(NHC)copper(I)-catalyzed [3+2] cycloaddition of azides and Mono- Or disubstituted alkynes

Article abstract of DOI:10.1002/chem.200600961

A versatile and highly efficient catalyst for the Huisgen cycloaddition reaction has been developed. Previously isolated or in situ generated azides yielded 1,2,3-triazoles with differently substituted alkynes in the presence of a [(NHC)CuBr] complex (NHC

Full text of DOI:10.1002/chem.200600961

FULL PAPER
DOI: 10.1002/chem.200600961
7558
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 7558 – 7564

FULL PAPER
A
C
H
T
R
E
U
N
G
(NHC)Copper(i)-Catalyzed [3+2] Cycloaddition of Azides and Mono- or
Disubstituted Alkynes
[
a]
[b]
[b]
[a]
Silvia Díez-Gonzµlez, Andrea Correa, Luigi Cavallo, and Steven P. Nolan*
Abstract: A versatile and highly effi-
cient catalyst for the Huisgen cycload-
dition reaction has been developed.
Previously isolated or in situ generated
azides yielded 1,2,3-triazoles with dif-
ferently substituted alkynes in the pres-
lent yields were obtained in all cases.
This catalytic system fulfils the require-
ments of “click chemistry” with its
mild and convenient conditions, nota-
bly in water or solvent free reactions
and simple isolation with no purifica-
tion step. Furthermore, for the first
time, an internal alkyne was successful-
ly used in this copper-catalyzed cyclo-
addition reaction. DFT calculations on
this particular system allowed for the
proposition of a new mechanistic path-
way for disubstituted alkynes.
Keywords: alkynes · azides · click
chemistry · copper · N-heterocyclic
carbenes
ence of
a
[(NHC)CuBr] complex
(NHC = N-heterocyclic carbene). Ex-
tremely high reaction rates and excel-
Introduction
dition reaction and even modulate the reactivity of the
copper salt.
As part of our continuing efforts to broaden the scope of
[9]
[
[
1]
2]
The reaction of azides and alkynes yielding 1,2,3-triazoles
is the most popular Huisgen 1,3-dipolar cycloaddition.
Since the recent discovery of copper(i) as an efficient and
regiospecific catalyst for this process, it has become the
best “click” reaction to date and found a myriad of appli-
cations in chemical synthesis, biology and material science.
Most often, catalytic systems enabling this transformation
consist of a copper(II) salt and a reducing agent. Metallic
NHC-containing (NHC = N-heterocyclic carbene) transi-
[10]
tion-metal complexes, we recently reported the efficiency
[
3]
of [(NHC)CuCl] complexes in the hydrosilylation of carbon-
[
4]
[11]
yl compounds.
The remarkable stability of these com-
[
5]
plexes toward heat, oxygen and moisture prompted us to
test them in the Huisgen cycloaddition.
[3b]
[6]
copper or clusters can also be employed but little atten-
tion has been paid to cuprous salts due to their inherent
thermodynamic instability and the formation of undesired
alkyne-alkyne coupling products observed in their presen-
Results and Discussion
First, the two most commonly used carbene ligands, IPr
[
3a]
[7]
[8]
ce. On the other hand, nitrogen- or phosphorus-based
(N,N’-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)
IMes (N,N’-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene),
were tested (Table 1). While reaction of benzyl azide and
and
I
ligands have been shown to protect Cu during the cycload-
[11b]
phenylacetylene in the presence of [(IPr)CuCl]
under
standard cycloaddition conditions only led to partial conver-
sion to triazole 3a, an important increase in yield was ob-
[
a] Dr. S. Díez-Gonzµlez, Prof. Dr. S. P. Nolan
Institute of Chemical Research of Catalonia (ICIQ)
Av. Païso, Catalans 16, 43007 Tarragona (Spain)
Department of Chemistry, University of New Orleans
[12]
served with [(IMes)CuCl] (entries 1 and 2). Interestingly,
[11a]
its saturated analogue, [(SIMes)CuCl]
(SIMes = N,N’-
bis(2,4,6-trimethylphenyl)-4,5-dihydro-imidazol-2-ylidene),
was even more efficient (entry 3). Moreover, replacing the
chloride on the copper center by a bromide further acceler-
ated the reaction (entry 4). Poor conversions were obtained
with organic solvents such as THF, CH Cl or tBuOH, but
2
000 Lakeshore Drive, New Orleans, LA 70148 (USA)
Fax : (+34)977-920-224
E-mail: snolan@iciq.es
[
b] Dr. A. Correa, Prof. Dr. L. Cavallo
2
2
Dipartimento di Chimica, Universitµ di Salerno
Via Salvador Allende, Baronissi (SA), 84081 (Italy)
pleasantly, a strong acceleration was observed in water
entry 5). It is well recognized that Diels–Alder reactions
(
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
[13]
can be greatly accelerated in water, but there are fewer
Chem. Eur. J. 2006, 12, 7558 – 7564ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7559

