Aromatic nitrogen donors for efficient copper(I)-NHC CuAAC under reductant-free conditions

Article abstract of DOI:10.1002/ejoc.201000046

Copper(I)-catalysed azide-alkyne cycloaddition (CuAAC) has been successfully conducted under reductant-free conditions. The catalytic system consisted of a combination of a copper(I)-N-heterocyclic carbene complex and aromatic Ndonors. The catalyst is sta

Full text of DOI:10.1002/ejoc.201000046

FULL PAPER
DOI: 10.1002/ejoc.201000046
Aromatic Nitrogen Donors for Efficient Copper(I)–NHC CuAAC under
Reductant-Free Conditions
Marie-Laure Teyssot,[a] Lionel Nauton,[a,b] Jean-Louis Canet,[b,c] Federico Cisnetti,[a,b]
Aurélien Chevry,[a] and Arnaud Gautier*[a,b]
Keywords: Click chemistry / CuAAC / Heterocycles / Carbenes / Copper
Copper(I)-catalysed azide–alkyne cycloaddition (CuAAC)
has been successfully conducted under reductant-free condi-
tions. The catalytic system consisted of a combination of a
copper(I)–N-heterocyclic carbene complex and aromatic N-
donors. The catalyst is stable and can be stored, thus render-
ing the reaction valuable for routine use.
Introduction
The emergence of “click chemistry” as a new way of cate-
gorizing organic reactions involving simple, selective, modu-
lar, high-yielding and easily workable transformations has
facilitated an extraordinary expansion in the number of mo-
lecules available for medicinal chemistry, biology and mate-
rials science.[1] Among these synthetic “click” tools, cop-
per(I)-catalysed azide–alkyne cycloaddition (CuAAC) has
received unrivalled attention.[2] The CuAAC procedure
classically requires the presence of a sacrificial reducing
agent such as ascorbic acid or TCEP [tris(2-carboxyethyl)-
phosphane] to form the copper(I) species from a copper(II)
source. The discovery of ligand-accelerating effects in
CuAAC, despite increasing the reaction rate, has allowed
both copper catalyst and reducing agent loadings to be dra-
matically reduced. The ligands (Figure 1) are usually aro-
matic N-donors, for example, triazole [1, TBTA: tris(benz-
yltriazolylmethyl)amine], benzimidazole [2, (BimC4A)3] and
phenanthroline (3, bathophenanthrolinedisulfonic acid
disodium salt).[3]
Nevertheless, few homogeneous catalytic systems giving
rapid and efficient catalysis without the aid of a reducing
reagent are available (Figure 2). This is important because
ascorbic acid, dehydroascorbate and other byproducts have
been reported to interact with azo amides, lysine and guan-
idine.[4] Also, in the case of lanthanide probes, ascorbic acid
is known to act as a luminescence quencher.[5] In this con-
text, the highly crowded [Cu(C186tren)]Br (4) introduced by
Figure 1. N-donor ligands that accelerate CuAAC.
Vincent and co-workers exhibits very good stability towards
oxygen, thereby allowing a catalyst loading as low as
10–3 mol-% with an impressive turnover number.[6] On the
other hand, this high catalytic efficiency is achieved at the
expense of the high temperature needed for the reactions.
Pericàs and co-workers recently reported a contracted ver-
sion of the tripodal ligand 1.[7] The stable complex 5
(0.5 mol-%) can be used in neat or “on water” conditions.
(Aminoarenethiolato)copper(I) 6, which exhibits excellent
thermal stability, is also able to promote CuAAC at low
loading (1 mol-%).[8] Unfortunately, the reactions cannot be
conducted in water, and organic solvents such as dichloro-
methane are preferred. Finally, the seminal work of Nolan
[a] Clermont Université, Université Blaise Pascal, Laboratoire
SEESIB,
B. P. 10448, 63000 Clermont Ferrand, France
Fax: +33-4-73407717
E-mail: arnaud.gautier@univ-bpclermont.fr
[b] CNRS, UMR 6504, SEESIB,
63177 Aubiere, France
[c] Clermont Université, ENSCCF, Laboratoire SEESIB,
B. P. 10448, 63000 Clermont Ferrand, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000046.
Figure 2. Oxygen-stable catalysts 4–9.
Eur. J. Org. Chem. 2010, 3507–3515
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3507

M.-L. Teyssot, L. Nauton, J.-L. Canet, F. Cisnetti, A. Chevry, A. Gautier
FULL PAPER
and co-workers on N-heterocyclic carbenes (NHC) has bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene, 13] and
demonstrated the remarkable stability of neutral and cat- [CuCl(IPr)] [IPr 1,3-bis(2,6-diisopropylphenyl)imid-
=
ionic copper(I)–NHCs 7 and 8 towards moisture, heat and azolin-2-ylidene, 14]. In all cases, the observed exchange is
oxygen allowing CuAAC to occur, in some cases, at ppm slower than the NMR timescale, and separated signals are
catalyst loadings. Here again, the catalytic efficiency is observed.
achieved at the expense of neat or “on water” conditions.[9]
Inspired by these results, we recently reported that the
combination of the CuI–NHCs [Cu(SIMes)Cl] [SIMes =
1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene] with
aromatic nitrogen donors such as 1,10-phenanthroline af-
fords the well-defined copper(I)–NHC 9.[10] The CuAAC
reaction catalysed by 9 takes place efficiently in solution, at
room temperature and in the total absence of a reducing
agent. In this article we now report our complete experi-
mental data concerning the advantages of combining CuI–
NHCs with aromatic N-donors.
We then took advantage of the separated signals to esti-
mate the values of the binding constant by using Equa-
tion (1) derived from reaction (2). The values are presented
in Table 1.
Results and Discussion
Copper(I)–NHC/Phenanthroline Equilibria
K = [CuCl(NHC)(N-donor)]/{[CuCl(NHC)][N-donor]}
(1)
In our preliminary communication we reported the re-
versible association of 1,10-phenanthroline (10) with
[CuCl(SIMes)]. Unexpectedly, the equilibrium constant was
found to be rather low for a copper(I)–phenanthroline com-
plex (K = 250 –1), and this was believed to be one of the
key features of its catalytic efficiency.[10] Typical of ligand-
exchange phenomena occurring on the NMR timescale, the
1H and 13C NMR spectra of a mixture of 7a and phen-
anthroline (1:1) revealed an extreme broadening of the
phenanthroline signals, whereas the carbene signature re-
(2)
Table 1. Equilibrium constants.
