Novel water-soluble phosphatriazenes: Versatile ligands for Suzuki-Miyaura, Sonogashira and Heck reactions of nucleosides

Article abstract of DOI:10.1039/c6ra19039a

Two new water-soluble phosphatriazene ligands have been synthesized as versatile ligands for complexation reactions with Pd(OAc)₂ and utilized for catalyzing column-free Suzuki-Miyaura cross-coupling of various purine and pyrimidine halonucleosides in water. The water-solubility of the catalytic system simplified the isolation of the cross-coupled products to mere filtration, while the catalytically active solution in the filtrate was recycled eight times. A novel copper-free Sonogashira coupling protocol for the nucleosides has also been established via a one-pot synthesis of FV-100, a nucleoside-based drug in phase 3 clinical trials for herpes zoster or shingles treatment. Application of the Heck reaction was demonstrated by the synthesis of another antiviral drug: BVDU.

Full text of DOI:10.1039/c6ra19039a

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: A. Kapdi, S.
Bhilare, V. Gayakhe, A. Ardhapure, Y. S. Sanghvi, C. Schulzke and Y. B. Borozdina, RSC Adv., 2016, DOI:
10.1039/C6RA19039A.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Please do not adjust margins
Page 1 of 11
RSC Advances
View Article Online
DOI: 10.1039/C6RA19039A
Journal Name
ARTICLE
Novel Water-Soluble Phosphatriazenes: Versatile Ligands for
Suzuki-Miyaura, Sonogashira and Heck Reactions of Nucleosides
Received 00th January 20xx,
Accepted 00th January 20xx
Shatrughn Bhilare,[a] Vijay Gayakhe,[a] Ajaykumar V. Ardhapure,[a] Yogesh S. Sanghvi,[b] Carola
Schulzke,[c] Yulia Borozdina,[c] Anant R. Kapdi*[a]
DOI: 10.1039/x0xx00000x
Two new water-soluble phosphatriazene ligands have been synthesized as versatile ligands for complexation
reactions with Pd(OAc)2 and utilized for catalyzing column-free Suzuki-Miyaura cross-coupling of various purine
and pyrimidine halonucleosides in water. Water-solubility of the catalytic system simplified the isolation of the
cross-coupled products by mere filtration, while the catalytically active solution in the filtrate was recycled eight
times. A novel copper-free Sonogashira coupling protocol for the nucleosides has also been established via a one-pot
synthesis of FV-100, a nucleoside-based drug in phase 3 clinical trials for herpes zoster or shingles treatment.
Application of the Heck reaction was demonstrated by the synthesis of another antiviral drug: BVDU.
www.rsc.org/
Multifunctional nucleosides, nucleotides or oligonucleotides1 have did not permit recycling of the catalyst or isolating the products in a
proved to be molecules of synthetic and biological importance given column-free manner.
their applications as antivirals2, anticancer drugs3 and as fluorescent To address this gap, we report herein the discovery of two new
biological probes4. An exponential rise in the synthesis of water-soluble phosphatriazene ligands (PTAPS 1a and PTABS
nucleoside-based therapeutic5,6 drugs has been brought about by 1b), which in combination with Pd(OAc)2 produce a powerful
efficient metal-catalyzed cross-coupling7 functionalization strategies catalyst for the Suzuki-Miyaura cross-coupling of all four
for both purines and pyrimidines. In particular, palladium-catalyzed halonucleosides in water as the reaction solvent. Greater water-
cross-coupling8 processes have contributed immensely to the growth solubility of the resultant catalytic system allows column-free17
of this field. Amongst others, palladium-catalyzed Suzuki-Miyaura9, isolation of the cross-coupled products and ability to recycle the
Sonogashira10 and Heck11 reactions have proved to be powerful tools catalyst.
in the hands of synthetic chemists facilitating greener and nucleosides and the application of Heck alkenylation for the
sustainable solutions for the modification of such structural motifs. synthesis of fluorescent nucleosides further demonstrates the
Copper-free Sonogashira cross-coupling of
In recent years, sustainability in coupling processes has been potential of the technology as unique and environmentally
associated with the employment of environmentally benign reaction attractive for drug discovery.
solvents12, recyclability of the catalyst and column-free product
Scheme 1: a) Synthesis of water-soluble PTABS and PTAPS ligands. b)
isolation as crucial characteristics.13 Often, catalytic transformations
Single crystal X-ray for PTAPS (CCDC 1489309). Ellipsoids are shown with
of nucleosides have exclusively been performed in aprotic polar
solvents without the possibility of recyclability of the catalytic
system.8b Water, in this regard could and should become the solvent
of choice8b,14 advancing the sought-after optimized sustainable
approach in particular when combined with recyclability. There are
examples in the literature reported by Shaughnessy, Hocek and
others in which water is used in combination with organic solvents
(most commonly MeCN) for the palladium-catalyzed Suzuki-
Miyaura reaction of purine and pyrimidine nucleosides.15 Only
recently, our research group presented the application of water-
50% probability.
soluble
Pd−imidate
complexes
of
the
type
[trans-
[Pd(imidate)2(PTA)2] (PTA = 1,3,5-triaza-7-phosphaadamantane) as
catalysts for synthesis of modified nucleosides in water.16 Although
good yields of the products were obtained, the respective protocol
The novel water-soluble ligands, PTAPS (1a) and PTABS (1b)
(where PS is propane sultonate and BS is butane sultonate) were
synthesized by simply stirring PTA with the respective sultones in
acetone under reflux conditions (Scheme 1). Besides confirming the
structures by general characterization techniques (NMR, IR, EA),
single crystal X-ray analysis was performed on 1a revealing the
[a]
Dr. Anant R. Kapdi, Mr. Vijay Gayakhe, Mr. Shatrughna Bhilare
Department of Chemistry
Institute of Chemical Technology
Matunga, Mumbai-400019
E-mail: ar.kapdi@ictmumbai.edu.in
Dr. Yogesh Sanghvi
Rasayan Inc. 2802, Crystal Ridge Road, Encinitas,
California, 92024-6615, United States of America
Prof. Dr. Carola Schulzke, Dr. Yulia Borodin
Institute for Biochemie
[b]
[c]
Ernst-Moritz-Arndt-Universität Greifswald
Felix-Hausdorff-Str. 4, 17489 Greifswald, Germany
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 2 of 11
ARTICLE
Journal Name
expected structure with three water molecules co-crystallised in the prevents
16
crystal lattice (see Supporting Information for more details). The chromatographic purification was carried out).
DOI: 10.1039/C6RA19039A
a
direct isolation of the products (column
View Article Online
PTAPS (1a) and water molecules created an extensive H-bonding
three dimensional network throughout the lattice, emphasizing the
excellent water solubility of the ligand. Based on this data we
believe that although, 1b did not yield crystals suitable for X-ray
characterization, both reagents are expected to have similar H-
bonding network.
Scheme 2: Palladium-catalyzed column-free Suzuki-Miyaura coupling of
halonucleosides in neat water.
To investigate the applications of the two new ligands for cross-
coupling processes, we initially examined these in the
palladium-catalyzed Suzuki-Miyaura cross-coupling of
halonucleosides in water. Preliminary observations revealed the
formation of a homogeneous solution in course of the reaction
between Pd(OAc)2 and ligands. This is a crucial observation as
it allows a column-free isolation of the products and renders the
catalytic system recyclable. Subsequently, screening studies
were undertaken, (Table 1) identifying the combination of
Pd(OAc)2/1b as the most efficient in catalyzing the coupling
reaction between 5-iodo-2ꞌ-deoxyuridine and benzofuran-2-
boronic acid at 1.0 mol% Pd(OAc)2 and 2.0 mol% 1b catalyst
loading.
Table 1: Screening studies for Suzuki-Miyaura coupling of nucleosides in
water.
aArylboronic acid (0.75 mmol), halonucleoside (0.5 mmol), Pd(OAc)2
(1.0 mol%), PTABS 1b (2.0 mol%), 3 mL H2O, Et3N (1.0 mmol) at 80
oC for 3-12 hrs. bIsolated yields by filtration. cIsolated yields after
column chromatography. dIsolated yields for the reaction carried out by
replacing Pd(OAc)2/1b with 1 mol% [Pd(Sacc)2(PTA)2] for 6 hrs with
product isolated by column chromatography.
Time
(h)
Yielda
%
No.
Catalyst
Ligand
Temp 0C
1
2
Pd(OAc)2
Pd(OAc)2
-
80
80
6
6
35b
52b
Next, an extensive investigation of various halonucleoside/aryl
boronic acid combinations was undertaken (Scheme 2). The
Pd/1b catalyst was found to be efficient in coupling all four
PTA
3
4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
TPPTS
PTAPS
PTABS
PTABS
PTABS
PTABS
PTABS
PTABS
80
80
6
3
69b
82b
88b
78b
70b
75
unprotected halonucleosides namely, 2’-deoxy-uridine,
-
cytidine, -adenosine and -guanosine with variety of
a
5
80
3
arylboronic acids in good to excellent yields. For comparison
purpose yields for column-free isolation (filtration of solids) as
well as after column chromatography are summarized in
Scheme 2. The yields for the cross-coupled products using 1st
generation [trans-[Pd(saccharinate)2(PTA)2] complex16b is also
shown where products were isolated after chromatography and
it required extended reaction times These results clearly support
the higher efficiency of the 2nd generation Pd/1b catalytic
system available for the modification of nucleosides today. The
sustainability of this catalytic system was tested next by
recycling an important consideration for a green coupling
process (Scheme 3).
6
60
3
7
R.T.
80
6
8c
9d
10e
3
80
6
65
80
12
60
Reaction conditions: 0.5 mmol of 5-IdU, 0.75 mmol of 2-benzofuranyl
boronic acid, 1.0 mol% of catalyst, 2.0 mol% of ligand, 1.0 mmol of
triethylamine, 3 ml of solvent (H2O), isolated yields by filtration
a
b
c
method, isolated yields by column chromatography, 1.0 mol% of
d
catalyst and 1.0 mol% of ligand, 0.5 mol% of catalyst and 1.0 mol%
of ligand, e 0.1 mol% of catalyst and 0.2 mol% of ligand.
Scheme 3: Recyclability studies for column-free Suzuki-Miyaura cross-
coupling using water-soluble PTABS (1b) ligand with Pd(OAc)2.
Notably, a column-free isolation protocol for the product could
be established. Equally important is the fact that the discovered
catalyst system is an order of magnitude more efficient than our
1st generation [trans-[Pd(imidate)2(PTA)2]16 complexes
reflected by reducing the reaction time to half. This is most
probably due to the latter’s limited water-solubility, which also
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 11
RSC Advances
Please do not adjust margins
Journal Name
ARTICLE
Table 2: Screening studies for Sonogashira couplingViewofArt5ic-leioOdnol-in2e-
DOI: 10.1039/C6RA19039A
deoxycytidine with phenyl acetylene.
