Synthesis and photophysical characterisation of fluorescent 8-(1 H-1,2,3-triazol-4-yl)adenosine derivatives

Article abstract of DOI:10.1002/ejoc.200900018

A series of 8-(1-H-1,2,3-triazol-4-yl)-substituted adenosine derivatives have been symthesised by using Sonogashira cross-coupling and click chemistry. The use of click chemistry enables an easy access to different substituents in the 4- posilion of the triazole ring. The modified nucleosides show high absorptivities due to a single strongly allowed electronic transition and, for some of the derivatives, high quantum yields in organic as well as in water solution making them promising as fluorescent probes in nucleic acid contexts. Furthermore, the different substituents of the 1,2,3-triazole makes the wavelength of emission tunable without changing the absorption properties substantially. Wiley-VCH Verlag GmbH & Co. KGaA.

Full text of DOI:10.1002/ejoc.200900018

FULL PAPER
DOI: 10.1002/ejoc.200900018
Synthesis and Photophysical Characterisation of Fluorescent
8-(1H-1,2,3-Triazol-4-yl)adenosine Derivatives
Christine Dyrager,[a] Karl Börjesson,[b] Peter Dinér,[a] Annelie Elf,[a] Bo Albinsson,[b]
L. Marcus Wilhelmsson,[b] and Morten Grøtli*[a]
Keywords: Nucleoside derivatives / Click chemistry / Sonogashira coupling / Fluorescence / Triazoles / Nitrogen heterocy-
cles / Density functional calculations
A series of 8-(1H-1,2,3-triazol-4-yl)-substituted adenosine
derivatives have been synthesised by using Sonogashira
cross-coupling and click chemistry. The use of click chemis-
try enables an easy access to different substituents in the 4-
position of the triazole ring. The modified nucleosides show
high absorptivities due to a single strongly allowed electronic
transition and, for some of the derivatives, high quantum
yields in organic as well as in water solution making them
promising as fluorescent probes in nucleic acid contexts.
Furthermore, the different substituents of the 1,2,3-triazole
makes the wavelength of emission tunable without changing
the absorption properties substantially.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Adenosine have previously been functionalized in the 8-
position resulting in nucleoside analogues with fluorescent
properties.[13,14] Our approach to modified fluorescent nu-
cleosides involves the functionalisation of adenosine in the
8-position with differently substituted triazole rings by
using a 1,4-regioselective copper-catalyzed azide/alkyne cy-
cloaddition (CuAAC).[15] The 1,3-dipolar cycloaddition,
often referred to as click chemistry, have been used in vari-
ous applications, e.g. organic synthesis, drug discovery, and
chemical biology[16] and has successfully been exploited in
conjugation of various molecules to oligonucleotides.[17]
The use of click chemistry allows the 4-substituent of the
1,2,3-triazole ring to be easily varied, through the use of
different azides, which enables tuning of the electronic and
optical properties of the nucleoside analogues.
In this paper, we present the synthesis and photophysical
characterisation of a series of 8-(1H-1,2,3-triazol-4-yl)aden-
osine analogues showing promising photophysical proper-
ties such as high fluorescence quantum yields (up to 64%),
high absorptivities (up to 24000 –1 cm–1), and, thus, high
brightness (absorptivityϫquantum yield) as well as tunable
emission wavelengths.
Introduction
The field of fluorescent nucleic acid base analogues has
expanded significantly in recent years. There have been re-
ported a number of fluorescent nucleosides with an artifi-
cial nucleobase or modified nucleobase,[1] which have been
used to study the structures of nucleic acids[2,3] and their
biological functions such as replication, transcription, re-
combination and repair.[4,5] Several fluorescent pyrimidine
analogues have been reported, e.g. the tricyclic cytosine an-
alogues 1,3-diaza-2-oxophenothiazine (tC)[6,7] and its oxo
analogue tCO,[8] which have high fluorescence quantum
yields even after incorporation into single- and double-
stranded DNA. Furthermore, the phenylpyrrolocytosine is
designed to engage guanine with an additional hydrogen
bond[9] as well as the furan-modified pyrimidines that have
been shown to detect abasic sites[3] and binding of ligands
to RNA.[5] However, most of the fluorescent nucleobase an-
alogues are purine derivatives. Among them, 2-aminopurine
(2-AP) is the most frequently used.[10] 2-AP has a high
quantum yield (Φ = 0.68) at a physiological pH and is selec-
tively excited by light of lower energy than the natural nu-
cleic acid bases. Other commercially available fluorescent
purine analogues are the pteridines, 3-methylisoxanthop-
terin (3MI),[11] and 6-methylisoxanthopterine (6MI).[12]
Results and Discussion
[a] Medicinal Chemistry, Department of Chemistry, University of
Gothenburg,
Synthesis
Kemivägen 10, 41296 Gothenburg, Sweden
Fax: +46-31-7723840
E-mail: grotli@chem.gu.se
Starting from commercially available adenosine (1), 8-
bromoadenosine (2) was easily obtained by using bromine
[b] Department of Chemical and Biological Engineering/Physical
Chemistry, Chalmers University of Technology,
Kemivägen 10, 41296 Gothenburg, Sweden
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
in
a sodium acetate buffer as described previously
(Scheme 1).[18] The hydroxy groups in the 3Ј- and 5Ј-posi-
tion of compound 2 were protected with a tetraisopropyldi-
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M. Grøtli et al.