S. P. Nolan et al.
[
a]
Table 1. Catalyst optimization studies.
reactivity of [(SIMes)CuBr]. Only oily or low melting-point
triazoles led to long or incomplete reactions. In these instan-
ces improved results were obtained by either increasing the
reaction temperature (3c) or increasing the catalyst loading
(
3j).
Although organic azides are generally safe and stable
Entry
[Cu] (mol%)
[(IPr)CuCl] (5)
[(IMes)CuCl] (5)
[(SIMes)CuCl] (5)
[(SIMes)CuBr] (5)
[(SIMes)CuBr] (5)
[(SIMes)CuBr] (0.8)
CuBr
Solvent [mL]
t [h]
Yield [%]
1
2
3
4
5
6
7
A
C
H
T
R
E
U
N
G
water/tBuOH (3)
water/tBuOH (3)
water/tBuOH (3)
water/tBuOH (3)
water (1)
18
18
18
9
0.5
0.3
1
18
65
93
95
98
98
0
[16]
toward water and oxygen, those of low molecular weight
can be difficult to handle. Therefore, a methodology that
avoids their isolation is desirable. Pleasantly, azides gener-
ated in situ from the corresponding halides reacted at room
temperature to efficiently yield triazoles 3 (Scheme 2).
ACHTREUNG
[17]
A
C
H
T
R
E
U
N
G
[18]
A
C
H
T
R
E
U
N
G
A
C
H
T
R
E
U
N
G
A
C
H
T
R
E
U
N
G
neat
neat
[19]
Again, water was the best solvent for this transformation.
[
a] Isolated yields are the average of at least two runs.
To ensure short reaction times and, in the case of benzyl
halides, minimize any decomposition of the starting materi-
al, 5 mol% of copper complex was used. However, at lower
catalyst loading the reaction still proceeded to completion
with excellent yields. For example, from benzyl bromide, 3a
was isolated in 86% yield after 3 h of reaction in the pres-
ence of 3 mol% of [(SIMes)CuBr] or 86% yield after 18 h
in the presence of 2 mol% of copper complex.
examples of 1,3-dipolar cycloadditions in aqueous media
[14]
with no organic co-solvents.
[4]
It is important to note that according to “click laws”, no
precautions to exclude oxygen were taken in any of these
reactions. No copper disproportionation with precipitation
of metal copper, was observed in aqueous medium which
I
shows the high ability of NHC groups to stabilize Cu spe-
Benzyl chloride was successfully used in the preparation
of 3a; methyltriazole 3n could easily be prepared from
methyl iodide avoiding the hazardous methyl azide. No
cies. Furthermore, neat reactions proceeded smoothly with
no detectable formation of undesirable byproducts
[15]
(
entry 6).
ing could be lowered to
.8 mol% with no loss of activi-
The catalyst load-
0
ty, ensuring straightforward re-
action workups. Under opti-
mized conditions, no formation
of 3a was observed with CuBr
(
entry 7), even after prolonged
reaction time and higher cata-
lyst loading, highlighting the
key role of the ligand.
We then investigated the
scope of this catalytic system.
Results are presented in
Scheme 1. All reactions pro-
ceeded smoothly to completion
after short reaction times and
triazoles 3 were isolated in ex-
cellent yield and high purity
after simple filtration or extrac-
tion.
Electron-rich, electron-poor
and/or hindered alkynes gave
good yields. Enynes were also
good reaction partners. For the
organic azides, benzylic but also
alkyl and aryl azides reacted in
very short reaction times. In
general, no significant differ-
ence of reactivity was observed
when examining reactants with
varied electronic properties, as
required for click reactions.
Scheme 1. Solvent-free [(SIMes)CuBr]-catalyzed formation of triazoles. [a] Reaction at 458C. [b] 2 mol% [(SI-
This is probably due to the high Mes)CuBr].
