Four-fold click reactions: Generation of tetrahedral methane- and adamantane-based building blocks for higher-order molecular assemblies

Article abstract of DOI:10.1039/b912189g

A modular concept for the generation of achiral and chiral non-racemic tetrahedral tectons from common precursors was developed. The tectons presented here are based on tetraphenylmethane or 1,3,5,7-tetraphenyladamantane core structures. They are obtained through high-yielding four-fold click reactions, using either the tetraazido or the tetraalkyne precursors. In most cases, the tetratriazoles are obtained as pure products after simple washing with water and methanol. The side chains of the tectons prepared include a self-complementary DNA dimer, obtained from a 3′-azidonucleoside and a phosphoramidite. The concept allows for a variation of the "sticky ends", leading to tecton or ligand libraries.

Full text of DOI:10.1039/b912189g

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Four-fold click reactions: Generation of tetrahedral methane- and
adamantane-based building blocks for higher-order molecular assemblies†
Oliver Plietzsch,a Christine Inge Schilling,a Mariyan Tolev,a,b Martin Nieger,c Clemens Richert,a,b
Thierry Muller*a and Stefan Bra¨se*a
Received 22nd June 2009, Accepted 4th August 2009
First published as an Advance Article on the web 14th September 2009
DOI: 10.1039/b912189g
A modular concept for the generation of achiral and chiral non-racemic tetrahedral tectons from
common precursors was developed. The tectons presented here are based on tetraphenylmethane or
1,3,5,7-tetraphenyladamantane core structures. They are obtained through high-yielding four-fold click
reactions, using either the tetraazido or the tetraalkyne precursors. In most cases, the tetratriazoles are
obtained as pure products after simple washing with water and methanol. The side chains of the tectons
prepared include a self-complementary DNA dimer, obtained from a 3¢-azidonucleoside and a
phosphoramidite. The concept allows for a variation of the “sticky ends”, leading to tecton or ligand
libraries.
precursors. This copper-catalyzed cycloaddition reaction – leading
exclusively to 1,4-substituted triazoles – has already served for
Introduction
the polyfunctionalization of rigid structures11 and the synthesis
of higher-order interlocked structures.12 Numerous examples of
the formation of dendrimers are known;13 even six-1b and twelve-
fold14 derivatization reactions of Th-symmetric C60 fullerene cores
have been achieved via click chemistry. However, to the best of
our knowledge, this reaction has not yet been used to decorate
tetrahedral core structures with diverse sticky sites in a modular
fashion.
We have previously reported on the synthesis of tetrakis(4-
azidophenyl) compounds and their energetic potential.15 Here we
describe an optimized synthesis of methane- and adamantane-
based tetraphenylazides and their use in four-fold click re-
actions. Furthermore, access to the corresponding tetrakis(4-
ethynylphenyl)methane and their four-fold click reaction has also
been investigated.
Recently, we initiated a program on the syntheses of organic
building blocks or ligands for higher-order molecular assemblies.1
Organic tectons – from the Greek word for ‘builder’ – have been
specifically designed to self-assemble either through hydrogen
bonding2 or, in the presence of metal ions, via coordination
bonds,3 leading to higher-order molecular assemblies.4 Amongst
the different possible molecular networks, diamondoid ones, based
on tetrahedral tectons, figure among the best known examples.5
Other 3-D lattices are conceivable based on the self-assembly
of tetrahedral tectons. Their formation can be expected to be
dependent on the flexibility of the tectons in question. Undesirable
flexibility may be avoided by choosing rigid core stuctures,2c,6
favouring the better-studied diamondoid networks.7
In order to develop an efficient strategy for the preparation of
diverse rigid 3-D tetrahedral building blocks, based on identical
core structures, we sought a general method for attaching different
“sticky ends” – functional groups enabling the supramolec-
ular self-assembly – onto tetrakisphenylmethane and 1,3,5,7-
tetrakisphenyladamantane core structures. The sticky ends were to
include short DNA chains that allow the generation of assemblies
based on the formation of Watson–Crick duplexes.8 We decided
to explore the so-called click chemistry9 – a Huisgen 1,3-dipolar
cycloaddition reaction between organic azides10 and alkynes –
in order to generate different building blocks using common
Results and discussion
Synthesis of tetrakis(4-azidophenyl)methane or -adamantane
In
a
previous communication in this journal,15 we pre-
sented four-fold azidation of tetrakis(4-iodophenyl)methane and
-adamantane. These transformations, however, provided the de-
sired tetraazides in moderate yields only in some cases, along
with lower-substituted homologues. As a consequence, we sought
a more efficient route to prepare the respective tetraazides. We
started to explore tetraazidation reactions via the tetradiazonium
salts, generated from the corresponding tetraamines. The latter
have been obtained according to literature-known procedures (see
ESI†).16
First, tetraazidation of the 4,4¢,4¢¢,4¢¢¢-methanetetraylte-
traaniline (5) was investigated (Table 1, entries 1–3). Using
trimethylsilyl azide either in the presence of isoamyl nitrite
and sulfuric acid (entry 1), or in combination with t-butyl
nitrite without acid (entry 2), gave compound 7 in moderate to
acceptable yield. The best results were achieved under classical
aInstitut fu¨r Organische Chemie and Center for Functional Nanostructures
(CFN), Universita¨t Karlsruhe (TH) – Karlsruhe Institute of Technology
(KIT), Fritz-Haber-Weg 6, 76131, Karlsruhe, Germany. E-mail: Stefan.
Braese@kit.edu; Fax: +49 (0)721 608 8581; Tel: +49 (0)721-608-2902
bInstitut fu¨r Organische Chemie, Universita¨t Stuttgart, 70569, Stuttgart,
Germany
cLaboratory of Inorganic Chemistry, University of Helsinki, 00014, Helsinki,
Finland
† Electronic supplementary information (ESI) available: Detailed experi-
mental procedures for compounds 5, 6, 9 and 10; NMR spectra of 5g,h and
MALDI-TOF-MS of 5i,j. CCDC reference numbers 734783 (1a), 734784
(4a), and 734785 (7). For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b912189g
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Table 1 Tetraazidation via the diazonium salts
Entry Reactant Nitrite
Azide
Acid
Solvent Yield (%)
1
2
3
4
5
5
5
5
6
6
C5H11ONO TMSN3 H2SO4 DMF
16
t-BuONO
TMSN3
NaN3
—
MeCN 55
H2O
H2O
NaNO2
NaNO2
HCl
HCl
—
79
0
NaN3
t-BuONO
TMSN3
MeCN 80
conditions with sodium azide and sodium nitrite in the presence
of hydrochloric acid (entry 3). Caution: sodium azide is potentially
explosive. Furthermore, the evolution of hydrazoic acid is possible
under acidic conditions. Tetraazide 7 was obtained as a pure
product in 79% yield after extraction. No further purification by
column chromatography was necessary. The structure of 7 was
confirmed by X-ray crystallography (Fig. 2).‡ Surprisingly, when
the optimized conditions established for the methane core were
applied to the adamantane derivative, complete decomposition
of the starting material was observed (entry 4). Fortunately, the
desired tetraazido adamantane derivative could be obtained in
high yield in the presence of trimethylsilyl azide and t-butyl nitrite
(entry 5).
Fig. 1 Structures of target compounds 1–4.
‡ Crystal structure determinations: All single-crystal X-ray diffraction
studies were carried out on a Nonius Kappa-CCD diffractometer at 123(2)
˚
K using MoKa radiation (l = 0.71073 A). Direct methods (SHELXS-
97)20 were used for structure solution and refinement was carried out using
SHELXL-9720 (full-matrix least-squares on F2). Hydrogen atoms were
localized by difference electron density determination and refined using
a riding model. A semi-empirical absorption correction was applied for
4a. The absolute structure of 4a was determined by refinement of Flack’s
x-parameter (x = 0.01(6)).21 1a: pale yellow, C57H40N12 - 2C3H7NO, M =
1039.20, crystal size 0.40 ¥ 0.16 ¥ 0.04 mm, monoclinic, space group C2/c
◦
˚
˚
˚
(No. 15): a = 29.701(6) A, b = 8.996(2) A, c = 20.844(4) A, b = 109.53(2) ,
3
-3
˚
V = 5248.9(19) A , Z = 4, r(calcd) = 1.315 Mg m , F(000) = 2184, m =
0.084 mm-1, 20477 reflexes (2qmax = 50 ◦), 4625 unique [Rint = 0.073], 356
parameters, 37 restraints, R1 (I > 2s(I)) = 0.085, wR2 (all data) = 0.231,
Fig. 2 Molecular structure of tetrakis(4-azidophenyl)methane (7) (dis-
placement parameters are drawn at the 50% probability level).
-3
˚
GOOF = 1.05, largest diff. peak and hole +1.173/-0.824 e A (in the
solvent DMF). 4a: colorless crystals, C66H52N12 - 4CHCl3, M = 1490.67,
¯
crystal size 0.40 ¥ 0.25 ¥ 0.15 mm, tetragonal, space group P4 (No. 81): a =
3
˚
˚
˚
21.970(3) A, c = 6.972(1) A, V = 3365.3(8) A , Z = 2, r(calcd) = 1.471 Mg
m-3, F(000) = 1528, m = 0.547 mm-1, 17869 reflexes (2qmax = 55 ◦), 7550
unique [Rint = 0.034], 425 parameters, R1 (I > 2s(I)) = 0.050, wR2 (all
data) = 0.132, GOOF = 1.06, largest diff. peak and hole +0.909/-0.456 e
Synthesis of tetrakis(4-ethynylphenyl)methane and adamantane
derivatives
-3
For the syntheses of tetraalkynes 9 and 10, literature known
procedures were employed, yielding the desired products in
excellent overall yields (see ESI).16c
With both types of organic building block precursors in hand,
we began to explore suitable protocols for the four-fold click
reactions.