FULL PAPER
silyl group (TIPDS) making compound 3 much more solu- the cycloaddition reactions to completion, and products
ble in organic solvents.[19] The TMS-protected alkyne was 6a–6c were obtained in high yields (73–99%).
installed by using a Sonogashira coupling protocol, and
Compounds 6d and 6e were prepared according to the
general method B, in which compound 5 was treated with
the crude azide (preformed from NaN3 and the correspond-
ing alkyl bromide in water) by using CuSO4/sodium ascorb-
ate and TBTA in DMSO.
compound 4 was obtained in good yields (80%).[14]
The azides required for preparation 6f–6i were synthe-
sized by a proline-promoted CuI-catalyzed coupling reac-
tion in DMSO (general method C).[21] Compound 5, CuI
and TBTA were added directly to the reaction mixture con-
taining the crude azide and allowed to react under micro-
wave-assisted heating at 60 °C for 5 min. This two-step one-
pot procedure generated 6f–6i in moderate yields (51–61%).
Nucleoside derivative 6d was deprotected, in order to inves-
tigate the photochemical properties for the adenine deriva-
tives in water. Compound 6d was treated with 1  TBAF in
THF overnight leading to the water-soluble compound 7d
in 98% yield after column chromatography.
Photophysical Characterisation
Molar absorptivities and quantum yields for the nucleo-
side derivatives (6a–6i) were determined in THF. All deriva-
tives show similar absorption properties; the molar extinc-
tion coefficient varies between 16000 and 24000 –1 cm–1,
and the absorption maximum varies between 289 and
296 nm (Table 1). Furthermore, the nucleosides with ali-
phatic substituents (6a–6e) show a very similar absorption
envelope (Figure 1). This similarity is not very surprising,
because the conjugated π-system of these compounds ends
at the triazole ring, and the non-conjugated part has a very
small influence on the spectroscopic properties. The absorp-
tion envelope for these compounds (6a–6e) is more struc-
tured and slightly blueshifted compared to the derivatives
Scheme 1. Reagents and conditions: (a) Br2/NaOAc buffer, 83%;
(b) tetraisopropyldisiloxane dichloride, pyridine, 65%; (c) TMS/
acetylene, Pd(PPh3)2Cl2, CuI, NEt3, THF, 50 °C, 50 min, 80%; (d)
NH3 (aq. 25%)/EtOAc (1.5:1, v/v), room temp., 14 h, 81%; (e) ge-
neral procedure A–C, see Exp. Sect.; (f) TBAF (1  in THF;
2 equiv.), THF, room temp., overnight, 99%.
Table 1. Photophysical characterisation of absorption and fluores-
cence properties of compounds 6a–6i in THF.
Deprotection of the TMS group was performed under
basic conditions (NH3 in ethyl acetate) to yield the terminal
alkyne 5. The 1,2,3-triazole ring was synthesised by using a
copper-catalyzed [3+2]-cycloaddition between the alkyne 5
and the corresponding azide. This reaction allows the 4-
substituent of the 1,2,3-triazole ring to be easily varied,
through the use of various azides. Compounds 6a–6c were
prepared by a copper-catalyzed [3+2]-cycloaddition accord-
ing to the general method A. The reaction was carried out
as a two-step one-pot reaction in which compound 5 was
treated with the preformed crude triflic azide (obtained
from NaN3 and triflic anhydride in dichloromethane/
water)[20] in the presence of tris[(1-benzyl-1H-1,2,3-triazol-
4-yl)methyl]amine (TBTA) and sodium ascorbate by using
microwave-assisted heating at 60 °C for 5 min. The copper
present in the crude azide products was sufficient to drive
Compound
R
Absmax Emmax
ε
ΦF
[nm]
[nm]
[–1 cm–1]
6a
6b
6c
benzyl
1-phenylethyl
pyridin-4-ylme-
thyl
isopentyl
pentyl
3-aminophenyl
4-methoxyphenyl 294
290
289
289
344
342
346
16000
21000
16000
0.64
0.63
0.49
6d
6e
6f
6g
6h
6i
289
289
296
343
342
402
370
368
396
18000
17000
24000
23000
21000
21000
0.62
0.62
0.38
0.03
0.05
0.05
4-tolyl
4-chlorophenyl
294
294
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Fluorescent 8-(1H-1,2,3-Triazol-4-yl)adenosine Derivatives
with aromatic substituents (6g–6i). The fluorescence prop-
erties show a larger deviation between the aliphatic and aro-
matic nucleosides. The derivatives with aliphatic substitu-
ents (6a–6e) have very similar properties with an emission
maximum around 344 nm. In addition, they exhibit high
quantum yields (0.49–0.64), structured emissions, and com-
parably small Stokes’ shifts (53–57 nm). The emission maxi-
mum for the nucleosides with the aromatic substituents (6f–
6i) are redshifted (25–55 nm) compared to the aliphatic de-
rivatives (6a–6e). The aromatically substituted nucleosides
(6g–6i) show low quantum yields (0.03–0.05) and large
Stokes’ shift (74–102 nm). In contrast, nucleoside 6f ex-
hibits a high fluorescence quantum yield (0.38) despite the
conjugation between the aromatic substituent and the tri-
azole ring. Furthermore, it shows the strongest absorption
(24000 –1cm–1) and largest Stokes shift (106 nm). The tune-
ability in emission wavelength is very interesting and is
potentially useful in fluorescence resonance energy transfer
experiments, where the emission wavelength should energeti-
cally overlap the absorption of the acceptor. In fact, the
energy of the emission of the nucleosides matches the en-
ergy of the absorption of our previously characterized base
analogues tC/tCO,[7,8] and thus, constitutes promising nu-
cleic acid FRET donor candidates.