Co-Catalyst
(mol %)
Temp
(0C)
Yielda
Ligand
Solvent
Time
(%)
-
-
-
-
-
80
80
80
80
80
80
80
80
80
80
40
60
100
H2O:ACN
H2O:ACN
H2O:ACN
H2O:ACN
H2O:ACN
H2O:ACN
H2O:ACN
H2O:ACN
H2O
24 hr
8 hr
3 hr
45 min
24 hr
24 hr
24 hr
24 hr
24 hr
12 (24 hr)
24 hr
15
60
70
75
65
66
40
15
42
The enhanced solubility exhibited by the Pd/1b catalytic
system permits convenient recycling of the catalytically active
TPA
PTAPS
PTABS
PTABS
PTABS
PTABS
PTABS
PTABS
PTABS
PTABS
PTABS
PTABS
metal that
remains in the aqueous solution while the
CuI (1.0)
CuI (2.0)
precipitated product can be simply isolated via filtration. The
exact nature of the catalytic complex present in solution is still
uncertain, however, and the possibility of a homotopic catalyst
or stabilized nanoparticles cannot be ruled out. The column-free
protocol was applied to the reaction of 5-iodo-2ꞌ-deoxyuridine
and benzofuran-2-boronic acid at 1.0 mol% Pd(OAc)2 and 2.0
mol% 1b, which at the end of the reaction was simply filtered
-
-
-
-
-
-
-
ACN
45 (69)
56
70
H2O:ACN
H2O:ACN
H2O:ACN
3 hr
30 min
65
1
Reaction conditions: 0.5 mmol of 5-IdC, 1.0 mmol of phenyl acetylene, 1.0
mol% of Pd(OAc)2, 2.0 mol% of ligand, 1.0 mmol of triethylamine, 3 ml of
solvent, H2O:ACN(1:1), isolated yields, 0.5 mol% of catalyst and 1.0
mol% of ligand, c 0.1 mol% of catalyst and 0.2 mol% of ligand.
to furnish high purity cross-coupled product (confirmed by H
NMR and HPLC). The filtrate containing the catalytic system
was found to be fully active for seven more consecutive cycles.
In the ninth catalytic application a slight drop in the yield was
observed. This protocol constitutes the first reported example of
recyclability achieved for the palladium-catalyzed Suzuki-
Miyaura cross-coupling of halonucleosides with arylboronic
acids in water.19 To check the amount of catalyst leaching/metal
contamination during synthesis of biologically active
nucleosides, the cross-coupled products were analysed by
Inductively-Coupled-Plasma Mass Spectrometry (ICP-MS)
after the 1st and the 8th cycle. The results revealed negligible
amounts (ppb levels) of palladium in these samples.
a
b
Given the reactivity of the catalyst system, we investigated the scope
of the copper-free Sonogashira coupling reactions. Differently
substituted alkynes when cross-coupled provided good yields of the
alkynated product without much influence of any electronic effects
(Scheme 4).
Scheme 4: Sonogashira coupling of 5-iodo-2-deoxycytidine with alkynes.
Encouraged by the positive Suzuki-Miyaura coupling results, we
decided to explore the potential of the Pd/1b catalytic system for the
copper-free Sonogashira coupling of halonucleosides with alkynes in
water. In recent years the palladium-catalyzed Sonogashira11
coupling reaction has proven to be a powerful synthetic tool for
installation of alkyne groups. This protocol has led to the synthesis
of fluorescent nucleosides with applications as biological probes.20
Despite its importance, the Sonogashira reaction suffers from a
major limitation. It requires the use of stoichiometric amounts of
copper co-catalyst, which might also contaminate the modified
nucleosides. Copper-free Sonogashira21 couplings have been
reported in the literature for general substrates. However, only one
report22 has highlighted its potential for the alkynylation of 5-iodo-
2ꞌ-deoxyuridine in the mixed H2O/CH3CN solvent system,
emphasizing the need for an improved and more general protocol for
the copper-free Sonogashira coupling of halonucleosides. Here, we
first investigated the utility of the phosphatriazene ligands with
Pd(OAc)2 for coupling reactions with 5-iodo-2ꞌ-deoxycytidine.
Screening studies performed on the substrate in H2O/CH3CN
revealed an outstanding activity of the new Pd/1b catalytic system
(Table 2). Notably, the pronounced acceleration of the catalytic
transformation by PTABS/Pd allowed the coupling to take place in
just 45 minutes as compared to several hours in the case of PTA/Pd
and Pd/1a systems. However, for this reaction type the isolation was
done by subjecting the crude product to column chromatographic
purification (column-free was not feasible due to lower purity
attainment).
aReaction conditions: 0.5 mmol of 5-IdC, 1.0 mmol of alkyne, 1.0 mol% of
Pd(OAc)2, 2.0 mol% of 1b, 1.0 mmol of triethylamine, 3 ml of H2O:ACN(1:1),
bisolated yields.
Next, we utilized the Sonogashira coupling for synthesis of an
antiviral nucleoside FV-100 starting with 5-iodo-2ꞌ-
deoxyuridine.23 In literature, the synthesis of FV-100 via
similar procedure yielded only 54% of the desired product with
large amounts of copper co-catalyst added.23d,e Our initial
attempts for the cross-coupling resulted in the formation of two
inseparable products (see supporting information for details).
These products were characterized as desired FV-100 and the
intermediate (alkynated product). To drive this reaction to
completion,
we
envisaged
a
sequential
one-pot
Sonogashira/cyclization24 protocol. Therefore, the first step
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 4 of 11
ARTICLE
Journal Name
involves the Sonogashira coupling of the substituted In conclusion, we have synthesized and characterized novel
View Article Online
phenylacetylene with 5-iodo-2ꞌ-deoxyuridine, which, upon water-soluble phosphatriazine ligands (1aDOanI:
d 1b) a u lized
10.1039/Cnd6RA1ti9039A
completion, is followed by copper iodide mediated them together with Pd(OAc)2 as catalytic systems for cross-
a
cyclization reaction. Our protocol allowed the synthesis of FV- coupling reactions. The potential utility of new water soluble
100 and other molecules of similar structural features in high catalytic system was clearly demonstrated by several C-C bond
yields, which are a magnitude better than those from general forming reactions. First, we established the Suzuki-Miyaura
routes reported in the literature (Characterization data compared cross-coupling of halonucleosides in water exploiting the
to literature for FV-100 was found to be identical for the recycling of the catalytic system and column-free isolation of
isolated product).25
the coupled products. Second, implementation of copper-free
The Heck alkenylation reaction10,26 is yet another darling of Sonogashira coupling in aqueous media was a crucial step
cross-coupling reactions utilized by both academia and industry towards the development of an efficient one-pot sequential
alike. Its applications range from simple to complex to organic Sonogashira/cyclization methodology leading to the synthesis
molecules of biological relevance. Given the foregoing success of an antiviral drug FV-100. Third, the Heck/Suzuki-Miyaura
with the Pd/1b catalytic system, we decided to explore the one-pot sequential synthesis of fluorescent nucleosides and the
possibility of assembling fluorescent nucleosides via one-pot efficient synthesis of another antiviral drug BVDU were also
sequential Heck/Suzuki-Miyaura27 coupling reactions (Scheme achieved in high yields. Clearly, these results support and
5). The experimental details are summarized in SI. The unique validate the value of the new Pd/1b catalyst system for the
feature of the protocol comprise the initial selective C-I bond assembly of wide range of molecules in a simple, efficient and
activation (in the presence of C-Br on the styrene synthon) economical way. Use of this catalyst may hold unprecedented
using new Pd/1b system, followed by a Suzuki-Miyaura versatility for the metal-mediated modification of a variety of
coupling in the presence of S-Phos/Pd catalytic system in modified nucleosides and a step closer towards greener
H2O/CH3CN mixture. The resultant nucleosides were found to chemistry and improved sustainability.
exhibit very good fluorescence properties due to extended
conjugation. Therefore, these nucleosides may serve as Experimental Section
:
building-blocks for construction of DNA probes.
Scheme 5: One-pot sequential Heck/Suzuki-Miyaura coupling.
All reactions were carried out under nitrogen atmosphere in schlenk
tubes using schlenk system with magnetic stirring. Unless otherwise
stated, all reagents were purchased from commercial suppliers and
used without further purification. All solvents used were distilled
from appropriate drying agents prior to use. All solvents employed
in reactions were purged with nitrogen at least for 15 minutes prior
to use. UV absorptions study was performed locally. Reactions were
monitored by thin layer chromatography using TLC silica gel 60 F254
precoated plates (Merck). Visualization was accomplished by
irradiation with UV light. C, H, and N analyses were carried out
locally. NMR data (1H, 13C and 31P) were recorded locally 500 MHz
spectrometers. Mass spectral analysis was carried out locally.
Synthesis of PTAPS (1a) & PTABS (1b):
Procedure:
To a clean and dry schlenk tube, which is evacuated and flushed
with nitrogen, added TPA (0.786 mg, 5.0 mmol) and acetone (25
ml), stirred the solution at ambient temperature till solution becomes
practically colorless. Then, added sultone (1, 3-propane sultone (1.32
ml, 15 mmol) for 1a and 1, 4-butane sultone (1.53 ml, 15 mmol) for
1b) drop wise and allow refluxing for 24 h. Then reaction mixture
cooled to R.T. and precipitated solid was separated by filtration u/N2
atmosphere. The product was washed several times with acetone and
dried well under vacuum to obtain a white solid in 92% (1.28 g ) for
1a and 88% (1.29 g ) for 1b.
Finally, to further demonstrate the potential of the Pd/1b system, we
investigated the synthesis of a commercially important antiviral drug
Brivudine (BVDU)28. Recently, we reported on the use of 1st
generation [trans-[Pd(saccharinate)2(PTA)2] complex for Heck
reaction in CH3CN.19 Taking advantage of the enhanced water
solubility exhibited by the Pd/1b system, the catalytic reaction
between 5-iodo-2ꞌ-deoxyuridine and methyl acrylate was now
possible in a H2O/CH3CN mixture furnishing the coupled product in
87% yield (Scheme 6). Hydrolysis followed by NBS-mediated
bromination, allowed the synthesis of BVDU in an overall yield of
72% over three synthetic steps with identical characterization data to
that reported in literature was obtained for the product. Two key
achievements of the novel protocol are the reduction in the amount
of CH3CN used and the lowered metal content in the final product
because the catalytic system exhibits such good water solubility.
Scheme 6: Efficient synthesis of anti-viral drug BVDU.
PTAPS (1a)
IR 3410, 2999, 2956, 1675, 1205, 1193, 1170, 1039, 1026, 809, 581,
559, 535, 521 cm-1.
