Sequential one-pot ruthenium-catalyzed azide-alkyne cycloaddition from primary alkyl halides and sodium azide

Article abstract of DOI:10.1021/jo200134a

An experimentally simple sequential one-pot RuAAC reaction, affording 1,5-disubstituted 1H-1,2,3-triazoles in good to excellent yields starting from an alkyl halide, sodium azide, and an alkyne, is reported. The organic azide is formed in situ by treating the primary alkyl halide with sodium azide in DMA under microwave heating. Subsequent addition of [RuClCp*(PPh ₃)₂] and the alkyne yielded the desired cycloaddition product after further microwave irradiation.

Full text of DOI:10.1021/jo200134a

NOTE
pubs.acs.org/joc
Sequential One-Pot Ruthenium-Catalyzed Azide-Alkyne
Cycloaddition from Primary Alkyl Halides and Sodium Azide
Johan R. Johansson,* Per Lincoln, Bengt Nordꢀen, and Nina Kann
Division of Chemistry and Biochemistry, Department of Chemical and Biological Engineering, Chalmers University of Technology,
SE-41296 Gothenburg, Sweden
S Supporting Information
b
ABSTRACT: An experimentally simple sequential one-pot RuAAC reaction,
affording 1,5-disubstituted 1H-1,2,3-triazoles in good to excellent yields
starting from an alkyl halide, sodium azide, and an alkyne, is reported. The
organic azide is formed in situ by treating the primary alkyl halide with sodium
azide in DMA under microwave heating. Subsequent addition of [RuClCp*-
(PPh3)2] and the alkyne yielded the desired cycloaddition product after further
microwave irradiation.
Table 1. RuAAC Reaction To Form Triazole 1 with an
ne of the most well-known click reactions, the copper-
Alkyne/Azide Ratio of 1:1 in Different Solvents
O
catalyzed azide-alkyne cycloaddition reaction (CuAAC)
to form 1,4-disubstitued triazoles,1 has found numerous applica-
tions, not only within the organic chemistry community but also
in other areas such as bioconjugation and materials science.2
More recently, Fokin and Jia have reported a versatile ruthenium-
catalyzed azide-alkyne cycloaddition reaction (RuAAC) that
gives access to the isomeric 1,5-substituted triazoles, using a
[RuClCp*] catalyst with different ligands under either conven-
tional heating3 or microwave conditions.4 However, applications
of the RuAAC reaction are as yet less prevalent in comparison
to the CuAAC reaction.5 Recently a mild and efficient base-
catalyzed metal-free reaction, giving access to 1,5-diaryl-substituted
triazoles, has also been disclosed. Despite the many advantages in
terms of mild reaction conditions, facile isolation, and purifica-
tion, as well as environmental benefits, this reaction is limited to
aryl alkynes and aryl azides as substrates.6
solvent
conv, % solvent conv, %
solvent
conv, %
dioxane
THF
∼95
100
100
DMA
∼95
<5
H2O
∼5
∼10
∼5
DMSO
CH3CN
THF/H2O 3:1
2-MeTHF
∼5
CH3CN/H2O 3:1
obtained. However, the use of DMA as solvent afforded complete
consumption of the alkyne but with competing formation of
dimerization byproduct9 to a larger extent than when THF was
used. However, by using 2 equiv of the azide, this side reaction could
be suppressed. Since the formation of alkyl azides from alkyl halides
and sodium azide is normally performed in polar solvents such as
DMSO, DMF, or water, DMA was thus the obvious choice for a
one-pot procedure. Fokin and Jia have reported the isolation of
[RuClCp*] tetraazadiene complexes when an excess of the azide
was used or when the azide was added to the catalyst before the
alkyne, and found such species to be catalytically inactive.3b This was
not the case for the substrates used in our study, however.
We then explored the possibility of developing a one-pot
procedure for the RuAAC starting directly from an alkyl halide.