Entry
Copper(I)–NHC
Ligand
K [mol–1]
mained unchanged. Interestingly,
a different picture
emerges with the bulkier 2,9-dimethyl-1,10-phenanthroline
(11) (neocuproine; Figure 3). The signals of 7a and 11 are
accompanied by signals corresponding to the [CuCl(neocu-
proine)(SIMes)] complex, which indicates a slower ligand
exchange even though some enlargements of signals are still
observed. Three other representative copper(I)–NHCs were
examined: [CuCl(IMes)] [IMes = 1,3-bis(2,4,6-trimethyl-
phenyl)imidazolin-2-ylidene, 12], [CuCl(SIPr)] [SIPr = 1,3-
1
2
3
4
5
[CuCl(SIMes)]
[CuCl(SIMes)]
[CuCl(IMes)]
[CuCl(SIPr)]
[CuCl(IPr)]
Phenanthroline
Neocuproine
Neocuproine
Neocuproine
Neocuproine
250
ca. 140
ca. 120
ca. 6
ca. 3
At first, the equilibrium constant appears to be strongly
influenced by steric factors. Regarding the nature of the
aromatic N-donor, the increase in the steric bulk (from 10
to 11) results in a weaker association (Table 1, Entries 1 and
2). The same behaviour is observed for the NHC: the intro-
duction of isopropyl groups at the 2- and 6-positions simi-
larly results in a dramatic decrease in the association
(Table 1, Entries 2 and 4, 3 and 5). We then considered the
possibility of combining the steric factors (quantifiable by
the %Vbur factor) with the binding energy. The %Vbur pa-
rameter has been proposed for metal–NHCs as a quantifier
of part of the first coordination sphere (centred on the
metal atom) occupied by the carbene ligand.[11] We then
naturally attempted to correlate the values of %Vbur with
the energy required to form the [CuCl(NHC)(N-donor)]
complex. For that we selected the four NHCs studied
(SIMes, IMes, SIPr and IPr) and added SIMet [SIMet =
1,3-dimethylimidazolidin-2-ylidene] and IMet [IMet = 1,3-
dimethylimidazolin-2-ylidene], which are two carbenes with
lower steric hindrance (Figure 4).
Figure 3. 1H NMR spectra of copper(I)–NHCs and neocuproine
(CDCl3, 400 MHz, c = 0.017 ).
3508
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3507–3515

Aromatic Nitrogen Donors for Efficient Copper(I)–NHC CuAAC
The energies were then plotted versus %Vbur for the dif-
ferent [Cu(NHC)]s as depicted in Figure 5. The energies
correlate well with the %Vbur values calculated for each
complex. The graph shows that neocuproine associates
more easily with complexes in which NHCs are of low hin-
drance, in accord with experimental observations. Thus, for
a fixed ligand, steric effects drive the equilibrium.
Figure 4. Equilibrium between the Cu–NHC and neocuproine and
the carbenes selected for the study.
Copper(I)–NHC Screening
In our preliminary communication, we report that,
among the few aromatic nitrogen donors added to
[CuCl(SIMes)], phenanthroline provides one of the best
catalytic activities.[10] Here, we also screen the effect of
NHCs 12–14 with 10 on the model reaction of phenyl-
acetylene (15) with benzyl azide (16) [reaction (3), Table 3].
The results presented in Table 3 show that only
[CuCl(SIMes)] and [CuCl(IMes)] catalyse the formation of
17.[9a] Here again, the addition of 10 greatly increases the
isolated yields (Entries 1 vs. 2 and 3 vs. 4), 7a being a better
catalyst than 12.
First of all, optimization performed on complex 9 with
the Gaussian 03 package of software was found to give re-
sults similar to those of the corresponding X-ray analysis,
which confirmed the ability of this program to reproduce
the structures of our complexes.[12] The geometries of
[CuCl(NHC)], [CuCl(NHC)(neocuproine)] and neocupro-
ine were then freely optimized in the gas phase, and the
binding energies were determined. These calculated energies
include the association of the neocuproine with the cop-
per(I) centre, the distortion of the complex from a linear to
a tetrahedral geometry and the variation of bond lengths
(especially for the chloride atom). The %Vbur values, which
refer to the [Cu(NHC)] part of the complexes, are extracted
from the optimized complexes and are compared, when
possible, with X-ray data. The %Vbur values were calculated
by using the SambVca program.[11c] To account only for the
carbene–copper moiety, the chloride ion was excluded from
the coordinate file, and a sphere of 3.5 Å was centred on
the copper atom. Importantly, this implies that the metal–
C distances are automatically adjusted to the values found
in the calculations or X-ray analyses and are not fixed at
a standard distance (usually 2.10 Å) as is done in regular
calculations (Table 2).
(3)
Table 3. Catalytic effect of copper(I)–NHCs in CuAAC.
Entry
Copper(I)–NHC
Additive
Yield [%]
1
2
3
4
5
6
7
8
[CuCl(SIMes)] (7a)
[CuCl(SIMes)] (7a)
[CuCl(IMes)] (12)
[CuCl(IMes)] (12)
[CuCl(SIPr)] (13)
[CuCl(SIPr)] (13)
[CuCl(IPr)] (14)
none
phenanthroline (10)
none
10
78
15
49
0
Ͻ10
0
Ͻ10
Table 2. %Vbur values for [Cu(NHC)].
%Vbur
phenanthroline (10)
none
phenanthroline (10)
none
phenanthroline (10)
SIPr
IPr
SIMes
IMes
SIMet
29.2
IMet
28.8
Calcd.
X-ray
53.4
48.7
50.3
48.5
43.2
39.2
41.5
[CuCl(IPr)] (14)
Screening of Additives
Having selected 7a as the best copper(I) precatalyst, we
then screened a selection of 19 aromatic N-donors [reac-
tion (4), Figure 6]. This collection of additives can be cast
into two subsets: mono- and bidentates, derivatives of dif-
ferent pyridines and 1,10-phenanthrolines. Special attention
was paid to the collection of pyridines, commercially avail-
able pyridines bearing electron-donating and -withdrawing
groups.
Figure 5. Correlation between the %Vbur values and the binding
energies.
(4)
Eur. J. Org. Chem. 2010, 3507–3515
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3509

M.-L. Teyssot, L. Nauton, J.-L. Canet, F. Cisnetti, A. Chevry, A. Gautier
FULL PAPER
furnished the expected complex in 71% yield as a deep-
purple microcrystalline solid. This material is stable for
months at room temperature in the presence of air and
light. Unfortunately, we were unable to grow crystals suit-
1
able for X-ray analysis. The H and 13C NMR spectra of
18 in CDCl3 reveal an extreme broadening of the 4,7-
dichloro-1,10-phenanthroline signals, evocative of the solu-
tion behaviour of 9 (Figure 7).
Figure 6. Screening of additives.
In the phenanthroline series, the hindered neocuproine
exhibits nearly no activity with other additives of lower
steric hindrance displaying better efficiencies. The efficien-
cies increase in roughly the following order: neocuproine Ͻ
4,7-dimethoxy-1,10-phenanthroline Ͻ bathophenanthroline
Ͻ 1,10-phenanthroline Ͻ 4,7-dichloro-1,10-phenanthroline.
Both 2,2Ј-bipyridine and 4,4Ј-dimethoxy-2,2Ј-bipyridine
were also tested, but their contribution, albeit being benefi-
cial, is poorer than that of the best phenanthroline. Interest-
ingly, inspection of the pyridine derivatives revealed the
existence of two subgroups. Pyridine and compounds pos-
sessing electron-withdrawing groups are inactive (2- and 4-
acetyl-, 4-cyanopyridine). In contrast, the introduction of
electron-donating substituents at the 2- and 4-positions re-
sults in a dramatic increase in the yield. For example, 2-
and 4-aminopyridine as well as 4-pyrrolidinyl- and 4-meth-
oxypyridine led to yields of 55, 77, 70 and 95%, respec-
tively. Both 4-amino- and 4-(dimethylamino)pyridines gave
good yields (77 and 84%, respectively), which demonstrates
that catalysis can be enhanced regardless of the substitution
pattern at the nitrogen atom.