1H NMR (500 MHz, D2O) δ 5.07 (d, J = 11.4 Hz, 2H), 4.87 (d, J =
11.7 Hz, 2H), 4.65 (d, J = 13.8 Hz, 1H), 4.49 (d, J = 13.8 Hz, 1H),
4.41 (d, J = 6.0 Hz, 2H), 4.00 (t, J = 14.0 Hz, 2H), 3.90 (dd, J =
14.5, 8.8 Hz, 2H), 3.17 – 3.11 (m, 2H), 2.99 (t, J = 7.2 Hz, 2H), 2.28
– 2.20 (m, 2H). 13C NMR (126 MHz, D2O) δ 79.1, 69.4, 61.1, 53.0,
52.8, 47.4, 45.8, 45.6, 15.6. 31P NMR (151 MHz, D2O) δ -83.87.
Anal. Calcd for C9H18N3O3PS: C, 38.70; H, 6.50; N, 15.05; S, 11.48.
Found: C, 38.62; H, 6.41; N, 14.97; S, 11.42.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 11
RSC Advances
Please do not adjust margins
Journal Name
PTABS (1b)
ARTICLE
133.2, 126.0, 125.7, 121.8, 109.2, 87.6, 84.8, 70.1, 60.9, 45.4. ESI-
View Article Online
IR 3419, 3003, 2960, 1675, 1451, 1210, 1171, 1044, 1024, 810, 612, MS (m/z) = 311 (M+ + H+).
DOI: 10.1039/C6RA19039A
582, 559, 528, 522 cm-1. H NMR (500 MHz, D2O) δ 4.97 (d, J = 5-(Dibenzofuran-4-yl)-2’-deoxyuridine (4d):
1
11.1 Hz, 2H), 4.79 (d, J = 11.7 Hz, 2H), 4.59 (d, J = 13.8 Hz, 1H), Representative procedure was followed by using 5-IdU (177 mg, 0.5
4.43 (d, J = 13.7 Hz, 1H), 4.32 (d, J = 6.2 Hz, 2H), 4.02 – 3.77 (m, mmol) and 4-(dibenzofuranyl)boronic acid (159 mg, 0.75 mmol),
4H), 2.95 (dd, J = 15.5, 7.5 Hz, 4H), 1.97 – 1.84 (m, 2H), 1.82 – yielded 4d (150 mg, 76% by filtration while 162 mg, 82 % by
1.70 (m, 2H). 13C NMR (125 MHz, D2O) 78.7, 69.3, 62.1, 53.0, column chromatography) in 3 h as white solid. UV absorption in
52.6, 49.7, 45.7, 45.4, 21.1, 18.0. 31P NMR (151 MHz, D2O) δ - methanol (125 µM) λmax=286 nm. 1H NMR (500 MHz, DMSO-d6) δ
83.79. Anal. Calcd for C10H20N3O3PS: C, 40.95; H, 6.87; N, 14.33; 11.62 (s, 1H), 8.41 (s, 1H), 8.12 (d, J = 7.4 Hz, 1H), 8.06 (d, J = 7.7
S, 10.93. Found: C, 40.87; H, 6.79; N, 14.28; S, 10.84.
Hz, 1H), 7.67 (t, J = 7.8 Hz, 2H), 7.49 (t, J = 7.7 Hz, 1H), 7.38 (t, J =
7.6 Hz, 2H), 6.28 (t, J = 6.7 Hz, 1H), 5.29 (d, J = 3.8 Hz, 1H), 4.87
(t, J = 4.9 Hz, 1H), 4.27 (s, 1H), 3.81 (d, J = 2.9 Hz, 1H), 3.54 (s,
2H), 2.29 – 2.14 (m, 2H). 13C NMR (125 MHz, DMSO-d6) δ 161.7,
155.3, 152.9, 150.0, 140.1, 128.3, 127.6, 123.8, 123.6, 123.2, 122.8,
121.1, 120.3, 117.8, 111.7, 108.8, 87.6, 84.5, 70.5, 61.4, 39.9. ESI-
MS (m/z) = 395 (M+ + H+). Anal. Calcd for C21H18N2O6: C, 63.96;
H, 4.60; N, 7.10. Found: C, 63.85; H, 4.64; N, 6.98.
Representative procedure:
To a solution of Palladium acetate (1.12 mg, 1.0 mol %) and PTABS
ligand (2.93 mg, 2.0 mol %) in degassed water (1.0 ml) at ambient
temperature under N2 added halo nucleoside (0.5 mmol) and the
solution stirred for 5 min at 80°C. After that reaction mixture
allowed to cool at room temperature and then added aryl boronic
acid (0.75 mmol) along with triethylamine (0.14 ml, 1 mmol) and
degassed water (2.0 ml). The resulting solution was then stirred at
80°C for 3-12 hours. The reaction progress was observed by TLC
analysis, after the completion of the reaction, filtered the precipitated
solid on Buchner funnel and washed with water (2 ml X 3 times)
followed by ethyl acetate (2 ml X 2 times) and diethyl ether (2 ml) to
afford the desired product as a solid.
5-(2-Benzofuranyl)-2'-deoxycytidine (4e) [16a]
:
Representative procedure was followed by using 5-IdC (177 mg, 0.5
mmol) and 2-benzofuranyl boronic acid (162 mg, 1 mmol) , yielded
4e (136 mg, 79% by filtration while 141 mg, 82% by column
chromatography) in 3 h as white solid. UV absorption in methanol
(125 µM) λmax=322, 271, 261 nm. 1H NMR (500 MHz, DMSO-d6) δ
8.50 (s, 1H), 7.71 (s, 1H), 7.56 (t, J = 7.1 Hz, 2H), 7.24 (dtd, J =
18.5, 7.3, 1.2 Hz, 2H), 6.99 (s, 1H), 6.93 (s, 1H), 6.15 (t, J = 6.3 Hz,
1H), 5.22 (d, J = 4.2 Hz, 1H), 5.12 (t, J = 4.7 Hz, 1H), 4.23 (s, 1H),
3.80 (d, J = 3.4 Hz, 1H), 3.69 – 3.53 (m, 2H), 2.26 – 2.02 (m, 2H).
13C NMR (125 MHz, DMSO-d6) δ 162.0, 154.5, 153.6, 150.5,
142.6, 129.0, 124.8, 123.7, 121.3, 111.9, 103.7, 98.1, 88.1, 86.2,
70.2, 61.1, 45.9. ESI-MS (m/z) = 344 (M+ + H+). Anal. Calcd for
C17H17N3O5: C, 59.47; H, 4.99; N, 12.24. Found: C, 59.41; H, 5.05;
N, 12.34.
5-(2-Benzofuranyl)-2'-deoxyuridine (4a)[16a]
:
Representative procedure was followed by using 5-IdU (177 mg, 0.5
mmol) and 2-benzofuranyl boronic acid (122 mg, 0.75 mmol) ,
yielded 4a (151 mg, 88% by filtration while 161 mg, 94 % by
column chromatography) in 3h as off-white solid. UV absorption in
1
methanol (125 µM) λmax=246,323 nm. H NMR (500 MHz, DMSO-
d6) δ 11.72 (s, 1H), 8.70 (s, 1H), 7.58 (d, J = 7.4 Hz, 1H), 7.50 (d, J
= 8.1 Hz, 1H), 7.30 (s, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.17 (t, J = 7.4
Hz, 1H), 6.19 (t, J = 6.3 Hz, 1H), 5.28 (d, J = 4.2 Hz, 1H), 5.20 (t, J
= 4.1 Hz, 1H), 4.30 (s, 1H), 3.84 (d, J = 2.8 Hz, 1H), 3.74 – 3.59 (m,
2H), 2.25 – 2.15 (m, 2H). 13C NMR (125 MHz, DMSO-d6) δ 160.7,
153.4, 149.7, 149.4, 137.5, 129.1, 124.7, 123.4, 121.4, 111.2, 105.1,
104.3, 87.9, 85.5, 70.4, 61.2, 40.8. ESI-MS (m/z) = 345 (M+ + H+).
5-(Phenanthren-9-yl)-2'-deoxycytidine (4f) [16a]
:
Representative procedure was followed by using 5-IdC (177 mg, 0.5
mmol) and 9-phenanthrenyl boronic acid (222 mg, 1 mmol) , yielded
4f (117 mg, 55% by filtration while 111 mg, 58 % by column
chromatography) in 6 h as off-white solid. UV absorption in
methanol (125 µM) λmax=298, 254 nm. 1H NMR (500 MHz, DMSO-
d6): δ 8.85 (dd, J = 14.4, 8.2 Hz, 2H), 7.99 (t, J = 7.4 Hz, 1H), 7.92
(s, 1H), 7.76 (d, J = 4.7 Hz, 1H), 7.73−7.51 (m, 5H), 7.25 (s, 1H),
6.24 (dt, J = 10.1, 6.8 Hz, 1H), 6.14 (s, 1H), 5.18 (dd, J = 9.7, 4.2
Hz, 1H), 4.75 (dt, J = 14.0, 5.0 Hz, 1H), 4.20− 4.09 (m, 1H),
3.76−3.68 (m, 1H), 3.48−3.37 (m, 2H), 2.19−1.98 (m, 2H). 13C
NMR (125 MHz, DMSO-d6): δ 164.6, 155.3, 141.1, 131.7, 131.6,
131.4, 130.8, 130.6, 130.6, 130.1, 129.2, 129.2, 127.6, 127.4, 127.3,
127.2, 126.2, 106.3, 87.6, 85.4, 70.7, 61.4, 52.4. ESI-MS (m/z) =
392 (M+ + H+). Anal. Calcd for C23H21N3O4: C, 68.47; H, 5.25; N,
10.42. Found: C, 68.33; H, 5.17; N, 10.31.
5-(Phenanthren-9-yl)-2'-deoxyuridine (4b)[16a]
:
Representative procedure was followed by using 5-IdU (177 mg, 0.5
mmol) and 9-phenanthrenyl boronic acid (167 mg, 0.75 mmol) ,
yielded 4b (117 mg, 58% by filtration while 129 mg, 64 % by
column chromatography) in 6 h as white solid. UV absorption in
methanol (125 µM) λmax=254 nm. 1H NMR (500 MHz, DMSO-d6) δ
11.57 (s, 1H), 8.83 (t, J = 8.2 Hz, 2H), 8.11 (s, 1H), 7.96 (d, J = 7.6
Hz, 1H), 7.82 – 7.52 (m, 6H), 6.27 (t, J = 6.6 Hz, 1H), 5.23 (d, J =
4.0 Hz, 1H), 4.82 (t, J = 4.6 Hz, 1H), 4.21 (s, 1H), 3.76 (d, J = 3.1
Hz, 1H), 3.52 – 3.39 (m, 2H), 2.26 – 2.10 (m, 2H). 13C NMR (125
MHz, DMSO-d6) δ 163.0, 150.9, 139.7, 131.4, 130.7, 130.2, 130.1,
129.1, 129.0, 127.6, 127.3, 127.1, 127.1, 127.1, 123.4, 123.2, 114.2,
87.8, 84.8, 70.7, 61.3, 40.4. ESI-MS (m/z) = 405 (M+ + H+). Anal.