7560
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Chem. Eur. J. 2006, 12, 7558 – 7564

A
C
H
T
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[3+2] Cycloaddition
FULL PAPER
Table 2. [(SIMes)CuBr]-Catalyzed 1,3-dipolar cycloadditions of benzyl
A
H
R
U
G
[
a]
azides and 3-hexyne.
R
Copper free
A
H
R
U
G
H
p-NO
3o
3p
>5%
>5%
80%
59%
2
[
a] NMR conversion.
observed in the absence of copper. To the best of our knowl-
edge, this work represents the first intermolecular copper-
catalyzed [3+2] cycloaddition of an azide and an internal
alkyne.
For internal alkynes, no acceleration rate was observed in
water. This fact might indicate distinct mechanistic pathways
for terminal and internal alkynes.
Although the copper ion is generally considered a poor p-
back-donating ion, a very recent report from Thompson and
Bradley showed the essential role of ancillary ligands in de-
Scheme 2.
generated azides. [a] From benzyl chloride. [b] From benzyl chloride, T
708C. [c] Reaction at 458C. [d] From methyl iodide.
A
C
H
T
R
E
U
N
G
[(SIMes)CuBr]-Catalyzed formation of triazoles from in situ
[28]
termining its coordination to alkynes.
DFT calculations
=
+
on the [(SIMes)Cu
of comparison, [(MeCN) Cu
ACHTREUNG
(EtCꢀCEt)] complex and, for the sake
+
A
H
R
U
G
2
competitive formation of NÀH triazoles, resulting from the
addition of an inorganic azide to the alkyne, was detected
with this catalytic system.
light on the different catalytic behavior of these systems
with respect to internal alkynes.
The binding energies, DEbind, reported in Table 3, indicate
that p-coordination of the internal EtCꢀCEt alkyne to [(SI-
Traditionally, the starting point of the catalytic cycle for
the copper-catalyzed Huisgen reaction is considered to be
+
À1
Mes)Cu] is favored by almost 25 kcalmol relative to co-
[3a,20]
+
the formation of a Cu–acetylide complex,
which pre-
ordination to [(MeCN) Cu] . Decomposition of the total
2
cludes internal alkynes as cycloaddition partners. Moreover,
DFT calculations have shown that a hypothetical activation
toward cycloaddition via coordination of the copper(I) to
the alkyne (without its deprotonation) implies a higher ener-
binding energy as DEbind =DEprep + DEinter indicates that the
major difference between the two cationic Cu systems de-
rives from the DEprep contribution, which is some
À1
+
25 kcalmol higher for the [(MeCN) Cu] system. This
2
[21]
getic barrier than the one without metal catalyst. Synthe-
energy difference is reasonable since alkyne coordination to
[
22]
+
sis of 4,5-disubstituted triazoles can be achieved thermally
although regioselective reactions are limited in scope.
[(MeCN) Cu] requires the noticeable bending of the
2
[23]
+
[(MeCN) Cu] fragment from the strongly preferred linear
2
[29]
Other reported approaches to the preparation of this family
geometry
to a MeCNÀCuÀNCMe angle of 105.28 in
[24]
+
of triazoles rely on different metals or Lewis acids as cata-
[(MeCN) Cu
A
H
R
U
G
2
[25]
[26]
+
lysts or on ring strain release from cyclooctyne.
Mes)Cu] system where very little structural rearrangement
The high activity of [(SIMes)CuBr] in the Huisgen cyclo-
addition prompted us to test its reactivity with internal al-
kynes. In a preliminary experiment, we noticed that the re-
action of benzyl azide with diphenylacetylene proceeded
smoothly at 708C, even under copper-free conditions. From
a less activated alkyne, triazoles 3o–p were formed in fair to
good yields after heating at
is required for p-coordination of the alkyne, with the final
complex reaching the preferred linear two-coordination.
[29]
However, the interaction energy, DEinter, between the de-
+
formed EtCꢀCEt and the deformed [(SIMes)Cu] or
+
[(MeCN) Cu] systems is rather similar. This indicates that
2
the p-bonding/backbonding contribution to the Cu–alkyne
this temperature for 48 h
+
ꢀ
CEt and for the [(SIMes)Cu
A
H
R
U
G
[27]
Table 3. DFT derived properties for free EtC
2
(
Table 2). Optimization stud-
+
AHCTREUNG
ies showed that both, copper
salt and NHC ligand are essen-
tial for this transformation.