1
Figure 7. Aromatic part of the H NMR spectrum of complex 18.
Thus, although the signature of [CuCl(SIMes)] appears
clearly, the signals of 4,7-dichloro-1,10-phenanthroline are
considerably broadened. Importantly, 18 conserves its in-
tegrity in solution for days. This was not the case for 9,
which decomposes in solution exposed to air after several
hours (in the solid state, the reddish crystals of 9 are stable
for months). Also significant is that the addition of hetero-
cycles containing electron-donating groups (i.e., 4,7-dimeth-
oxy-1,10-phenanthroline, 4-methoxypridine) to [CuCl-
(SIMes)] solutions exposed to air results in a rapid decom-
position of the complexes with concomitant formation of a
reddish unidentified solid. The difference with 18 is proba-
bly a result of the lower electron-donating ability of the 4,7-
dichloro-1,10-phenanthroline, which makes the complex
less susceptible to oxidation, and thus it is more likely that
the reaction goes to completion.
Overall, [CuCl(SIMes)(Phen)] (9) and notably
[CuCl(SIMes)(4,7-dichloro-1,10-phenanthroline)] (18) are
well suited for the CuAAC reaction, the latter giving the
best results (Scheme 1).
Quantum Studies of the Complexes
As we were unable to grow crystals of 18, we used
Gaussian quantum optimization [B3LYP at the 6-31g(d,p)
level of theory] to reveal its structure. Structures of the com-
plexes of 18 and [CuCl(SIMes)(4-DMAP)2] (19) were opti-
mized by this method (Figure 8 and Table 4).
The geometry of 7a was determined by X-ray diffraction;
an important feature of this complex is the linear copper
geometry. When aromatic N-donors are added, the copper
centre adopts a distorted tetrahedral environment, a conse-
quence of the non-equivalent steric and/or electronic envi-
Scheme 1. The two best catalysts resulting from CuAAC screening.
Synthesis of Complex 18
Complex 18 is easily accessible: addition of pentane to a ronment around the copper atom. This is not surprising as
dichloromethane solution containing equimolar quantities the tetrahedral geometry has been reported for many mixed
of [CuCl(SIMes)] and 4,7-dichloro-1,10-phenanthroline σ-aromatic N-donor complexes. Elongation of the copper–
3510
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3507–3515

Aromatic Nitrogen Donors for Efficient Copper(I)–NHC CuAAC
(5)
Table 5. Solvent effect.
Entry
Solvent
Isolated yield [%]
1
2
3
4
5
MeOH
EtOH
CH2Cl2
DMF
87
92
82
40
37
DMSO
Next, the scope and limitations of the reaction were ex-
amined by using a representative collection of azides and
alkynes in methanol (Figure 9). In agreement with our pre-
liminary report, electron-rich (20) and -poor aromatic az-
ides (21) are well tolerated. Propionic acid (22) is reluctant
to react, probably because of protonation of the aromatic
N-donor.[10] Propargylamine reacts well with alkyl azides to
furnish 23–27 in good isolated yields, regardless of the
length of the chain. Finally, 18 also catalyses the reaction
with ammonium compound 28 to furnish the bis(triazole)
29. We were also interested in the triazole moiety as a po-
tential ligand for metals (Figure 10). We thus turned our
attention to 2-(azidomethyl)pyridine (30), which reacts ef-
ficiently with 15 to furnish the potent “inverse click chela-
tor” 31 in almost quantitative yield. Indeed, this compound
has recently been published as a copper(II) and silver(I)
clamp.[13] Because of our interest in potential ligands for
other metals, we focused on dipicolinic acid (DPA) deriva-
tives that are well known for their propensity to complex
lanthanides.
Figure 8. Optimized structures of 7a, 9, 18 and 19.
Table 4. Bond lengths and angles of interest for complexes 7a, 9,
18 and 19.
Bond lengths [Å]
Cu–Cl
Cu–N
Cu–N
Cu–C
7a[a]
9[a]
2.009
2.347
2.323
2.316
2.453
–
–
1.882
1.916
1.906
1.906
1.892
2.114
2.069
2.064
2.070
2.128
2.069
2.064
2.070
9[b]
18[b]
19[b]
Bond angles [°]
C–Cu–Cl
N–Cu–N
N–Cu–Cl
N–Cu–Cl
7a[a]
9[a]
178.5
120.5
108.8
108.6
108.7
–
–
99.9
109.1
109.3
107.7
–
77.4
80.3
79.7
98.6
102.0
109.1
109.3
100.7
9[b]
18[b]
19[b]
[a] X-ray data. [b] Quantum calculations.
chloride bond in the original [CuCl(SIMes)] is also a signifi-
cant feature of the four-coordinate complexes of copper(I),
the Cu–Cl bond length being between 2.32 and 2.45 Å. The
switch from bidentate to monodentate ligands results in a
decompression of the N–Cu–N angles (from ca. 80° for bi-
dentate ligands to ca. 100° for monodentate ligands) and a
rotation of the two heterocycles around the copper–nitro-
gen axis, which places the two 4-DMAP groups in a quasi-
parallel position with the mesityl moieties.
Scope and Limitations
First of all the solvent effect was evaluated on the model
reaction by using 1% loading of 18 after 18 h [reaction (5),
Table 5]. As can be seen, 18 not only efficiently catalyses
the CuAAC reaction in environmentally friendly alcoholic
solvents (MeOH and EtOH), but the reaction can also be
performed in dichloromethane. However, the efficiency is
significantly reduced when using strong polar aprotic sol-
vents such as DMF and DMSO.
Figure 9. Some example of the CuAAC reaction catalysed by 18.
Eur. J. Org. Chem. 2010, 3507–3515
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3511

M.-L. Teyssot, L. Nauton, J.-L. Canet, F. Cisnetti, A. Chevry, A. Gautier
FULL PAPER
of compounds, from basic alkynes and azides to more
elaborate carbohydrates. Importantly, 18 can be stored and
is easily synthesized from commercially available starting
materials. We believe that this aspect renders its routine use
very attractive.
Experimental Section
General: All commercially available reagents were used as received.
TLC was performed with 250 µm silica gel 60 plates with a 254 nm
fluorescent indicator. NMR spectra were recorded in the Fourier-
transform mode with a Bruker Avance 400 (1H at 400 MHz, 13C at
100 MHz) spectrometer at 25 °C. Spin multiplicity is described by
using the following abbreviations: s = singlet, d = doublet, t =
triplet, m = multiplet and br. = broad. Chemical shifts are given
in ppm and coupling constants (J) in Hz. Standard carbohydrate
numbering is used in the NMR assignment of compounds 36–39.