Figure 2. Absorption (solid line) and emission (dashed line) spectra
of compound 7d in water (top). Calculated oscillator strengths and
energies for the singlet–singlet electronic transitions below
50000 cm–1 (bottom).
logue. In fact, the brightness value as a monomer (not
within a base stack) is calculated to be 9000 –1 cm–1, which
is more than twice the value of 2-aminopurine under similar
conditions.[10,22]
Theoretical Evaluation
In order to gain further insights on the potential energy
surface of the adenine–triazole bond, a series of density
funtional theory (DFT) calculations were performed giving
a conformational analysis of the triazole ring and the ade-
nine ring of the model compound 9-methyl-8-(1H-1,2,3-tri-
azol-4-yl)adenine. A relaxed energy scan of the torsional
angle (ω) at the B3LYP/6-31G(d) level shows that the two
rings are coplanar in the global minimum having the methyl
groups in an anti arrangement (ω = 180°, conformer A,
Figure 3). Rotation of the triazole ring leads to a local mini-
Figure 1. Absorption (solid line) and emission (dashed line) of nu-
cleoside 6a–6i at room termperature in THF. The sharp peak at
347 nm for the weakly fluorescent derivatives is due to Raman scat-
tering.
Because hydrogen bonding often has a strong influence mum, in which the methyl groups are positioned syn to each
on the fluorescence quantum yield, one of the more promis- other, but in this conformer the two rings are not coplanar
ing derivatives 6d was deprotected to yield 7d (Scheme 1), (ω = 22°) due to the steric repulsion between the triazole
and the photophysical properties of 7d were measured in ring and the adenine ring (conformer B, Figure 3).
water. The absorption maximum (282 nm) is slightly blue-
The global and local minima (conformer A and B) and
shifted (7 nm) in water compared to that in THF, and the the transition state (TSROT) for the rotation between the
vibronic structure disappears (Figure 2). Furthermore, the two minima was optimised at the B3LYP/6-311G(d,p) level
emission maximum (354 nm) is slightly redshifted, and the of theory.[23] The calculation shows that the global mini-
vibronic structure is lost.
mum is 6.7 kcalmol–1 (conformer A, Figure 4) more stable
The redshift of the emission is commonly observed in than the local minimum (conformation B), and the transi-
highly polar and hydrogen-bonding solvents and is usually tion state for the rotation is located 7.5 kcalmol–1 above
explained by a larger stabilisation of the excited state com- the global minimum. This suggests that the main conformer
pared to the ground state. Importantly, the high fluores- populated in the ground state is conformer A. The global
cence quantum yield is retained in water (Φ = 0.50), which minimum is furthermore shallow enough to allow a quite
makes compound 7d a very promising fluorescent base ana- broad distribution of torsional angles in the ground state.
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M. Grøtli et al.
FULL PAPER
This electronic tranistion is dominated by the HOMO Ǟ
LUMO+1 configuration (see Supporting Information).
Furthermore, this transition is quite strong (f = 0.7) and
isolated from other strong electronic transitions (Table S1).
It is thus reasonable to assign the lowest absorption band
of the studied compounds to this single, strongly allowed
electronic transition. By looking at the dominating configu-
rations for this transition it is also possible to predict that
the formal single bond between the adenine and triazol
moieties in the ground state is gaining bond order in the
excited state (see orbital diagrams, Figure 4) and, thus, a
planarized excited state would result. Furthermore, the ef-
fect on the electronic transitions by twisting the molecular
planes were investigated. The lowest electronic transition of
the model compound blueshifts upon twisting the dihedral
angle, and this might explain why the absorption spectrum
is slightly broader than the emission and also why the calcu-
lated transition energy (for the co-planar compound) is
slightly lower than experimentally observed.
Figure 3. Potential energy surface and electrostatic potential of the
model compound 9-methyl-8-(triazol-4-yl)adenine. Energies are
calculated at the B3LYP/6-311G(d,p) level of theory.
Finally, the effect of substitution on the triazol ring was
investigated by replacing the methyl group in the model
compound by either a conjugated (4-tolyl) or a non-conju-
gated (benzyl) substituent. Very marginal redshifts along
with slightly increased oscillator strengths were observed
(not shown) in accordance with the experimental observa-
tions.
Molecular orbital calculations of electronic transitions
were made for the DFT-optimized model compound. The
calculated electronic transitions agree very well with the ex-
perimentally observed spectrum, as is usually the case for
the INDO-based methods applied on “simple” heteroarom-
atic compounds.[24] The lowest singlet electronic transition
(S0 Ǟ S1) for the model with co-planar adenine and triazole
rings (conformer A) is calculated to be at 31700 cm–1
(315 nm), which is slightly lower in energy than observed.