˚
A
(near the solvent CHCl3). 7: yellow crystals, C25H16N12, M = 484.50,
crystal size 0.30 ¥ 0.15 ¥ 0.10 mm, monoclinic, space group C2/c (No. 15),
◦
˚
˚
˚
-3
a = 18.878(1) A, b = 7.137(1) A, c = 18.265(1) A, b = 111.37(1) , V =
3
˚
2273.5(4) A , Z = 4, r(calcd) = 1.416 Mg m , F(000) = 1000, m =
0.094 mm-1, 8191 reflexes (2qmax = 55 ◦), 2578 unique [Rint = 0.046], 168
parameters, R1 (I > 2sI)) = 0.051, wR2 (all data) = 0.116, GOOF = 1.01,
-3
˚
largest diff. peak and hole +0.287/-0.252 e A .
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Table 2 Four-fold click reaction with the tetraazido cores
Entry Reactant
R
Solvent
Product Yield (%)
Fig. 3 Molecular structure of 1a (displacement parameters are drawn at
the 50% probability level).
1
2
3
4
5
6
7
8
7
8
8
7
8
7
8
7
8
7
8
Ph
Ph
Ph
CH2OH
CH2OH
t-BuOH/H2O 1a
t-BuOH/H2O 2a
DMSO/H2O 2a
t-BuOH/H2O 1b
DMSO/H2O 2b
97
0
99
amounts according to NMR of the crude mixture, but could not
be isolated (entry 11).
76
11a
92
(S)-CHOHMe t-BuOH/H2O 1c
(R)-CHOHMe DMSO/H2O 2c
p-C6H4CN
p-C6H4CN
CH2NH2
88b
91
Click reactions with the tetrakis(4-ethynylphenyl) cores
t-BuOH/H2O 1d
DMSO/H2O 2d
t-BuOH/H2O 1e
DMSO/H2O 2e
9
10
11
90c
94
Next, the four-fold click reaction was performed with the
tetrakis(4-ethynylphenyl) cores 9 and 10 and a series of com-
mercial or readily available azides (Table 3). To start with,
the previously optimized conditions were tested. Tetrakis(4-
ethynylphenyl)methane was reacted in a mixture of t-BuOH/H2O,
whereas for the adamantane derivative, a DMSO/H2O mixture
was used. When reacted with phenylazide, both cores delivered the
CH2NH2
Trace
a Ref. 15. b Based on recovery of the starting material. c Yield determined
by NMR.
Click reactions with tetrakis(4-azidophenyl) cores
Table 3 Four-fold click reactions with the tetraalkyne cores
Initially, the original click conditions developed by Fokin and
Sharpless9b,c (sodium ascorbate, copper sulfate pentahydrate in
t-BuOH/H2O 1:1) were explored (Table 2). When tetrakis(4-
azidophenyl)methane was reacted with ethynylbenzene, the de-
sired tetrakistriazole 1a was obtained in excellent yield (entry 1).
Single crystals of 1a were grown in a solution of DMF/acetone by
slow evaporation of the solvents, and its structure was confirmed
by X-ray crystallography (Fig. 3).‡ Running the same reaction
with adamantane derivative 8 resulted in complete recovery
of the starting materials (entry 2). Only when t-BuOH was
replaced by DMSO was 1,3,5,7-tetrakis(4-(4-phenyl-1,2,3-triazol-
1-yl)phenyl)adamantane (2a) formed, in nearly quantitative yield
(entry 3).
With the conditions optimized for both cores, a series of
different alkynes were “clicked” with both tetraazides. In the
methane core series, the corresponding tetraazides were obtained
in good to excellent yields in all cases (entries 4, 6, 8 and 10).
These examples show once more the compatibility of the click
reaction conditions with a wide range of functional groups.
For the adamantane core, the same tolerance was observed; the
yields of the tetraazido-adamantanes are, however, generally lower
mainly due to solubility problems, which increase with increasing
polarity of the product (entries 7 and 9). Tetraol 2b was only
obtained in 11%, mostly due to loss of product during column
chromatography (entry 5). Tetraamine 2e probably formed in trace
Entry Reactant R
Solvent
Product Yield (%)
1
2
3
4
5
6
7
8
9
10
9
10
9
10
9
10
9
10
9
Ph
Ph
p-C6H4F
p-C6H4F
p-C6H4NO2
p-C6H4NO2
(S)-BnCHCO2Et
(S)-BnCHCO2Et
(S)-BnCHCO2H
(S)-BnCHCO2H
t-BuOH/H2O 3a
DMSO/H2O 4a
t-BuOH/H2O 3b
DMSO/H2O 4b
t-BuOH/H2O 3c
DMSO/H2O 4c
t-BuOH/H2O 3d
DMSO/H2O 4d
t-BuOH/H2O 3e
DMSO/H2O 4e
99
72
97
86
92
Trace
85
64
88
0
9
10
11
12
m,m-C6H3(CO2H)2 t-BuOH/H2O 3f
m,m-C6H3(CO2H)2 DMSO/H2O 4f
82
60
10
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corresponding tetratriazoles 3a and 4a in nearly quantitative yield
(entries 1 and 2). Single crystals of compound 4a were obtained
by slow evaporation of a saturated solution of 4a in chloroform,
and the X-ray crystallographic structure was determined (Fig. 4).‡
Subsequently, a series of different azides were clicked onto our
cores. The methane core delivered as before the four-fold click
products in good to excellent yields after simple washing of the
crude product with water and methanol (entries 1, 3, 5, 7, 9
and 11). It is worth mentioning that even tetraacids (entry 9)
and octaacids (entry 12) can be prepared in high yields. For the
adamantane core, we observed generally good to excellent yields of
the corresponding tetratriazoles, except when solubility problems
of the reactants or the products occurred. This resulted in either
very low yields or no reaction at all (entries 6 and 10). We were,
however, surprised to observe that tetradicarboxyphenyl derivative
4f could be isolated in 60% yield (entry 12). This is all the more
satisfying as these octaacids represent an interesting building block
for higher-order molecular assemblies.
Fig. 5 Space-filling representation of the unit cells of 7 parallel to the
b-axis (top), 1a parallel to the b-axis (middle left without solvent, middle
right with included solvent DMF) and 4a parallel to the c-axis (bottom
left without solvent, bottom right with included solvent CHCl3).
and 3¢-azido-N6-benzoyl-2¢,3¢-dideoxycytidine17 were thus added
four times to this core to give 4g and 4h in high yields.18 To
explore the synthesis of tectons with DNA chains in solution,
tetranucleoside 4g was coupled to the 3¢-phosphoramidite of
2¢-deoxyadenosine, following a modification of a protocol for
solution-phase DNA syntheses.19 In situ oxidation led to fully
protected octanucleoside 4i, which proved easy to isolate, as it
formed a solid at the organic–aqueous interface during aqueous
extraction. Two-step deprotection of 4i then gave 4j with four
self-complementary DNA chains in moderate yield after HPLC
purification of an analytical sample. These results demonstrate the
versatility of the current approach and open up a new avenue to
DNA-based nanostructuring.8
Fig. 4 Molecular structure of one independent molecule of 4a (displace-
ment parameters are drawn at the 50% probability level).
In the light of using our tetratriazoles as building blocks for
porous periodic networks, we were also interested in the packing
of our molecules in the crystalline state. Fig. 5 shows the space-
filling representation of the unit cells of azide 7 and triazoles 1a
and 4a. The respective apparent porosities22,23 of 22% (1a) and 30%
(4a) are very high, and clearly indicate a high potential of these
compounds to act as building blocks in highly porous networks,
once equipped with suitable sticky sites.
Conclusions
We have used and adapted click chemistry for a highly effective and
modular approach to generate different organic tectons based on
common precursors. The tetrakis[(triazolyl)phenyl]methane and
-adamantane derivatives 1–4 were obtained in excellent yields
and purities, in most cases after simple washing with water and
methanol, without need for further purification by column chro-
matography (Fig. 1). Some of these structures represent interesting
building blocks for the generation of molecular architectures. Both
routes offer access to similar triazoles having virtually the same
Click reactions to introduce self-complementary DNA chains
Finally, our methodology was extended to the four-fold cy-
cloaddition of 3¢-azido-2¢,3¢-dideoxynucleosides to tetraethynyl
core 10 (Scheme 1). Both 3¢-azido-2¢,3¢-dideoxythymidine (AZT)
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13C NMR spectra were recorded on a Bruker AVANCE 400
(100 MHz) or AVANCE DRX 500 (125 MHz) spectrometer as
solutions in CDCl3, DMSO-d6 or MeOH-d4. Chemical shifts
are expressed in parts per million (ppm, d) downfield from
tetramethylsilane (TMS) and are referenced to CHCl3 (77.4 ppm),
DMSO (39.5 ppm) or MeOH (49.1 ppm) as internal standard.
The multiplicity was analyzed by DEPT and is described as
follows: + = primary or tertiary C-atom (positive signal), - = sec-
ondary C-atom (negative signal) and q = quaternary C-atom (no
signal).
MS (EI) (electron impact mass spectrometry): Finnigan MAT
90 (70 eV). The molecular fragments are quoted as the relation
between mass and charge (m/z), the intensities as a percentage
value relative to the intensity of the base signal (100%). The
abbreviation [M+] refers to the molecular ion.
MALDI-TOF mass spectra were acquired on a Bruker RE-
FLEX IV spectrometer using a nitrogen laser (l = 337 nm) and
software XACQ 4.0.4 and XTOF 5.1.0. Fully protected DNA
hybrids were measured in linear, positive mode. Deprotected DNA
hybrids were measured in linear, negative mode. MALDI matrix
mixture for DNA hybrids was 2,4,6-trihydroxyacetophenone
(0.3 M in EtOH) and diammonium citrate (0.1 M in H2O) at
a ratio of 2/1 (v/v). Calculated masses are average masses (m/z)
found are those for the unresolved pseudomolecular ion peaks
([M + H]+ or [M - H]-). The accuracy of mass determination with
the external calibration used is approximately 0.1.
UV-VIS spectra were recorded on a Lambda 25 spectrometer
from Perkin Elmer, using the software Lambda. The detection was
at 259.8 nm, using quartz cuvettes with a thickness of 1 cm.
