Modulation of the electronic properties of non-innocent (E, E)-dibenzylideneacetone for palladium(0)-mediated heck alkenylation of 5-iodo-2′-deoxyuridine and scale-up studies

Article abstract of DOI:10.1055/s-0034-1379962

Subtle modulation of the electronic properties of the dibenzylideneacetone (dba) ligand allows the development of an efficient protocol for the Heck alkenylation of 5-iodo-2′-deoxyuridine. This protocol enables the large-scale synthesis of commercially important nucleoside building blocks. The isolation of one key molecule was accomplished under column-free conditions on a 10-gram scale.

Full text of DOI:10.1055/s-0034-1379962

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 1163–1169
paper
1163
A. R. Kapdi et al.
Paper
Synthesis
Modulation of the Electronic Properties of Non-innocent
(E,E)-Dibenzylideneacetone for Palladium(0)-Mediated Heck
Alkenylation of 5-Iodo-2′-deoxyuridine and Scale-Up Studies
Anant R. Kapdi*a
O
Ajay Ardhapurea
Yogesh S. Sanghvib
Ar
Ar
Ar
O
Ar
H
O
I
Pd
N
a Institute of Chemical Technology, Mumbai, Nathalal Road, Ma-
tunga, Mumbai-400019, India
ar.kapdi@ictmumbai.edu.in
b Rasayan Inc., 2802 Crystal Ridge Road, Encinitas, CA 92024-
6615, USA
Pd
Ar = 4-MeOC6H4
O
O
N
O
O
N
O
DMTrO
O
Ar
Ar
H
O
( )
Pd2(dba-4,4'-OMe)3 (2.5 mol%)
TBAB (1.0 equiv)
N
CF3
N
6
HO
N
H
H
+
Dedicated to Professor Richard K. Taylor on his 65th birthday
Et3N (2.0 equiv), DMF (2 mL),
80 °C, 3 h
O
H
N
H
N
CF3
DMTrO
( )6
O
O
HO
Received: 24.09.2014
Accepted after revision: 08.12.2014
Published online: 10.02.2015
In recent years several examples have also emerged in
the literature that support the rate-enhancing effect exert-
ed by simple modulation of the electronic properties of the
dibenzylideneacetone ligand.13,14 Fu and co-workers have
demonstrated, through their work on the intramolecular
Heck reactions of unactivated alkyl halides, that instead of
employing [Pd2(dba-4,4′-H)3], the use of [Pd2(dba-4,4′-
OMe)3] provided better selectivity towards the formation of
cyclized product.15 Similar observations were also reported
by Fairlamb and co-workers for the C–H bond arylation of
unprotected adenine nucleosides where significant im-
provements in yields were observed with changes in the
electronic properties of the dibenzylideneacetone ligand.16
Therefore, we were inspired to develop a more efficient C–C
bond-forming protocol for the synthesis of modified nucleo-
sides by careful modulation of the electronic properties of
the dibenzylideneacetone ligand.
Modified nucleosides are important biomolecules and
their assembly via metal-mediated cross-coupling has be-
come an attractive alternative to the classical synthetic ap-
proach in recent years. In particular, palladium-catalyzed
cross-coupling reactions such as Suzuki–Miyaura, Stille,
and Heck reactions have become an indispensable synthet-
ic tool due to ease of handling.17
Derivatization of different nucleosides using these types
of C–C bond-forming technologies has been routinely per-
formed under relatively mild conditions.18,19 One such mol-
ecule is the 2′-deoxyuridine-linker 1 (Figure 1) that has at-
tracted much attention due to its application for post-syn-
thesis conjugation of diagnostic oligonucleotides useful as a
fluorescent tag or an affinity probe. The only reported syn-
thesis for obtaining molecule 1 involved the cross-coupling
of the toxic mercuric salt of 2′-deoxyuridine with a substi-
tuted acrylamide linker in low yield.20 It is therefore of im-
portance to develop a more efficient synthetic protocol
with scale-up possibility. In this regard, we herein report
DOI: 10.1055/s-0034-1379962; Art ID: ss-2014-n0586-op
Abstract Subtle modulation of the electronic properties of the diben-
zylideneacetone (dba) ligand allows the development of an efficient
protocol for the Heck alkenylation of 5-iodo-2′-deoxyuridine. This pro-
tocol enables the large-scale synthesis of commercially important nu-
cleoside building blocks. The isolation of one key molecule was accom-
plished under column-free conditions on a 10-gram scale.