While 3o was formed in 34%
conversion when the reaction
was carried out with 5 mol%
of CuBr, no significant forma-
tion of 3o or 3p (<5%) was
+
+
Property
Free EtCꢀCEt
NHC-Cu EtCꢀCEt
A
H
R
U
G
2
Cu EtCꢀCEt
EtCꢀCEt bond [Š]
1.226
2281
180.0
1.2541.263
2120
167.0
À1
CꢀC freq [cm
]
2069
161.7
2.016
À17.6
+31.0
À48.6
CꢀCÀEt angle [8]
CuÀC bond [Š]
–
–
–
–
2.049
À1
DEbind [kcalmol
DEprep [kcalmol
DEinter [kcalmol
]
]
]
À41.0
À1
+4.8
À1
À45.8
Chem. Eur. J. 2006, 12, 7558 – 7564ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7561

S. P. Nolan et al.
interaction is similar between the two systems. Insight can
be obtained from structural and spectroscopic properties
from Strem. Flash column chromatography was performed on silica gel
1
13
6
0 (230–400 mesh). H and C Nuclear Magnetic Resonance (NMR)
[28,30]
spectra were recorded on a 300 MHz spectrometer at room temperature.
such as those reported in Table 3.
In both complexes
Chemical shifts (d) are reported with respect to tetramethylsilane as in-
the CꢀC triple bond is significantly longer than in the free
alkyne, and a remarkable deviation of the CꢀCÀEt angle
from linearity, some 15–208, occurs. Moreover, the CꢀC
1
13
ternal standard in ppm. Assignments of some H and C NMR signals
rely on COSY and/or HMBC experiments. Elemental analyses were per-
formed at Robertson Microlit Laboratories, Inc., Madison, NJ, USA.
AHCTREUNG
stretching frequency in the two Cu complexes is about 150–
À1
2
00 cm lower than in the free alkyne. This indicates that
(
p-backbonding is quite remarkable in both complexes, and
in line with similar strong p-backbonding contributions re-
THF (18 mL) overnight at room temperature outside of the glovebox.
After filtration of the reaction mixture through a plug of Celite, the fil-
trate was mixed with hexane to form a precipitate. A second filtration af-
I
[28]
ported for other Cu complexes. Finally, comparison be-
1
+
forded the title complex as an off-white solid (0.808 g, 71%). H NMR
tween the properties of the [(SIMes)Cu
A
H
R
U
G
Ar
+
(300 MHz, [D
(
6
]acetone): d=7.01 (s, 4H, H ), 4.16 (s, 4H, NCH
2
), 2.37
): d=
02.6 (C, NCN), 138.5 (C, C ), 135.3 (CH, C ), 135.0 (C, C ), 129.7
[
(MeCN) Cu
A
C
H
T
R
E
U
N
G
(EtCꢀCEt)] complexes indicates that p-back-
2
13
3 3 3
s, 12H, ArCH ), 2.29 (s, 6H, ArCH ); C NMR (75 MHz, CDCl
bonding should be more relevant for the latter complex.
It is clear that the presence of a strong s-donor ligand on
the copper center enhances its catalytic activity in this cyclo-
addition reaction. We believe that the widely accepted reac-
Ar
Ar
Ar
2
Ar
(CH, C ), 51.0 (CH , NCH ), 21.0 (CH , ArCH ), 18.0 (CH , ArCH ); el-
2
2
3
3
3
3
emental analysis calcd (%) for C21
H
2
26BrCuN (449.89): C 56.06, H 5.83,
N 6.23; found: C 55.98, H 5.64, N 6.21.
[3a,21]
General procedure for the [3+2] cycloaddition of azides and terminal al-
kynes: In a vial fitted with a screw cap, azide 1 (1.0 mmol), alkyne 2
tion pathway for terminal alkynes
is still applicable with
our system. However, the beneficial effect of the NHC
allows for the activation of disubstituted alkynes to proceed
by a p-alkyne complex (Scheme 3).
(
1.05 mmol) and [(SIMes)CuBr] (3.6 mg if 0.8 mol% or 9 mg if 2 mol%)
were loaded. The reaction was allowed to proceed at room temperature
1
(unless otherwise noted) and monitored by H NMR analysis of aliquots.