IR (infrared spectroscopy) was performed on a FT-IR Bruker
IFS 88 instrument. IR spectra of solids were recorded in KBr, and
as thin films on KBr for oils and liquids. The position of the absorp-
-1
˜
tion band is given in wave numbers n in cm . The forms and inten-
sities of the bands were characterized as follows: vs = very strong
(0–10% T), s = strong (10–40% T), m = medium (40–70% T), w =
weak (70–90% T), vw = very weak (90–100% T), br = broad.
Routine monitoring of reactions was performed using sil-
ica gel coated aluminium plates (Merck, silica gel 60, F254),
which were analyzed under UV-light at 254 nm and/or dipped
into a solution of molybdatophosphate (5% phosphomolybdic
acid in ethanol, dipping solution) or ninhydrin solution (3 g
of ninhydrin in 100 mL of ethanol) and heated with a heat
gun. Solvent mixtures are given as volume/volume. DNA hy-
brids were purified on Nucleosil 120-5 reverse-phase C4 HPLC
column (250 ¥ 4.6; Macherey-Nagel, Du¨ren, Germany) at a
flow rate of 1 mL min-1 and detection at 260 nm. Solvents,
reagents and chemicals were purchased from Aldrich, Fluka and
Acros. Standard nucleosides 3¢-phosphoramidites were obtained
from Proligo (Hamburg, Germany). Tetrazole solution (0.45 M
in acetonitrile, for DNA synthesis) and t-butyl hydroperoxide
Scheme 1 Synthesis of tetrahedral tectons with nucleosidic “sticky ends”.
angles in good to excellent yields. Therefore, depending on the
accessibility of starting materials, either one of the precursors
(azide or alkyne) can be chosen for tecton design.
Experimental
General methods
1H NMR spectra were recorded on a Bruker AVANCE 400
(400 MHz) or AVANCE DRX 500 (500 MHz) spectrometer as
solutions in CDCl3, DMSO-d6 or MeOH-d4. Chemical shifts are
expressed in parts per million (ppm, d) downfield from tetram-
ethylsilane (TMS) and are referenced to CHCl3 (7.26 ppm), DMSO
(2.50 ppm) or MeOH (3.31 ppm) as the internal standard. All
coupling constants are absolute values and J values are expressed
in Hertz (Hz). The description of signals include: s = singlet, bs =
broad singlet, d = doublet, t = triplet, q = quartet, m = multiplet.
The data are described according to a first-order analysis. The
signal abbreviations include: Ar-H = aromatic proton.
˚
solution (5.5 M in decane over 4 A molecular sieves) were
from Sigma/Aldrich (Deisenhofen, Germany). Tetrahydrofuran
was distilled from sodium/benzophenone under argon prior
to use. Dichloromethane, ethyl acetate and diethyl ether were
distilled from calcium hydride. Solid materials were powdered.
All reactions involving moisture-sensitive reactants were executed
under an argon atmosphere using oven-dried and/or flame-dried
glassware. All other solvents, reagents and chemicals were used as
purchased unless stated otherwise.
4738 | Org. Biomol. Chem., 2009, 7, 4734–4743
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◦
Tetrakis(4-azidophenyl)methane (7). 4,4¢,4¢¢,4¢¢¢-Methanete-
trayltetraaniline (5) (1.50 g, 3.93 mmol, 1.0 equiv.) was suspended
in water (30 mL) and the reaction mixture was cooled to –5 ◦C. At
this temperature conc. sulfuric acid (15 mL) was added slowly and
the suspension turned to a dark clear solution. Then, a solution
of sodium azide (1.23 g, 17.7 mmol, 4.5 equiv.) in water (9 mL)
was added dropwise under a strong evolution of gas. Caution:
sodium azide is potentially explosive. Furthermore, the evolution
of hydrazoic acid is possible under acidic conditions. The reaction
mixture was stirred for 2 h at room temperature. After this, the
formed precipitate was filtered off, washed with water (100 mL)
and dried in vacuo to give tetrakis(4-azidophenyl)methane (7)
(1.43 g, 75%) as a grey solid. Rf 0.30 (cyclohexane/EtOAc 25:1);
dH (400 MHz; CDCl3) 6.86 (8 H, d, J 8.8, Arm-H), 7.06 (8 H, d,
J 8.8, Aro-H) ppm; dC (100 MHz; CDCl3) 63.3 (Cq(Ar)4), 118.4
(+, Co-Ar), 132.1 (+, Cm-Ar), 138.2 [Cq-Ar(N3)], 142.9 [Cq-Ar(C)]
ppm; n/cm-1 (DRIFT) 3032wv, 2544vw, 2412vw, 2252w, 2124s,
1601m, 1577w, 1501s, 1413w, 1290s, 1192 m, 1130w, 1119w,
1017w, 945vw, 911vw, 829m, 757vw, 701vw, 671w, 634vw, 555m,
538m, 414vw; m/z (EI) 484 (M+, 100%), 456 (35), 317 (M+ - 12N,
12), 240 (M+ - C6H4N12, 9); C25H16N12 calcd. 484.1621; found
484.1623 [M+].
argon at 100 C. CuSO4·5H2O (3.60 mg, 0.01 mmol, 0.2 equiv.),
sodium ascorbate (5.20 mg, 0.03 mmol, 0.4 equiv.), solved in H2O
(0.5 mL), and the corresponding alkyne (0.83 mmol, 12 equiv.)
◦
were added slowly. It was stirred for 48 h at 100 C, taken-up in
CHCl3 (20 mL) and washed with H2O (2 ¥ 20 mL), brine (2 ¥
20 mL) and H2O (2 ¥ 20 mL). The solvent was removed under
reduced pressure. The crude product was taken-up in CHCl3
(30 mL) and dried over MgSO4.
General procedure for the synthesis of tetrakis(1,2,3-triazol-4-yl)-
phenyl derivatives 3, methane series
Tetrakis(4-ethynylphenyl)methane (9) (0.10 g, 0.24 mmol, 1.0
equiv.) was suspended in 10 mL tBuOH/H2O. Then CuSO4·5H2O
(6.00 mg, 0.02 mmol, 0.1 equiv.), sodium ascorbate (19.0 mg,
0.10 mmol, 0.4 equiv.) and the corresponding azide (1.44 mmol,
6.0 equiv.) were added subsequently. The reaction mixture was
stirred for 72 h at 70 ◦C. Then the precipitate was filtered off
and washed with H2O (20 mL) and methanol (10 mL) to give the
four-fold click product.
General procedure for the synthesis of tetrakis(1,2,3-triazol-4-yl)-
phenyl derivatives 4, adamantane series
1,3,5,7-Tetrakis(4-azidophenyl)adamantane
(8). 1,3,5,7-
1,3,5,7-Tetrakis(4-ethynylphenyl)adamantane (10) (70.0 mg,
Tetrakis(4-aminophenyl)adamantane (6) (96.0 mg, 0.19 mmol,
0.13 mmol, 1.0 equiv.) were dissolved in DMSO (10 mL) under
1.0 equiv.) was dissolved under argon in acetonitrile (10 mL) at
◦
◦
t
argon at 100 C. CuSO4·5H2O (6.50 mg, 0.03 mmol, 0.2 equiv.),
0
C. BuONO (0.14 mL, 119 mg, 1.15 mmol, 6.0 equiv.) and
sodium ascorbate (10.3 mg, 0.05 mmol, 0.4 equiv.), solved in H2O
(0.5 mL), and the corresponding alkyne (0.78 mmol, 6.0 equiv.)
were added slowly. It was stirred for 48 h at 100 ◦C, taken-up
in CHCl3 (20 mL) and washed with H2O (2 ¥ 20 mL), brine
(2 ¥ 20 mL) and H2O (2 ¥ 20 mL). The solvent was removed
under reduced pressure. The crude product was taken-up in CHCl3
(30 mL) and dried over MgSO4.
TMSN3 (0.13 mL, 114 mg, 0.99 mmol, 5.0 equiv.) were added
dropwise and the reaction mixture was stirred for several hours at
room temperature until the reaction was complete (controlled by
TLC). The solvent was removed under reduced pressure and the
crude product purified by flash chromatography on silica gel using
cyclohexane/CH2Cl2 (2:1) as eluent to give 1,3,5,7-tetrakis(4-
azidophenyl)adamantane (8) (98.0 mg, 80%) as a yellowish solid.
Rf 0.28 (cyclohexane/CH2Cl2 1:1); dH (400 MHz; CDCl3) 2.10
(12 H,s, Ad-CH2), 7.02 (8 H, d, J 8.5, Aro-H), 7.45 (8 H, d, J 8.5,
Arm-H); dC (100 MHz; CDCl3) 39.0 (Cq-Ad), 47.2 (-, Cs-Ad),
118.7 (+, Cm-Ar), 126.3 (+, Co-Ar), 138.1 (Cq, Ar-Ad), 145.8
(Cq, Arp-N3); n/cm-1 (DRIFT) 3395vw, 3244vw, 3033w (CAr-H),
2929w, 2851w, 2574vw, 2419w, 2326vw, 2259w, 2127m, 1953vw,
1893vw, 1768vw, 1604w, 1575w, 1508m, 1445w, 1413w, 1356w,
1296m, 1190w, 1130w, 1014w, 892vw, 822m, 770w, 671w, 561w,
532w; l (CHCl3)/nm 256 (e/dm3 mol-1 cm-1 6568).
Tetrakis(4-(4-phenyl-1,2,3-triazol-1-yl)phenyl)methane
(1a).
The product was isolated after filtration and washing as a yellow
solid (179 mg, 97%). dH (400 MHz; DMSO-d6) 7.39 (4 H, t, J 7.5,
Arp-H), 7.51 (8 H, t, J 7.5, Arm-H), 7.64 (8 H, d, J 8.8, Aro(N)-H),
7.96 (8 H, d, J 7.5, Aro-H), 8.02 (8 H, d, J 8.8, Arm(N)-H),
9.33 (4 H, s, H-triazole) ppm; dC (100 MHz; DMSO-d6) 63.9
(Cq-(Ar)4), 119.6 (CH-triazole), 120.1 [+, Cm-Ar(N)], 125.3 (+,
Co-Ar), 126.3 (+, Cp-Ar), 129.0 (+, Cm-Ar), 130.2 (+, Cq-Ar),
131.7 [+, Co-Ar(N)], 134.8 [Cq-Ar(N)], 146.00 [Cq-Ar(C)], 147.30
(Cq-triazole) ppm; n/cm-1 (DRIFT) 3127vw, 3064vw, 2926vw,
2269vw, 1922vw, 1711vw, 1606vw, 1514w, 1482w, 1457vw, 1433vw,
1410vw, 1351vw, 1230w, 1184vw, 1121vw, 1093vw, 1073vw, 1038w,
1027w, 993w, 916vw, 830w, 765w, 695w, 678vw, 631vw, 561vw,
504vw, 460vw; m/z (FAB): 893 ([MH+], 100%), 865 ([MH+ - N2],
11), 588 ([MH+-C24H16], 40); C57H41N12: calcd. 893.3577, found
893.3569 [MH+].