IR spectra were recorded with a Shimadzu FTIR-8400S spectrome-
ter equipped with an ATR module (neat) or by using KBr pellets
(KBr). High-resolution mass spectra were recorded with a Q-TOF
micro spectrometer (Waters) in electrospray positive mode by using
an internal (H3PO4) and external lock mass (leucine–enkephalin:
[M + H]+: m/z = 556.2766). All calculations were conducted by
using density functional theory (DFT) as implemented in the
Gaussian 03 program.[12] Geometry optimizations were performed
by using the restricted B3LYP exchange and correlation functional
with the double-ζ 6-31G(d,p) basis set. Harmonic frequency analy-
sis based on analytical second derivatives was used to characterize
the optimized geometries as local minima. The spectroscopic data
for compounds 17, 20–23, 30–31 and the corresponding starting
azides[15] have been reported in the literature. [CuCl(SIMes)],
[CuCl(IMes)], [CuCl(SIPr)] and [CuCl(Pr)] were synthesized ac-
cording to literature procedures.[16] 4,7-Dichloro-1,10-phen-
anthroline is commercially available or alternatively can be synthe-
sized.[17]
Figure 10. Synthesis of metal chelators.
Azide 32, which can be synthesized on a multigram scale,
exhibits unprecedented stability compared with aromatic
azides, which are known to be sometimes photodegrad-
able.[14] The reaction of 32 in methanol affords triazoles 33–
35 in less than 30 min. The high reaction rate is probably
caused by the presence of electron-withdrawing groups on
the DPA moiety as electron-poor azides are known to react
faster.
Finally, the ability of 18 to catalyse the [3+2] cycload-
dition of carbohydrates was also tested (Figure 11). For this
purpose, two protected ribopyranoses functionalized at the
anomeric position were selected, one with a propargyl
alcohol, the other with an azide group. In both cases, al-
though the reactions require 18 h to reach completion, the
CuAAC reaction occurs cleanly at 2 mol-% loading and af-
fords good isolated yields for 37 and 39. The efficiency of
this slower reaction demonstrates the high stability of 18 in
the presence of air.
NMR Estimation of Equilibrium Constants: A 0.033  stock solu-
tion of neocuproine (12.5 mg, 0.06 mmol) in CDCl3 (1.8 mL) and
0.033  solutions of each complex [CuCl(NHC)] (SIMes: 4.0 mg;
IMes: 4.0 mg; SIPr: 4.9 mg; IPr: 4.0 mg; 0.01 mmol) in CDCl3
(1.8 mL) were prepared. A neocuproine solution (0.3 mL) was
added to each [CuCl(NHC)] solution (0.3 mL), and the light- to
dark-orange mixtures were transferred to 5 mm NMR tubes. Im-
mediately after mixing, 1H NMR spectra (16 scans) of each sample
and the reference neocuproine (0.3 mL solution diluted with
0.3 mL of CDCl3) were recorded. The spectra were calibrated with
the solvent signal (δ = 7.26 ppm). Integrals were measured, and the
signal of the highest chemical shift, which corresponds to the com-
plex [CuCl(neocuproine)(NHC)], was normalized to 1. The ratio
of [CuCl(neocuproine)(NHC)]/[free neocuproine], calculated from
integral values, and the value of [neocuproine]tot = 0.017  allowed
each equilibrium constant to be estimated.
Screening of the Additives: Benzyl azide, phenylacetylene (2 mmol
each), [(SIMes)CuCl] (0.02 mmol, 1 mol-%) and the additive
(0.02 mmol, 1 mol-%) were mixed in tBuOH/water (1:1, 4 mL). The
reaction mixture was stirred overnight, water (4 mL) was added,
and the resulting solid was filtered, washed with pentane and dried
in an oven at 85 °C.
Figure 11. Synthesis of “clicked” -ribopyranose derivatives.
Conclusions
We have reported herein that [CuCl(SIMes)(4,7-dichloro-
1,10-phenanthroline)] (18) is an efficient catalyst for [2+3]
azide–alkyne cycloaddition in the absence of a reducing
[CuCl(SIMes)(4,7-dichloro-1,10-phenanthroline)]
(SIMes)] (201 mg, 0.50 mmol, 1.0 equiv.) was dissolved in dichloro-
methane (5 mL). Under stirring, 4,7-dichloro-1,10-phenanthroline
(18):
[CuCl-
agent. The CuAAC reaction can be applied to a large range (174 mg, 0.70 mmol, 1.4 equiv.) was added portionwise. The solu-
3512
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3507–3515

Aromatic Nitrogen Donors for Efficient Copper(I)–NHC CuAAC
tion turned immediately deep-red. Pentane (25 mL) was added
slowly over 20 min, after which the solution was stirred for a fur-
ther 30 min. The resulting suspension was filtered, the solid washed
with pentane and dried under vacuum to furnish 230 mg
34.0 ppm. HRMS (ESI+): calcd. for C15H16N5O 282.1335; found
282.1365.
1,3-Bis(N,N-dimethylprop-2-ynylammonio)propane Dibromide (28):
N,N,NЈ,NЈ-Tetramethyl-1,3-propanediamine (2.00 g, 15.4 mmol,
1.0 equiv.) and propargyl bromide (6.70 g, 46 mmol, 3.0 equiv.,
80 % w/w in toluene) were added sequentially to acetonitrile
(30 mL). An exothermic reaction ensued, during which a white so-
lid formed. The solution was stirred overnight, and the solid was
filtered, washed with diethyl ether and dried in air to afford 3.40 g
(0.35 mmol, 71%) of a deep-purple solid. IR (KBr): ν = 3377, 3205,
˜
2915, 1629, 1608, 1489, 1438, 1415, 1271, 850, 837, 732, 702,
574 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.4–8.2 (br., 4 H,
Hphen), 7.7–7.5 (br., 2 H, Hphen), 6.90 (s, 4 H, HArMes), 3.85 (s, 4
H, CH2), 2.27 (s, 6 H, CH3), 2.22 (s, 12 H, CH3) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 138.4, 136.6, 136.4, 129.9, 51.0, 21.3,
18.3 ppm (carbene C and 1,10-phenanthroline signals were not de-
tected). HRMS (ESI+): calcd. for C33H32Cl2CuN4 617.1300; found
617.1280.
of a white solid (60%). IR (KBr): ν = 3427, 3184, 3014, 2968, 2918,
˜
1
2119, 1475, 1448, 1386, 1176, 1004, 906, 887, 711 cm–1. H NMR
4
(400 MHz, [D6]DMSO): δ = 4.60 (d, JH,H = 2.4 Hz, 4 H, CH2),
3
4.12 (t, JH,H = 4.2 Hz, 2 H, CϵCH), 3.48 (m, 4 H, CH2), 3.20 (s,
12 H, Me), 2.32 (m, 2 H, CH2) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 82.5, 70.7, 60.1, 55.0, 51.1, 17.3 ppm. C13H22Br2N2
(368.15): calcd. C 42.65, H 6.06, N 7.65; found C 43.02, H 6.44, N
7.35.