Calcd for C23H20N2O5: C, 68.31; H, 4.98; N, 6.93. Found: C, 68.18;
H, 4.89; N, 6.82.
5-(Thiophen-3-yl)-2'-deoxycytidine (4g) [29a]
:
Representative procedure was followed by using 5-IdC (177 mg, 0.5
mmol) and 3-thienylboronic acid (192 mg, 1.5 mmol) , yielded 4g
(111 mg, 72% by filtration while 116 mg, 75% by column
chromatography) in 3 h as off-white solid. UV absorption in
5-(Thiophen-3-yl)-2'-deoxyuridine (4c) [16a]
:
1
methanol (125 µM) λmax=297 nm. H NMR (500 MHz, DMSOd6) δ
Representative procedure was followed by using 5-IdU (177 mg, 0.5
mmol) and 3-thienyl boronic acid (192 mg, 1.5 mmol) , yielded 4c
(124 mg, 80% by filtration while 135 mg, 87 % by column
chromatography) in 3 h as off-white solid. UV absorption in
methanol (125 µM) λmax=296, 277 nm. 1H NMR (500 MHz,
DMSO-d6) δ 11.54 (s, 1H), 8.47 (s, 1H), 7.97 (s, 1H), 7.58 – 7.39
(m, 2H), 6.24 (t, J = 6.0 Hz, 1H), 5.35 – 5.27 (m, 2H), 4.32 (s, 1H),
3.84 (s, 1H), 3.66 (d, J = 8.5 Hz, 2H), 2.23 (ddd, J = 15.6, 10.7, 5.2
Hz, 2H). 13C NMR (125 MHz, DMSO-d6) δ 162.1, 149.7, 137.1,
7.98 (s, 1H), 7.62 (dd, J = 29.1, 24.8 Hz, 3H), 7.16 (d, J = 4.7 Hz,
1H), 6.47 (s, 1H), 6.20 (t, J = 6.4 Hz, 1H), 5.23 (d, J = 3.6 Hz, 1H),
5.05 (s, 1H), 4.23 (s, 1H), 3.79 (d, J = 2.9 Hz, 1H), 3.57 (dd, J =
24.1, 11.5 Hz, 2H), 2.20 – 2.03 (m, 2H). 13C NMR (125 MHz,
DMSO-d6) δ 163.3, 154.2, 140.1, 133.8, 128.0, 127.1, 123.3, 103.0,
87.3, 85.2, 70.1, 61.0, 45.4. ESI-MS (m/z) = 310 (M+ + H+).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 6 of 11
ARTICLE
Journal Name
12.2, 5.7 Hz, 1H). 13C NMR (125 MHz, DMSO-d6): δ 155.9, 151.7,
5-(Dibenzofuran-4-yl)-2’-deoxycytidine (4h) [16a]
:
View Article Online
Representative procedure was followed by using 5-IdC (177 mg, 0.5 150.1, 149.7, 141.1, 129.6, 125.4, 125.2, 1D1O9I.:01,0.8180.319,/C865R.4A1,97013.92A,
mmol) and 4-(dibenzofuranyl)boronic acid (212 mg, 1 mmol) , 62.0, 45.0, 36.8. ESI-MS (m/z) = 374 (M+ + H+). Anal. Calcd for
yielded 4h (138 mg, 70% by filtration while 143 mg, 73% by C17H19N5O3: C, 59.81; H, 5.61; N, 20.52. Found: C, 59.68; H, 5.46;
column chromatography) in 6 h as white solid. UV absorption in N, 20.44.
methanol (125 µM) λmax=243, 285 nm. 1H NMR (500 MHz, DMSO- 8-(2-Benzofuranyl)-2'-deoxyguanosine (4m) [29b]
:
d6) δ 8.13 (t, J = 7.1 Hz, 1H), 7.98 (s, 1H), 7.67 (d, J = 8.2 Hz, 1H), Representative procedure was followed by using 8-BrdG (173 mg,
7.48 (t, J = 7.7 Hz, 1H), 7.44 – 7.33 (m, 2H), 6.46 (s, 1H), 6.22 (t, J 0.5 mmol) and 2-benzofuranyl boronic acid (161 mg, 1 mmol) ,
= 6.6 Hz, 1H), 5.19 (d, J = 4.0 Hz, 1H), 4.83 (t, J = 4.8 Hz, 1H), 4.18 yielded 4m (138 mg, 72% by filtration) in 12 h as off-white solid.
1
(s, 1H), 3.74 (d, J = 3.1 Hz, 1H), 3.51 – 3.40 (m, 1H), 2.18 – 2.02 UV absorption in methanol (125 µM) λmax=320 nm. H NMR (500
(m, 1H). 13C NMR (125 MHz, DMSO-d6) δ 163.6, 155.8, 155.0, MHz, DMSO-d6) δ 10.97 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.66 (dd,
154.0, 141.7, 129.1, 128.0, 124.6, 124.2, 123.8, 123.5, 121.5, 121.3, J = 8.3, 0.6 Hz, 1H), 7.45 – 7.37 (m, 2H), 7.34 – 7.28 (m, 1H), 6.60
118.4, 112.2, 103.0, 87.7, 85.5, 70.7, 61.5, 40.9. ESI-MS (m/z) = (s, 2H), 6.46 (t, J = 7.2 Hz, 1H), 5.21 (d, J = 3.2 Hz, 1H), 4.99 – 4.91
394 (M+ + H+). Anal. Calcd for C21H19N3O5: C, 64.12; H, 4.87; N, (m, 1H), 4.46 – 4.36 (m, 1H), 3.81 (dd, J = 8.7, 5.1 Hz, 1H), 3.68 –
10.68. Found: C, 64.01; H, 4.79; N, 10.58.
3.60 (m, 1H), 3.50 (dt, J = 11.0, 5.4 Hz, 1H), 2.13 (ddd, J = 13.0,
8-(2-Benzofuranyl)-2'-deoxyadenosine (4i) [16a]
:
6.8, 3.1 Hz, 1H). 13C NMR (125 MHz, DMSO-d6) δ157.0, 154.6,
Representative procedure was followed by using 8-BrdA (165 mg, 153.9, 152.4, 146.3, 137.8, 128.0, 126.1, 124.1, 122.3, 118.2, 111.8,
0.5 mmol) and 2-benzofuranyl boronic acid (161 mg, 1 mmol) , 108.4, 88.3, 84.8, 71.4, 62.4, 37.6. ESI-MS (m/z) = 384 (M+ + H+).
yielded 4i (145 mg, 79% by filtration while 160 mg, 87% by column 8-(4-Methoxyphenyl)-2'-deoxyguanosine (4n) [15b]
:
chromatography) in 6 h as off-white solid. UV absorption in Representative procedure was followed by using 8-BrdG (173 mg,
methanol (125 µM) λmax=324, 255 nm. 1H NMR (500 MHz, DMSO- 0.5 mmol) and 4-methoxyphenylboronic acid (152 mg, 1 mmol) ,
d6) δ 8.19 (s, 1H), 7.89 – 7.33 (m, 7H), 6.63 (t, J = 6.8 Hz, 1H), 5.37 yielded 4n (149 mg, 80% by filtration) in 12 h as off-white solid. UV
(t, J = 22.3 Hz, 2H), 4.56 (s, 1H), 4.01 – 3.88 (m, 1H), 3.78 – 3.48 absorption in methanol (125 µM) λmax=282 nm. 1H NMR (500 MHz,
(m, 2H), 2.34 – 2.23 (m, 1H). 13C NMR (125 MHz, DMSO-d6) δ DMSO-d6) δ 10.74 (s, 1 H), 7.58 (d, J=8.55 Hz, 2 H) , 7.09 (d,
156.2, 154.3, 152.6, 149.8, 144.9, 140.7, 127.2, 126.1, 123.6, 122.0, J=9.16 Hz, 2 H) , 6.38 (br. s., 2 H) , 6.04 (t, J=7.32 Hz, 1 H) , 5.15
119.4, 111.3, 109.4, 88.1, 85.3, 71.0, 61.9, 45.1. ESI-MS (m/z) = (d, J=4.27 Hz, 1 H), 4.99 (t, J=6.1 Hz, 1 H), 4.32 - 4.36 (m, 1 H) ,
368 (M+ + H+). Anal. Calcd for C18H17N5O4: C, 58.85; H, 4.66; N, 3.83 (s, 3 H), 3.76-3.79 (m, 1 H) , 3.59 - 3.69 (m, 1 H) , 3.53 (dt,
19.06. Found: C, 58.73; H, 4.71; N, 18.96.
J=12.06, 5.88 Hz, 1 H), 1.99 (ddd, J=13.12, 6.41,2.44 Hz, 1H). 13C
NMR (125 MHz, DMSO-d6) δ 160.3, 158.8, 153.0, 152.0, 147.3,
8-(3,4-(Methylenedioxy)phenyl)-2'-deoxyadenosine (4j) [16a]
:
Representative procedure was followed by using 8-BrdA (165 mg, 130.7, 122.7, 117.0, 114.2, 100.2, 87.9, 84.7, 71.2, 62.1, 55.3, 36.4.
0.5 mmol) and 3,4-(methylenedioxy)phenyl boronic acid (166 mg, 1 ESI-MS (m/z) = 374 (M+ + H+).
mmol) , yielded 4j (154 mg, 83% by column chromatography) in 12 8-(p-Tolyl)-2'-deoxyguanosine (4o) [29c]
:
h as off-white solid. UV absorption in methanol (125 µM) λmax=298 Representative procedure was followed by using 8-BrdG (173 mg,
1
nm. H NMR (500 MHz, DMSO-d6): δ 8.13 (s, 1H), 7.52−6.99 (m, 0.5 mmol) and p-tolylboronic acid (136 mg, 1 mmol), yielded 4o
5H), 6.15 (s, 3H), 5.54 (s, 1H), 5.26 (s, 1H), 4.46 (s, 1H), 3.87 (s, (141 mg, 79% by filtration ) in 12 h as off-white solid. UV
1H), 3.73−3.45 (m, 2H), 2.15 (s, 2H). 13C NMR (125 MHz, DMSO- absorption in methanol (125 µM) λmax=298 nm. 1H NMR (500 MHz,
d6): δ 156.6, 152.4, 150.8, 150.5, 149.4, 148.1, 124.5, 123.7, 119.6, DMSO-6) δ 8.1d3 (s, 1H), 7.59 (d, J = 7.9 Hz, 2H), 7.40 (t, J = 12.1
110.0, 109.2, 102.3, 88.9, 86.2, 72.0, 62.8, 45.9. ESI-MS (m/z) = Hz, 4H), 6.13 (dd, J = 8.3, 6.4 Hz, 1H), 5.60 (dd, J = 8.4, 3.7 Hz,
372 (M+ + H+). Anal. Calcd for C17H17N5O5: C, 54.98; H, 4.61; N, 1H), 5.24 (d, J = 3.9 Hz, 1H), 4.45 (s, 1H), 3.87 (s, 1H), 3.72 – 3.48
18.86. Found: C, 54.88; H, 4.54; N, 18.77.
(m, 2H), 2.40 (s, 3H), 2.13 (dd, J = 12.7, 6.1 Hz, 1H). 13C NMR (125
MHz, DMSO-d6) δ 156.5, 152.2, 151.0, 150.2, 140.3, 129.7, 127.1,
8-(4-(Methylthio)phenyl)-2'-deoxyadenosine (4k) [16a]
:
Representative procedure was followed by using 8-BrdA (165 mg, 119.5, 88.8, 86.1, 71.9, 62.7, 37.6, 21.4. ESI-MS (m/z) = 358 (M+ +
0.5 mmol) and 4-(methylthio)phenyl boronic acid (168 mg, 1 mmol) H+).