General procedure for the synthesis of tetrakis(1,2,3-triazol-1-yl)-
phenyl derivatives 1, methane series
Tetrakis(4-azidophenyl)methane (7) (0.10 g, 0.21 mmol, 1.0
equiv.) was suspended in 10 mL tBuOH/H2O. Then CuSO4·5H2O
(5.20 mg, 0.02 mmol, 0.1 equiv.), sodium ascorbate (16.4 mg,
0.08 mmol, 0.4 equiv.) and the corresponding alkyne (1.26 mmol,
6.0 equiv.) were added subsequently. The reaction mixture was
stirred for 72 h at 70 ◦C. Then the precipitate was filtered off
and washed with H2O (20 mL) and methanol (10 mL) to give the
four-fold click product.
1,3,5,7-Tetrakis(4-(4-phenyl-1,2,3-triazol-1-yl)phenyl)adaman-
tane (2a). The product was isolated in quantitative yields
(254 mg, 99%) as a bright-yellow solid. Rf 0.69 (n-pentane/EtOAc
200:1); dH (400 MHz; CDCl3) 2.30 (12 H, s, Ad-CH2), 7.44–7.57 (20
H, m, C6H5), 7.92 (8 H, d, J 7.2, Arm-H), 7.80 (8 H, d, J 7.2, Aro-
H), 8.20 (4 H, s, triazole-H); dC (100 MHz; CDCl3) 39.4 (Cq, Ad),
46.9 (–, Cs, Ad-CH2), 117.6 (+, C-5, triazole-CH), 120.5 (+, C-8,
Co-Ph), 125.8 (+, C-3, Arm-Ph), 128.4 (+, C-10, Cp-Ph), 128.9 (+,
C-9, Cm-Ph), 129.7 (+, C-2, Aro-triazole), 135.4 (Cq, C-7, C6H5),
General procedure for the synthesis of tetrakis(1,2,3-triazol-1-yl)-
phenyl derivatives 2, adamantane series
1,3,5,7-Tetrakis(4-azidophenyl)adamantane (8) (40.0 mg,
0.07 mmol, 1.0 equiv.) were solved in DMSO (10 mL) under
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137.0 (Cq, C-4, Ar-triazole), 148.4 (Cq, C-1, Ar-Ad), 149.3 (Cq,
C-6, triazole); n/cm-1 (DRIFT) 3439vw, 3122w (CAr-H), 3098w,
3056w, 2928vw (C CH), 1600w (N N), 1556w, 1505w, 1482w,
1353w, 1229w, 1074w, 1042w, 994w, 910w, 827w, 758m, 691m,
661w, 538w, 520w; m/z (FAB) 1014 ([MH+], 100%), 1015 (78),
1016 (26), 985 ([M - C4H3]+Na, 15); C66H53N12 calcd. 1013.4516;
found 1013.4530 [MH+].
reddish oil (18 mg, 88%). dH (400 MHz; CDCl3/MeOH-d4) 1.58
(12 H, d, J 6.5, CH3), 2.10 (12 H, s, Ad-CH2), 5.06 [4 H, q, J
6.1, CH3CH(OH)], 7.58–7.60 (8 H, m, Aro-H), 7.66–7.68 (8 H, m,
Arm-H), 7.95 (4 H, s, triazole-H); dC (100 MHz; CDCl3/MeOH-
d4) 23.0 [+, CH3CH(OH)], 39.2 (Cq, Ad), 48.7 (–, Cs, Ad-CH2),
62.5 (+, CH(OH)), 120.4 (+, C-5, triazole-CH), 126.3 (+, C-2,
Co-Ar), 126.6 (+, C-3, Cm-Ar), 137.9 (Cq, C-4, Ar-triazole), 145.4
(Cq, C-6, triazole), 149.4 (Cq, Ar-Ad); n/cm-1 (KBr) 3356br (OH),
=
=
Tetrakis(4-(4-hydroxymethyl-1,2,3-triazol-1-yl)phenyl)methane
(1b). The crude product was purified by washing with an
additional 20 mL of dichloromethane and could be isolated as a
yellowish solid (111 mg, 76%). dH (400 MHz; DMSO-d6) 4.58–4.62
(8 H, m, CH2), 5.32–5.37 (4 H, m, OH), 7.50–7.54 (8 H, m, Aro-H),
7.92–7.95 (8 H, m, Arm-H), 8.67 (4 H, s, H-triazole); dC (100 MHz;
DMSO-d6) 55.0 (–, CH2OH), 62.8 (Cq-(Ar)4), 119.8 (+, CH–
triazole), 120.9 (+, Cm-Ar), 131.7 (+, Co-Ar), 137.4 [Cq-Ar(N)],
142.8 (Cq–triazole), 146.0 [Cq-Ar(C)]; n/cm-1 (DRIFT) 3315br
(OH), 2410vw, 2320vw, 2251vw, 2123w, 2083w, 1911vw, 1601vw,
1577vw, 1502w, 1413vw, 1289vw, 1192vw, 1130vw, 1017vw, 911vw,
829vw, 731vw, 670vw, 671vw, 623vw, 555vw, 537vw, 452vw, 442vw,
407vw; m/z (FAB) 709 ([MH+], 8%); C37H33O4N12 calcd. 709.2748;
found 709.2750 [MH+].
=
2975w (CAr-H), 2927 m (C CH), 2852 m (CH3), 2414w, 2258w,
=
2125m, 1902 vw, 1688w, 1605 w (N N), 1576w, 1509m, 1445w,
1411m, 1358m, 1291m, 1230m, 1190w, 1107m, 1042m, 989w, 951w,
893w, 835m, 785m, 735w, 702w, 672w, 563w; m/z (FAB) 885 (24)
([MH+], 24%) 815 (M - C4H5O, 73), 774 (M - C4H7ON3, 15), 745
(M - C8H13O2, 100), 675 (M - C12H18O3, 79); C50H53O4N12: calcd.
885.4313; found 885.4315 [MH+].
Tetrakis(4-(4-(4-cyanophenyl)-1,2,3-triazol-1-yl)phenyl)methane
(1d). The product was isolated as a brownish solid (186 mg,
91%). dH (400 MHz; DMSO-d6) 7.65 (8 H, d, J 8.8, Aro(N)-H),
7.98–8.07 (16 H, m, Arm(N)-H, Arm(CN)-H), 8.12 (8 H, d, J 8.4,
Aro(CN)-H), 9.33 (4 H, s, H-triazole); dC (100 MHz; DMSO-d6)
64.0 (Cq-(Ar)4), 110.5 (Cq-CN), 118.8 (CN), 120.2 [+, Cm-Ar(N)],
121.4 (+, CH-triazole), 125.9 [+, Co-Ar(CN), Cq-Ar(CN)], 131.8
[+, Co-Ar(N)], 133.1 [+, Cm-Ar(CN)], 134.6 [Cq-Ar(N)], 145.7
(Cq-triazole), 146.2 [Cq-Ar(C)]; n/cm-1 (DRIFT) 3423vw, 3136vw,
2225w, 2125vw, 1919vw, 1780vw, 1614w, 1558vw, 1514w, 1490w,
1443vw, 1409vw, 1346vw, 1275vw, 1237vw, 1180vw, 1142vw,
1036vw, 994vw, 969vw, 919vw, 830w, 748vw, 625vw, 577vw,
554vw, 509vw, 451vw, 429vw, 419vw; m/z (FAB): 993 ([MH+],
1,3,5,7-Tetrakis(4-(4-hydroxymethyl-1,2,3-triazol-1-yl)phenyl)-
adamantane (2b)15. The crude product was purified by flash
chromatography on silica gel using CH2Cl2/MeOH (5:1) as eluent
and could be isolated as a bright yellow solid (6 mg, 11% yield).
Rf 0.40 (CH2Cl2/MeOH 5:1). dH (400 MHz; CDCl3/MeOH-d4)
2.15 (12 H, s, Ad-CH2), 4.61 (8 H, s, CH2OH), 7.53 (8 H, d, J
8.8, Aro-H), 7.60 (8 H, d, J 8.8, Arm-H), 7.98 (4 H, s, H-triazole)
ppm; dC (100 MHz; CDCl3) 39.1 (Cq, Ad), 46.5 (-, Cs, Ad-CH2),
7%), 965 ([MH+ - N2], 2), 91 ([C7H7 ], 25); C61H37N16 calcd.
+
55.3 (-, Cs, CH2OH), 120.2 (Ct, CH CCH2OH), 120.3 (+, Cm,
993.3387, found 993.3393 [MH+].
=
Ar), 126.3 (+, Co, Ar), 135.0 (Cq, Arp), 148.4 (Cq, Ar-Ad), 149.3
(CH=CCH2OH) ppm; n/cm-1 (DRIFT) 3365w, 2923w, 2853w,
1609vw, 1519w, 1378w, 1262w, 1238w, 1184w, 1040w, 836w, 788w,
761vw, 700vw, 560w; UV/VIS (CHCl3): lmax (A) = 227 (0.015), 255
(0.028), 472 (0.011) nm; m/z (FAB) 829 ([MH+], 100%), 733 (10),
731 (22), 573 (26), 529 (32), 485 (30), 419 (100); C46H45O4N12: calcd.
829.3681, found 829.3694 [MH+]. C46H45O4N12 calcd. 829.3687;
found 829.3694 [MH+].