After total consumption of the starting azide, the solid product was col-
lected by filtration and washed with water and pentane. When the corre-
sponding triazole was an oil or a low-melting point solid, the reaction
4
mixture was poured in an aqueous NH Cl/diethyl ether mixture. After
extraction of the aqueous phase with diethyl ether, the combined organic
layers were washed with brine, dried over magnesium sulfate, filtered
and evaporated. In all examples, the crude products were estimated to be
1
greater than 95% pure by H NMR. Reported yields are isolated yields
and are the average of at least two runs.
General procedure for the [3+2] cycloaddition of in situ-generated
azides and terminal alkynes: The procedure described above was fol-
lowed using an alkyl halide 4 (1.0 mmol), NaN
an alkyne 2 (1.05 mmol) in water (1 mL).
3
(68 mg, 1.05 mmol) and
4
-Cyclohexenyl-1-(4-nitrobenzyl)-1H-1,2,3-triazole (3 f): Using the gener-
al procedure, from 4-(azidomethyl)-4-nitrobenzene (1e) (0.176 g) and 1-
ethynylcyclohex-1-ene (2 f) (0.118 mL), the title compound was isolated
1
as a light yellow solid after filtration (0.263 g, 93%). H NMR (300 MHz,
Ar
3
CDCl ): d=8.17 (d, J=8.6 Hz, 2H, H ), 7.41 (s, 1H, NCH=), 7.40 (d,
Scheme 3. Proposed mechanism for the cycloaddition of internal alkynes.
Ar
J=8.6 Hz, 2H, H ), 6.51 (brs, 1H, =CHCH
2 2
), 5.62 (s, 2H, NCH ), 2.40–
2
.23 (m, 2H, cyclohexenyl), 2.23–2.11 (m, 2H, cyclohexenyl), 1.80–1.56
1
3
(
m, 4H, cyclohexenyl); C NMR (75 MHz, CDCl
3
): d=150.2 (C, NC=),
47.8 (C, C ), 142.1 (C, C ), 128.3 (CH, C ), 126.8 (C, C=CHCH ),
2
), 124.1 (CH, C ), 118.5 (CH, NCH=), 52.8 (CH ,
Conclusion
Ar
Ar
Ar
1
1
2
Ar
25.5 (CH, C=CHCH
2
We have developed a versatile and highly efficient catalytic
system for the Huisgen cycloaddition. Previously isolated or
in situ generated azides yield 1,2,3-triazoles in water or sol-
vent-free conditions in extremely short reaction times. The
unprecedented use of an internal alkyne in this copper-cata-
lyzed transformation has also been described. Further syn-
thetic applications and mechanistic studies addressing the
role of the NHC ligand in this transformation are currently
ongoing in our laboratories.
2 2 2 2 2
NCH ), 26.2 (CH ), 25.1 (CH ), 22.2 (CH ), 22.0 (CH ); elemental analy-
sis calcd (%) for C15
16 4 2
H N O (284.31): C 63.37, H 5.67, N 19.71; found: C
6
3.49, H 5.36, N 19.35.
1
-Heptyl-4-phenyl-1H-1,2,3-triazole (3g): Using the general procedure
from 1-azidoheptane (1g) (0.176 g) and phenylacetylene (2a) (0.11 mL),
the title compound was isolated as a white solid after filtration (0.225 g,
1
Ar
9
3%). H NMR (300 MHz, CDCl
(s, 1H, NCH=), 7.48–7.40 (m, 2H, H ), 7.40–7.29 (m, 1H, H ), 4.40 (t,
J=7.2 Hz, NCH ), 2.04–1.88 (m, 2H, NCH CH ), 1.43–1.19 (m, 8H,
CH CH CH CH CH ), 0.87 (t, J=6.7 Hz, CH ); C NMR (75 MHz,
CDCl ): d=147.5 (C, NC=), 130.6 (C, C ), 128.7 (CH, C ), 127.9 (CH,
3
): d=7.85 (d, J=7.1 Hz, 2H, H ), 7.75
Ar
Ar
2
2
2
1
3
2
2
2
2
3
3
Ar
Ar
3
Ar
Ar
C
), 125.5 (CH, C ), 119.4(CH, N CH=), 50.2 (CH
heptyl), 30.2 (CH , heptyl), 28.6 (CH , heptyl), 26.3 (CH
CH , heptyl), 13.9 (CH ); elemental analysis calcd (%) for C15
(243.35): C 74.03, H 8.70, N 17.27; found: C 73.79, H 8.60, N 17.18.
