
Br
HO2C
O
N
O
N
NH
NH
HO
HO
O
O
O
O
Ph
OH
BVDU
OH
CVU
N
N
N
HO
N
O
OH OH
1
Figure 1 Examples of alkene-modified nucleosides with medical or
biochemical applications
Although Heck couplings in aqueous solvents are well
precedented,16 there are no examples of the Heck coupling
of nucleosides in water to our knowledge. Herein we re-
SYNLETT 2011, No. 20, pp 2963–2966
Advanced online publication: 11.11.2011
DOI: 10.1055/s-0031-1289886; Art ID: S07411ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
1

2964
J. H. Cho et al.
LETTER
port that a catalyst derived from Pd(OAc)2 alone or in the
presence of a water-soluble ligand promotes the coupling
of 5-IdU and alkenes in water under mild conditions.
To identify potential catalyst systems, the Heck coupling
of 5-IdU and butyl acrylate (2) to make butyl (E)-3-(2¢-
deoxyurid-5-yl)propenoate (3) was performed in the pres-
ence of catalysts derived from Pd(OAc)2 alone or in com-
bination with tri(3-sulfonatophenyl)phosphine trisodium
salt (TPPTS, Figure 2), sodium (2-cyclohexylphosphi-
no)ethane sulfonate (DCPES), or tri(2,4-dimethyl-5-sul-
fonatophenyl) trisodium salt (TXPTS). The initial
screening was performed in H2O–MeCN (2:1) at 65 °C
(Scheme 1). Conversion to adduct 3 was monitored using
RP-HPLC (Figure 3). After 15 minutes, reactions cata-
lyzed by Pd(OAc)2 alone or in combination with TPPTS
had proceeded to approximately 75% conversion. The
DCPES-derived catalyst had given approximately 20%
conversion, while no conversion had occurred with the
TXPTS-derived catalyst. After one hour, both the ligand-
free and TPPTS systems had reached nearly 100% con-
version to product. The DCPES system required two
hours to reach completion, while the TXPTS catalyst sys-
tem showed no activity after three hours.
Figure 3 Reaction profile for coupling of 5-IdU and butyl acrylate
using Pd(OAc)2 alone or in combination with water-soluble phos-
phine ligands
Table 1 Optimization of the Coupling of 5-IdU and Cyclohexenone
O
O
Pd(OAc)2 (5 mol%)
TPPTS (0–15 mol%)
O
NH
5-IdU +
base (0–2 equiv)
H2O–MeCN (1:1)
80 °C
HO
N
O
O
P
4
SO3Na
P
Cy2P
3
5
OH
3
SO3Na
SO3Na
Entry Ligand (mol%) Base (equiv) Time (h) Ratio 5-IdU/5a
TPPTS
TXPTS
DCPES
1
2
3
4
5
6
7
8
9
none
none
1
96:4
96:3
99:1
Figure 2 Water-soluble ligands screened for Heck coupling of
5-IdU
TPPTS (15)
none
none
1
Na2CO3 (2)
Na2CO3 (2)
Et3N (0.15)
Et3N (1.2)
Et3N (2)
Et3N (2)
1.5
1
BuO2C
O
TPPTS (10)
none
1:99
Pd(OAc)2 (5 mol%)
ligand (0–12.5 mol%)
NH
CO2Bu
5-IdU +
1
80:20
1:99
1:99
1:99
99:1
HO
N
O
Et3N (2 equiv)
H2O–MeCN (2:1)
65 °C
O
none
1
2
3
OH
none
0.5
0.5
1
Scheme 1
TPPTS (10)
none
Et3N (0.15)
Na2CO3 (2)
Further optimization using Pd(OAc)2 alone or with
TPPTS was performed using the coupling of 5-IdU and 2-
cyclohexen-1-one (4) in H2O–MeCN (1:1) at 80 °C
(Table 1). Reactions did not proceed in the absence of
base (entries 1 and 2). Using sodium carbonate as the base
gave no conversion in the absence of TPPTS, but com-
plete conversion to product was observed when TPPTS
was used with Na2CO3 (entries 3 and 4). In contrast, the
ligand-free catalyst system did work when Et3N was used
as the base. At least one equivalent of the base was re-
quired for complete conversion (entries 5–7). Using
TPPTS as ligand in the presence of Et3N gave a similar
rate of conversion to the ligand-free catalyst (entry 8).
10
none
Et3N (0.5)
Na2CO3 (2)
1
99:1
a Determined by relative RP-HPLC peak area observed at l = 287 nm.
ically active species. The phosphine-free coupling was
then attempted using a catalytic amount of Et3N and stoi-
chiometric Na2CO3, but no conversion occurred (entries 9
and 10). Although Et3N is capable of forming the active
catalyst species and Na2CO3 is a competent base for the
Heck coupling in the presence of TPPTS, the combination
of bases provided an inactive catalyst system.