1,3,5,7-Tetrakis(4-(4-(4-cyanophenyl)-1,2,3-triazol-1-yl)phenyl)-
adamantane (2d). 21.0 mmol of the azide were used following the
general procedure with identical equivalents and the product was
isolated as a bright yellow solid (10 mg, 40% yield) after successive
washing with methanol. dH (500 MHz; CDCl3/MeOH-d4) 2.34
(12 H, s, Ad-CH2), 7.73 (8 H, d, J 9.5, Aro(Ad)-H), 7.75 (8 H, d, J
9.0, Arm(CN)-H), 7.85 (8 H, d, J 8.7, Arm(Ad)-H), 8.04 (8 H, d, J
8.2, Aro(CN)-H), 8.30 (4 H, s, triazole-H); dC (125 MHz; CDCl3)
39.5 (Cq, Ad), 46.9 (-, Cs, Ad-CH2), 111.9 [+, Cq, Ar(CN)], 118.0
(Cq, CN), 118.6 (+, CH-triazole), 120.7 [Co-Ar(Ad)], 126.1 [+,
Cm-Ar(CN)], 126.6 [+, Cm-Ar(Ad)], 132.8 [+, Co-Ar(CN)], 134.5
[Cq, triazole-Ar(CN)], 135.2 (Cq, Ar(Ad)-triazole), 146.7 (Cq,
triazole), 149.6 (Cq, Ar-Ad); n/cm-1 (DRIFT) 3418vw, 3092vw,
3066vw, 2928vw, 2853vw, 2228w, 1926vw, 1685vw, 1613w, 1601w
Tetrakis(4-(4-(2-(S)-hydroxyethyl)l-1,2,3-triazol-1-yl)phenyl)-
methane (1c). The product was obtained as a brown powder
(146 mg, 92%). dH (400 MHz; DMSO-d6) 1.47 (12 H, d, J 6.4,
CH3), 4.88–4.96 (4 H, m, CHOH), 5.42 (4 H, d, J 4.3, OH), 7.50
(8 H, d, J 8.7, Aro-H), 7.95 (8 H, d, J 8.7, Arm-H), 8.64 (4 H, s,
H-triazole); dC (100 MHz; DMSO-d6) 23.6 (+, CH3), 61.4 (+,
CHOH), 63.6 (Cq-(Ar)4), 119.5 (+, CH–triazole), 119.6 (+, Cm-
Ar), 131.5 (+, Co-Ar), 134.9 [Cq-Ar(N)], 145.4 [Cq-Ar(C)], 153.7
(Cq–triazole); n/cm-1 (DRIFT): 3369w, 2976vw, 2898vw, 1776vw,
1606vw, 1551vw, 1512w, 1441vw, 1410vw, 1370vw, 1324vw,
1233vw, 1182vw, 1103vw, 1085vw, 1041w, 988vw, 894vw, 817vw,
744vw, 673vw, 625vw, 561vw, 541vw, 465vw; m/z (FAB) 765
([MH+], 18%), 719 ([MH+ - C2H5O], 4), 577 ([MH+ - C10H9N3],
=
(N N), 1521w, 1495w, 1442vw, 1405w, 1360vw, 1271w, 1176vw,
1105vw, 1036w, 1016w, 993w, 840w, 828w, 654w, 553w; m/z (FAB)
1113 ([MH+], 100%), 1115 (41), 1114 (87), 1085 (15), 990 (21).
Tetrakis(4-(4-aminomethyl-1,2,3-triazol-1-yl)phenyl)methane
(1e). The product was isolated as a brown solid (136 mg, 94%).
dH (400 MHz; DMSO-d6) 4.18 (8 H, s, CH2), 7.48–7.58 (8 H, m,
Aro-H), 7.81–7.89 (8 H, m, Arm-H, 8.73 (s, 8 H, NH2), 8.90 (4
H, s, H-triazole) ppm; dC (100 MHz; DMSO-d6) 41.7 (CH2), 62.8
(Cq-(Ar)4), 119.8 (+, CH-triazole), 120.9 (+, Cm-Ar), 131.7 (+, Co-
Ar), 132.9 (Cq-triazole), 137.4 [Cq-Ar(N)], 146.0 [Cq-Ar(C)] ppm;
n/cm-1 (DRIFT) 3279w, 3139w, 1668w, 1606w, 1513w, 1439w,
1412w, 1349w, 1232w, 1181w, 1044w, 990w, 826w, 745vw, 615vw,
+
2), 492 ([C28H26N7O2 ], 5); C41H41N4O12 calcd. 765.3374; found
765.3380 [MH+].
1,3,5,7-Tetrakis(4-(4-(2-(R)-hydroxyethyl)-1,2,3-triazol-1-yl)-
phenyl)adamantane (2c). 23.0 mmol of the azide were used
following the general procedure with identical equivalents. The
product was isolated as a crude product (50% conversion) as
4740 | Org. Biomol. Chem., 2009, 7, 4734–4743
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560w, 414vw; m/z (FAB) 705 ([MH+], 1%); C37H37N16 calcd.
Ad-CH2), 116.6 (+, CH-triazole), 116.7 (+, JC-F 23, C-8, Arm-F),
122.4 (+, C-2, Co-Ar), 122.5 (+, C-3, Cm-Ar), 125.8 (+, JC-F 25,
C-9, Aro-F), 128.1 (Cq, C-4, Arp-triazole), 133.3 (Cq, JC-F 3, C-7,
ArF), 148.3 (Cq, C-5, triazole), 149.5 (Cq, C-1, Ar-Ad), 162.4
(Cq, JC-F 249, C-10, ArF); dF ([1H]; 376 MHz; CDCl3) –111.97 (s,
705.3387; found 705.3384 [MH+].
Tetrakis(4-(1-phenyl-1,2,3-triazol-4-yl)phenyl)methane
(3a).
The product was isolated following the general procedure as a
yellow solid (212 mg, 99%). dH (400 MHz; DMSO-d6) 7.47 (8 H,
d, J 8.5, Aro-H), 7.52 (4 H, t, J 7.5, Arp(N)-H), 7.64 (8 H, d, J
7.5, Arm(N)-H), 7.93–7.99 (16 H, m, Arm-H, Aro(N)-H), 9.31 (4
H, s, H-triazole) ppm; dC (100 MHz; DMSO-d6) 64.3 (Cq-(Ar)4),
119.7 (+, CH-triazole), 112.0 [+, Co-Ar(N)], 125.1 (+, Cm-Ar),
128.1 [Cq-Ar(triazole)], 128.7 [+, Cp-Ar(N)], 129.9 [+, Cm-Ar(N)],
131.0 (+, Co-Ar), 136.6 [Cq-Ar(N)], 146.1 [Cq-Ar(C)], 146.9
(Cq-triazole) ppm; n/cm-1 (DRIFT) 3065vw, 1722vw, 1598vw,
1504vw, 1488vw, 1466vw, 1427vw, 1348vw, 1230vw, 1192vw,
1154vw, 1039vw, 993vw, 970vw, 914vw, 829vw, 758vw, 689vw,
614vw, 561vw, 527vw, 497vw; m/z (FAB) 893 ([MH+], 48%),
865 ([MH+ - N2], 10), 588 ([M+ - C24H16], 55); C57H40N12 calcd.
893.3572; found 893.3580 [MH+].
F-Ar); n/cm-1 (DRIFT) 3415w, 3140w (CAr-H), 2926w (C CH),
=
=
2852w (CAd-H), 1606w (N N), 1517m, 1496m, 1446w, 1409w,
1356w, 1228 m (C-F), 1156w, 1093w, 1037w, 994w, 837m, 782w,
790vw, 619w, 533w; m/z (FAB) 1085 ([MH+], 95%), 1086 (76),
1087 (27), 647 (53), 136 (67).
Tetrakis(4-(1-(4-nitrophenyl)-1,2,3-triazol-4-yl)phenyl)methane
(3c). The product was isolated as a reddish solid without further
purification (237 mg, 92%). dH (400 MHz; DMSO-d6) 7.34 (8 H,
d, J 8.8, Aro-H), 7.94 (8 H, d, J 8.8, Arm-H), 8.25 (8 H, d, J 8.6,
Aro(NO2)-H), 8.49 (8 H, d, J 8.6, Arm-(NO2)-H), 9.50 (4 H, s,
H-triazole) ppm; dC (100 MHz; DMSO-d6) 64.2 (Cq-(Ar)4), 120.1
(+, CH-triazole), 120.4 [+, Co-Ar(NO2)], 125.5 (+, Cm-Ar), 125.6
[+, Cm-Ar(NO2)], 128.3 [Cq-Ar(triazole)], 131.0 (+, Co-Ar), 140.8
[Cq-Ar(N)], 146.0 [Cq-Ar(C)], 146.7 (Cq-triazole), 147.4 (Cq-NO2)
ppm; n/cm-1 (DRIFT) 3378m, 3087m, 2932m, 2450vw, 2255vw,
2123m, 2089w, 1925vw, 1781vw, 1597m, 1524 s, 1441w, 1408m,
1344 s, 1311m, 1229m, 1176w, 1111m, 1030m, 1017m, 991 s, 854m,
828m, 750m, 686w, 633w, 558w, 534w; m/z (FAB) 1072 ([M+], 1%).