When benzyl bromide (2 equiv), sodium azide (2 equiv),
3-ethynylpyridine (1 equiv), and 6 mol % of [RuClCp*-
(PPh3)2] were mixed in DMA and heated to 100 °C for
30 min in a microwave reactor in a one-pot procedure, only traces
of product were obtained and most of the alkyne remained
One restriction of organic reactions involving azides is that the
selection of commercially available aryl and alkyl azides is limited,
and also the fact that low molecular weight organic azides,
especially those with a low carbon-to-nitrogen ratio, are con-
sidered to be highly energetic and potentially explosive.7 For the
CuAAC reaction, this problem has been addressed by developing
one-pot procedures where the organic azide is generated in situ.8
However, for the RuAAC reaction affording 1,5-disubstitued
triazoles, no such convenient method has been reported. We here
report a simple sequential one-pot procedure, starting from
primary alkyl halides and sodium azide, that avoids handling of
the neat hazardous alkyl azide.
Initially, as a test reaction, the RuAAC reaction between benzyl
azide and 3-ethynylpyridine was studied in different solvents under
microwave heating with [RuClCp*(PPh3)2] as the catalyst, and the
results are summarized in Table 1. Ethers like dioxane, THF, and
2-MeTHF gave full conversion of the alkyne. In polar solvents
such as DMSO, acetonitrile, and water or mixtures of water with
an organic solvent, low or only trace amounts of product were
Received: January 19, 2011
Published: March 09, 2011
r
2011 American Chemical Society
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|

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NOTE
Scheme 1. Sequential One-Pot RuAAC Reactiona
participate in the cycloaddition reaction but react more slowly
compared to primary azides.3b,c Another limitation is that the
presence of acidic groups (carboxylic acid or boronic acid) in the
alkyl halide or alkyne substrate inhibited the reaction and no
triazole product was formed in these reactions. Likewise, pyridine
or amine functionalities in the form of the HCl- or HBr-salt
present in the substrates were not tolerated. Further work is in
progress to investigate if the scope of the sequential one-pot
reaction can be expanded to include also these classes of
substrates.
In summary, a simple and practical sequential one-pot method
for the generation of 1,5-disubstituted 1,2,3-triazoles has been
developed. We hope this method will increase the use of the
RuAAC reaction by enabling direct use of the more easily
accessible primary halides, thus avoiding the hazardous handling
of alkyl azides. We envision that this procedure can find many
applications in the pharmaceutical industry for making small
focused libraries of the 1,5-regioisomer difficult to access by
other means.
a 2.0 equiv of alkyl halide, 2.0 equiv of sodium azide, and 1.0 equiv of
alkyne was used.
unreacted. This can be due to a side reaction of the ruthenium
catalyst with sodium azide.10 However, this problem can easily be
overcome by simply running the reaction as a sequential one-pot
procedure instead. When the alkyne and catalyst were added after the
generation of the alkyl azide, full conversion of the alkyne to 1,5-
disubstituted 1,2,3-triazole was obtained. The 1,5-substitution pat-
tern was confirmed by 2D NOESY experiments. The use of
[RuClCp*COD] as the catalyst was also investigated at several
different temperatures ranging from ambient temperature to 100 °C;
however, the conversion was much lower under these conditions.
With this novel sequential one-pot procedure in hand
(Scheme 1), the scope of the method was investigated with a
range of different alkyl halides and alkynes. The results are
summarized in Table 2.
Benzylic bromides (entries 2-5, 7, and 11), as well as other
activated halides such as methyl 2-bromoacetate (entry 1),
afforded 1,5-disubstituted 1,2,3-triazoles in good to excellent
yields. Aliphatic bromides gave slower reactions but otherwise
performed well and the desired cycloaddition products were
obtained in good yields when the temperature was increased
from 80 to 100 °C for the first step and from 100 to 120 °C for the
subsequent cyclization reaction. When the internal alkyne pent-
2-yn-1-ol was used (entry 2) a ∼1:1 mixture of the two isomers
was formed. This is in contrast with results reported by Weinreb
for similar propargylic alcohols,3c where only one isomer is
obtained. To understand if the reaction conditions used in our
method gave rise to this regionselectivity, the RuAAC reaction
between benzyl azide and pent-2-yn-1-ol catalyzed by [RuClCp*-
(PPh3)2] was performed in benzene at 100 °C for 20 min in a
microwave reactor. However, the same regioisomeric ratio as
previously was obtained, and we thus conclude that the regios-
electivity is substrate dependent in this particular case. Small
halides of low molecular weight were problematic, probably due
to the instability and potential decomposition of the correspond-
ing azide at the reaction temperature. However, despite the low
boiling point of methyl azide (21 °C),11 the triazole was obtained
in 18% yield when methyl iodide (entry 8) was used in a sealed
microwave vial at 80 °C in a microwave reactor. (CAUTION!