Conclusions
A series of adenine derivatives have been synthesised by
using Sonogashira cross coupling and click chemistry. The
click chemistry provides a means of easy tuning of the fluo-
rescence properties of the nucleosides. The wavelength of
the emission can be varied up to 60 nm by using different
azide derivatives, without changing the absorption proper-
ties substantially. Most importantly, the nucleosides show
high absorptivities due to a single strongly allowed elec-
tronic transition and, for one of the derivatives, high fluo-
rescence quantum yields in organic as well as in water solu-
tion.
The target compounds have an intact hydrogen-bonding
pattern ensuring specific interactions with thymine, which
together with excellent photophysical properties make the
modified nucleosides promising as fluorescent probes in nu-
cleic acids. We are currently developing the synthesis of the
deoxyadenosine analogues, which are to be incorporated
into DNA and photophysically characterised as base ana-
logues.
Experimental Section
General: All reagents and solvents were of analysis or synthesis
grade. 1H and 13C NMR spectra were recorded with a JEOL JNM-
EX 400-spectrometer at 400 and 100 MHz, respectively, in CDCl3
or [D6]DMSO. Chemical shifts are reported in ppm with the sol-
vent residual peak as internal standard (CHCl3: δH= 7.26 ppm;
Figure 4. Frontier orbitals for the model compound 9-methyl-8-
(1H-1,2,3-triazol-4-yl)adenine.
CDCl3: δC= 77.0 ppm; [D6]DMSO: δH= 2.50 ppm, δC =
1518
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Fluorescent 8-(1H-1,2,3-Triazol-4-yl)adenosine Derivatives
39.52 ppm). IR spectra were recorded with a Perkin–Elmer 16PC
FT-IR spectrometer. The reactions were monitored by thin-layer
chromatography (TLC), on silica-plated aluminium sheets (Silica
gel 60 F254, E. Merck) and detecting spots by UV light (254 and
365 nm). Flash chromatography was performed on Merck Silica
gel 60 (0.040–0.063 mm). Microwave heating was performed with a
Biotage Initiator microwave apparatus, with a fixed hold time at
the desired reaction temperature (wattage was automatically varied
to maintain the desired temperature). High-resolution mass spec-
8-[1-(Pyridin-4-ylmethyl)-1H-1,2,3-triazol-4-yl]-3Ј,5Ј-O-(tetraiso-
propyldisiloxane-1,3-diyl)adenosine (6c): The title compound was
synthesised according to the general procedure A. The residue was
dissolved in EtOAc (40 mL) and washed with brine (2ϫ5 mL). The
organic phase was dried (MgSO4), filtered, concentrated and puri-
fied by column chromatography (dichloromethane/MeOH, 16:1).
Compound 5 (0.10 g, 0.19 mmol) and 4-picolylamine (22 mg,
0.21 mmol) gave 6c (92 mg, 73 %) as a white foam. Rf = 0.21
1
(dichloromethane/MeOH, 16:1). H NMR (CDCl3): δ = 0.99–1.23
trometric data (nanospray FT-ICR-MS) were obtained from (m, 28 H), 3.55 (br. s, 1 H), 3.98–4.06 (m, 3 H), 5.05 (d, J = 5.9 Hz,
BioAnser, Sahlgrenska Science Park, Gothenburg, Sweden.
1 H), 5.53–5.64 (m, 3 H), 6.16 (br. s, 2 H), 6.93 (s, 1 H), 7.13 (br.
s, 2 H), 8.17–8.21 (m, 2 H), 8.59 (s, 2 H) ppm. 13C NMR (CDCl3):
δ = 12.7, 12.8, 13.2, 13.3, 17.1, 17.1, 17.3, 17.4, 17.5, 17.5, 17.5,
53.0, 62.4, 71.7, 74.3, 82.2, 90.2, 119.7, 122.4, 125.5, 139.9, 142.1,
Method A. General Procedure for the Synthesis of 6a–6c: NaN3
(6.6 equiv.) was dissolved in water and dichloromethane (0.03 mL/
mmol NaN3, respectively). The solution was cooled to 0 °C, and
triflic anhydride (3.3 equiv.) was added dropwise to the cooled solu-
tion. The reaction mixture was stirred vigorously at 0 °C for 2 h,
and the solution was extracted with dichloromethane. The organic
phase was washed with saturated aqueous NaHCO3 to give a
crude triflic azide solution. Benzylamine (22 mg, 0.21 mmol),
CuSO4·5H2O (0.02 equiv.) and NaHCO3 (1.1 equiv.) were dissolved
in water (0.36 mL/mmol amine), and the crude triflic azide solution
was added followed by MeOH until the solution became homogen-
eous. The reaction mixture was stirred at room temperature for
30 min. Compound 5 (0.1 g, 0.187 mmol), TBTA (0.06 equiv.) and
-ascorbic acid sodium salt (0.11 equiv.) were added, and the reac-
143.0, 150.6, 150.7, 152.9, 155.4 ppm. IR (KBr): ν = 696, 884, 1038,
˜
1085, 1133, 1466, 1581, 1607, 1643, 2866, 2945 cm–1. HRMS (FT-
ICR-MS): calcd. for C30H46N9O5Si2 [M + H] 668.3155; found
668.3138.