Key words Heck alkenylation, dibenzylideneacetone, scale-up, nucle-
osides, 5-iodo-2′-deoxyuridine
Palladium-catalyzed cross-coupling reactions are pow-
erful carbon–carbon (C–C) and carbon–heteroatom bond-
forming reactions that have found applications in a variety
of fields. These processes, in particular Suzuki–Miyaura,1
Stille,2 Sonogashira,3 Buchwald–Hartwig4 amination, and
Heck5 alkenylation reactions, have commonly been used to
test the range of application of novel palladium cata-
lysts/precatalysts. The employment of strongly σ-donating
ligands in combination with common palladium precursors
has allowed researchers to develop efficient catalytic sys-
tems to address synthetically challenging problems. One of
the most commonly applicable phosphine-free palladi-
um(0) precursors is the air-stable complex [Pd2dba-H3] first
reported by Ishii.6–9 Elaborate studies to understand the ef-
fect of ‘non-innocent’ dba-H on the catalytic activity of dif-
ferent cross-coupling reactions have been systematically
carried out by Fairlamb and co-workers.10,11 Amatore and
Jutand, through their studies involving cyclic voltammetry,
chronoamperometry, and UV spectroscopic experiments
have also provided support for the involvement of the dba-
H ligand in catalytic cycles of these processes.12
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1163–1169

1164
A. R. Kapdi et al.
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Synthesis
our findings on the effect of modulation of the electronic
properties of the dibenzylideneacetone ligand on the cata-
lytic activity of Heck alkenylation reaction of 5-iodo-2′-de-
oxyuridine with different linkers providing an easy access
to compounds analogous to molecule 1, and in the process
develop a more efficient protocol for accessing molecule 1.
Scale-up studies of molecule 1 have also been performed
with a column-free protocol for purification of the nucleo-
side as one of the unique features of the new processes re-
ported herein.
At the outset of our screening studies (Table 1), varia-
tion in solvent (entries 1–5) revealed that N,N-dimethyl-
formamide was the only solvent giving any kind of reactivi-
ty under the given conditions. Although lower concentra-
tions of catalyst loading would be beneficial for the
synthesis of nucleosides, 2.5 mol% was found to be the opti-
mum catalyst concentration to obtain better yields of the
product (entries 6–10). Changes in the amount of base, sol-
vent, or additive (TBAB) brought about a slight improve-
ment in yield. To study the catalyst, several different palla-
dium(0) and palladium(II) phosphine free precursors were
employed (entries 23–29). Most of the palladium(II) pre-
cursors failed to furnish the desired product, while an inter-
esting effect was observed in the case of substituted
[Pd2(dba-4,4′-X)3] complexes. Interestingly, increasing the
electron-density using a methoxy substituent on the diben-
zylideneacetone ligand brought about an appreciable im-
provement in yield (entry 28), whereas a retarding effect
was observed with an electron-withdrawing substituent
(CF3) on the dibenzylideneacetone (entry 29). To the best of
our knowledge this is the first report of any such enhance-
ment being observed for the Heck alkenylation of nucleo-
sides brought about by simple modulation of the electronic
properties of the dibenzylideneacetone ligand. Drastic im-
provement in the yield as well as reduction in reaction time
was observed when a soluble base triethylamine was em-
ployed instead of sodium acetate (entries 30 and 31). This
resulted in the reduction of reaction time from 18 hours to
only 3, making this protocol synthetically attractive. From
all these results it was decided to employ [Pd2(dba-4,4′-
OMe)3] as the catalyst in the presence of triethylamine as
the soluble base in N,N-dimethylformamide.