1,3,5,7-Tetrakis(4-(1-phenyl-1,2,3-triazol-4-yl)phenyl)adaman-
tane (4a). The product was isolated as yellow oil without further
purification (95 mg, 72% yield). Rf 0.22 (CH2Cl2/cyclohexane 3:1);
dH (400 MHz; CDCl3) 2.13 (12 H, s, Ad-CH2), 7.43–7.51 (20 H,
m, C6H5), 7.77 (8 H, d, J 8.0, Aro-H), 7.90 (8 H, d, J 8.0, Arm-H),
8.23 (4 H, s, triazole-H-6); dC (100 MHz; CDCl3) 39.1 (Cq, Ad),
46.9 (–, Cs, Ad-CH2), 117.5 (+, C-6, triazole-CH), 120.3 (+, C-8,
Co-Ph), 125.6 (+, C-3, Cm(Ar)-Ad), 125.8 (+, C-2, Co(Ar)-Ad),
128.1 (+, C-10), 128.6 (Cq, C-1, Ar-Ad), 129.6 (+, C-9), 136.9
(Cq, C-4, Arp-triazole), 148.0 (Cq, C-7), 149.3 (Cq, C-7, triazole);
(S,S,S,S)-4,4¢,4¢¢,4¢¢¢-Methanetetrayltetra-4-phenyl-1H-1,2,3-
triazole-1-acetic acid tetraethyl ester (3d). The product was
isolated as brown solid (264 mg, 85%). dH (400 MHz; DMSO-
d6) 1.16 (t, 12 H, J 7.1, CH3), 3.29–3.68 (8 H, m, CH2-Ph), 4.18
(q, 8 H, J 7.1, CH2CH3) 5.87–5.91 (4 H, m, NCHCH2), 7.14–
7.25 (20 H, m, Arp(Ph)-H, Aro(Ph)-H, Aro-H), 7.30 (8 H, d, J
8.3, Arm(Ph)-H), 7.77 (8 H, d, J 8.4, Arm-H), 8.72 (4 H, s, H-
triazole) ppm; dC (100 MHz; DMSO-d6) 13.9 (+, CH3), 36.6 (-,
CH2Ph), 61.8 (-, CH2CH3), 64.3 (Cq-(Ar)4), 70.7 (+, CHCO),
121.5 (+, CH-triazole), 124.7 (+, Cp-Ar(Ph), Cm-Ar), 126.9 [Cq-
Ar(triazole)], 128.3 [+, Co-Ar(Ph)], 128.9 [+, Cm-Ar(Ph)], 130.9 (+,
Co-Ar), 135.9 [Cq-Ar(Ph)], 146.1 [Cq-Ar(C)], 147.3 (Cq-triazole),
168.9 (Cq-CO) ppm; n/cm-1 (DRIFT) 3139vw, 3062w, 3029w,
2980w, 2936vw, 1745m, 1604w, 1494w, 1455w, 1372w, 1336w,
1231w, 1194w, 1080w, 1019w, 976w, 909vw, 830w, 750w, 701w,
608vw, 560vw, 543vw, 477vw, 415vw; m/z (FAB): 1293 ([MH+],
4%), 1265 ([MH+ - N2], 8).
n/cm-1 (DRIFT) 3141w, 3052w (CAr-H), 2927 m (C CH), 2898w,
2850w (CAd-H), 2125vw, 1670w, 1597 m (N N), 1493m, 1465m,
=
=
1426m, 1408m, 1349m, 1290w, 1228m, 1118w, 1037m, 1018m,
993m, 909w, 837m, 783m, 758m, 689m, 554w; m/z (FAB) 1013
([MH+], 100%), 1015 (77), 1016 (33), 985 ([M - C4H3]+Na, 10),
895 (9); C66H53N12 calcd. 1013.4516; found 1013.4510 [MH+].
Tetrakis(4-(1-(4-fluorophenyl)-1,2,3-triazol-4-yl)phenyl)methane
(3b). The product was isolated as a yellowish solid without
further purification (225 mg, 97%). dH (400 MHz; DMSO-d6)
7.46 (8 H, d, J 8.6, Aro-H), 7.48–7.53 (8 H, m, Arm(F)-H), 7.93
(8 H, d, J 8.6, Arm-H), 7.98–8.03 (8 H, m, Aro(F)-H), 9.28 (4 H,
s, H-triazole) ppm; dC (100 MHz; DMSO-d6) 64.2 (Cq-(Ar)4),
116.7 [+, JC-F 23, Cm-Ar(F)], 119.9 (+, CH-triazole), 122.2 [+, JC-F
9, Co-Ar(F)], 125.1 (+, Cm-Ar), 128.0 [Cq-Ar(triazole)], 130.9
(+, Co-Ar), 133.1 [JC-F 3, Cq-Ar(F)], 146.1 [Cq-Ar(C)], 146.9
(Cq-triazole), 161.6 (JC-F 246, Cq-F) ppm; dF ([1H]; 376 MHz;
DMSO-d6) –112.88 (s, F-Ar); n/cm-1 (DRIFT) 3462vw, 3142vw,
2265vw, 1605vw, 1516m, 1490w, 1446vw, 1410vw, 1345vw,
1294vw, 1227m, 1191vw, 1157w, 1121vw, 1091vw, 1036w, 1020w,
994w, 969vw, 836m, 791w, 749vw, 706vw, 519w, 559vw, 524vw;
m/z (FAB) 965 ([MH+], 25%); C57H37F4N12 calcd. 965.3195;
found 965.3211 [MH+].
(S,S,S,S)-4,4¢,4¢¢,4¢¢¢-(1,3,5,7-Adamantane)tetrayltetra-4-phe-
nyl-1H-1,2,3-triazole-1-acetic acid tetraethyl ester (4d). The
crude triazole could be purified by flash chromatography on
silica gel using cyclohexane/EtOAc (1:1) as eluent and isolated
as colorless oil (118 mg, 64% yield). Rf 0.29 (cyclohexane/EtOAc
1:1); dH (400 MHz; CDCl3) 1.21 (12 H, t, J 7.1, CH2CH3) 2.21
(12 H, s, Ad-CH2), 3.54 (8 H, d, J 6.5, CH2Ph), 4.21 (8 H, q, J
7.1, CH2CH3), 5.64 (4 H, t, J 7.5, NCHCH2), 7.08–7.25 (20 H,m,
C6H5), 7.55 (8 H, d, J 8.5, Aro-H), 7.83 (8 H, d, J 8.5, Arm-H),
7.90 (4 H, s, triazole-H); dC (100 MHz; CDCl3) 13.8 (+, CH2CH3),
38.8 (–, Cs, CH2Ph), 39.1 (Cq, Ad), 46.94 (–, Ad-CH2), 62.3 (–,
Cs, CH2CH3), 63.9 (+, CHCH2Ph), 119.4 (+, CH-triazole), 125.4
(+, C-2, Co-Ar), 125.6 (+, C-3, Cm-Ar), 127.4 (+, Cp-Ph), 128.3
(Cq, Ar-triazole), 128.6 (+, Co-Ph), 128.8 (+, Cm-Ph), 134.6 (Cq,
1,3,5,7-Tetrakis(4-(1-(4-fluorophenyl)-1,2,3-triazol-4-yl)phenyl)-
adamantane (4b). 65.0 mmol of the alkyne were used following
the general procedure and the same equivalents. The product
was isolated as cream-colored solid (61 mg, 86% yield). Rf 0.22
(CH2Cl2/cyclohexane, 3:1); dH (400 MHz; CDCl3) 2.27 (12 H, s,
Ad-H), 7.24 (8 H, m, ArF-H), 7.62 (8 H, d, J 8.5, Arm-H), 7.78
(8 H, m, ArF -H), 7.92 (8 H, d, J 8.5, Aro-H), 8.16 (4 H, s,
triazole-H); dC (100 MHz; CDCl3) 39.3 (Cq, Ad), 47.1 (–, Cs,
=
Ar-Ad), 147.2 (Cq, C6H5), 149.1 (Cq, triazole), 168.1 (Cq, C O);
n/cm-1 (DRIFT) 3464vw, 3141w (CAr-H), 3031w, 2981w, 2932w
=
=
=
(C CH), 2852w (CAd-H), 1745 m (C O), 1605w (N N), 1496m,
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1454 m (CH2), 1409w, 1357w, 1196m, 1115w, 1080w, 1018m, 976w,
894vw, 840w, 785w, 751w, 701m, 571w, 514w; m/z (FAB) 1413
(59%), 1414 ([MH+], 57), 154 (100).
0.1 Torr over silica, yielding 279 mg (0.17 mmol, 93%) of the
title compound as a colorless solid. dH (500 MHz; DMSO-d6)
1.82 (12 H, s, CH3), 2.20 (12 H, bs, CH2), 2.71, 2.83 (2 ¥ 4 H,
2 m, H2¢,H2¢¢), 3.69, 3.73 (2 ¥ 4 H, 2 m, H5¢,H5¢¢), 4.30 (4 H,
m, H4¢), 5.28 (4 H, t, J 5.1, OH), 5.40 (4 H, m, H3¢), 6.46 (4
H, t, J 6.5, H1¢), 7.72 (8 H, d, J 7.7, Ar-H), 7.84 (4 H, s, H6),
7.85 (8 H, d, J 7.7, Ar-H), 8.77 (4 H, s, H5-triazole), 11.36 (4
H, s, NH); dC (125 MHz; DMSO-d6) 12.2 (C-Me), 37.1 (C2¢),
39.2 (Cq-ad, hidden under the solvent peak), 46.2 (C-ad), 59.3
(C3¢), 60.7 (C5¢), 83.8 (C1¢), 84.3 (C4¢), 109.6 (Cq-C5), 120.7 (C4-
triazole), 125.0 (C-Ar), 125.8 (C-Ar), 128.2 (Cq-Ar), 136.2 (C6),
146.5, 149.4 (2Cq, triazole,Ar), 150.4, 163.7 (2Cq, CO); HRMS
(APCI) m/z: C82H85N20O16 calcd 1605.6447; found 1605.6448
[MH+].
(S,S,S,S)-4,4¢,4¢¢,4¢¢¢-Methanetetrayltetra-4-phenyl-1H-1,2,3-
triazole-1-acetic acid (3e). The desired click product was ob-
tained without further purification (241 mg, 85%). dH (400 MHz;
DMSO-d6) 3.21–3.58 (8 H, m, CH2-Ph), 5.42–5.68 (4 H, m,
CHCH2), 7.03–7.18 (20 H, m, Aro(Ph)-H, Arp(Ph)-H, Aro-H),
7.21–7.26 (8 H, m, Arm(Ph)-H), 7.63–7.76 (8 H, m, Aro-H), 8.63
(4 H, s, H-triazole); dC (100 MHz; DMSO-d6) 31.2 (–, CH2Ph),
64.4 (Cq-(Ar)4), 66.8 (+, CHCO), 119.7 (+, CH-triazole), 124.6 [+,
Cp-Ar(Ph), Cm-Ar)], 126.5 [Cq-Ar(triazole)], 128.1 [+, Co-Ar(Ph)],
128.7 [(Cm-Ar(Ph)], 130.8 (+, Co-Ar), 131.4 [Cq-Ar(Ph)], 145.4
[Cq-Ar(C)], 146.0 [Cq-triazole], 169.6 (Cq-CO); n/cm-1 (DRIFT)
3283m, 3030m, 2972m, 1742m, 1604w, 1497m, 1455w, 1367w,
1195m, 1082w, 1019w, 978w, 897w, 827m, 749w, 701m, 674w, 571w,
428vw, 415vw; m/z (FAB): 1181 (M+, 1%).