General Procedure for the CuAAC Reaction: [CuCl(SIMes)] (1 mol-
%) was added to a solution of 0.25  azide (1 equiv.) and 0.25–
0.5  alkyne (1–2 equiv.) in methanol (total volume: 4 mL). 4,7-
Dichloro-1,10-phenanthroline (1 mol-%) was added, the solution
turned red-orange, and stirring was continued overnight. Alterna-
tively, 18 (1 mol-%) was added. Unless indicated otherwise, the
solution was stirred overnight, water (10 mL) was added, and the
crude reaction mixtures were extracted with ethyl acetate, dried
with MgSO4 and concentrated to furnish pure products.
1,3-Bis{N,N-dimethyl[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-
ammonio}propane Dibromide (29): The solvent was evaporated and
the product was crystallized from a minimum amount of methanol.
Yield: 85%. IR (KBr): ν = 3416, 3111, 3066, 1629, 1438, 1057,
˜
1
896, 721 cm–1. H NMR (400 MHz, [D6]DMSO): δ = 8.77 (s, 2 H,
H
triazole), 7.3 (m, 10 H, HAr), 5.77, (m, 4 H, CH2), 4.9 (m, 4 H,
2-(4-Aminomethyl-1H-1,2,3-triazol-1-yl)-N-phenylacetamide Hydro-
CH2), 3.5 (m, 4 H, CH2), 3.22 (s, 12 H, Me), 2.6 (m, 2 H, CH2)
ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 135.6, 135.2, 128.8,
128.6, 128.2, 128.0, 59.1, 57.4, 53.0, 50.0, 17.1 ppm. C27H36Br2N8
(634.45): calcd. C 51.28, H 5.74, N 17.72; found C 51.43, H 6.02,
N 17.51.
chloride (24): Yield: 80%. IR (neat): ν = 3267, 3205, 3120, 3076,
˜
1
3001, 1676, 1604, 1556, 1261, 866, 756 cm–1. H NMR (400 MHz,
[D6]DMSO): δ = 10.79 (s, 1 H, NH), 8.46 (s, 2 H, NH2), 8.23 (s, 1
H, Htriazole), 7.62–7.02 (m, 5 H, HAr), 5.42 (s, 2 H, CH2), 4.14 (s, 2
H, CH2) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 164.0, 139.9,
138.5, 128.4, 126.0, 123.7, 119.2, 53.3, 33.9 ppm. HRMS (ESI+):
calcd. for C11H14N5O 232.1198; found 232.1198.
Dimethyl 4-Azidopyridine-2,6-dicarboxylate (32): A mixture of di-
methyl 4-chloropyridine-2,6-dicarboxylate (2.2 g, 9.56 mmol) and
sodium azide (6 g, 10 equiv.) in DMF (30 mL) was heated at 50 °C
overnight. The yellow reaction mixture was allowed to cool to room
temperature and poured into cold water (80 mL) under vigorous
stirring. Compound 1 precipitated immediately from the solution,
and filtration afforded 2.0 g (90%) of a pale-yellow solid. IR (neat):
2-(4-Aminomethyl-1H-1,2,3-triazol-1-yl)-N-(2,4,6-trimetylphenyl)-
acetamide Hydrochloride (25): Yield: 80 %. IR (neat): ν = 3281,
˜
3130, 3014, 1670, 1529, 1236, 848 cm–1. 1H NMR (400 MHz, [D6]-
DMSO): δ = 9.98 (s, 1 H, NH), 8.54 (br. s, 3 H, NH3), 6.68 (s, 1
H, Htriazole), 5.45 (s, 2 H, HAr), 4.12 (s, 2 H, CH2), 3.68 (s, 2 H,
CH2), 2.21 (s, 3 H, Me), 2.11 (s, 6 H, Me) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 163.9, 139.9, 135.6, 134.7, 131.6,
128.8, 125.9, 51.6, 33.8, 20.4, 18.30 ppm. HRMS (ESI+): calcd. for
C14H20N5O 274.1668; found. 274.1673.
ν = 3075, 2960, 2122, 1753, 1718, 1594, 1445, 1351, 1273, 1250,
˜
1190, 1158 cm–1. 1H (400 MHz, [D6]DMSO): δ = 7.93 (s, 2 H, HPy),
4.03 (s, 6 H, Me) ppm. 13C NMR (400 MHz): δ = 164.4, 151.7,
149.9, 118.0, 53.4 ppm. C9H8N4O4 (236.18): calcd. C 45.77, H 3.41,
N 23.72; found C 45.24, H 3.42, N 23.82.
6-(4-Aminomethyl-1H-1,2,3-triazol-1-yl)-N-phenylcaproamide Hy-
Dimethyl 4-[4-(2-Hydroxyethyl)-1H-1,2,3-triazol-1-yl]pyridine-2,6-
dicarboxylate (33): The product precipitated from solution and was
isolated from the reaction mixture by simple filtration. White solid.
drochloride (26): Yield: 81%. IR (neat): ν = 3263, 2939, 1654, 1599,
˜
1541, 1500, 1444, 1161, 844 cm–1
.
1H NMR (400 MHz, [D6]-
DMSO): δ = 10.00 (s, 1 H, NH), 8.44 (s, 3 H, NH3), 8.18 (s, 1 H,
Yield: Ͼ95%. IR (KBr): ν = 1759, 1726, 1599, 1438, 1246, 1058,
˜
3
Htriazole), 7.60 [d, 3J(H,H) = 7.9 Hz, 2 H, HAr], 7.27 (t, JH,H
=
1
1053, 786, 758 cm–1. H NMR (400 MHz, CDCl3): δ = 8.67 (s, 2
7.7 Hz, 2 H, HAr), 7.00 (t, 3JH,H = 7.3 Hz, 1 H, HAr), 4.40 (t, 3JH,H
= 7.0 Hz, 2 H, CH2), 4.08 (br., 2 H, CH2), 2.30 (t, JH,H = 7.3 Hz,
H, HPy), 8.29 (s, 1 H, Htriazole), 3.99 (s, 6 H, Me), 3.90 (s, 2 H,
CH2), 3.01 (s, 2 H, CH2) ppm. 13C NMR (400 MHz, [D6]DMSO):
δ = 163.8, 149.6, 146.7, 144.8, 121.2, 116.7, 59.8, 52.9, 29.1 ppm.
C13H14N4O5 (306.28): calcd. C 50.98, H 4.61, N 18.29; found C
50.99, H 4.42, N 18.29.
3
2 H, CH2), 1.83 (m, 2 H, CH2), 1.65 (m, 2 H, CH2), 1.25 (m, 2 H,
CH2) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 171.0, 140.0,
139.3, 128.5, 124.3, 122.8, 119.0, 49.2, 36.0, 33.8, 29.5, 25.4,
24.4 ppm. HRMS (ESI+): calcd. for C15H22N5O 288.1824; found.
288.1814.
Dimethyl 4-(4-Phenyl-1H-1,2,3-triazol-1-yl)pyridine-2,6-dicarboxyl-
ate (34): The product precipitated from solution and was isolated
2-(4-Aminomethyl-1H-1,2,3-triazol-1-yl)-N-naphthalen-1-ylacet- from the reaction mixture by simple filtration. Pale-yellow solid.
amide Hydrochloride (27): Yield: 83%. IR (neat): ν = 3252, 3221, Yield: Ͼ95%. IR (neat): ν = 3125, 2957, 1750, 1717, 1599, 1446,
˜
˜
3045, 1676, 1546, 1402, 1346, 1274, 1053, 802 cm–1 1H NMR 1251, 1223, 1153, 1119, 1047, 1019, 987, 947, 892, 782, 756,
.