O
O
H
H
O
N
CF3
N
N
H
O
N
O
DMTrO
HO
1
Figure 1 2′-Deoxyuridine-based C5-linker molecule; DMTr = 4,4′-di-
methoxytrityl
Heck alkenylation of 5-iodo-2′-deoxyuridine with dif-
ferent linkers has been routinely performed under palladi-
um-catalyzed conditions using phosphine as the ligand.21
Although the reactivity of these catalytic systems towards
such transformations has been high, the phosphine-based
byproducts make the overall process synthetically less at-
tractive. To overcome this problem we envisaged the possi-
bility of employing easily accessible [Pd2(dba-4,4′-H)3] as a
ligand-free22 palladium(0) precursor for the Heck reaction
of DMTr-protected 5-iodo-2′-deoxyuridine with different
linkers and set about performing screening studies.
Table 1 Optimization Study for Heck Reaction of 5′-O-DMTr-5-iodo-2′-deoxyuridine
O
O
N
O
O
H
H
O
I
( )6
N
N
CF3
N
N
H
H
H
H
catalyst, TBAB
base, solvent
N
N
CF3
O
O
N
( )6
+
O
O
O
DMTrO
DMTrO
HO
HO
1
Entry
Catalyst
Catalyst (mol%)
TBAB (equiv)
Base (equiv)
Solvent
Temp (°C) Time (h)
Yield (%)
28
Solvent screening study
1
2
3
4
5
[Pd2(dba-4,4′-H)3]
[Pd2(dba-4,4′-H)3]
[Pd2(dba-4,4′-H)3]
[Pd2(dba-4,4′-H)3]
[Pd2(dba-4,4′-H)3]
2.5
2.5
2.5
2.5
2.5
1.0
1.0
1.0
1.0
1.0
NaOAc (2.5)
NaOAc (2.5)
NaOAc (2.5)
NaOAc (2.5)
NaOAc (2.5)
DMF (2 mL)
NMP (2 mL)
80
80
80
80
80
18
18
18
18
18
a
–
a
toluene (2 mL)
xylene (2 mL)
dioxane (2 mL)
–
a
–
a
–
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A. R. Kapdi et al.
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Synthesis
Table 1 (continued)
Entry
Catalyst
Catalyst (mol%)
TBAB (equiv)
Base (equiv)
Solvent
Temp (°C) Time (h)
Yield (%)
Effect of catalyst concentration
6
7
[Pd2(dba-4,4′-H)3]
[Pd2(dba-4,4′-H)3]
[Pd2(dba-4,4′-H)3]
[Pd2(dba-4,4′-H)3]
[Pd2(dba-4,4′-H)3]
2.5
1.0
1.0
1.0
1.0
1.0
NaOAc (2.5)
NaOAc (2.5)
NaOAc (2.5)
NaOAc (2.5)
NaOAc (2.5)
DMF (2 mL)
DMF (2 mL)
DMF (2 mL)
DMF (2 mL)
DMF (2 mL)
80
80
80
80
80
18
18
18
48
48
28
26
1.5
8
1.0
<10
<10
<10
9
0.75
0.25
10
Impact of base (equiv)
11
12
13
14
15
[Pd2(dba-4,4′-H)3]
2.5
2.5
2.5
2.5
2.5
1.0
1.0
1.0
1.0