-Heptyl-4-(4-methoxyphenyl)-1H-1,2,3-triazole (3h): Using the general
2
, NCH
2 2
), 31.4(CH ,
, heptyl), 22.4
2
2
2
(
2
3
21 3
H N
Experimental Section
1
General considerations: All reagents were used as purchased. Copper(I)
bromide and sodium tert-butoxide were stored under argon in a glove-
box. 1,3-Bis-(2,4,6-trimethylphenyl)imidazolium chloride (SIMes·HCl)
procedure from 1-azidoheptane (1g) (0.176 g) and 1-ethynyl-4-methoxy-
benzene (2g) (0.136 mL), the title compound was isolated as a white
1
solid after filtration (0.255 g, 93%). H NMR (300 MHz, CDCl
3
): d=7.76
[
31]
Ar
was synthesized according to literature procedures or can be purchased
(d, J=8.8 Hz, 2H, H ), 7.66 (s, 1H, NCH=), 6.96 (d, J=8.8 Hz, 2H,
7562
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H
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[3+2] Cycloaddition
FULL PAPER
Ar
H
), 4.37 (t, J=7.2 Hz, NCH
NCH CH ), 1.42–1.21 (m, 8H, CH
); C NMR (75 MHz, CDCl ): d=159.4(C, C ), 147.5 (C, NC=),
2
), 3.84(s, 3H, OC H
3
), 2.00–1.83 (m, 2H,
3o and 3p could not be purified by recrystallization and the crude prod-
uct was purified by flash chromatography on silica gel.
2
2
2
CH CH CH CH
2
2
2
3
Ar
), 0.88 (t, J=6.8 Hz,
1
3
CH
26.9 (CH, C ), 123.4(C, C ), 118.6 (CH, NCH=), 114.1 (CH, C ), 55.2
CH , NCH ), 50.3 (CH , OCH ), 31.5 (CH , heptyl), 30.3 (CH , heptyl),
8.6 (CH heptyl), 26.4(CH heptyl), 22.5 (CH heptyl), 14.0
CH ); elemental analysis calcd (%) for C16 O (273.37): C 70.30,
H 8.48, N 15.37; found: C 69.98, H 8.79, N 15.24.
-(3-Fluorophenyl)-1-heptyl-1H-1,2,3-triazole (3i) : a) Using the general
3
3
1
-Benzyl-4,5-diethyl-1H-1,2,3-triazole (3o): Using the general procedure
Ar
Ar
Ar
1
(
2
(
from benzyl azide 1a (0.133 g) and after purification by flash chromatog-
raphy on silica gel (pentane/diethyl ether 1:1), the title compound was
2
2
3
3
2
2
,
2
,
2
,
1
2
isolated as a colorless oil (0.153 g, 71%). H NMR (300 MHz, CDCl
):
),
3
CH
2
3
H
23
N
3
Ar
Ar
d=7.42–7.27 (m, 3H, H ), 7.21–7.18 (m, 2H, H ), 5.48 (s, 2H, NCH
.65 (q, J=7.6 Hz, CH CH ), 2.52 (q, J=7.6 Hz, CH CH
7.6 Hz, CH CH ), 0.96 (t, J=7.6 Hz, CH
CDCl ): d=146.39 (C, NC=), 146.34 (C, NC=), 135.4(C, C ), 128.88
(CH, C ), 128.81 (CH, C ), 128.1 (CH, C ), 51.8 (CH
(CH , CH CH ), 15.9 (CH , CH CH ), 14.2 (CH ), 13.3 (CH
(215.29): C 72.52, H 7.96, N 19.52; found:
2
2
2
3
2
3
), 1.28 (t, J=
2 3
CH ); C NMR (75 MHz,
1
3
4
2
3
Ar
procedure from 1-azidoheptane (1g) (0.176 g) and 1-ethynyl-3-fluoroben-
zene (2i) (0.121 mL), the title compound was isolated as an off-white
solid after extraction (0.233 g, 89%). b) Using the general procedure
from 1-bromoheptane (4g) (0.157 mL) and 1-ethynyl-3-fluorobenzene
3
Ar
Ar
Ar
2
, NCH
2
), 18.5
2
2
3
2
2
3
3
3
); elemental
analysis calcd (%) for C13
17 3
H N
(
2i) (0.121 mL), the title compound was isolated as a white solid after ex-
C 72.43, H 7.83, N 19.45.