Method B. General Procedure for the Synthesis of 6d–6e: NaN3
(23 equiv.) was added to a solution of the appropriate 1-bromoalkyl
derivative (10 equiv.) in water (0.53 mL/mmol NaN3), and the reac-
tion mixture was refluxed for 20 h. The water phase was extracted
with dichloromethane (2ϫ10 mL), and the combined organic lay-
ers were washed with water (10 mL), dried with MgSO4,and the
solvent was removed under reduced pressure. The generated azide
tion mixture was heated in a microwave cavity at 60 °C for 5 min. was added to a solution of compound 5 (1 equiv.), TBTA
The solvent was removed under reduced pressure, and care was
taken not to let the solid residual run dry. The crude product was
purified by column chromatography.
(0.05 equiv.), -ascorbic acid (0.1 equiv.), CuSO4 (0.05 equiv.) in
DMSO (2.7 mL/mmol adenosine derivative), and the reaction mix-
ture was heated in the microwave cavity at 60 °C for 5 min. The
reaction mixture was diluted with water (10 mL), and the water
phase was extracted with EtOAc (4ϫ10 mL). The combined or-
ganic layers were washed with brine (2 ϫ 10 mL), dried with
MgSO4, and the solvent was removed under reduced pressure. The
crude product was purified by column chromatography (toluene/
EtOAc, 1:1).
8-(1-Benzyl-1H-1,2,3-triazol-4-yl)-3Ј,5Ј-O-(tetraisopropyldisiloxane-
1,3-diyl)adenosine (6a): The title compound was synthesised ac-
cording to the general procedure A. The crude product was purified
by column chromatography (toluene/EtOAc, 1:2). Compound 5
(0.1 g, 0.187 mmol) and benzylamine (22.0 mg, 0.205 mmol) gave
6a (0.126 g, 99%) as a white foam. Rf = 0.25 (toluene/EtOAc, 1:2).
1H NMR (CDCl3): δ = 1.00–1.18 (m, 28 H), 3.39 (br. s, 1 H), 3.99– 8-(1-Isopentyl-1H-1,2,3-triazol-4-yl)-3Ј,5Ј-O-(tetraisopropyldi-
4.06 (m, 3 H), 5.03–5.04 (m, 1 H), 5.54–5.64 (m, 3 H), 5.84 (br. s,
2 H), 6.94 (d, J = 1.1 Hz, 1 H), 7.32–7.38 (m, 5 H), 8.09 (s, 1 H),
8.19 (s, 1 H) ppm. 13C NMR (CDCl3): δ = 12.8, 12.8, 13.2, 13.3,
17.1, 17.2, 17.3, 17.4, 17.5, 17.5, 17.6, 54.6, 62.7, 71.9, 74.4, 82.3,
90.2, 119.8, 125.1, 128.5, 129.2, 129.4, 133.9, 139.6, 142.6, 150.7,
siloxane-1,3-diyl)adenosine (6d): The title compound was synthe-
sised according to the general procedure B. The crude product was
purified by column chromatography (toluene/EtOAc, 1:1). Com-
pound 5 (100 mg, 0.187 mmol) and 1-bromo-3-methylbutane
(283 mg, 1.87 mmol) gave 6d (106 mg, 87%) as a white foam. Rf =
1
152.8, 155.3 ppm. IR (KBr): ν = 695, 884, 1037, 1085, 1131, 1466,
0.20 (1:1 toluene/EtOAc). H NMR (CDCl3): δ = 0.96–0.97 (m, 6
˜
1580, 1641, 2866, 2945 cm–1. HRMS (FT-ICR-MS): calcd. for
C31H47N8O5Si2 [M + H] 667.3203; found 667.3212.
H), 1.01–1.19 (m, 28 H), 1.56–1.67 (m, 1 H), 1.81–1.86 (m, 2 H),
3.43 (s, 1 H), 4.02–4.07 (m, 3 H), 4.43–4.46 (m, 2 H), 5.05 (d, J =
6.2 Hz, 1 H), 5.56–5.59 (m, 1 H), 5.98 (s, 2 H), 6.91 (s, 1 H), 8.16
(s, 1 H), 8.19 (s, 1 H) ppm. 13C NMR (CDCl3): δ = 12.8, 12.8,
13.2, 13.3, 17.1, 17.2, 17.3, 17.4, 17.5, 17.5, 17.6, 22.3, 25.5, 39.0,
49.1, 62.8, 72.0, 74.4, 82.3, 90.2, 119.8, 124.9, 139.1, 142.8, 150.7,
8-[1-(1-Phenylethyl)-1H-1,2,3-triazol-4-yl]-3Ј,5Ј-O-(tetraisopropyldi-
siloxane-1,3-diyl)adenosine (6b): The title compound was synthe-
sised according to the general procedure A. The residue was dis-
solved in EtOAc (40 mL) and washed with brine (2ϫ5 mL). The
organic phase was dried (MgSO4), filtered, concentrated and puri-
fied by column chromatography (toluene/EtOAc, 1:1). Compound
5 (0.10 g, 0.19 mmol) and (1-phenylethyl)amine (25 mg, 0.21 mmol)
gave 6b (86.4 mg, 86%) as a white foam. Rf = 0.28 (toluene/EtOAc,
152.8, 155.3 ppm. IR (KBr): ν = 696, 884, 1037, 1087, 1133, 1298,
˜
1467, 1581, 1642, 2867, 2947 cm–1. HRMS (FT-ICR-MS): calcd.
for C29H51N8O5Si2 [M + H] 647.3516; found 647.3488.