1.0
NaOAc (2.0)
NaOAc (2.5)
NaOAc (3.0)
NaOAc (3.5)
NaOAc (4.0)
DMF (2 mL)
DMF (2 mL)
DMF (2 mL)
DMF (2 mL)
DMF (2 mL)
80
80
80
80
80
18
18
18
18
18
28
28
38
37
34
[Pd2(dba-4,4′-H)3]
[Pd2(dba-4,4′-H)3]
[Pd2(dba-4,4′-H)3]
[Pd2(dba-4,4′-H)3]
Impact of concentration
16
17
18
[Pd2(dba-4,4′-H)3]
2.5
2.5
2.5
1.0
1.0
1.0
NaOAc (3.0)
NaOAc (3.0)
NaOAc (3.0)
DMF (1 mL)
DMF (2 mL)
DMF (4 mL)
80
80
80
18
18
18
25
38
28
[Pd2(dba-4,4′-H)3]
[Pd2(dba-4,4′-H)3]
Impact of TBAB (equiv)
19
20
21
22
[Pd2(dba-4,4′-H)3]
2.5
2.5
2.5
2.5
0
NaOAc (3.0)
NaOAc (3.0)
NaOAc (3.0)
NaOAc (3.0)
DMF (2 mL)
DMF (2 mL)
DMF (2 mL)
DMF (2 mL)
80
80
80
80
18
18
18
18
5
34
38
36
[Pd2(dba-4,4′-H)3]
[Pd2(dba-4,4′-H)3]
[Pd2(dba-4,4′-H)3]
0.5
1.0
2.0
Catalyst screening study
23
24
25
26
27
28
29
[Pd2(dba-4,4′-H)3]
2.5
5.0
5.0
5.0
5.0
2.5
2.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
NaOAc (3.0)
NaOAc (3.0)
NaOAc (3.0)
NaOAc (3.0)
NaOAc (3.0)
NaOAc (3.0)
NaOAc (3.0)
DMF (2 mL)
DMF (2 mL)
DMF (2 mL)
DMF (2 mL)
DMF (2 mL)
DMF (2 mL)
DMF (2 mL)
80
80
80
80
80
80
80
18
18
18
18
18
18
18
38
a
PdCl2
–
a
[K2PdCl4]
–
a
Pd(OAc)2
–
a
Pd/C
–
[Pd2(dba-4,4′-OMe)3]
[Pd2(dba-4,4′-CF3)3]
49
8
Selection of base
30
31
[Pd2(dba-4,4′-OMe)3]
[Pd2(dba-4,4′-OMe)3]
2.5
2.5
1.0
1.0
NaOAc (3.0)
Et3N (2.0)
DMF (2 mL)
DMF (2 mL)
80
80
18
3
49
64
Impact of reaction temperature
32
[Pd2(dba-4,4′-OMe)3]
[Pd2(dba-4,4′-OMe)3]
[Pd2(dba-4,4′-OMe)3]
2.5
2.5
2.5
1.0
1.0
1.0
Et3N (2.0)
Et3N (2.0)
Et3N (2.0)
DMF (2 mL)
DMF (2 mL)
DMF (2 mL)
80
60
40
3
8
64
57
48
33
34
18
a No reaction.
Our next focus was to further study the effect of change
in electronic properties of the dibenzylideneacetone ligand
on the Heck alkenylation of DMTr-protected and unprotect-
ed 5-iodo-2′-deoxyuridine with different linkers (Table 2).
To assess the generality of the observed rate differences in
Heck alkenylation, three palladium(0) precursors were em-
ployed, namely [Pd2(dba-4,4′-H)3], [Pd2(dba-4,4′-OMe)3],
and [Pd2(dba-4,4′-CF3)3]. First, we investigated this reaction
under the given set of conditions using triethylamine as the
base.
