First ligand-free, microwave-assisted, Heck cross-coupling reaction in pure water on a nucleoside-application to the synthesis of antiviral BVDU

Article abstract of DOI:10.1039/c4ra09798j

For the first time, a palladium catalyzed Heck cross-coupling reaction between 5-iodo-2′-deoxyuridine and various acrylate derivatives was performed using ligand-free conditions and microwave assistance in pure water. Those new conditions allowed a totally aqueous access to antiviral BVDU in higher yield than that reported (56 vs. 31% for three steps).

Full text of DOI:10.1039/c4ra09798j

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First ligand-free, microwave-assisted, Heck cross-
coupling reaction in pure water on a nucleoside –
application to the synthesis of antiviral BVDU†
Cite this: RSC Adv., 2014, 4, 46926
a
´
ab
Received 21st June 2014
Accepted 16th September 2014
*
Gwenaelle Herve and Christophe Len
´
¨
DOI: 10.1039/c4ra09798j
www.rsc.org/advances
For the first time, a palladium catalyzed Heck cross-coupling reaction we reported that Heck reaction can be performed in sole water
between 5-iodo-20-deoxyuridine and various acrylate derivatives was using Pd(II) as catalyst in presence of NEt3 as base under mild
performed using ligand-free conditions and microwave assistance in conditions using microwave irradiations. Two sources of
pure water. Those new conditions allowed a totally aqueous access to hydrosoluble, commercially available and inexpensive palla-
antiviral BVDU in higher yield than that reported (56 vs. 31% for three dium Pd(II) have been tested: Na2PdCl4 and Pd(OAc)2. Con-
steps).
cerning the choice of the base, various possibilities were
applicable. In our hands, NEt3 was chosen for two main
reasons: (i) it is a common inexpensive base and (ii) Shaugh-
nessy demonstrated that NEt3 was able to reduce the Pd(II)
precatalyst to the Pd(0) active species.6 The acrylate pattern has
been chosen since its ester moiety can, in theory, be the starting
point of various organic functions such as a,b-unsaturated
carboxylic acid for the formation of the CVU, an effective tool for
ligation in DNA and RNA (Fig. 1)9 or as bromovinyl group for the
formation of the antiviral BVDU (Fig. 1).10
DNA and RNA have always been a source of inspiration for
chemists. Consequently, synthetic nucleosides have attracted
considerable attention especially due to their potential biolog-
ical properties.1 One of the many modications which have
been made to the structure of regular nucleoside in an attempt
to enhance chemotherapeutic potential is the introduction of a
C–C bond on the pyridine and purine moiety. In this regard,
palladium-catalyzed cross-coupling reactions have proven to be
convenient and efficient methods.2 Among all C–C coupling
reactions, Suzuki–Miyaura has been widely used in the eld of
nucleoside chemistry either in organic solvents or in aqueous
conditions in order to create a sp2–sp2 bound.3 Nevertheless,
Heck reaction is certainly the most common method to intro-
duce an alkenyl group on nucleosides. Various methodologies
starting from mercuriated nucleosides or halonucleosides have
been reported in organic medium such as DMF and dioxan
most oen in presence of ligand.4 Even if the Heck cross-
couplings in aqueous solvents are well documented,5 surpris-
ingly only few recent examples of this reaction performed on
nucleosides in aqueous conditions have been described.6,7 To
the best of our knowledge there is no example of Heck cross-
coupling reaction on nucleoside in pure water. Our recent work
on green Suzuki reaction in water led us to explore other C–C
coupling reactions for the obtention of a larger library.8 Herein
Initial Heck cross-coupling reaction was performed using
deprotected 5-iodo-20-deoxyuridine (1) and methylacrylate (2) in
presence of Pd(II) and NEt3 in sole water at 80 ꢀC under
microwave irradiations in order to isolate compound
3
(Table 1). In accordance with our previous results on Suzuki
cross-coupling reactions, ligand-free reaction was studied. In
the presented work, the reaction time was determined by HPLC
monitoring either until no more conversion of the starting
material 1 was observed or within maximum time of one hour.
For this methodology different amounts of Pd(II) (1–10 mol%)
were tested (Table 1).
From those experiments one could see that the amount of
catalysts and the temperature have an impact on Heck cross-
coupling. Na2PdCl4 and Pd(OAc)2 were not very efficient when
a
´
´
`
Transformations Integrees de la Matiere Renouvelable, UTC-ESCOM, Centre de
`
Recherche de Royallieu, BP 20529, F-60200 Compiegne, France. E-mail: christophe.
len@utc.fr; Fax: +33 (0)3 44 97 15 91
bDepartment of Chemistry, University of Hull, Hull, HU6 7RX, England, UK
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra09798j
Fig. 1 CVU and BVDU structures.
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Table 1 Ligand-free Heck coupling of 5-iodo-20-deoxyuridine (1) with Table 2 Ligand-free Heck coupling of 5-iodo-20-deoxyuridine (1)
methylacrylate (2) in water as the sole solvent with acrylate derivatives in sole water
Entry
1
R
Product
Yielda (%)
Entry
Pd(II) (mol%)
T (ꢀC)
t (min)
3a (%)
1
2
3
4
5
6
7
8
9
10
Na2PdCl4 (1)