(400 MHz, [D6]DMSO): δ = 10.69 (s, 1 H, NH), 8.32 (s, 1 H, 692 cm–1
.
1H NMR (400 MHz, [D6]DMSO): δ = 9.84 (s, 1 H,
Htriazole), 8.81 (s, 2 H, HPy), 7.99 (d, JH,H = 8.2 Hz, 2 H, HAr),
Htriazole), 8.27 (d, JH,H = 7.5 Hz, 1 H, HAr), 7.95 (d, 3J
=
3
3
H,H
7.3 Hz, 1 H, HAr), 7.79 (d, 3JH,H = 8.0 Hz, 1 H, HAr), 7.70 (d, 3JH,H 7.53 (dd, JH,H = 7.3, 8.2 Hz, 2 H, HAr), 7.43 (t, JH,H = 7.3 Hz, 1
3
3
3
= 7.3 Hz, 1 H, HAr), 7.65–7.54 (m, 2 H, HAr), 7.50 (t, JH,H
=
H, HAr), 3,99 (s, 6 H, Me) ppm. 13C NMR (100 MHz, [D6]DMSO):
7.7 Hz, 1 H, HAr), 5.64 (s, 2 H, CH2), 4.5–4.0 (br., 2 H, CH2) ppm.
δ = 163.8, 149.6, 148.0, 144.7, 129.4, 129.0, 128.6, 125.3, 119.9,
13C NMR (100 MHz, [D6]DMSO): δ = 165.1, 140.4, 133.7, 132.8, 116.8, 52.9 ppm. HRMS (ESI+): calcd. for C17H14N4O4Na
128.1, 127.6, 126.1, 126.0, 125.7, 125.5, 122.8, 121.5, 52.3,
361.0913; found 361.0899.
Eur. J. Org. Chem. 2010, 3507–3515
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3513

M.-L. Teyssot, L. Nauton, J.-L. Canet, F. Cisnetti, A. Chevry, A. Gautier
FULL PAPER
Dimethyl 4-[4-(2-Bromoethyl)-1H-1,2,3-triazol-1-yl]pyridine-2,6-di-
tions. IR (neat): ν = 2118, 1726, 1315, 1282, 1261, 1250, 1222, 1124,
˜
carboxylate (35): Pale-yellow solid. Yield: Ͼ95%. IR (neat): ν =
1095, 1070, 1026, 710 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 7.89–
˜
3508, 1737, 1591, 1446, 1292, 1265, 1238, 1045, 995 cm–1. 1H NMR
7.81 (m, 6 H, HAr), 7.40 (t, JH,H = 7.5 Hz, 3 H, HAr), 7.24 (t,
3
(400 MHz, CDCl3): δ = 8.72 (s, 2 H, HPy), 8.20 (s, 1 H, Htriazole), 3JH,H = 8.3 Hz, 2 H, HAr), 7.18 (t, JH,H = 7.2 Hz, 4 H, HAr), 5.80
3
4.05 (s, 6 H, Me), 3.74 (t, 3JH,H = 6.4 Hz, 2 H, CH2), 3.41 (t, 3JH,H
(dd, J2,3 = 4.0, J3,4 ≈ 3.5 Hz, 1 H, 3-H), 5.48 (m, 1 H, 4-H), 5.42
3 2 3
3
3
= 6.4 Hz, 2 H, CH2) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.9, (d, J1,2 = 4.6 Hz, 1 H, 1-H), 4.25 (dd, J5a,5b = 12.5, J4,5a
=
2
3
149.7, 146.4, 144.8, 121.7, 116.9, 53.0, 32.0, 28.8 ppm. HRMS 3.2 Hz, 1 H, 5a-H), 4.08 (dd, J5a,5b = 12.5, J4,5b = 5.4 Hz, 1 H,
(ESI+): calcd. for C13H13BrN4O4Na 391.0018; found 391.0020.
5b-H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 165.7, 165.5, 165.1,
133.5 (2 C), 133.4, 130.0, 129.9, 129.8, 129.5, 129.3, 129.2, 128.6,
128.5 (4 C), 87.8, 68.7, 67.2, 66.7, 63.2 ppm. HRMS (ESI+): calcd.
for C26H21N3O7Na 510.1277; found 510.1268.
Propargyl 2,3,4-Tri-O-benzoyl-β- -ribopyranoside (36): 2,3,4-Tri-O-
D
benzoyl-β--ribopyranosyl bromide (2.00 g, 3.80 mmol)[18] was sus-
pended in propargyl alcohol (9.49 g, 10 mL, 169.3 mmol,
45 equiv.). This mixture was heated at 100 °C until complete dissol-
ution occurred. Excess propargyl alcohol was evaporated under
vacuum, and the resulting dark oil was taken up in CH2Cl2 (20 mL)
and treated with activated charcoal to give 1.65 g of a viscous oil
(87%). (NMR analysis revealed the presence of around 10% of a
[1-(2,3,4-Tri-O-benzoyl-β-D-ribopyranosyl)-1H-1,2,3-triazol-4-yl]-
methanol (39): Tri-O-benzoyl-β--ribopyranosyl azide (168.5 mg,
0.33 mmol) and propargyl alcohol (37.4 mg, 0.66 mmol, 2 equiv.)