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Table 2 Effect of Modulation of Electronic Properties on Heck Reaction of 5-Iodo-2′-deoxyuridine
O
O
N
H
H
O
I
alkene
N
N
Pd2(dba-4,4'-X)3 (2.5 mol%)
TBAB (1.0 equiv)
O
N
+
alkene
O
O
Et3N (2.0 equiv), DMF (2 mL)
80 °C, 3 h
RO
RO
HO
HO
1–6
Entry
Alkene
R
Yield (%) with catalyst employed
[Pd2(dba-4,4′-H)3]
[Pd2(dba-4,4′-OMe)3]
[Pd2(dba-4,4′-CF3)3]
H
N
H
N
CF3
CF3
( )6
1
2
DMTr (1)
H (2)
30
64
13
O
O
O
H
N
H
N
( )6
25
75
10
O
O
3
4
DMTr (3)
H (4)
57
63
71
77
31
45
O
O
O
F
H
N
F
F
5
6
H (5)
H (6)
51
69
62
88
39
27
O
O
OMe
It is apparent that dba-4,4′-X ligands play a major role in
determining the reactivity of the catalytic system. In most
cases, appreciable differences in reactivity were observed
with the [Pd2(dba-4,4′-OMe)3] complex, outperforming all
others irrespective of the substrate (DMTr-protected or un-
protected 5-iodo-2′-deoxyuridine). Although, with increase
in chain length of the linker a more pronounced effect could
be observed. It is, at present, difficult to predict the exact
reason for such an observation, however a nanoparticular
pathway (similar to the ones reported by Jeffrey22c and
de Vries22a for phosphine-free Heck reactions) seems more
of a possibility. Although, the involvement of substituted
dba-4,4′-X ligands could be directly involved in the rate-de-
termining oxidative addition step.10c This process could be
accelerated by the donating properties of the dba-4,4′-X li-
gands.
iodo-2′-deoxyuridine with the 6-acryloyl-N′-trifluoroace-
tyl-1,6-diaminohexane linker23 on a 5.0-mmol (3.28 g) scale
using [Pd2(dba-4,4′-OMe)3] as the catalyst (Table 3).
For the purification of the cross-coupled product 1, a
liquid antisolvent purification method24,25 was viewed as a
viable option for the isolation of the nucleoside as it is less
energy intensive and ideal for scale-up processes, it has im-
proved handling, and it is contaminant free. The crude
product on dissolution in dichloromethane was stirred at
0–5 °C and slow addition of toluene as the antisolvent re-
sulted in the precipitation of compound 1, which was fil-
tered, washed with pentane resulting in 61% of pure isolat-
ed product (confirmed by LCMS, NMR, and HPLC). Excellent
reproducibility was observed when the reaction was re-
peated on a 5.0- and 15-mmol scale (Table 3).
To the best of our knowledge, this is most efficient,
high-yielding nonchromatographic protocol for the synthe-
sis of DMTr-protected nucleoside 1. It should also be men-
tioned that the process for C–C bond formation developed
herein is mild enough to sustain an acid-labile (DMTr) and a
base-labile (TFA) group during this reaction.
These results encouraged us to explore the possibility of
developing an efficient and more importantly a column-
free protocol for the synthesis of fully protected nucleoside
1. The reaction conditions developed herein were employed
to carry out the catalytic cross-coupling reaction of the 5-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1163–1169

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Table 3 Scale-Up Synthesis of DMTr-Protected Nucleoside 1 (Column-Free Purification Protocol by Liquid Antisolvent Precipitation)
Scale-up
Amount
Solvent (mL)
Yield (%) (Weight)
Nucleoside
Alkene
Catalyst
TBAB
5.0 mmol
Et3N
10 mmol
1st
5.0 mmol
(3.28 g)
5.0 mmol
(1.33 g)
0.12 mmol
(0.14 g)
DMF (10)
DMF (10)
DMF (15)
DMF (30)
61%
(2.42 g)
(1.61 g)
(1.01 g)
2nd
3rd
4th
5.0 mmol
(3.28 g)
5.0 mmol
(1.33 g)
0.12 mmol
(0.14 g)
5.0 mmol
(1.61 g)
10 mmol
(1.01 g)
61%
(2.48 g)
7.61 mmol
(5.0 g)
7.61 mmol
(2.02 g)
0.19 mmol
(0.21 g)
7.61 mmol
(2.45 g)
15.22 mmol
(1.54 g)
61%
(3.7 g)
15.23 mmol
(10.0 g)
15.23 mmol
(4.04 g)
0.38 mmol
(0.42 g)
15.23 mmol
(4.90 g)
30.44 mmol
(3.08 g)
60%
(7.3 g)
An efficient and environmentally friendly protocol for
the large-scale synthesis of DMTr-protected C5-modified
nucleosides has been made possible through the simple
modulation of the electronic properties of the dibenzylid-
eneacetone ligand in the phosphine-free palladium(0) pre-
cursor [Pd2(dba-4,4′-X)3]. The electron-donating substitu-
ent (OMe) on the dibenzylideneacetone ligand [Pd2(dba-
4,4′-OMe)3] significantly improved the product yield over
its electron-withdrawing (CF3) substituent during cross-
coupling reactions of nucleosides. Scale-up of the synthetic
process for compound 1 was also demonstrated with 10
grams of substrate with excellent reproducibility. Further-
more, the product isolation without chromatography
makes this protocol very attractive for further scale-up and
applicable to the synthesis of other nucleoside analogues.