Na2PdCl4 (5)
Na2PdCl4 (5)
Na2PdCl4 (10)
Pd(OAc)2 (1)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
80
80
100
80
80
80
100
80
80
60
60
30
60
60
60
30
60
30
15
<5b
30b
35b,c
87
90
<5b
35b
43b,c
90
2
3
4
5
6
7
8
9
90
45
45
45
40
45
35
60
90
80
75b
a
Isolated yields. b Full conversion of starting material was not achieved.
Presence of 20-deoxyuridine.
c
used in low amounts at 80 ꢀC (Table 1, entries 1, 2, 5 and 6). In
those cases a full conversion of the starting material could not
be obtained during the rst one hour. An increase of the
temperature (100 ꢀC vs. 80 ꢀC) led to the apparition of the
dehalogenated 20-deoxyuridine (Table 1, entries 3 and 7). To
minimize this side-reaction, one potent option was to raise the
amount of palladium (10 mol% vs. 1–5 mol%) (Table 1, entries
4, 8–10). In those new conditions, Pd(OAc)2 was the best palla-
dium source for this cross-coupling reaction. Indeed full
conversion of 5-iodo-20-deoxyuridine (1) was achieved in one
hour and cross-coupled product 3 isolated in 90% yield (Table 1,
entry 8). A decrease of reaction time was studied (Table 1,
entries 9 and 10) and the same efficiency was obtained aer 30
minutes of microwaves activation (Table 1, entry 9).
Based on these results, Heck cross-coupling of 5-iodo-20-
deoxyuridine (1) with various acrylate derivatives (Table 2) was
carried out using the optimized conditions (Table 1, entry 9).
Our method was very efficient with the shortest acrylate
chains since it permit to furnish compounds 3 and 4 in 90%
yields (Table 2, entries 1 and 2). Butylacrylate and t-butylacrylate
are known to be less soluble in water compared to methyl- and
ethylacrylate. Our method still furnished compounds 5 and 7 in
45% yield even if the starting esters presented lipophilic prop-
erties (Table 2, entries 3 and 5). To the best of our knowledge,
isobutylacrylate has never been used in Heck cross-coupling
reaction on nucleosides. It showed the same low solubility as
butyl- and t-butylacrylate in water and original product 6 was
isolated in 45% yields (Table 2, entry 4). Because the introduc-
tion of a heteroatom on the carbonated chain of the acrylate
might allow access to more evolved compounds, we undertook
to examine the behavior of 2-chloro-, 2-hydroxylethylacrylate
and its corresponding cyclic ether in our totally aqueous Heck
conditions. The presence of the chlorine or of the oxygen atoms
10
51
a
Isolated yields (see ESI for purication procedure).
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did not seem to change the lipophilic properties of the reactant. BVDU via CVU is now, for the rst time, totally feasible in pure
Consequently compounds 8, 9 and 10, which have also never water in absence of other solvent. Indeed, starting from totally
been described before, were isolated in the same range of yields deprotected 5-iodo-20-deoxyuridine (1), we were able to obtain
(Table 2, entries 6–8). In order to modulate the structure, BVDU in sole water in three successive steps: free-ligand
substitution of the ester by amido and cyano groups was microwaves-assisted Heck cross-coupling; hydrolysis and
studied. By applying our methodology, we could isolate Hunsdiecker reaction (Scheme 1). In our hands, BVDU was
compounds 11 and 12 in respectively 60% and 51% yields.
obtained with a better total yield compared with the literature
It has to be noted that traditional organic Heck couplings of (56% vs. 31%).11
the less hindered reactants (methylacrylate and ethylacrylate)
have already been reported in the literature.4g,11–14 Concerning
more hindered and lipophilic acrylates, Shaugnessy and Hocek
Conclusions
reported independently the obtention of 5 using aqueous In conclusion, the rst ligand-free Heck cross-coupling of a
conditions (H2O/CH3CN).6,7 In 2004, Agrofoglio reported the nucleoside, under microwave irradiations, in pure water has
synthesis of 7 using polystyrene-based solid-supports at 100 ꢀC been described starting from 5-iodo-20-deoxyuridine (1). Ten
in DMA for 24 h.15 Finally cross-coupled products 11 and 12 compounds were isolated in modest to very good yields (40–
were briey described in the literature using reuxing DMF as 90%). Furthermore a greener synthesis of CVU and well-known
solvent.4d,16 Effectiveness of our method is difficult to compare antiviral BVDU have been proposed. Those two compounds
with reported works as many different reaction parameters such were respectively isolated in 80% and 56% yields.
as the nature of the solvent, the presence of ligand, catalyst
concentration, temperature,. were different. Yields obtained
by the present method are similar to those published when a
Notes and references
short chain compounds were used (compounds 3 and 4) and
lower for compounds with higher lipophilicity (compounds 5
and 7). Concerning the cyanovinyl derivative, our methodology
is as efficient as the one reported in literature. The acrylamide
was obtained in a slightly lower yield. Anyway the use of water as
sole solvent, the low amount of palladium (10 mol%), the
absence of ligand and the use of an alternative heating source
such as microwaves are major advantages in the eld of
sustainable chemistry.
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