, yielded 4k (147 mg, 79% by column chromatography) in 12 h as 8-(4-Biphenyl)-2'-deoxyguanosine (4p) [16a]
:
off white solid. UV absorption in methanol (125 µM) λmax=280 nm. Representative procedure was followed by using 8-BrdG (173 mg,
1H NMR (500 MHz, DMSO-d6): δ 8.13 (s, 1H), 7.59 (d, J = 7.9 Hz, 0.5 mmol) and 4-biphenylboronic acid (198 mg, 1 mmol) , yielded
2H), 7.40 (t, J = 12.1 Hz, 4H), 6.13 (dd, J = 8.3, 6.4 Hz, 1H), 5.60 4p (155 mg, 74% by filtration) in 12 h as off-white solid. UV
(dd, J = 8.4, 3.7 Hz, 1H), 5.24 (d, J = 3.9 Hz, 1H), 4.45 (s, 1H), 3.87 absorption in methanol (125 µM) λmax=309 nm. 1H NMR (500 MHz,
(s, 1H), 3.72−3.48 (m, 2H), 2.40 (s, 3H), 2.13 (dd, J = 12.7, 6.1 Hz, DMSO-d6) δ 10.79 (s, 1H), 8.15 – 7.92 (m, 4H), 7.78 (d, J = 8.3 Hz,
1H). 13C NMR (125 MHz, DMSO-d6): δ 156.5, 152.2, 151.0, 150.2, 2H), 7.67 – 7.52 (m, 3H), 6.45 (s, 2H), 6.18 (t, J = 7.3 Hz, 1H), 5.13
140.3, 129.7, 127.1, 119.5, 88.8, 86.1, 71.9, 62.7, 37.6, 21.4. ESI- (d, J = 4.2 Hz, 1H), 5.02 (t, J = 5.6 Hz, 1H), 4.31 (s, 1H), 3.80 (d, J =
MS (m/z) = 374 (M+ + H+). Anal. Calcd for C17H19N5O3S: C, 54.68; 2.7 Hz, 1H), 3.72 – 3.53 (m, 2H), 2.06 (dd, J = 13.1, 6.4 Hz, 1H).
H, 5.13; N, 18.75. Found: C, 54.55; H, 5.02; N, 18.62.
13C NMR (125 MHz, DMSO-d6): δ 157.0, 153.5, 152.5, 150.2,
147.4, 133.3, 132.8, 129.0, 128.5, 128.2, 128.1, 127.5, 127.2, 126.7,
8-(p-Tolyl)-2'-deoxyadenosine (4l) [16a]
:
Representative procedure was followed by using 8-BrdA (165 mg, 117.6, 88.1, 84.9, 71.4, 62.4, 37.0. ESI-MS (m/z) = 420 (M+ + H+).
0.5 mmol) and p-tolylboronic acid (136 mg, 1 mmol), yielded 4l Anal. Calcd for C22H21N5O4: C, 63.00; H, 5.05; N, 16.70. Found: C,
(133 mg, 78% by filtration while 143 mg, 84% by column 63.09; H, 5.16; N, 16.79.
chromatography) in 12 h as white solid. UV absorption in methanol Recyclability study of column-free Suzuki-Miyaura cross-
1
(125 µM) λmax=301, 227 nm. H NMR (500 MHz, DMSO-d6): δ coupling using water-soluble PTABS ligand with Pd(OAc)2:
8.15 (s, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.2 Hz, 4H), 6.15 To a solution of Palladium acetate (2.24 mg, 1.0 mol %) and PTABS
(t, J = 7.3 Hz, 1H), 5.56 (s, 1H), 5.30 (d, J = 18.0 Hz, 1H), 4.47 (s, ligand (5.86 mg, 2.0 mol %) in degassed water (2.0 ml) at ambient
1H), 3.88 (s, 1H), 3.74−3.49 (m, 2H), 2.56 (s, 3H), 2.14 (dd, J = temperature under N2 added 5-IdU (354 mg, 1.0 mmol) and the
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 11
RSC Advances
Please do not adjust margins
Journal Name
ARTICLE
solution stirred for 5 min at 80°C. After that reaction mixture H+). Anal. Calcd for C18H19N3O5: C, 60.50; H, 5.36; N, 11.76.
View Article Online
allowed to cool at room temperature and then added 2-benzofuranyl Found: C, 60.42; H, 5.27; N, 11.66.
DOI: 10.1039/C6RA19039A
boronic acid (243 mg, 1.5 mmol) along with triethylamine (0.28 ml, 5-((4-Fluorophenyl)ethynyl)-2’-deoxycytidine (6d):
2.0 mmol) and degassed water (4.0 ml). The resulting solution was Representative procedure was followed by using 1-ethynyl-4-
then stirred at 80°C for 3 hours. The reaction progress was observed fluorobenzene, yielded 6d (120 mg, 70%) as off-white solid. UV
1
by TLC analysis, after the completion of the reaction, the reaction absorption in methanol (125 µM) λmax=284, 306 nm. H NMR (500
mixture directly filtered on Buchner funnel, aqueous filtrate MHz, DMSO-d6) δ 8.30 (s, 1H), 7.78 (s, 1H), 7.67 – 7.57 (m, 2H),
collected. The collected catalytic aqueous filtrate was recharged with 7.21 (t, J = 8.9 Hz, 2H), 7.08 (s, 1H), 6.09 (t, J = 6.3 Hz, 1H), 5.18
5-IdU (354 mg, 1.0 mmol), 2-benzofuranyl boronic acid (243 mg, (d, J = 42.2 Hz, 2H), 4.22 – 4.17 (m, 1H), 3.77 (d, J = 3.2 Hz, 1H),
1.5 mmol), triethylamine (0.14 ml, 0.5 mmol) and the reaction was 3.58 (dd, J = 29.5, 11.6 Hz, 2H), 2.14 (ddd, J = 12.8, 5.8, 3.8 Hz,
again continued with reported conditions.
Sonogashira coupling of 5-iodo-2’-deoxycytidine with alkynes:
Representative procedure:
1H), 1.99 (dt, J = 13.0, 6.4 Hz, 1H). 13C NMR (125 MHz, DMSO) δ
164.1, 163.8, 153.7, 145.3, 133.9, 119.3, 116.1, 93.1, 89.8, 87.8,
85.8, 81.8, 70.3, 61.2, 41.2. ESI-MS (m/z) = 346 (M+ + H+). Anal.
To a solution of Palladium acetate (1.12 mg, 1.0 mol %) and PTABS Calcd for C17H16N3O4F: C, 59.13; H, 4.67; N, 12.17. Found: C,
ligand (2.93 mg, 2.0 mol %) in degassed water: acetonitrile solution 59.05; H, 4.60; N, 12.08.
(1:1, 1.0 ml) at ambient temperature under N2 added 5-iodo-2’- 5-((4-Propylphenyl)ethynyl)-2’-deoxycytidine (6e) [29e]
:
deoxycytidine (177 mg, 0.5 mmol) and the solution stirred for 5.0 Representative procedure was followed by using 1-ethynyl-4-
min at 80°C. After that reaction mixture allowed to cool at room propylbenzene, yielded 6e (144 mg, 78%) as off-white solid. UV
temperature and then added phenyl acetylene derivative (1.0 mmol) absorption in methanol (125 µM) λmax=273 nm. 1H NMR (500
along with triethylamine (0.14 ml, 1.0 mmol) and degassed MHz, DMSO-d6) δ 8.25 (s, 1H), 7.71 (s, 1H), 7.46 (d, J = 8.1 Hz,
water:acetonitrile solution (1:1, 2.0 ml). The resulting solution was 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.94 (s, 1H), 6.09 (t, J = 6.5 Hz, 1H),
then stirred at 80°C for 45 min. After the completion of the reaction, 5.18 (d, J = 4.3 Hz, 1H), 5.07 (t, J = 5.0 Hz, 1H), 4.19 (td, J = 7.7,
the solvent was removed in vacuo and the resultant residue obtained 3.9 Hz, 1H), 3.77 (dd, J = 6.6, 3.2 Hz, 1H), 3.65 – 3.50 (m, 2H), 2.53
was purified using column chromatography in the CH2Cl2/MeOH (t, J = 7.5 Hz, 2H), 2.17 – 1.94 (m, 2H), 1.60 – 1.49 (m, 2H), 0.84 (t,
solvent system (96:4) to afford the desired product (4a-e) as a white J = 7.3 Hz, 3H). 13C NMR (125 MHz, DMSO-d6) δ 164.2, 153.8,
solid.
145.0, 143.2, 131.6, 128.8, 120.1, 94.3, 90.1, 87.8, 85.8, 81.3, 70.3,
5-(Phenylethynyl)-2’-deoxycytidine (6a) [29d]
:
61.3, 41.2, 37.5, 24.2, 13.9. ESI-MS (m/z) = 370 (M+ + H+). Anal.