NMR data (1H or 13C) were recorded on Bruker Avance 400 spectrom-
eters. HPCL-MS analyses were performed on a Shimadzu Prominence
spectrometer. The ionization mechanism used was electrospray in
positive and negative ion full scan mode using MeCN as solvent and
N2 gas for desolvation. IR spectra were recorded on a Perkin-Elmer
spectrophotometer 16F PC FTIR, by preparing KBr pellets. C, H and N
analyses were carried out with a Carlo Erba instrument.
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Heck Alkenylation of 5-Iodo-2‘-deoxyuridine; General Procedure
1H NMR (400 MHz, CDCl3): δ = 7.85 (s, 1 H), 7.41–7.39 (m, 2 H), 7.31–
7.22 (m, 8 H), 6.98–6.83 (m, 6 H), 6.28–6.25 (m, 1 H), 4.50–4.48 (m, 1
H), 4.11–4.05 (m, 3 H), 3.78 (s, 3 H), 3.76 (s, 3 H), 3.43–3.40 (m, 2 H),
2.57–2.54 (m, 1 H), 2.31–2.26 (m, 1 H), 1.57–1.53 (m, 2 H), 1.34–1.26
(m, 3 H), 0.91–0.87 (m, 3 H).
13C NMR (101 MHz, CDCl3): δ = 167.3, 161.4, 158.6, 149.4, 144.2,
141.5, 135.8, 135.4, 135.3, 129.9, 127.9, 127.0, 119.8, 113.2, 110.0,
86.8, 86.5, 86.0, 72.0, 64.1, 55.1, 41.2, 30.4, 18.9, 13.5.
A solution of precatalyst [Pd2(dba-4,4′-OMe)3] (2.5 mol%) in anhyd
DMF (1.0 mL) was stirred for 5 min at r.t. under N2. Then, nucleoside
(0.5 mmol) along with TBAB (0.5 mmol) were added and the solution
stirred for 5 min at 80 °C. Thereafter, Et3N (1.0 mmol) and alkene
linker (0.5 mmol) were also added with DMF (1.0 mL). The resulting
solution was then stirred at 80 °C for 3.0 h. When the reaction was
complete, the solvent was removed under vacuo and the resultant
residue obtained was purified by column chromatography (CH2Cl2–
MeOH, 96:4) to afford the desired product as a white solid. Spectro-
scopic data matched those for previously reported compounds in the
literature: 1,20 4,26 5,27 and 6.28
MS (ESI, –): m/z = 655 [M – H+].
Anal. Calcd for C37H40N2O9: C, 67.67; H, 6.14; N, 4.27. Found: C, 67.54;
H, 6.01; N, 4.13.