1
traction (0.240 g, 92%). H NMR (300 MHz, CDCl
NCH=), 7.65–7.52 (m, 2H, H ), 7.43–7.34 (m, 1H, H ), 7.08–6.97 (m,
1
1
3
): d=7.76 (s, 1H,
4,5-Diethyl-1-(4-nitrobenzyl)-1H-1,2,3-triazole (3p): Using the general
procedure from 4-(azidomethyl)-4-nitrobenzene (1e) (0.176 g) and after
purification by flash chromatography on silica gel (diethyl ether), the
Ar
Ar
Ar
H, H ), 4.41 (t, J=7.3 Hz, NCH
.20 (m, 8H, CH CH CH CH CH
): d=160.4(d, J=244 Hz, C, C-F), 146.5 (C, NC=), 132.8
2
), 2.02–1.89 (m, 2H, NCH
2 2
CH ), 1.43–
); C NMR
1
3
1
2
2
2
2
3
), 0.89 (t, J=6.7 Hz, CH
3
title compound was isolated as a yellow oil (0.130 g, 48%). H NMR
Ar
Ar
(
(
75 MHz, CDCl
d, J=8.5 Hz, C, C ), 130.3 (d, J=8.5 Hz, CH, C ), 121.2 (CH, C ),
3
(300 MHz, CDCl ): d=8.21 (d, J=8.7 Hz, H ), 7.30 (d, J=8.7 Hz, H ),
3
Ar
Ar
Ar
5.58 (s, 2H, NCH ), 2.67 (q, J=7.5 Hz, CH CH ), 2.55 (q, J=7.5 Hz,
2
2
3
Ar
1
19.8 (CH, NCH=), 114.7 (d, J=21 Hz, CH, C ), 112.4(d, J=23 Hz,
2 3 2 3 2 3
CH CH ), 1.30 (t, J=7.5 Hz, CH CH ), 1.01 (t, J=7.5 Hz, CH CH );
Ar
13
CH, C ), 50.4(CH
CH , heptyl), 26.3 (CH
tal analysis calcd (%) for C15
Found: C 68.87, H 7.99, N 15.85.
-tert-Butyl-1-heptyl-1H-1,2,3-triazole (3j): Using the general procedure
from 1-azidoheptane (1g) (0.176 g), 3,3-dimethylbut-1-yne (2j)
0.13 mL), and 2 mol% [(SIMes)CuBr], the title compound was isolated
2
, NCH
, heptyl), 22.4(CH
(261.34): C 68.94, H 7.71, N 16.08.
2
), 31.4(CH
2
, heptyl), 30.2 (CH
2
, heptyl), 28.6
3
C NMR (75 MHz, CDCl ): d=147.71 (C), 147.66 (C), 147.63 (C), 142.6
Ar
Ar
Ar
(
2
2
2
, heptyl), 13.9 (CH
3
); elemen-
2 2 2
(C, C ), 127.7 (CH, C ), 124.1 (CH, C ), 50.7 (CH , NCH ), 18.4(CH ,
H
20FN
3
2 3 2 2 3 3 3
CH CH ), 15.8 (CH , CH CH ), 14.1 (CH ), 13.5 (CH ); elemental analy-
sis calcd (%) for C H N O (260.29): C 59.99, H 6.20, N 21.52; found: C
1
3
16
4
2
6
0.34, H 6.33, N 21.76.
4
Calculation details: The DFT calculations were performed at the BP86/
GGA level using the Gaussian03 package. The split-valence + 1 polari-
zation function SVP basis set of Ahlrichs was used for H, C and N.