Tetrakis[4-(1-N4-benzoyl-2¢,3¢-dideoxycytidine-3¢-yl-1,2,3-tri-
azol-4-yl)phenyl]adamantane (4h). Samples of 3¢-azido-N4-
benzoyl-2¢,3¢-dideoxycytidine (267 mg, 0.75 mmol) and tetrakis(4-
ethynylphenyl)adamantane (10) (100 mg, 0.19 mmol) were dis-
solved in DMSO (4.5 mL). A mixture of CuSO4·5H2O (18.6 mg,
75.0 mmol) and sodium ascorbate (29.2 mg, 0.15 mmol) in water
(500 mL) was added, and the reaction mixture was stirred for
10 h at r.t. After TLC analysis (cyclohexane/CH2Cl2, 1:1 and
CHCl3/MeOH, 85:15) showed disappearance of the starting
material, CH2Cl2 (50 mL) was added. The resulting mixture
was transferred to a centrifuge vial, and the resulting precipitate
isolated after centrifugation. The crude product was washed with
CH2Cl2 (2 ¥ 10 mL) and water (2 ¥ 10 mL). The product
thus obtained was dried over silica at 0.1 Torr, yielding 357 mg
(0.18 mmol, 98%) of a slightly yellow solid. dH (500 MHz; DMSO-
d6) 2.21 (12H, bs, CH2), 2.75, 3.07 (2 ¥ 4 H, 2 m, H2¢,H2¢¢), 3.72,
3.82 (2 ¥ 4 H, 2 m, H5¢,H5¢¢), 4.47 (4 H, bs, H4¢), 5.41–5.39 (8 H,
m, OH, H3¢), 6.41 (4 H, m, H1¢), 7.43 (4H, bs, H5), 7.52 (8 H, t,
J 7.3, Bz-H), 7.63 (4H, t, J 7.3, Bz-H), 7.73 (8 H, d, J 7.7, Ar-H),
7.87 (8 H, d, J 7.7, Ar-H), 8.03 (8 H, d, J 7.3, Bz-H), 8.54 (4 H,
d, J 6.6, H6), 8.77 (4 H, s, H5-triazole), 11.27 (4 H, bs, NH); dC
(125 MHz; DMSO-d6) 38.4 (C2¢), 39.2 (Cq-ad, hidden under the
solvent peak), 46.2 (C-ad), 58.8 (C3¢), 60.3 (C5¢), 85.3 (C4¢), 86.4
(C1¢), 96.2 (C5), 120.7 (C4-triazole), 125.0 (C-Ar), 125.8 (C-Ar),
128.2 (Cq-Ar), 128.3 (C-Bz), 128.4 (C-Bz), 132.7 (C-Bz), 133.1
(Cq), 145.1 (C6), 146.5, 149.4 (2Cq, triazole, Ar), 154.2, 163.1,
167.3 (3Cq, 2CO, C4); HRMS (ESI) m/z: C106H96N24O16Na2 calcd
1003.3610 [M + 2Na]2+; found: 1003.3606.
Tetrakis(4-(1-(3,5-dicarboxyphenyl)-1,2,3-triazol-4-yl)phenyl)-
methane (3f). The product was isolated as a brownish solid
(245 mg, 82%). dH (400 MHz; DMSO-d6) 7.24–7.30 (8 H, m,
Aro-H,), 7.78–7.81 (8 H, m, Arm-H), 8.38 (4 H, s, Ar(CO2H)2-
H), 8.53 (8 H, s, Ar(N)-H), 9.38 (4 H, s, H-triazole), 13.71 (8
H, s, CO2H) ppm; dC (100 MHz; DMSO-d6): 64.5 (Cq-(Ar)4),
119.9 (+, CH-triazole), 121.1 [C-Ar(CCO2H)] 125.2 [+, Cm-
Ar], 127.9 [Cq-Ar(triazole)], 128.0 [Cq-Ar(N)] 131.0 (+, Co-Ar),
131.1 [C-Ar(CCO2H)2, C-Ar(CO2H)], 146.2 [Cq-Ar(C)], 147.3
(Cq-triazole), 168.6 (CO2H) ppm; n/cm-1 (DRIFT) 3088w, 2124w,
1718w, 1602w, 1460w,1414w, 1224w, 1060vw, 1017vw, 898vw,
827vw, 760w, 670vw, 536vw, 440vw, 412vw; m/z (FAB) 1245
([MH+], 1%), 232 (C10H6N3O4 , 54).
+
1,3,5,7-Tetrakis(4-(1-(3,5-dicarboxyphenyl)-1,2,3-triazol-4-yl)-
phenyl)adamantane (4f). The pure product was separated after
the reaction via filtration as a grey solid and washed with MeOH
and CHCl3 (106 mg, 60%). dH (500 MHz; CDCl3) 2.23 (12 H, s,
Ad-CH2), 7.76 (8 H, d, J 7.8, Arm-H), 7.99 (8 H, d, J 7.7, Aro-H),
8.52 (4 H, s, CHC(CO2H)2), 8.69 (8 H, s, 2 ¥ CHC(CO2H)), 9.58 (4
H, s, triazole-H); dC (125 MHz; CDCl3) 39.1 (–, Ad-CH2), 46.2 (–,
Cq), 119.5 (+, CH-triazole), 123.5 (+, 2 ¥ CH(CCO2H), 125.2 (+,
C-2, Co-Ar), 125.9 (+, C-3, Cm-Ar), 127.7 (+, C-4, Ar-triazole),
133.9 (Cq, Ar-Ad), 137.2 [Cq, C(CO2H)], 147.6 (Cq, CH(CCO2H),
149.8 (Cq, triazole), 165.9 (Cq, C=O); n/cm-1 (DRIFT) 3070w
=
(CAr-H), 1714m, 1602w (N N), 1461w, 1422w, 1237m, 1059w,
(DMT-APCNET)4TTPA (4i). Tetranucleoside 4g (52.0 mg,
32.4 mmol) and the 3¢-b-cyanoethyl-N,N¢-diisopropylphos-
phoramidite of N6-benzoyl-2¢-deoxy-5¢O-(dimethoxytrityl)adeno-
sine (169 mg, 194 mmol, 6.0 eq) were mixed, coevaporated from
dry MeCN (3 ¥ 2.5 mL), and dissolved in dry THF (2 mL)
under argon. The stirred solution was treated dropwise with a
solution of tetrazole (0.45 M, 2 mL). After 24 h, a solution
of t-butylhydroperoxide (500 mL, 5.5 M in decane) was added
dropwise, followed by stirring for 45 min. The reaction mixture
was added to ethyl acetate (10 mL) in a centrifuge vial, leading to
the precipitation of a solid that was isolated by centrifugation.
The solid was washed with ethyl acetate (3 ¥ 7 mL). The
fully protected octanucleosidic product thus obtained (mixture
of RP/SP diastereomers) was dried over silica at 0.1 Torr, yielding
127 mg (27 mmol, 83%) of a colorless solid. HRMS (ESI)
m/z: calcd for C246H232N44O48P4: 2348.8111 [M + 2H]2+; found
1016w, 902w, 762w, 705w, 672w, 578w; m/z (FAB) 1365 ([MH+],
100%), 1356 (74), 1357 (41).
1,3,5,7-Tetrakis[4-(1-2¢,3¢-dideoxythymidin-3¢-yl-1,2,3-triazol-
4-yl)phenyl]adamantane (4g). 3¢-Azido-2¢,3¢-dideoxythymidine
(199 mg, 0.75 mmol) and 1,3,5,7-tetrakis(4-ethynylphenyl)-
adamantane (10) (100 mg, 0.19 mmol) were dried for 1 h at 0.1 Torr,
and then dissolved in DMSO (1.5 mL). A slurry of CuSO4·5 H2O
(18.6 mg, 0.07 mmol) and sodium ascorbate (29.2 mg, 0.15 mmol)
in water (500 mL) was added, and the resulting mixture was stirred
for 10 h at r.t. After TLC analysis showed full conversion of 1,3,5,7-
tetrakis(4-ethynylphenyl)adamantane, the reaction mixture was
diluted with ethyl acetate (5 mL), and added to water (10 mL)
in a centrifuge vial. A precipitate formed that was isolated by
centrifugation. The solid was washed with ethyl acetate (3 ¥ 15 mL)
and water (2 ¥ 15 mL), leading to a product that was dried at
4742 | Org. Biomol. Chem., 2009, 7, 4734–4743
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2348.8115; MS (MALDI-TOF): calcd. for C246H232N44O48P4 4695
[MH+]; found 4698.
6 (a) X. Wang, M. Simard and J. D. Wuest, J. Am. Chem. Soc., 1994, 116,
12119–12120; (b) B. F. Hoskins and R. Robson, J. Am. Chem. Soc.,
1989, 111, 5962–5964; (c) A recent example: Y.-B. Men, J. Sun, Z.-T.
Huang and Q. Zheng, Angew. Chem., Int. Ed., 2009, 48, 2873–2876.
7 J. D. Wuest, Chem. Commun., 2005, 5830–5837.
(AT)4TTPA (4j). A sample of fully protected DNA hybrid
4i (55.0 mg, 11.7 mmol) was treated with saturated aqueous
ammonia (25%, 1 mL) and heated to 55 ◦C for 24 h while
stirring. Caution: saturated aqueous ammonia builds up pressure
when heated, and a pressure-resistant vessel should be employed.