Large-Scale Heck Alkenylation of 5-Iodo-2′-deoxyuridine via
Column-Free Protocol; General Procedure
(E)-3-[1-(5-{[Bis(4-methoxyphenyl)(phenyl)methoxy]methyl}-4-
hydroxytetrahydrofuran-2-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrim-
idin-5-yl]-N-[6-(2,2,2-trifluoroacetamido)hexyl]acrylamide (1)20
A solution of precatalyst [Pd2(dba-4,4′-OMe)3] (2.5 mol%) in anhyd
DMF (5 mL) was stirred for 5 min at r.t. under N2. Then, nucleoside (5
mmol) along with TBAB (5 mmol) were added and the solution
stirred for 5 min at 80 °C. Thereafter, Et3N (10 mmol) and alkene
linker (5 mmol) were also added with DMF (5 mL). The resulting solu-
tion was then stirred at 80 °C for 3.0 h. The mixture was poured into
ice-cold water (500 mL) and the resultant mixture was stirred vigor-
ously for 30 min. This solution was then extracted with CH2Cl2 (3 ×
100 mL) and the combined organic layer was evaporated in vacuo to
give a solid residue. The solid obtained was subsequently dissolved in
CH2Cl2 (50 mL). The solution was cooled with ice and stirred on a
magnetic stirrer. To this solution was slowly added toluene to precipi-
tate out the desired product 1 which was later recrystallized (EtOH,
20 mL) to provide pure product (2.42 g, 61%) identical to that reported
by Lyttle and co-workers.20
Yield: 0.258 g (64%).
IR (KBr): 3424, 3080, 2934, 1705, 1609, 1508, 1251, 1178, 1033, 829
cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 11.55 (s, 1 H), 9.40 (s, 1 H), 8.03–
8.01 (m, 2 H), 7.34–7.17 (m, 8 H), 7.09–6.84 (m, 5 H), 6.18–6.15 (m, 1
H), 5.29 (s, 1 H), 4.23 (s, 1 H), 3.89–3.86 (m, 1 H), 3.72 (s, 3 H), 3.70 (s,
3 H), 3.22–3.09 (m, 6 H), 2.35–2.14 (m, 2 H), 1.52–1.39 (m, 5 H), 1.32–
1.25 (m, 5 H).
13C NMR (101 MHz, DMSO-d6): δ = 165.7, 162.1, 158.2, 156.4 (q, J = 38
Hz, COCF3), 149.5, 145.0, 142.8, 135.7, 132.3, 129.8, 127.9, 127.8,
126.7, 122.1, 117.5 (q, J = 288 Hz, CF3), 113.3, 109.5, 85.6, 85.5, 84.6,
70.2, 63.9, 54.9, 29.0, 28.2, 26.0, 25.9.
19F NMR (376 MHz, DMSO-d6): δ = –77.09.
MS (ESI): m/z = 795 [M + H+].
Anal. Calcd for C41H45F3N4O9: C, 61.96; H, 5.71; N, 7.05. Found: C,
61.82; H, 5.63; N, 6.95.
Acknowledgement
We thank the Department of Science and Technology-India for DST
Inspire Faculty Award (IFA12-CH-22) for A.R.K. The Alexander von
Humboldt Foundation is also thanked for the equipment grant to
A.R.K.
(E)-3-{1-[4-Hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2,4-
dioxo-1,2,3,4-tetrahydropyrimidin-5-yl}-N-[6-(2,2,2-trifluoro-
acetamido)hexyl]acrylamide (2)
Yield: 0.184 g (75%).
IR (KBr): 3439, 2942, 1721, 1671, 1556, 1477, 1294, 988 cm–1
.
Supporting Information
1H NMR (400 MHz, DMSO-d6): δ = 11.56 (s, 1 H), 9.41 (s, 1 H), 8.27 (s,
1 H), 8.06 (s, 1 H), 7.12–6.98 (m, 4 H), 6.17–6.13 (m, 1 H), 5.27–5.25
(m, 1 H), 5.16–5.14 (m, 1 H), 4.27 (s, 1 H), 3.80 (s, 1 H), 3.68–3.55 (m,
2 H), 3.17–3.10 (m, 4 H), 2.17–2.13 (m, 2 H), 1.48–1.43 (m, 4 H), 1.29–
1.22 (m, 4 H).
13C NMR (101 MHz, DMSO-d6): δ = 165.6, 162.0, 156.8 (q, J = 39 Hz,
COCF3), 149.4, 142.5, 132.1, 121.7, 117.5 (q, J = 289 Hz, CF3), 109.2,
87.6, 84.6, 70.0, 61.0, 29.0, 28.1, 26.0, 25.9.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379962.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1163–1169

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