were dissolved in methanol (1.2 mL). [CuCl(SIMes)] (2mol-%) and
4,7-dichloro-1,10-phenanthroline (2 mol-%) were added to the re-
action mixture, which was stirred overnight. After solvent evapora-
tion, the product was filtered through a short SiO2 plug, which was
washed with acetone to give 182.1 mg of a crystalline solid (90%
product with the opposite anomeric configuration.) IR (neat): ν =
˜
1723, 1316, 1284, 1262, 1126, 1106, 1096, 1070, 1059, 1026,
709 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 8.05 (d, 3JH,H = 7.0 Hz,
3
3
yield). IR (neat): ν = 1724, 1316, 1280, 1264, 1108, 1096, 1070,
˜
2 H, HAr), 8.00 (d, JH,H = 7.0 Hz, 2 H, HAr), 7.85 (d, JH,H
=
1025, 710 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 8.27 (s, 1 H,
7.0 Hz, 2 H, HAr), 7.55–7.48 (m, 3 H, HAr), 7.33–7.26 (m, 6 H,
3
3
3
Ar), 5.82 (dd, 3J2,3 = 3.5, J3,4 = 4.2 Hz, 1 H, 3-H), 5.62 (m, 1 H,
Htriazole), 8.18 (d, JH,H = 7.2 Hz, 2 H, HAr), 7.93 (d, JH,H
=
H
7.2 Hz, 2 H, HAr), 7.78 (d, 3JH,H = 7.2 Hz, 2 H, HAr), 7.70 (t, 3JH,H
= 7.5 Hz, 1 H, HAr), 7.63–7.53 (m, 4 H, HAr), 7.45–7.32 (m, 4 H,
HAr), 6.67 (d, J1,2 = 8.5 Hz, 1-H), 6.49 (dd, J2,3 = 3.1, J3,4
3.0 Hz, 1 H, 3-H), 6.19 (dd, J1,2 = 8.5, J2,3 = 3.1 Hz, 1 H, 2-H),
5.80 (ddd, J3,4 = 3.0, J4,5a = 8.1, J4,5b = 5.0 Hz, 1 H, 4-H), 4.68
3
3
3
4-H), 5.55 (dd, J2,3 = 3.5, J1,2 = 2.3 Hz, 1 H, 2-H), 5.32 (d, J1,2
= 2.3 Hz, 1 H, 1-H), 4.43–4.33 (m, 2 H, OCH2CϵCH), 4.28 (dd,
3
3
3
2J5a,5b = 13.1, J4,5a = 2.0 Hz, 1 H, 5a-H), 4.12 (dd, J5a,5b = 13.1,
3
2
=
3
3
3J4,5b = 2.8 Hz, 1 H, 5b-H), 2.51 (t, JH,H = 2.5 Hz, 2 H, CϵCH)
4
3
3
3
ppm. 13C NMR (CDCl3, 100 MHz): δ = 166.2, 165.9, 165.2, 133.3,
133.3, 133.2, 130.1, 130.0, 129.8, 129.9, 129.6, 129.4, 128.4 (6 C),
97.1, 78.3, 77.4, 68.5, 67.7, 66.1, 61.6, 55.1 ppm. HRMS (ESI+):
calcd. for C29H24O8Na 523.1369; found 523.1377.
2
3
(m, 2 H, CH2OH), 4.54 (dd, J5a,5b = 11.2, J4,5a = 8.1 Hz, 1 H,
2
3
5a-H), 4.40 (dd, J5a,5b = 11.2, J4,5b = 5.0 Hz, 1 H, 5b-H), 4.29
(br., 1 H, OH) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 166.1,
165.7, 165.2, 150.1, 134.7, 134.5, 134.4, 130.7, 130.4, 130.3, 129.8,
129.7, 128.5 (6 C), 122.5, 84.5, 70.0, 69.5, 67.9, 64.6, 56.8 ppm.
HRMS (ESI+): calcd. for C29H25N3O8Na 566.1539; found
566.1539.
[4-(2,3,4-Tri-O-benzoyl-β-D-ribopyranosylmethyl)-1H-1,2,3-triazol-
1-yl]methylbenzene (37): Propargyl 2,3,4-tri-O-benzoyl-β--ribo-
pyranoside (300 mg, 0.60 mmol) and benzyl azide (16) (160 mg,
1.20 mmol, 2 equiv.) were dissolved in methanol. [CuCl(SIMes)]
(2 mol-%) and 4,7-dichloro-1,10-phenanthroline (2 mol-%) were
added, and the reaction mixture was stirred overnight. After evapo-
ration of the solvent, the product was purified by SiO2 column
chromatography (CH2Cl2/AcOEt, 9:1, v/v) to give 283.5 mg (75%
Supporting Information (see footnote on the first page of this arti-
cle): Coordinate files for 18 and 19, procedure for calculating %Vbur
and NMR spectra of the previously unpublished compounds.
yield) of a white crystalline solid. IR (neat): ν = 1723, 1451, 1362,
˜
Acknowledgments
1316, 1286, 1262, 1126, 1107, 1097, 1070, 1048, 1025 cm–1
.
1H
3
NMR (CDCl3, 400 MHz): δ = 7.94 (d, JH,H = 7.4 Hz, 4 H), 7.78
(d, JH,H = 7.4 Hz, 2 H), 7.53–7.39 (m, 4 H), 7.34–7.27 (m, 3 H),
7.25–7.19 (m, 8 H) (HAr, Htriazole), 5.71 (dd, J2,3 ≈ J3,4 ≈ 4 Hz, 1
H, 3-H), 5.50 (m, 1 H, 4-H), 5.44 (AB system, JH,H = 15.0 Hz, 2
H, NCH2), 5.41 (m, 1 H, 2-H), 5.15 (d, J1,2 = 1.4 Hz, 1 H, 1-H),
4.85 (d, JH,H = 12.0 Hz, 1 H, OCH2Ctriazole), 4.69 (d, JH,H
The authors thank Prof. L. Cavallo, University of Salerno, for help-
ful advice and discussions.
3
3
3
2
[1] a) C. W. Tornøe, M. Meldal in Peptides: The wave of the future
(Eds.: M. Lebl, R. A. Houghten), Kluwer Academic Publish-
ers, Dordrecht, 2001, pp. 263–264; b) H. C. Kolb, M. G. Finn,
K. B. Sharpless, Angew. Chem. Int. Ed. 2001, 40, 2004–2021; c)
C. W. Tornøe, C. Christensen, M. Meldal, J. Org. Chem. 2002,
67, 3057–3064.
3
2
2
=
2
12.0 Hz, 1 H, OCH2Ctriazole), 4.23 (d, J5a,5b = 12.5 Hz, 1 H, 5a-
H), 4.02 (dd, J5a,5b = 12.5, J4,5b = 2.3 Hz, 1 H, 5b-H) ppm. 13C
2
3
NMR (CDCl3, 100 MHz): δ = 166.2, 165.9, 165.2, 134.4, 133.3 (2
C), 133.1, 130.0, 130.0, 129.8, 129.8, 129.6, 129.4, 129.2, 128.9, [2] a) M. Meldal, C. W. Tornøe, Chem. Rev. 2008, 108, 2952–3015;
b) V. D. Bock, H. Hiemstra, J. H. van Maarseveen, Eur. J. Org.
Chem. 2006, 51–68; c) H. C. Kolb, K. B. Sharpless, Drug Dis-
covery Today 2003, 8, 1128–1137.
126.2, 128.4 (6 C), 97.9, 68.6, 67.6, 66.3, 61.5, 61.4, 54.4 ppm; the
signals of triazole and the phenyl quaternary carbon atoms overlap
with other resonances. HRMS (ESI+): calcd. for C36H31N3O8Na
656.2009; found 656.1998.
[3] a) For TBTA, see: P. Apputkkuttan, W. Dehaen, V. V. Fokin,
E. Van der Eycken, Org. Lett. 2004, 6, 4223–4225; b) for
(BimC4A)3, see: V. O. Rodionov, S. I. Presolski, S. Gardinier,
Y.-H. Lim, M. G. Finn, J. Am. Chem. Soc. 2007, 129, 12696–
12704; c) for bathophenanthrolinedisulfonic acid, see: W. G.
Lewis, F. G. Magallon, V. V. Fokin, M. G. Finn, J. Am. Chem.
Soc. 2004, 126, 9152–9153.