The reaction generating methyl azide and other small alkyl azides
is potentially explosive and can be dangerous to scale up. The
reaction should only be carried out in a microwave reactor that
can withstand an explosion of the reaction vial.) Primary alkyl
chlorides (entries 12-14) reacted more slowly compared to
the alkyl bromides and needed higher reaction temperatures
to obtain moderate to excellent yields of the corresponding
products.
’ EXPERIMENTAL SECTION
General Information. Chemicals were obtained from commercial
suppliers and used without purification unless otherwise noted.
[RuClCp*(PPh3)2] (orange solid) was purchased from Strem Chemi-
cals Inc. and used as such. All microwave reactions were carried out in a
Biotage Series 60 Initiator (actual vial temperature was monitored with
an IR sensor), using fixed hold time. Abbreviations for NMR are the
following: s, singlet; d, doublet; t, triplet; q, quartet; br s, broad singlet;
app, apparent. Chemical shifts (δ) are given in ppm relative to the
solvent residual peak (CHCl3: 7.26 ppm for 1H NMR and 77.23 ppm for
13C NMR; and DMSO: 2.50 ppm for 1H NMR and 39.5 ppm for 13
C
NMR) or an internal standard (TMS: 0.00 ppm for 1H NMR). The 1,5-
substitution pattern was confirmed for triazoles 5 and 9 by 2D NOESY
experiments.
General Procedure for Solvent Investigation. In a microwave
vial were placed 3-ethynylpyridine (20.6 mg, 0.20 mmol), 6 mol % of
[RuClCp*(PPh3)2] (9.6 mg, 0.012 mmol), and solvent (3 mL). Benzyl
azide (53.2 μL, 0.4 mmol) was added and the vial was sealed and flushed
with N2 for 1-2 min. The reaction mixture was heated to 100 °C for
30 min in a microwave reactor. The reaction was analyzed with LCMS
and TLC.
General Procedures A and B. In a microwave vial were placed
sodium azide (13.0 mg, 0.20 mmol or 26.0 mg, 0.40 mmol), alkyl halide
(see Table 2) (0.20 or 0.40 mmol) and DMA (3 mL). The reaction
mixture was heated to 80 °C (procedure A) or 100 °C (procedure B) for
10 min in a microwave reactor. CAUTION! The reaction generating
small alkyl azides is potentially explosive and can be dangerous to scale
up. The reaction should only be carried out in a microwave reactor that
can withstand an explosion of the reaction vial. The vial was uncapped
and the alkyne (0.10 or 0.20 mmol) was added followed by addition of
6 mol % of [RuClCp*(PPh3)2]. The vial was sealed and flushed with
nitrogen for 1-2 min without stirring. The reaction mixture was heated
to 100 (procedure A) or 120 °C (procedure B) for 30 min in a
microwave reactor. The resulting product mixture was purified by flash
chromatography on silica, using a gradient system of 0-30% ethyl
acetate in heptane followed by 0-30% methanol in CH2Cl2. Fractions
were collected by using UV-detection at 254 and/or 280 nm to obtain
the title product.
3-(1-Benzyl-1H-1,2,3-triazol-5-yl)pyridine (1): Following
general procedure A with use of benzyl bromide (23.9 μL, 0.20 mmol),
sodium azide (13.0 mg, 0.20 mmol), and 3-ethynylpyridine (10.3 mg,
0.10 mmol) provided 3-(1-benzyl-1H-1,2,3-triazol-5-yl)pyridine (1) as a
Secondary alkyl halides such as cyclohexyl bromide did not
afford any product in our case even at higher temperatures,
although previous reports show that secondary azides can
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NOTE
Table 2. Scope of the Sequential One-Pot RuAAC Reaction To Form 1,5-Disubstituted 1,2,3-Triazolesa
a 2.0 equiv of alkyl halide, 2.0 equiv of sodium azide, 1.0 equiv of alkyne, and 6 mol % of [RuClCp*(PPh3)2] in DMA was used. b Conditions A: heated to
80 °C for 10 min to generate the alkyl azide and 100 °C for 30 min for the cycloaddition step. Conditions B: heated to 100 and 120 °C, respectively.