These results show that the coupling can be accomplished
without the use of phosphine ligand when Et3N is used as
the base. We hypothesized that Et3N generates the catalyt-
Based on these results, the coupling of 5-IdU with butyl
acrylate (2), cyclohexenone (4), and styrene (6) was car-
Synlett 2011, No. 20, 2963–2966 © Thieme Stuttgart · New York

LETTER
Aqueous-Phase Heck Coupling of 5-Iodouridine and Alkenes
2965
ried out using the optimized conditions in the presence or 8-bromo-2¢-deoxyguanosine (8-BrdG) and 8-bromo-2¢-
absence of TPPTS (Table 2). The couplings were carried deoxyadenosine (8-BrdG) were also attempted, but only
out in H2O–MeCN (1:1) with two equivalents of Et3N.17 trace amounts of products were formed. Attempts to im-
Coupling of 5-IdU with butyl acrylate in the absence of prove the conversion by changing reaction conditions,
ligand gave the product 3 in 64% yield, while a higher such as base (NaOAc, CsOH, Na2CO3), solvent ratios,
yield (74%) was achieved when TPPTS was used as a temperatures (up to 120 °C), ligands (ligand-free, TPPTS,
ligand for this coupling. Compound 3 is a precursor to TXPTS, DCPES, t-Bu-Amphos), or additives (tetrabutyl-
BVDU.18 Cyclohexanone was coupled with 5-IdU to give ammonium halides) gave no improvement.
5 in 72% yield, which was identical to that achieved when
TPPTS was used as a ligand. Coupling of 5-IdU with sty-
rene to give 7 gave higher yields than were obtained with
alkenes 2 and 4. Again, the presence of TPPTS had no ef-
From results shown in Table 1 and Table 2, it was found
that a phosphine ligand was not required when Et3N was
used as the base. In contrast, our previous studies on the
Suzuki14a and Sonogashira15b couplings showed that wa-
ter-soluble phosphine ligands were required to generate
catalytically active species. Triethylamine appears to play
two roles in the ligand-free system. In addition to acting
as a base, Et3N appears to reduce the PdII precatalyst to the
Pd0 active species. This activation would likely involve
coordination of the amine followed by b-hydride elimina-
tion.19 Deprotonation of the resulting palladium-hydride
would give the Pd0 active species. Under ligand-free con-
ditions, the active species is likely colloidal palladium,
possibly stabilized by coordination of the amine. Since lit-
tle difference is seen between the yields obtained with and
without TPPTS, it is likely that TPPTS does not play a sig-
nificant role in the Et3N-mediated reactions. When sodi-
um carbonate is used as the base, TPPTS is required,
however. TPPTS is known to reduce Pd(OAc)2 to gener-
ate Pd0(TPPTS)n and phosphine oxide.20 Upon generation
of this active species, sodium carbonate is a competent
base for the coupling reactions.
fect on the isolated yield of the coupled product.
Table 2 Heck Couplings of 5-IdU
R
O
Pd(OAc)2 (5 mol%)
TPPTS (0 or 10 mol%)
NH
R
5-IdU +
HO
Et3N (2 equiv)
H2O–MeCN (1:1)
80 °C
N
O
O
OH
Entry Alkene Ligand
Product
Yield (%)a
BuO2C
O
N
NH
1
2
none
TPPTS
64
74
2
4
6
HO
O
O
OH
Interestingly, using catalytic amounts of Et3N relative to
the 5-IdU in the presence of sodium carbonate as the stoi-
chiometric base did not result in product formation. It is
possible that a higher Et3N/Pd ratio is required to generate
or stabilize the active species. Alternatively, sodium car-
bonate may not be a competent base for the Et3N-derived
catalyst.
3
O
O
N
NH
O
3
4
none
TPPTS
72
71
HO
O
OH
In conclusion, Pd(OAc)2 in the presence of Et3N provides
an effective catalyst for the aqueous-phase Heck coupling
of 5-IdU. Good yields were obtained with three prototyp-
ical Heck substrates, butyl acrylate, styrene, and cyclo-
hexenone. The coupling could be carried out on the
unprotected nucleoside. Attempts to extend this reaction
to bromonucleosides were unsuccessful, however.
5
Ph
O
N
NH
O
5
6
none
TPPTS
82
81
HO
O
OH
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
7
a Average isolated yield of two independent trials. All products were
pure as determined by 1H NMR and 13C NMR spectroscopy.
References and Notes
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2966
J. H. Cho et al.
LETTER
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reagents were purchased from commercial sources and used
as received. 5-IdU (0.3 mmol), Pd(OAc)2 (3.4 mg, 0.015
mmol), and TPPTS (17.1 mg, 0.03 mmol, if used) were
placed in a round-bottomed flask under nitrogen. Deoxy-
genated H2O–MeCN (1:1, 3 mL) was added to the reaction
vessel, followed by the addition of the alkene (1.2 mmol)
and Et3N (61.0 mg, 0.600 mmol). The reaction was heated in
an oil bath at 80 °C until RP-HPLC (C-18 column, eluted
with a gradient ranging from 10% MeOH in H2O to 100%
MeOH in H2O) or RP-TLC [C-18, H2O–MeOH (1:2) eluent]
showed complete conversion. The reaction mixture was
diluted to 10 mL with H2O–MeOH (1:1) and the pH was
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the crude product was purified by chromatography [RP-
SiO2, H2O → MeOH–H2O (60:40)].
Butyl (E)-3-(2¢-Deoxyurid-5-yl)propenoate (3): With no
phosphine. Yield: 75.0 mg (64%). 1H NMR (500 MHz,
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Hz, 1 H), 6.88 (d, J = 15.5 Hz, 1 H), 6.17 (dd, J = 6.5, 6.5 Hz,
1 H), 5.29 (d, J = 4.5 Hz, 1 H), 5.20 (t, J = 5.0 Hz, 1 H), 4.28–
4.31 (m, 1 H), 4.14 (t, J = 6.8 Hz, 2 H), 3.84 (dd, J = 7.0, 3.5
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