Representative procedure was followed by using phenyl acetylene Calcd for C20H23N3O4: C, 65.03; H, 6.28; N, 11.37. Found: C, 64.92;
(0.11 ml, 1 mmol), yielded 6a (123 mg, 75%) as off-white solid. UV H, 6.22; N, 11.28.
absorption in methanol (125 µM) λmax=286 nm. 1H NMR (500 MHz, Sequential one-pot Sonogashira-Cyclization reaction:
DMSO-d6) δ 8.28 (s, 1H), 7.73 (s, 1H), 7.56 (dd, J = 7.5, 1.8 Hz, Representative procedure:
2H), 7.41 – 7.29 (m, 3H), 6.98 (s, 1H), 6.09 (t, J = 6.4 Hz, 1H), 5.18 To a solution of Palladium acetate (1.12 mg, 1.0 mol%) and PTABS
(d, J = 3.0 Hz, 1H), 5.07 (t, J = 4.7 Hz, 1H), 4.19 (s, 1H), 3.81 – 3.74 ligand (2.93 mg, 2.0 mol%) in degassed water:acetonitrile solution
(m, 1H), 3.65 – 3.51 (m, 2H), 2.18 – 1.95 (m, 2H). 13C NMR (125 (1:1, 1.0 ml) at ambient temperature under N2 added 5-iodo-2’-
MHz, DMSO-d6) δ 164.2, 153.8, 145.3, 131.6, 128.8, 122.9, 94.1, deoxyuridine (177 mg, 0.5 mmol) and the solution stirred for 5.0
89.9, 87.8, 85.8, 82.0, 70.3, 61.3, 41.2.
min at 80°C. After that reaction mixture allowed to cool at room
temperature and then added phenyl acetylene (0.11 ml, 1.0 mmol)
5-((4-Pentylphenyl)ethynyl)-2’-deoxycytidine (6b) [29e]
:
Representative procedure was followed by using 1-ethynyl-4- along with triethylamine (0.14 ml, 1.0 mmol) and degassed
pentylbenzene, yielded 6b (135 mg, 68%) as off-white solid. UV water:acetonitrile solution (1:1, 2.0 ml). The resulting solution was
absorption in methanol (125 µM) λmax=273 nm. 1H NMR (500 MHz, then stirred at 80°C for 45 min. After the completion of the reaction,
DMSO-d6) δ 8.28 (s, 1H), 7.73 (s, 1H), 7.48 (d, J = 8.2 Hz, 2H), CuI (0.380 mg, 4.0 mol %), Triethylamine (3.5 ml) and methanol
7.20 (d, J = 8.2 Hz, 2H), 6.97 (s, 1H), 6.12 (t, J = 6.5 Hz, 1H), 5.21 (4.5 ml) was added and the solution was stirred for 4.0 h. After the
(d, J = 4.3 Hz, 1H), 5.10 (t, J = 5.0 Hz, 1H), 4.22 (td, J = 7.5, 3.8 Hz, completion of the reaction, the solvent was removed in vacuo and
1H), 3.79 (q, J = 3.4 Hz, 1H), 3.67 – 3.54 (m, 2H), 2.57 (t, J = 7.6 the resultant residue obtained was purified using column
Hz, 2H), 2.16 (ddd, J = 13.2, 6.0, 3.7 Hz, 1H), 2.01 (dt, J = 13.1, 6.5 chromatography in the CH2Cl2/MeOH solvent system (96:4) to
Hz, 1H), 1.55 (dt, J = 14.9, 7.5 Hz, 2H), 1.32 – 1.19 (m, 4H), 0.84 (t, afford the desired product as a white solid.
J = 7.1 Hz, 3H). 13C NMR (125 MHz, DMSO-d6) δ 164.2, 153.8, 3-(2′-Deoxy-ribofuranosyl)-6-(4-n-pentylphenyl)-2,3-
145.0, 143.4, 131.6, 128.8, 120.1, 94.3, 90.1, 87.8, 85.8, 81.3, 70.3, dihydrofuro[2,3-d]pyrimidin-2-one (7a) [29f]
:
61.3, 41.2, 35.3, 31.2, 30.8, 22.3, 14.3. ESI-MS (m/z) = 398 (M+ + Representative procedure was followed by using 1-ethynyl-4-
H+). Anal. Calcd for C22H27N3O4: C, 66.48; H, 6.85; N, 10.57. pentylbenzene, yielded 7a (149 mg, 75%) as off-white solid. UV
1
Found: C, 66.38; H, 6.77; N, 10.51.
5-((4-Methoxyphenyl)ethynyl)-2’-deoxycytidine (6c):
absorption in methanol (125 µM) λmax=281, 352 nm. H NMR (500
MHz, DMSO-d6) δ 8.80 (s, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.27 (d, J
Representative procedure was followed by using 4-ethynylanisole, = 7.9 Hz, 2H), 7.16 (s, 1H), 6.14 (t, J = 5.9 Hz, 1H), 5.28 (d, J = 4.2
yielded 6c (134 mg, 75%) as off-white solid. UV absorption in Hz, 1H), 5.16 (t, J = 4.9 Hz, 1H), 4.25 – 4.18 (m, 1H), 3.89 (d, J =
methanol (125 µM) λmax=275 nm. 1H NMR (500 MHz, DMSO-d6) δ 3.3 Hz, 1H), 3.69 – 3.55 (m, 2H), 2.56 (t, J = 7.3 Hz, 2H), 2.41 –
8.22 (s, 1H), 7.72 (s, 1H), 7.49 (d, J = 8.5 Hz, 2H), 6.94 (t, J = 11.7 2.33 (m, 1H), 2.10 – 2.01 (m, 1H), 1.59 – 1.47 (m, 2H), 1.21 (dt, J =
Hz, 3H), 6.09 (t, J = 6.1 Hz, 1H), 5.13 (d, J = 45.0 Hz, 2H), 4.19 (s, 14.1, 9.7 Hz, 4H), 0.81 (t, J = 6.7 Hz, 3H). 13C NMR (125 MHz,
1H), 3.74 (s, 4H), 3.57 (dt, J = 13.7, 12.8 Hz, 2H), 2.16 – 2.08 (m, DMSO-d6) δ 171.4, 154.3, 154.2, 144.4, 138.2, 129.4, 126.2, 124.9,
1H), 1.99 (dd, J = 12.9, 6.1 Hz, 1H). 13C NMR (125 MHz, DMSO- 107.3, 99.0, 88.5, 88.0, 69.9, 61.0, 41.6, 35.3, 31.2, 30.8, 22.3, 14.3.
d6) δ 164.1, 159.7, 153.7, 144.7, 141.5, 133.3, 114.8, 114.5, 94.2,
90.3, 87.8, 85.7, 80.3, 70.4, 61.3, 55.6. ESI-MS (m/z) = 358 (M+ +
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 8 of 11
ARTICLE
Journal Name
3-(2′-Deoxy-ribofuranosyl)-6-(4-n-pentylphenyl)-2,3-
dihydrofuro[2,3-d]pyrimidin-2-one (7b) [25]
12.4 Hz, 3H), 6.88 (d, J = 16.4 Hz, 1H), 6.15 (t, J = 6.4 Hz, 1H),
5.23 (d, J = 4.2 Hz, 1H), 5.14 (t, J = 4.8 HDz,O1I:H10),.140.3298/C–6R4A.129203(m9A,
View Article Online
:
Representative procedure was followed by using 4-ethynylanisole, 1H), 3.78 (d, J = 3.3 Hz, 1H), 3.67 – 3.55 (m, 2H), 2.19 – 2.09 (m,
yielded 7b (107 mg, 60%) as white solid. UV absorption in methanol 2H). 13C NMR (125 MHz, DMSO-d6) δ 162.5, 149.8, 138.5, 137.8,
(125 µM) λmax=285, 356 nm. 1H NMR (500 MHz, DMSO-d6) δ 8.75 129.1, 128.0, 127.7, 126.4, 121.6, 111.1, 87.8, 84.8, 70.3, 61.4, 40.3.
(s, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.07 (s, 1H), 7.02 (d, J = 8.8 Hz, ESI-MS (m/z) = 410 (M+ + H+). Anal. Calcd for C17H17N2O5Br: C,
2H), 6.15 (t, J = 6.0 Hz, 1H), 5.26 (d, J = 4.2 Hz, 1H), 5.14 (t, J = 5.1 49.89; H, 4.19; N, 6.85. Found: C, 49.79; H, 4.14; N, 6.76.
Hz, 1H), 4.24 – 4.18 (m, 1H), 3.91 – 3.86 (m, 1H), 3.77 (s, 3H), 3.69 5-(4-(Benzofuran-2-yl) styryl)-2'-deoxyuridine (9a):
– 3.56 (m, 2H), 2.40 – 2.32 (m, 1H), 2.09 – 2.01 (m, 1H). 13C NMR Representative procedure was followed by using 2-benzofuranyl
(125 MHz, DMSO-d6) δ 171.4, 160.4, 154.3, 154.1, 137.6, 126.6, boronic acid (161 mg, 1.0 mmol), yielded 9a (312 mg, 70%) as
121.3, 115.0, 107.5, 97.7, 88.5, 87.9, 69.9, 61.0, 55.7, 41.6.
yellow solid. UV absorption in methanol (125 µM) λmax =350 nm. 1H
NMR (500 MHz, DMSO-d6) δ 11.51 (s, 1H), 8.23 (s, 1H), 7.86 (d, J
= 8.3 Hz, 2H), 7.67 – 7.50 (m, 4H), 7.46 – 7.38 (m, 2H), 7.31 – 7.20
3-(2′-Deoxy-ribofuranosyl)-6-(4-n-propylphenyl)-2,3-
dihydrofuro[2,3-d]pyrimidin-2-one (7c) [29e]
:
Representative procedure was followed by using 1-ethynyl-4- (m, 2H), 6.96 (d, J = 16.5 Hz, 1H), 6.15 (t, J = 6.6 Hz, 1H), 5.29 –
propylbenzene, yielded 7c (129 mg, 70%) as off-white solid. UV 5.18 (m, 2H), 4.29 – 4.22 (m, 1H), 3.81 – 3.75 (m, 1H), 3.69 – 3.55
1
absorption in methanol (125 µM) λmax=281, 351 nm. H NMR (500 (m, 2H), 2.20 – 2.09 (m, 2H). 13C NMR (125 MHz,DMSO-d6) δ
MHz, DMSO-d6) δ 8.82 (s, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.30 (d, J 162.5, 155.4, 149.8, 138.8, 138.4, 132.9, 132.7, 129.3, 128.7, 127.2,
= 8.2 Hz, 2H), 7.19 (s, 1H), 6.18 (t, J = 6.1 Hz, 1H), 5.28 (d, J = 4.3 127.0, 125.4, 125.0, 122.4, 121.5, 111.4, 111.1, 102.3, 87.8, 84.8,
Hz, 1H), 5.15 (t, J = 5.2 Hz, 1H), 4.24 (dq, J = 8.4, 4.2 Hz, 1H), 3.92 70.3, 61.4, 35.4. ESI-MS (m/z) = 447 (M+ + H+). Anal. Calcd for
(q, J = 3.6 Hz, 1H), 3.73 – 3.59 (m, 2H), 2.58 (t, J = 7.5 Hz, 2H), C25H22N2O6: C, 67.26; H, 4.97; N, 6.27. Found: C, 67.15; H, 4.88;
2.40 (ddd, J = 13.4, 6.2, 4.4 Hz, 1H), 2.14 – 2.04 (m, 1H), 1.64 – N, 6.19.
1.53 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H). 13C NMR (125 MHz, DMSO- 5-(4-(Naphth-2-yl) styryl)-2'-deoxyuridine (9b):
d6) δ 171.4, 154.3, 154.1, 144.2, 138.2, 129.4, 126.3, 124.9, 107.3, Representative procedure was followed by using 2-benzofuranyl
99.1, 88.5, 88.0, 69.9, 61.0, 41.6, 37.4, 24.3, 14.0.
boronic acid (161 mg, 1.0 mmol), yielded 9b (310 mg, 68%) as
yellow solid. UV absorption in methanol (125 µM) λmax = 334 nm.