8-(1-Pentyl-1H-1,2,3-triazol-4-yl)-3Ј,5Ј-O-(tetraisopropyldisiloxane-
2:3). 1H NMR (CDCl3): δ = 1.00–1.22 (m, 28 H), 3.25 (t, J = 1,3-diyl)adenosine (6e): The title compound was synthesised accord-
7.3 Hz, 2 H), 3.42 (br. s, 1 H), 3.99–4.05 (m, 3 H), 4.64–4.68 (m, 2
H), 5.06 (d, J = 5.9 Hz, 1 H), 5.57 (t, J = 6.2 Hz, 1 H), 5.99 (br. s,
ing to the general procedure B. The crude product was purified by
column chromatography (toluene/EtOAc, 1:1). Compound 5
2 H), 6.78 (s, 1 H), 7.11–7.13 (m, 2 H), 7.21–7.29 (m, 3 H), 7.92 (s, (100 mg, 0.19 mmol) and 1-bromopentane (283 mg, 1.87 mmol)
1 H), 8.19 (s, 1 H) ppm. 13C NMR (CDCl3): δ = 12.8, 12.8, 13.2,
13.3, 17.1, 17.2, 17.3, 17.4, 17.5, 17.5, 17.6, 36.7, 52.0, 62.7, 71.9,
74.3, 82.3, 90.1, 119.8, 125.4, 127.4, 128.8, 129.1, 136.7, 138.7,
gave 6e (95 mg, 78%) as a white foam. Rf = 0.25 (toluene/EtOAc,
1:1). H NMR (CDCl3): δ = 0.85–0.89 (m, 3 H), 1.00–1.17 (m, 28
H), 1.31–1.36 (m, 4 H), 1.89–1.95 (m, 2 H), 3.55 (s, 1 H), 4.03–4.05
(m, 3 H), 4.36–4.40 (m, 2 H), 5.06 (d, J = 5.9 Hz, 1 H), 5.55–5.58
(m, 1 H), 6.20 (s, 2 H), 6.92 (s, 1 H), 8.16 (s, 2 H) ppm. 13C NMR
(CDCl3): δ = 12.7, 12.8, 13.2, 13.3, 13.9, 17.1, 17.1, 17.1, 17.3, 17.4,
1
142.6, 150.6, 152.8, 155.4 ppm. IR (KBr): ν = 698, 884, 1036, 1086,
˜
1131, 1466, 1581, 1641, 2866, 2944 cm–1. HRMS (FT-ICR-MS):
calcd. for C32H49N8O5Si2 [M + H] 681.3359; found 681.3398.
Eur. J. Org. Chem. 2009, 1515–1521
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1519

M. Grøtli et al.
FULL PAPER
17.5, 17.5, 17.5, 22.1, 28.6, 30.0, 50.7, 62.7, 71.9, 74.3, 82.2, 90.2,
142.5, 150.8, 152.9, 155.3 ppm. IR (KBr): ν = 697, 884, 1037, 1088,
˜
119.7, 125.0, 138.9, 142.7, 150.6, 152.7, 155.4 ppm. IR (KBr): ν =
1129, 1333, 1466, 1639, 2866, 2944 cm–1. HRMS (FT-ICR-MS):
˜
696, 884, 1037, 1087, 1134, 1296, 1466, 1580, 1643, 2867, calcd. for C31H47N8O5Si2 [M + H] 667.3203; found 667.3196.
2946 cm–1. HRMS (FT-ICR-MS): calcd. for C29H51N8O5Si2 [M +
H] 647.3516; found 647.3490.
8-[1-(4-Chlorophenyl)-1H-1,2,3-triazol-4-yl]-3Ј,5Ј-O-(tetraisopropyl-
disiloxane-1,3-diyl)adenosine (6i): The title compound was synthe-
sised according to the general procedure C. The crude product was
purified by column chromatography (toluene/EtOAc, 3:4). Com-
pound 5 (0.10 g, 0.19 mmol) and 1-chloro-4-iodobenzene (98 mg,
0.41 mmol) gave 6i as a white foam (76 mg, 59%). Rf = 0.29 (tolu-
Method C. General Procedure for the Synthesis of 6f–6i: NaN3
(5.3 equiv.) was added to a solution of CuI (0.2 equiv.), -proline
(0.4 equiv.), NaOH (0.4 equiv.) and 4-iodoanisole (48.2 mg,
0.206 mmol) in DMSO (2.5 mL/mmol NaN3). The reaction mix-
ene/EtOAc, 3:4). 1H NMR (CDCl3): δ = 1.01–1.25 (m, 28 H), 3.37
(br. s, 1 H), 4.02–4.09 (m, 3 H), 5.09 (d, J = 5.9 Hz, 1 H), 5.57–
5.60 (m, 1 H), 5.85 (s, 2 H), 6.95 (s, 1 H), 7.53 (d, J = 8.8 Hz, 2
H), 7.74 (d, J = 8.8 Hz, 2 H), 8.22 (s, 1 H), 8.60 (s, 1 H) ppm. 13C
NMR (CDCl3): δ = 12.8, 12.8, 13.2, 13.4, 17.1, 17.2, 17.6, 17.5,
17.5, 17.6, 17.6, 62.7, 71.9, 74.4, 82.4, 90.3, 120.0, 122.1, 123.1,
130.3, 135.0, 135.4, 140.1, 142.1, 150.8, 153.0, 155.4 ppm. IR
ture was heated in the microwave cavity at 120 °C for 5 min. Com-
pound 4 (50 mg, 0.094 mmol), TBTA (0.05 equiv.) and CuI
(0.05 equiv.) were added to the reaction mixture, and the reaction
mixture was heated in the microwave cavity at 60 °C for 5 min. The
reaction mixture was diluted with water (4 mL/mL DMSO), and
the water phase was extracted with EtOAc (4ϫ25 mL). The com-
bined organic layers were washed with brine (2ϫ5 mL), dried with
MgSO4, and the solvent was removed under reduced pressure. The
crude product was purified by column chromatography.