The solution was allowed to cool to room temperature and
water (2.5 mL) was added, followed by removal of remaining
ammonia with a gentle stream of N2, directed onto the surface
of the solution. Lyophilization to dryness gave 54.0 mg of an
intermediate free of base-labile protecting groups. A sample of this
crude product (8.0 mg) was dissolved in acetic acid (3 mL, 80%
aqueous solution, v/v) and stirred at r.t. for 1 h. After addition of
H2O/diethyl ether (18 mL, 1/1, v/v) and stirring for 30 min at r.t.,
a precipitate was isolated by centrifugation. The crude product was
washed with water (5 mL) and diethyl ether (3 ¥ 5 mL), followed by
drying at 0.1 Torr, to yield 5.6 mg of fully deprotected hybrid. The
solid was then dissolved in aqueous triethylammonium acetate
buffer (0.1 M, pH 7.0, 1.5 mL) containing 15% CH3CN. A sample
of this solution (100 mL) was subjected to RP-HPLC (C4 column,
gradient from 0% to 40% CH3CN in 80 min) to yield the title
compound 4j at a retention time (tR) of 50 min (yield 25%, as
determined by its absorption at 260 nm in the HPLC trace of the
crude); e260 used = 167000 L mol-1 cm-1; HRMS (ESI) m/z: calcd
for C122H128N40O36P4Na: 958.9436 [M + Na]3-; found: 958.9435;
MS (MALDI-TOF): calcd. for C122H128N40O36P4 2852 [M - H]-;
found 2855.
8 M. Meng, C. Ahlborn, M. Bauer, O. Plietzsch, S. A. Soomro, A. Singh,
T. Muller, W. Wenzel, S. Bra¨se and C. Richert, ChemBioChem, 2009,
10, 1335–1339.
9 (a) R. Huisgen, Angew. Chem., Int. Ed. Engl., 1963, 2, 565–598;
(b) R. Huisgen, J. Org. Chem., 1976, 41, 403–419; (c) C. W. Tornøe,
C. Christensen and M. Meldal, J. Org. Chem., 2002, 67, 3057–3064;
(d) H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem.,
Int. Ed., 2001, 40, 2004–2021; (e) V. V. Rostovtsev, L. G. Green,
V. V. Fokin and K. B. Sharpless, Angew. Chem., Int. Ed., 2002, 41,
2596–2599; (f) F. Himo, T. Lovell, R. Hilgraf, V. V. Rostovtsev, L.
Noodleman, K. B. Sharpless and V. V. Fokin, J. Am. Chem. Soc., 2005,
127, 210–216; (g) C. J. Hawker, V. V. Fokin, M. G. Finn and K. B.
Sharpless, Aust. J. Chem., 2007, 60, 381–383; (h) W. H. Binder and
R. Sachsenhofer, Macromol. Rapid Commun., 2007, 28, 15–54; (i) J.-F.
Lutz, Angew. Chem., Int. Ed., 2007, 46, 1018–1025; (j) A. D. Moorhouse
and J. E. Moses, ChemMedChem, 2008, 3, 715–723; (k) M. Meldal and
C. W. Tornoe, Chem. Rev., 2008, 108, 2952–3015.
10 (a) E. F. V. Scriven and K. Turnbull, Chem. Rev., 1988, 88, 297–368;
(b) A. K. Feldman, B. Colasson and V. V. Fokin, Org. Lett., 2004, 6,
3897–3899; (c) S. Bra¨se, C. Gil, K. Knepper and V. Zimmermann,
Angew. Chem., Int. Ed., 2005, 44, 5188–5240; (d) T. Schro¨der, M.
Gartner, T. Grab and S. Bra¨se, Org. Biomol. Chem., 2007, 5, 2767–
2769.
11 For example: (a) V. Aucagne and D. A. Leigh, Org. Lett., 2006, 8,
4505–4507; (b) S. G. Gouin, E. Vanquelef, J. M. Garc´ıa Ferna´ndez, C.
Ortiz Mellet, F.-Y. Dupradeau and J. Kovensky, J. Org. Chem., 2007,
72, 9032–9045; (c) Y. Li and A. H. Flood, Angew. Chem., Int. Ed., 2008,
47, 2649–2652.
12 J. D. Megiatto, Jr. and D. I. Schuster, Chem. Eur. J., 2009, 15, 5444–
5448.
13 (a) A. Dondoni, Chem. Asian J., 2007, 2, 700–708; (b) C. Ornelas,
J. R. Aranzaes, L. Salmon and D. Astruc, Chem. Eur. J., 2008, 14, 50–
64; (c) E. Boisselier, A. K. Diallo, L. Salmon, J. Ruiz and D. Astruc,
Chem. Commun., 2008, 4819–4821; (d) G. Franc and A. Kakkar, Chem.
Commun., 2008, 5267–5276; (e) K.-N. Lau, H.-F. Chow, M.-C. Chan
and K.-W. Wong, Angew. Chem., Int. Ed., 2008, 47, 6912–6916; (f) P.
Wu, X. Chen, N. Hu, U. C. Tam, O. Blixt, A. Zettl and C. R. Bertozzi,
Angew. Chem., Int. Ed., 2008, 47, 5022–5025; (g) R. E. Kohman and
S. C. Zimmerman, Chem. Commun., 2009, 794–796.
Acknowledgements
We gratefully acknowledge the financial support of the DFG,
Center for Functional Nanostructures (CFN, Projects C5.2 and
C5.3), the Konrad Adenauer foundation (grant to OP), as well as
the Henkel foundation (grant to CIS).
14 J. Iehl, R. Pereira de Freitas, B. Delavaux-Nicot and J.-F. Nierengarten,
Chem. Commun., 2008, 2450–2452.
15 C. I. Schilling and S. Bra¨se, Org. Biomol. Chem., 2007, 5, 3586–
3588.
16 (a) T. J. Zimmermann and T. J. J. Mu¨ller, Synthesis, 2002, 1157–
1162; (b) J.-H. Fournier, X. Wang and J. D. Wuest, Can. J. Chem.,
2003, 81, 376–380; (c) E. Galoppini and R. Gilardi, Chem. Commun.,
1999, 173–174; (d) Q. Wei, A. Lazzeri, F. Di Cuia, M. Scalari and E.
Galoppini, Macromol. Chem. Phys., 2004, 205, 2089–2096; (e) F. A.
Neugebauer, H. Fischer and R. Bernhardt, Chem. Ber., 1976, 109,
2389–2394.
References
1 (a) P. Pierrat, C. Re´thore´, T. Muller and S. Bra¨se, Synlett, 2008, 1706–
1710; (b) P. Pierrat, S. Vanderheiden, T. Muller and S. Bra¨se, Chem.
Commun., 2009, 1748–1750.
2 For selected reviews, see: (a) M. Simard, D. Su and J. D. Wuest,
J. Am. Chem. Soc., 1991, 113, 4696–4698; (b) P. Brunet, M. Simard and
J. D. Wuest, J. Am. Chem. Soc., 1997, 119, 2737–2738; (c) D. Laliberte´,
T. Maris and J. D. Wuest, J. Org. Chem., 2004, 69, 1776–1787; (d) J.-
H. Fournier, T. Maris and J. D. Wuest, J. Org. Chem., 2004, 69,
1762–1775.
3 For selected reviews, see: (a) M. Eddaoudi, D. B. Moler, H. Li, B.
Chen, T. M. Reineke, M. O’Keeffe and O. M. Yaghi, Acc. Chem. Res.,
2001, 34, 319–330; (b) J. L. C. Roswell and O. M. Yaghi, Microporous
Mesoporous Mater., 2004, 73, 3–14; (c) S. L. James, Chem. Soc. Rev.,
2003, 32, 276–288.
4 For selected reviews, see: (a) O. M. Yaghi, H. Li, C. Davis, D.
Richardson and T. L. Groy, Acc. Chem. Res., 1998, 31, 474–484; (b) C.
Janiak, Dalton Trans., 2003, 2781–2804; (c) M. O’Keeffe, M. Eddaoudi,
H. Li, T. Reineke and O. M. Yaghi, J. Solid State Chem., 2000, 152,
3–20; (d) C. Kaes, A. Katz and M. W. Hosseini, Chem. Rev., 2000, 100,
3553–3590; (e) M. W. Hosseini, Acc. Chem. Res., 2005, 38, 313–323;
(f) O. Fe´lix, M. W. Hosseini, A. De Cian and J. Fischer, Angew. Chem.,
Int. Ed. Engl., 1997, 36, 102–104.
17 R. Eisenhuth and C. Richert, J. Org. Chem., 2009, 74, 26–
37.
18 For the click reaction with thymidine derivatives, see for example:
(a) A. Rochdi, M. Taourirte, N. Redwane, S. Sebti, J. W. Engels and
H. B. Lazrek, Nucleosides, Nucleotides Nucleic Acids, 2003, 22, 679–
681; (b) Multiple click reactions with nucleic acid derivatives: L. Zhou,
A. Amer, M. Korn, R. Burda, J. Balzarini, E. De Clercq, E. R. Kern and
P. F. Torrence, Antiviral Chem. Chemother., 2005, 16, 375–383; (c) P.-Y.
Jin, P. Jin, Y.-A. Ruan, Y. Ju and Y.-F. Zhao, Synlett, 2007, 3003–3006.
19 M. C. de Koning, A. B. T. Ghisaidoobe, H. I. Duynstee, P. B. W. Ten
Kortenaar, D. V. Filippov and G. A. van der Marel, Org. Process Res.
Dev., 2006, 10, 1238–1245.
20 G. M. Sheldrick, Acta Crystallogr., Sect. A, 2008, 64, 112–
122.
21 H. D. Flack, Acta Crystallogr., Sect. A, 1983, 39, 876–881.
22 Porosity is defined as total potential solvent area volume per unit cell
volume: A. L. Spek, J. Appl. Crystallogr., 2003, 36, 7–13.
23 The packing indices are 58.2 (1a), 52.7 (4a) and 69.9 (7); see: A. I.
Kitajgorodskij, Molecular Crystals and Molecules, Academic Press,
New York, 1973.
5 (a) P. Brunet, E. Demers, T. Maris, G. D. Enright and J. D. West, Angew.
Chem., Int. Ed., 2003, 42, 5303–5306; (b) D. Laliberte´, T. Maris and
J. D. Wuest, Can. J. Chem., 2004, 82, 386–398.
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