1H NMR (500 MHz, DMSO-d6) δ 11.50 (s, 1H), 8.21 (d, J = 14.9
Hz, 1H), 7.86 (d, J = 7.4 Hz, 2H), 7.70 – 7.08 (m, 9H), 6.92 (dd,
One-pot sequential Heck/Suzuki-Miyaura coupling:
Representative Procedure:
To a solution of Palladium acetate (1.12 mg, 1.0 mol %) and PTABS 16.4 Hz, 2H), 6.18 – 6.11 (m, 1H), 5.28 – 5.16 (m, 2H), 4.29 – 4.22
ligand (2.93 mg, 2.0 mol %) in degassed water:acetonitrile solution (m, 1H), 3.81 – 3.75 (m, 1H), 3.68 – 3.55 (m, 2H), 2.14 (m, 2H). 13
C
(2:1, 1.0 ml) at ambient temperature under N2 added 5-iodo-2’- NMR (125 MHz, DMSO-d6) δ 162.5, 154.6, 149.8, 138.8, 138.4,
deoxyuridine (177 mg, 0.5 mmol) and the solution stirred for 5.0 129.3, 128.7, 127.2, 127.0, 125.4, 125.1, 125.0, 123.6, 122.4, 121.5,
min at 80°C. After that reaction mixture allowed to cool at room 111.4, 111.1, 110.4, 108.9, 102.3, 87.8, 84.8, 70.3, 61.4, 40.5. ESI-
temperature and then added 4-bromo styrene (0.078 ml, 1.2 mmol) MS (m/z) = 457 (M+ + H+). Anal. Calcd for C27H24N2O5: C, 71.04;
along with triethylamine (0.14 ml, 1.0 mmol) and degassed water: H, 5.30; N, 6.14. Found: C, 70.93; H, 5.24; N, 6.02.
acetonitrile solution (2:1, 2.0 ml). The resulting solution was then Synthesis of anti-viral drug BVDU via palladium-catalyzed Heck
stirred at 80°C for 18 hrs. The reaction progress was observed by reaction using the PTABS/Pd system:
TLC analysis, after the completion of the reaction, palladium acetate Step A: To a solution of Palladium acetate (2.24 mg, 1.0 mol %) and
(2.24 mg, 2 mol %) and S-phos ligand (5.8 mg, 4.0 mol %) along PTABS ligand (5.86 mg, 2.0 mol %) in degassed water: acetonitrile
with Aryl boronic acid (1.0 mmol) followed by addition of degassed solution (1:1, 2.0 ml) at ambient temperature under N2 added 5-iodo-
water:acetonitrile solution (2:1, 1.0 ml) at ambient temperature under 2’-deoxycytidine (354 mg, 1.0 mmol) and the solution stirred for 5
N2 added and the reaction mixture was stirred at 80oC for further 20 min at 80°C. After that reaction mixture allowed to cool at room
hrs. After the completion of the reaction, the solvent was removed in temperature and then added methyl acrylate (0.18 ml, 2.0 mmol)
vacuo and the resultant residue obtained was purified using column along with triethylamine (0.27 ml, 2.0 mmol) and degassed water:
chromatography in the CH2Cl2/MeOH solvent system (98:2) to acetonitrile solution (1:1, 4.0 ml). The resulting solution was then
afford the desired product as a yellow solid.
5-(4-Bromostyryl)-2'-deoxyuridine (8a):
Procedure:
stirred at 80°C for 4 h. After the completion of the reaction, the
solvent was removed in vacuo and the resultant residue obtained was
purified using column chromatography in the CH2Cl2/MeOH solvent
To a solution of Palladium acetate (1.12 mg, 1.0 mol %) and PTABS system (96:4) to afford the desired 10a product as a white solid (271
ligand (2.93 mg, 2.0 mol %) in degassed water:acetonitrile solution mg, 87%).
(2:1, 1.0 ml) at ambient temperature under N2 added 5-iodo-2’- Step-B (E)-5-[2-Carbomethoxyvinyl]-2′-deoxyuridine (dUMA) (265
deoxyuridine (177 mg, 0.5 mmol) and the solution stirred for 5.0 mg, 0.85 mmol) was dissolved in 1M NaOH (17 ml) and the mixture
min at 80°C. After that reaction mixture allowed to cool at room stirred for 3 h, filtered and filtrate adjusted to pH 4-6 with 1M HCl.
temperature and then added 4-bromo styrene (0.078 ml, 1.2 mmol) On cooling at 40C a white precipitate formed. This was filtered off
along with triethylamine (0.14 ml, 1.0 mmol) and degassed and washed with cold water (1 ml× 3 times) and acetone (1 ml x 2
water:acetonitrile solution (2:1, 2.0 ml). The resulting solution was times) and dried under vacuum to give 10b, white solid (280 mg, 91
then stirred at 80°C for 18 hrs. The reaction progress was observed %).
by TLC analysis, after the completion of the reaction, the solvent Step-C To a solution of (E)-5-(2-carboxyvinyl)-2’-deoxyuridine
was removed in vacuo and the resultant residue obtained was (280 mg, 0.84 mmol) in DMF (5 ml) was added K2CO3 (226 mg,
purified using column chromatography in the CH2Cl2/MeOH solvent 1.68 mmol) and the suspension stirred at room temperature for 15
system (98:2) to afford the desired product as off-white solid. min. Then added NBS (149 mg, 0.84 mmol) fraction-wise over 30
Yielded 8a (360 mg, 88%). 1H NMR (500 MHz, DMSO-d6) δ 11.47 min at ambient temperature. After completion of reaction, the
(s, 1H), 8.20 (s, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.36 (dd, J = 18.2, solvent was removed under vacuo and the resultant residue obtained
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 9 of 11
RSC Advances
Please do not adjust margins
Journal Name
ARTICLE
15) a) E. Mayer, L. Valis, R. Huber, N. Amann, H. AV. ieWwaAgrteicnleknOenclihnte,
was purified using column chromatography in CH2Cl2:MeOH
solvent system (96:4) to afford the desired product 10c, a white solid
(254 mg, 91%).
Synthesis, 2003, 15, 2335; b) E. C. Western, J. R. Daft, E. M. II
DOI: 10.1039/C6RA19039A
Johnson, P. M. Gannett, K. H. Shaughnessy, J. Org. Chem., 2003, 68,
6767; c) P. ꢀapek, M. Hocek, Synlett, 2005, 19, 3005; d) P. ꢀapek, R.
Pohl, M. Hocek, Org. Biomol. Chem., 2006, 4, 2278; e) M. Vrꢁbel, R.
Pohl, B. Klepetꢁꢂovꢁ, I. Votruba, M. Hocek, Org. Biomol. Chem., 2007,
5, 2849; f) M. Vrꢁbel, R. Pohl, I. Votruba, M. Sajadi, S. A. Kovalenko,
N. P. Ernsting, M. Hocek, Org. Biomol. Chem., 2008, 6, 2852; g) V.
Vongsutilers, J. R. Daft, K. H. Shaughnessy, P. M. Gannett, Molecules,
2009, 14, 3339; h) N. Fresneau, M. A. Hiebel, L. A. Agrofoglio, S.
Berteina-Raboin, Molecules, 2012, 17, 14409; i) T. Lussier, G. Herve,
G. Enderlin, C. Len, RSC Adv., 2014, 4, 46218. For more examples of
Palladium-catalyzed Suzuki-Miyaura modification of nucleosides or
nucleotides see: j) N. Amann, E. Pandurski, T. Fiebig, H. A.
Wagenknecht, Chem. Eur. J., 2002, 8, 4877; k) N. Amann, H. A.
Wagenknecht, Synlett, 2002, 5, 687; l) M. F. Jacobsen, E. E.
Ferapontova, K. V. Gothelf, Org. Biomol. Chem., 2009, 7, 905; m) A.
Okamoto, T. Inasaki, I. Saito, Tetrahedron Lett., 2005, 46, 791; n) N.
Fresneau, M. A. Hiebel, L. A. Agrofoglio, S. Berteina-Raboin,
Molecules, 2012, 17, 14409; o) E. Mayer, L. Valis, R. Huber, N.
Amann, H. A. Wagenknecht, Synthesis, 2003, 15, 2335; p) T. Lussier,
G. Herve, G. Enderlin, C. Len, RSC Adv., 2014, 4, 46218; q) V.
Vongsutilers, J. R. Daft, K. H. Shaughnessy, P. M. Gannett, Molecules,
2009, 14, 3339; r) A. A. H. Elmehriki, M. Suchy, K. J. Chicas, F.
Wojciechowski, R. H. E. Hudson, Artificial DNA: PNA & XNA, 2014,
5, e29174; s) A. Matarazzo, A. H. E. Hudson, Tetrahedron, 2015, 71,
1627.
(E)-5-[2-Carbomethoxyvinyl]-2′-deoxyuridine:(10a) [19]
:
1H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 8.38 (s, 1H), 7.32
(d, J = 15.8 Hz, 1H), 6.81 (d, J = 15.8 Hz, 1H), 6.08 (t, J = 6.4 Hz,
1H), 5.23 (d, J = 4.3 Hz, 1H), 5.14 (t, J = 5.1 Hz, 1H), 4.21 (dt, J =
8.6, 4.2 Hz, 1H), 3.75 (d, J = 3.3 Hz, 1H), 3.70 – 3.47 (m, 5H), 2.19
– 2.06 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 167.6, 162.1,
149.6, 144.4, 138.5, 116.5, 108.5, 88.0, 85.2, 70.1, 61.2, 51.7, 40.4.
(E)-5-[2-Carboxyvinyl]-2′-deoxyuridine (10b) [19]
:
1H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 11.58 (s, 1H), 8.34
(s, 1H), 7.24 (d, J = 15.8 Hz, 1H), 6.73 (d, J = 15.8 Hz, 1H), 6.09 (t,
J = 6.2 Hz, 1H), 5.19 (d, J = 31.0 Hz, 2H), 4.21 (s, 1H), 3.75 (d, J =
3.0 Hz, 1H), 3.57 (dd, J = 31.9, 11.6 Hz, 2H), 2.20 – 2.02 (m, 2H).
13C NMR (101 MHz, DMSO-d6) δ 168.4, 162.1, 149.6, 143.9,
137.9, 118.1, 108.7, 88.0, 85.1, 70.1, 61.2, 40.4.
(E)-5-[2-bromovinyl]-2′-deoxyuridine (BVDU) (10c) [19]
:
1H NMR (400 MHz DMSO-d6) δ 11.54 (s, 1H), 8.03 (s, 1H), 7.20
(d, J = 13.5 Hz, 1H), 6.81 (d, J = 13.5 Hz, 1H), 6.08 (t, J = 6.4 Hz,
1H), 5.23 (d, J = 4.2 Hz, 1H), 5.06 (t, J = 5.1 Hz, 1H), 4.22 – 4.17
(m, 1H), 3.74 (dd, J = 6.2, 2.9 Hz, 1H), 3.60 – 3.49 (m, 2H), 2.12 –
2.05 (m, 2H). 13C NMR 161.5, 149.4, 139.4, 129.8, 109.5, 106.4,
87.5, 84.4, 69.7, 60.9, 45.6.