(KBr): ν = 694, 884, 1036, 1090, 1128, 1332, 1466, 1503, 1580,
˜
1639, 2866, 2944 cm–1. HRMS (FT-ICR-MS): calcd. for
C30H44ClN8O5Si2 [M + H] 687.2657; found 687.2629.
8-[1-(3-Aminophenyl)-1H-1,2,3-triazol-4-yl]-3Ј,5Ј-O-(tetraisopropyl-
disiloxane-1,3-diyl)adenosine (6f): The title compound was synthe-
sised according to the general procedure C. The crude product was
purified by column chromatography (toluene/EtOAc, 1:3). Com-
pound 5 (50 mg, 0.09 mmol) and 3-iodoaniline (45 mg, 0.21 mmol)
gave 6f as a white foam (38 mg, 61%). Rf = 0.18 (toluene/EtOAc,
1:3). 1H NMR (CDCl3): δ = 1.02–1.25 (m, 28 H), 3.36 (s, 1 H),
4.02–4.10 (m, 5 H), 5.09 (d, J = 5.9 Hz, 1 H), 5.57–5.60 (m, 1 H),
5.83 (s, 2 H), 6.73 (d, J = 7.0 Hz, 1 H), 6.96 (s, 1 H), 7.04 (d, J =
7.7 Hz, 1 H), 7.13 (s, 1 H), 7.25–7.29 (m, 1 H), 8.22 (s, 1 H), 8.56
(s, 1 H) ppm. 13C NMR (CDCl3): δ = 12.8, 12.8, 13.2, 13.4, 17.1,
17.2, 17.3, 17.4, 17.5, 17.5, 17.6, 62.7, 71.9, 74.3, 82.3, 90.2, 106.9,
110.0, 115.7, 119.8, 123.2, 130.7, 137.4, 139.4, 142.4, 148.2, 150.7,
8-(1-Isopentyl-1H-1,2,3-triazol-4-yl)adenosine (7d): TBAF (1  in
THF, 0.56 mL) was added to a solution of compound 6d (45.0 mg,
0.07 mmol) in dry THF (5 mL), and the reaction mixture was
stirred at room temp. overnight. Dowex 50Wx8-400 (0.35 g) was
added to the mixture, and the solution was stirred for 20 min. The
Dowex was filtered off and washed with pyridine/MeOH/H2O
(3:1:1). The filtrate was co-evaporated with toluene to remove exess
of pyridine. Purification by column chromatography (CHCl3/
MeOH, 97:3 with 1% AcOH) gave 6 (28 mg, Ͻ 99%) as a white
powder. 1H NMR ([D6]DMSO): δ = 0.94 (d, J = 6.6 Hz, 6 H),
1.54–1.61 (m, 1 H), 1.80 (dd, J = 7.0, 14.3 Hz, 2 H), 3.53 (dddd, J
= 3.3, 3.7, 8.8, 9.2 Hz, 1 H), 3.70 (dt, J = 3.3, 3.7 Hz, 1 H), 3.97
(dd, J = 3.3, 8.9 Hz, 1 H), 4.20 (dt, J = 2.2, 2.6 Hz, 1 H), 4.52 (t,
J = 7.3 Hz, 2 H), 5.07 (q, J = 6.6, 12.1 Hz, 1 H), 5.14 (d, J =
4.4 Hz, 1 H), 5.27 (d, J = 6.2 Hz, 1 H), 5.73 (dd, J = 3.7, 9.2 Hz,
1 H), 6.65 (d, J = 6.6 Hz, 1 H), 7.49 (s, 2 H), 8.15 (s, 1 H), 8.69 (s,
1 H) ppm. 13C NMR ([D6]DMSO): δ = 19.2, 22.0, 22.7, 25.0, 38.4,
48.1, 62.2, 70.9, 71.6, 86.3, 89.3, 126.3, 138.1, 142.0, 150.0, 151.3,
154.3 ppm. HRMS (FT-ICR-MS): calcd. for C17H25N8O4 [M + H]
405.1992; found 405.1986.