[
32]
(
1
[33]
as a light yellow oil after extraction (0.212 g, 95%). H NMR (300 MHz,
CDCl ): d=7.19 (s, 1H, NCH=), 4.21 (t, J=7.4Hz, 2H, NC H ), 1.84–
.74(m, 2H, NCH CH ), 1.33–1.21 (m, CH CH CH CH CH ), 1.26 (s,
) (17H), 0.80 (t, J=6.8 Hz, CH ); C NMR (75 MHz, CDCl ): d=
, NCH ), 31.3 (CH
), 28.4(CH , heptyl), 26.2
CH ); elemental analysis
(223.36): C 69.91, H 11.28, N 18.81; found: C
3
2
The Stuttgart/Dresden relativistic small core pseudopotential was used
[
34]
1
2
2
2
2
2
2
3
for Cu. The total binding energy DEbind was decomposed as DEbind
=
1
3
CCH
1
3
3
3
DEprep + DEinter, where DEprep is the energy required to prepare (deform)
+
+
57.2 (C, NC=), 118.1 (CH, NCH=), 49.8 (CH
2
2
2
,
the free EtCꢀCEt, [(SIMes)Cu] and [(MeCN) Cu] systems to the final
2
+
heptyl), 30.4(C, CCH
CH , heptyl), 22.2 (CH
calcd (%) for C13
3
), 30.1 (CH
3
, CCH
3
2
geometry they have in the [(SIMes)Cu
A
H
R
U
G
2
Cu-
+
(
2
2
, heptyl), 13.8 (CH
2
3
A
H
R
U
G
+
H
25
N
3
the deformed EtCꢀCEt and the deformed [(SIMes)Cu]
or
+ [35]
7
0.01, H 11.56, N 18.76.
2
[(MeCN) Cu] systems.
2
-(1-Phenethyl-1H-1,2,3-triazol-4-yl)propan-2-ol (3l): Using the general
procedure from (2-azidoethyl)benzene (1l) (0.147 g) and 2-methylbut-3-
yn-2-ol (2l) (0.11 mL), the title compound was isolated as a white solid
1
after filtration (0.216 g, 94%). H NMR (300 MHz, CDCl
(
3
Ar
): d=7.39–7.21
Acknowledgements
Ar
m, 3H, H ), 7.19 (s, 1H, NCH=), 7.18–7.02 (m, 2H, H ), 4.54 (t, J=
7
6
.6 Hz, PhCH
2
), 3.19 (t, J=7.6 Hz, NCH
2
), 2.99 (brs, 1H, OH), 1.59 (s,
The National Science Foundation and the MURST of Italy (grant prin
004) are gratefully acknowledged for support of this work. S.D.G.
thanks the Education, Research and Universities Department of the
Basque Government (Spain) for a postdoctoral fellowship. We thank the
University of Ottawa, and especially Professor Deryn Fogg for hosting
our group while UNO was recovering from Hurricane Katrina.
1
3
H, CH ); C NMR (75 MHz, CDCl ): d=155.3 (C, NC=), 137.0 (C,
3
3
2
Ar
Ar
Ar
Ar
C
), 128.7 (CH, C ), 128.6 (CH, C ), 127.0 (CH, C ), 119.5 (CH,
NCH=), 68.3 (C, COH), 51.5 (CH , NCH ), 36.7 (CH , PhCH ), 30.4
); elemental analysis calcd (%) for C13 O (231.29): C 67.51, H
.41, N 18.17; fund: C 67.45, H 7.48, N 17.87.
-[2-(1,3-Dioxolan-2-yl)ethyl]-4-phenyl-1H-1,2,3-triazole (3m): Using the
2
2
2
2
(
CH
3
17 3
H N
7
1
general procedure from (2-azidoethyl)-1,3-dioxolane (1m) (0.143 g) and
phenylacetylene (2a) (0.11 mL), the title compound was isolated as a
[
[
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white solid after filtration (0.226 g, 92%). H NMR (300 MHz, CDCl
3
):
Ar
Ar
d=7.87–7.73 (m, 3H, H + NCH=), 7.47–7.28 (m, 3H, H ), 4.94 (t, J=
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OCH ), 3.92–3.84(m, 2H, OC ), 2.37–2.27 (m, 2H, NCH CH );
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2
2
H
2
2
2
1
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CH, OCHO), 65.0 (CH CH O), 45.3 (CH NCH ), 34.0 (CH
CH ); elemental analysis calcd (%) for C13 (245.28): C
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H N O
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mixture. After extraction of the aqueous phase with diethyl ether, the
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sulfate, filtered and evaporated. Due to their low melting point, triazoles
Chem. Eur. J. 2006, 12, 7558 – 7564ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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[
[
[
[
[
19] 3a could be prepared from benzyl bromide neat, but overnight reac-
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Received: July 5, 2006
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Published online: September 12, 2006
7564
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 7558 – 7564