[4] a) R. H. Nagaraj, D. R. Sell, M. Prabhakaram, B. J. Ortwerth,
V. M. Monnier, Proc. Natl. Acad. Sci. USA 1991, 88, 10257–
10261; b) M. R. Levengood, C. C. Kerwood, C. Chattejee,
W. A. van der Donk, ChemBioChem 2009, 10, 911–919.
2,3,4-Tri-O-benzoyl-β-D-ribopyranosyl Azide (38): Synthesized by
starting from tri-O-benzoyl-β--ribopyranosyl bromide.[19] After
workup, the crude product consisted essentially of a 4:1 mixture of
anomers. The latter could be separated by SiO2 column chromatog-
raphy (elution with cyclohexane/AcOEt, 2:1, v/v) to give the major
1
anomer in 63% yield. The pyranoid ring H NMR coupling con-
stants are consistent with a β-anomeric configuration and with a
mixture of rapidly interconverting 1C4 and 4C1 chair conforma-
3514
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3507–3515

Aromatic Nitrogen Donors for Efficient Copper(I)–NHC CuAAC
[5] Azoamides are reduced to semi-carbazides by ascorbic acid,
see: a) D. Urankar, J. Kosˇmrli, J. Comb. Chem. 2008, 10, 981–
985; ascorbic acid quenches the lanthanide excited state, see:
b) G.-L. Law, D. Parker, S. L. Richardson, K.-L. Wong, Dalton
Trans. 2009, 8481–8484; c) F. Kielar, C. P. Montgomery, E. J.
New, D. Parker, R. A. Poole, S. L. Richardson, P. A. Stenson,
Org. Biomol. Chem. 2007, 5, 2975–2982.
[6] N. Candelon, D. Lastécouères, A. Khadri Diallo, J. Ruiz Aran-
zaes, D. Astruc, J.-M. Vincent, Chem. Commun. 2008, 741–743.
[7] S. Özçubukçu, E. Ozkal, C. Jimeno, M. A. Pericàs, Org. Lett.
2009, 11, 4680–4683.
[8] P. Fabbrizzi, S. Cicchi, A. Brandi, E. Sperotto, G. van Koten,
Eur. J. Org. Chem. 2009, 31, 5423–5430.
[9] a) S. Díez-González, A. Correa, L. Cavallo, S. P. Nolan, Chem.
Eur. J. 2006, 12, 7558–7564; b) S. Díez-González, S. P. Nolan,
Angew. Chem. Int. Ed. 2008, 47, 8881–8884; c) S. Díez-
González, E. D. Stevens, S. P. Nolan, Chem. Commun. 2008,
4747–4749.
Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A.
Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W.
Chen, M. W. Wong, C. Gonzalez, J. A. Pople, Gaussian 03, Re-
vision D.01. Gaussian, Inc., Wallingford, CT, 2004..
[13] a) W. S. Brotherton, H. A. Michaels, J. T. Simmons, R. J. Clark,
N. S. Dalal, L. Zhu, Org. Lett. 2009, 11, 4954–4957; b) J. D.
Crowley, P. H. Bandeen, L. R. Hanton, Polyhedron 2009, 13,
70–83; c) for a recent review on triazole–metal chelating sys-
tems, see: H. Struthers, T. L. Mindt, R. Schibli, Dalton Trans.
2010, 39, 675–696.
[14] a) For a unique example of a 4-azido-DPA derivative, see: B.
Huang, M. A. Prantil, T. L. Gustafson, J. R. Paquette, J. Am.
Chem. Soc. 2003, 125, 14518–14530; b) for the decomposition
of azides, see: V. O. Rodionov, S. I. Presolski, D. Daz Daz, V. V.
Fokin, M. G. Finn, J. Am. Chem. Soc. 2007, 129, 12705–12712.
[15] a) For 17, see ref.[3a]; b) for 20 and 21, see: S. Chassaing, A.
Sani Souna Sido, A. Alix, M. Kumarraja, P. Pale, J. Sommer,
Chem. Eur. J. 2008, 14, 6713–6721; c) for 23, see: A. Maisonial,
P. Serafin, M. Traïkia, E. Debiton, V. Thery, D. J. Aitken, P.
Lemoine, B. Viossat, A. Gautier, Eur. J. Inorg. Chem. 2008,
298–305; d) for 26, see: L. P. Spencer, R. Altwer, P. Wei, L.
Gelmini, J. Gauld, D. W. Stephan, Organometallics 2003, 22,
3841–3854; e) for 27, see: W. S. Brotherton, H. A. Michaelis,
J. T. Simmons, R. J. Clark, N. S. Dalal, L. Zhu, Org. Lett. 2009,
11, 4954–4957.
[16] a) For [CuCl(SIMes)], see: P. de Frémont, N. M. Scott, E. D.
Stevens, T. Ramnial, C. Lightbody, C. L. B. Macdonald,
J. A. C. Clyburne, C. D. Abernethy, S. P. Nolan, Organometal-
lics 2005, 24, 6301–6309; b) for [CuCl(IMes)], see: S. Okamoto,
S. Tominaga, N. Saino, K. Kase, K. J. Shimoda, Organomet.
Chem. 2005, 690, 6001–6007; c) for [CuCl(SIPr)], see: L. A.
Goj, E. D. Blue, S. A. Delp, T. B. Gunnoe, T. R. Cundari,
A. W. Pierpont, J. L. Petersen, P. D. Boyle, Inorg. Chem. 2006,
45, 9032–9045; d) for [CuCl(IPr)], see: H. Kaur, F. K. Zinn,
E. D. Stevens, S. P. Nolan, Organometallics 2004, 23, 1157–
1160.
[10] M. L. Teyssot, A. Chevry, M. Traïkia, M. El-Ghozzi, D. Avign-
ant, A. Gautier, Chem. Eur. J. 2009, 15, 6322–6326.
[11] For the definition and applications of %Vbur, see: a) A. C. Hill-
ier, W. J. Sommer, B. S. Yong, J. L. Petersen, L. Cavallo, S. P.
Nolan, Organometallics 2003, 22, 4322–4326; b) L. Cavallo, A.
Correa, C. Costabile, H. Jacobsen, J. Organomet. Chem. 2005,
605, 5407–5413; c) for SambVca, a web application for the cal-
culation of the buried volume of N-heterocyclic carbene li-
gands, see: A. Poater, B. Cosenza, A. Correa, S. Giudice, F.
Ragone, V. Scarano, L. Cavallo, Eur. J. Inorg. Chem. 2009,
1759–1766.
[12] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, J. A. Montgomery, Jr., T.
Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar,
J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N.
Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y.
Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P.
Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R.
Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R.
[17] For 4,7-dichloro-1,10-phenanthroline, see: R. A. Altman, S. L.
Buchwald, Org. Lett. 2006, 8, 2779–2782.
Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morok- [18] R. Jeanloz, H. G. Fletcher, C. S. Hudson, J. Am. Chem. Soc.
uma, G. A. Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzew-
ski, S. Dapprich, A. D. Daniels, M. C. Strain, O. Farkas, D. K.
Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. V.
Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B. B.
Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L.
1948, 70, 4052–4054.
[19] R. Kumar, P. Tiwari, P. R. Maulik, A. K. Misra, Eur. J. Org.
Chem. 2006, 74–79.
Received: January 12, 2010
Published Online: May 7, 2010
Eur. J. Org. Chem. 2010, 3507–3515
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3515