16) a) A. R. Kapdi, V. Gayakhe, Y. S. Sanghvi, J. Garcia, P. Lozano, I. da
Silva, J. Perez, J. L. Serrano, RSC Adv., 2014, 4, 17567; b) V. Gayakhe,
A. Ardhapure, A. R. Kapdi, Y. S. Sanghvi, J. L. Serrano, L. Garcia, J.
Perez, J. Garcia, G. Sanchez, C. Fischer, C. Schulzke, J. Org. Chem.,
2016, 81, 2713.
A.R.K. and C.S. acknowledge The Alexander von Humboldt
Foundation for the research cooperation programme and is also
thanked for the equipment grant to A.R.K. We also thank the
University Grants Commission India for a UGC-SAP fellowship for
V.G., UGC-FRP position and funding for A. R. K. and a
UGC−CSIR fellowship for A.A and S.B.
17) For details on column-free protocol see: A. R. Kapdi, A. Ardhapure, Y.
S. Sanghvi, Synthesis, 2015, 47, 1163.
18) Recoverable and Recyclable Catalysts. Ed. M. Benaglia. Wiley, 2009.
19) Only example showing the recyclability in Heck alkenylation of
nucleosides was reported recently A. V. Ardhapure, Y. S. Sanghvi, A.
R. Kapdi, J. Garcia, G. Sanchez, P. Lozano, J. L. Serrano, RSC Adv.,
2015, 5, 24558.
20) For more examples of Palladium-catalyzed Sonogashira alkynylation of
nucleosides see: a) E. Petricci, M. Radi, F. Corelli, M. Botta,
Tetrahedron Lett., 2003, 44, 9181; b) N. K. Garg, C. C. Woodroofe, C.
J. Lacenere, S. R. Quake, B. M. Stoltz, Chem. Commun., 2005, 4551; c)
M. Hocek, M. Fotja, Org. Biomol. Chem., 2008, 6, 2233; d) J. H. Cho,
C. D. Prickett, K. H. Shaughnessy, Eur. J. Org. Chem., 2010, 3678; e)
D. K. Kolmel, L. J. Barandun, E. T. Kool, Org. Biomol. Chem., 2016,
14, 6407.
21) For general copper-free Sonogashira coupling protocols see: a) B.
Liang, M. Dai, J. Chen, Z. Yang, J. Org. Chem., 2005, 70, 391; b) T.
Ljungdahl, T. Bennur, A. Dallas, H. Emtenas, J. Martensson,
Organometallics, 2008, 27, 2490; c) Z. Gu, Z. Li, Z. Liu, Z. Wang, C.
Liu, J. Xiang, Catal. Commun., 2008, 2154; d) A. Komaromi, Z.
Novak, Chem. Commun., 2008, 4968; e) H. Zhong, J. Wang, L. Li, R.
Wang, Dalton Trans., 2014, 43, 2098.
22) L. Yuan, Z. Zhang, X. Xu, X. Zhou, Synth. Commun., 2014, 44, 1007.
23) a) C. McGuigan, C. J. Yarnold, G. Jones, S. Velazquez, H. Barucki, A.
Brancale, G. Andrei, R. Snoeck, E. De Clercq, J. Balzarini, J. Med.
Chem., 1999, 42, 4479; b) E. De Clercq, Nucleosides, Nucleotides and
Nucleic Acids, 2004, 23, 457; c) V. Aucagne, F. Amblard, L. A.
Agrofoglio, Synlett, 2004, 2406; d) C. McGuigan, R. N. Pathirana, R.
Snoeck, G. Andrei, E. De Clercq, J. Balzarini, J. Med. Chem., 2004, 47,
1847. e) M. Migliore, Antiviral Chemistry and Chemotherapy, 2010,
20, 107.
1) Chemistry of Nucleosides and Nucleotides. Vol. 3 Ed. L. B. Townsend.
Springer, 1994.
2) E. De Clercq, Nucleosides, Nucleotides and Nucleic Acids, 2009, 28,
586.
3) a) T. Robak, Clin. Cancer Drugs, 2014, 1, 2; b) L. P. Jordheim, D.
Durantel, F. Zoulim, C. Dumontet, Nat. Rev. Drug Discovery, 2013, 12,
447.
4) a)R. W. Sinkeldam, N. J. Greco, Y. Tor, Chem. Rev., 2010, 110, 2579;
b) A. A. Tanpure, M. G. Pawar, S. G. Srivatsan, Isr. J. Chem., 2013, 53,
366; c) A. Matarazzo, R. H. E. Hudson, Tetrahedron, 2015, 71, 1627.
5) a) Antiviral Nucleosides. Ed. C. Chu. Elsevier Science, 2003; b) Y. S.
Lee, S. M. Park, B. H. Kim, Bioorg. Med. Chem. Lett., 2009, 19, 1126.
6) V. L. Damaraju, S. Damaraju, J. D. Young, S. A. Baldwin, J. Mackey,
M. B. Sawyer, C. E. Cass, Oncogene, 2003, 22, 7524.
7) a) Metal-Catalyzed Cross-Coupling Reactions. Vol. 2 (Eds. A. de
Meijere, F. Diederich) Wiley−VCH, 2004; b) Cross-Coupling and
Heck-Type Reactions, Workbench Edition; Vol. 1−3. (Eds. G.
Molander, C. Wolfe, M. Larhed) Science of Synthesis. Thieme
Chemistry, 2013.
8) a) S. De Ornellas, T. J. Williams, C. G. Baumann, I. J. S. Fairlamb, In
C-H and C-X Bond Functionalization: Transition Metal Mediation.
(Ed. X. Ribas) RSC Catalysis Series No. 11, RSC, Dorchester, 2013; b)
K. H. Shaughnessy, Molecules, 2015, 20, 9419.
9) A. Suzuki, Angew. Chem. Int. Ed., 2011, 50, 6722.
10) a) Palladium Reagents in Organic Syntheses. Ed. R. F. Heck.
Academic: New York, 1985; b) Palladium Reagents and Catalysts. Ed.
J. Tsuji. Wiley: Chichester, 1995.
11) K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett., 1975, 16,
4467.
24) Sonogashira/cyclization strategy has been used for general substrates:
a) G. W. Kabalka, L. Wang, R. M. Pagni, Tetrahedron, 2001, 57, 8017;
b) S. Debnath, S. Mondal, J. Org. Chem., 2015, 80, 3940; c) K.
Shekarrao, P. P. Kaishap, S. Gogoi, R. C. Boruah, Adv. Synth. Catal.,
2015, 357, 1187. Sonogashira/cyclization strategy for obtaining FV-100
12) R. A. Sheldon, Green Chem., 2005, 7, 267.
13) Green Techniques for Organic Synthesis and Medicinal Chemistry.
(Eds. W. Zhang, B. W. Cue) Wiley, 2012.
14) a) H. C. Hailes, Org. Process Res. Dev., 2007, 11, 114; b) A. Chanda,
V. V. Fokin, Chem. Rev., 2009, 109, 725.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 10 of 11
ARTICLE
Journal Name
previously reported d) G. M. Luoni, C. McGuigan, G. Andrei, R.
View Article Online
Snoeck, E. De Clercq, J. Balzarini, Antiviral Chemistry and
Chemotherapy, 2004, 15, 333; e) M. J. Robbins, P. J. Barr, Tetrahedron
Lett., 1981, 22, 421 (although in this case it was not one-pot).
DOI: 10.1039/C6RA19039A
25) N. Fresneau, M.-A. Hiebel, L. A. Agrofoglio, S. Berteina-Raboin,
Tetrahedron Lett., 2012, 53, 1760.
26) For more examples of Palladium-catalyzed Heck alkenylation of
nucleosides see: a) V. Aucagne, S. Berteina-Raboin, P. Guenot, L. A.
Agrofoglio, J. Comb. Chem., 2004, 6, 717; b) P. Lagisetty, L. Zhang,
M. K. Lakshman, Adv. Synth. Catal., 2008, 350, 602; c) M. V.
Reddington, D. Cunningham-Bryant, Tetrahedron Lett., 2011, 52, 181;
d) J. Dadová, P. Vidláková, R. Pohl, L. Havran, M. Fojta, M. Hocek, J.
Org. Chem., 2013, 78, 9627; e) G. Herve, C. Len, RSC Adv., 2014, 4,
46926.
27) One-pot sequential Heck/Suzuki coupling strategy has been used for
general substrates: a) L. Joucla, G. Cusati, C. Pinel, L. Djakovitch, Adv.
Synth. Catal., 2010, 352, 1993; b) P. Cotugno, A. Monopoli, F.
Ciminale, N. Cioffi, A. Nacci, Org. Biomol. Chem., 2012, 10, 808.
28) X. Rabasseda, Drugs Today, 2003, 39, 359.
29) a) C. H. Macickova, R. Pohl, P. Horakova, L. Havran, J. Spacek, M.
Fojta, M. Hocek, Chem. Eur. J., 2011, 17, 5833; b) K. M. Rankin, M.
Sproviero, K. Rankin, P. Sharma, S. D. Wetmore, R. A. Manderville, J.
Org. Chem., 2012, 77, 10498; c) B. C. Train, S. A. Bilgesü, E. C.
Despeaux, V. Vongsutilers, P. M. Gannett, Chem. Res. Toxicol., 2014,
27, 1176; d) D. Rai, M. Johar, T. Manning, B. Agrawal, D. Y.
Kunimoto, R. Kumar, J. Med. Chem., 2005, 48, 7012; e) C. McGuigan,
H. Barucki, S. Blewett, A. Carangio, J. T. Erichsen, G. Andrei, R.
Snoeck, E. D. Clercq, J. Balzarini, J. Med. Chem., 2000, 43, 4993; f) A.
Angell, C. McGuigan, L. G. Sevillano, R. Snoeck, G. Andrei, E. D.
Clercq, J. Balzarini, Bioorg. Med. Chem. Lett., 2004, 14, 2397.
10 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 11 of 11
RSC Advances
View Article Online
DOI: 10.1039/C6RA19039A
Novel Water-Soluble Phosphatriazenes: Versatile Ligands for Suzuki-Miyaura, Sonogashira
and Heck Reactions of Nucleosides
Shatrughn Bhilare,[a] Vijay Gayakhe,[a] Ajaykumar V. Ardhapure,[a] Yogesh S. Sanghvi,[b] Carola Schulzke,[c]
Yulia Borozdina,[c] Anant R. Kapdi*[a]
Two new water-soluble phosphatriazene ligands have been synthesized as versatile ligands for
complexation reactions with Pd(OAc)2 and utilized for catalyzing column-free Suzuki-Miyaura cross-
coupling of various purine and pyrimidine halonucleosides in water. Novel copper-free Sonogashira and
one-pot FV-100 as well as synthesis of another antiviral drug BVDU are some of the other highlights.