152.9, 155.4 ppm. IR (KBr): ν = 693, 884, 1037, 1087, 1129, 1333,
˜
1465, 1638, 2865, 2944, 3356 cm–1. HRMS (FT-ICR-MS): calcd.
for C30H46N9O5Si2 [M + H] 668.3155; found 668.3127.
8-[1-(4-Methoxyphenyl)-1H-1,2,3-triazol-4-yl]-3Ј,5Ј-O-(tetraiso-
propyldisiloxane-1,3-diyl)adenosine (6g): The title compound was
synthesised according to the general procedure C. The crude prod-
uct was purified by column chromatography (toluene/EtOAc, 1:2).
Compound 5 (50 mg, 0.09 mmol) and 4-iodoanisole (48 mg,
0.21 mmol) gave 6g as a white foam (33 mg, 51%). Rf = 0.22 (tolu-
ene/EtOAc, 1:2). 1H NMR (CDCl3): δ = 1.04–1.24 (m, 28 H), 3.44
(br. s, 1 H), 3.86 (s, 3 H), 4.01–4.10 (m, 3 H), 5.09 (d, J = 5.9 Hz,
1 H), 5.56–5.60 (m, 1 H), 6.00 (s, 2 H), 6.98 (s, 1 H), 7.02 (d, J =
8.8 Hz, 2 H), 7.66 (d, J = 8.8 Hz, 2 H), 8.20 (s, 1 H), 8.52 (s, 1 H)
ppm. 13C NMR (CDCl3): δ = 12.8, 12.8, 13.2, 13.3, 17.1, 17.2, 17.3,
17.4, 17.5, 17.5, 17.6, 55.8, 62.7, 71.9, 74.4, 82.3, 90.3, 115.0, 119.9,
122.4, 123.3, 129.9, 139.6, 142.4, 150.8, 152.9, 155.4, 160.3 ppm.
Photophysical Measurements: All photophysical measurements
were performed in aqueous or THF solutions. Absorption spectra
were measured with a Varian Cary 4000 spectrophotometer. The
extinction coefficient of the different base analogues was deter-
mined by measuring the absorption of samples of known concen-
tration (duplicate measurements). Samples were prepared from
small amounts, in duplicate, typically 1 mg of compound dissolved
in known volumes of THF. The steady-state fluorescence was mea-
sured with a Spex Fluorolog 3 spectrofluorimeter (JY Horiba). The
quantum yields (QY) of the different nucleosides were measured
relative to quinine sulfate (QY = 0.55)[25] in 0.5  H2SO4 (aq.) with
the excitation wavelength of 314 nm.
IR (KBr): ν = 1035, 1090, 1252, 1519, 1651, 2866, 2943 cm–1
.
˜
HRMS (FT-ICR-MS): calcd. for C31H47N8O5Si2 [M + H]
638.3152; found 638.3124.
3Ј,5Ј-O-(Tetraisopropyldisiloxane-1,3-diyl)-8-[1-(4-tolyl)-1H-1,2,3-
triazol-4-yl]adenosine (6h): The title compound was synthesised ac-
cording to the general procedure C. The crude product was purified
by column chromatography (toluene/EtOAc, 1:1). Compound 5
(50 mg, 0.09 mmol) and 4-iodotoluene (45 mg, 0.21 mmol) gave 6h
Calculations: All DFT calculations were performed by using the
Jaguar program from Schrödinger Inc.[26] The potential energy sur-
face of the triazole–adenine bond of 9-methyl-8-(1H-1,2,3-triazol-
4-yl)adenine was investigated by a relaxed energy scan (36 points,
1
as a white foam (31 mg, 50%). Rf = 0.21 (toluene/EtOAc, 1:1). H
NMR (CDCl3): δ = 1.05–1.25 (m, 28 H), 2.44 (s, 3 H), 3.35 (br. s, 10° increment) at the B3LYP/6-31G(d) level of theory.[23] Structures
1 H), 4.02–4.10 (m, 3 H), 5.08 (d, J = 5.9 Hz, 1 H), 5.57–5.61 (m, A and B and transition state TSROT were further optimised at the
1 H), 5.79 (s, 2 H), 6.98 (s, 1 H), 7.34–7.36 (m, 2 H), 7.65–7.67 (m, 6-311G(d,p) level of theory and verified as either minima or saddle
2 H), 8.22 (s, 1 H), 8.57 (s, 1 H) ppm. 13C NMR (CDCl3): δ = 12.8, point by a frequency calculation. Singly substituted configurations
12.8, 13.2, 13.4, 17.1, 17.2, 17.4, 17.5, 17.5, 17.6, 17.6, 21.3, 62.8,
72.0, 74.4, 82.4, 90.3, 120.0, 120.8, 123.2, 130.5, 134.3, 139.7, 139.7,
based on the 10 highest occupied and 10 lowest unoccupied molec-
ular orbitals (200 configurations) were used in the configurational
1520
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1515–1521

Fluorescent 8-(1H-1,2,3-Triazol-4-yl)adenosine Derivatives
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Acknowledgments
This work was supported by grants from the Swedish Research
Council and the Knut and Alice Wallenberg Foundation.
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Received: January 9, 2009
Published Online: February 11, 2009
130, 12574.
Eur. J. Org. Chem. 2009, 1515–1521
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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