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NOTE
yellowish oil. Yield 19.4 mg (82%); 1H NMR (400 MHz, CDCl3) δ 8.68
(br d, J = 3.8 Hz, 1H), 8.53 (br s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.52 (dt,
J = 7.9 Hz, 1H), 7.35 (dd, J = 7.9, 4.8 Hz, 1H), 7.32-7.26 (m, 3H), 7.08-
7.03 (m, 2H), 5.57 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 150.8,
149.4, 136.3, 135.1, 135.0, 134.2, 129.2, 128.6, 127.2, 123.7, 52.3 (twþo
aromatic signals overlap); HRMS (ESI-TOF) calcd for C14H13N4
(M þ H) 237.1140, found 227.1148.
(m, 1H), 6.83 (d, J = 8.3 Hz, 2H), 4.39 (t, J = 7.1 Hz, 2H), 3.93 (t, J = 5.9
Hz, 2H), 3.55 (s, 3H), 2.10-2.01 (m, 2H), 1.82-1.72 (m, 2H); 13C
NMR (151 MHz, CDCl3) δ 158.8, 140.6, 134.4, 131.6, 129.6, 126.5,
121.0, 118.7, 114.5, 66.8, 48.3, 32.4, 27.2, 26.4; HRMS (ESI-TOF) calcd
for C16H20N5Oþ (M þ H) 298.1668, found 298.1673.
5-(3-Chloropropyl)-1-(naphthalen-2-ylmethyl)-1H-1,2,3-
triazole (7): Following general procedure A with use of 2-
(bromomethyl)naphthalene (45.1 mg, 0.20 mmol, purified by flash
chromatography), sodium azide (13.0 mg, 0.20 mmol), and 5-chloro-
pent-1-yne (10.7 μL, 0.1 mmol) provided 5-(3-chloropropyl)-
1-(naphthalen-2-ylmethyl)-1H-1,2,3-triazole (7) as a brownish oil.
Methyl 2-(5-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl)acetate (2):
Following general procedure A with use of methyl 2-bromoacetate
(18.9 μL, 0.20 mmol), sodium azide (13.0 mg, 0.20 mmol), and 3-ethyn-
ylpyridine (10.3 mg, 0.10 mmol) provided methyl 2-(5-(pyridin-3-yl)-
1H-1,2,3-triazol-1-yl)acetate as a brownish oil. Yield 19.1 mg (88%); 1H
NMR (400 MHz, CDCl3) δ 8.84-8.59 (m, 2H), 7.82 (s, 1H), 7.76 (d,
J = 7.9 Hz, 1H), 7.51-7.41 (m, 1H), 5.15 (s, 2H), 3.78 (s, 3H);
13C NMR (151 MHz, CDCl3) δ 166.9, 151.1, 149.3, 136.4, 135.9, 133.9,
1
Yield 16.7 mg (58%, purity 93%); H NMR (400 MHz, CDCl3) δ
7.86-7.76 (m, 3H), 7.60 (s, 1H), 7.54 (s, 1H), 7.52-7.47 (m, 2H),
7.32-7.25 (m, 1H), 5.70 (s, 1H), 3.46 (t, J = 6.0 Hz, 1H), 2.74 (t, J =
7.6 Hz, 2H), 1.98-1.90 (m, 2H); 13C NMR (101 MHz, CDCl3) δ
136.1, 133.4, 133.2, 133.1, 132.4, 129.3, 128.1, 128.0, 126.9, 126.8,
126.4, 124.8, 52.2, 43.7, 30.7, 20.5; HRMS (ESI-TOF) calcd for
C16H17ClN3þ (M þ H) 286.1111, found 286.1114.
þ
124.0, 123.2, 53.3, 49.3; HRMS (ESI-TOF) calcd for C10H11N4O2
(M þ H) 219.0882, found 219.0883.
(1-Benzyl-4-ethyl-1H-1,2,3-triazol-5-yl)methanol/(1-ben-
zyl-5-ethyl-1H-1,2,3-triazol-4-yl)methanol (3a/3b): Following
general procedure A with use of benzyl bromide (23.9 μL, 0.20 mmol),
sodium azide (13.0 mg, 0.20 mmol), and pent-2-yn-1-ol (8.4 mg, 0.10
mmol) provided a ∼1:1 mixture of the regioisomers of 3 as a yellowish-
brown oil. Yield 18.4 mg (85%); 1H NMR (400 MHz, CDCl3) δ 7.37-
7.12 (m, 5H), 5.58 (s, minor isomer) and 5.48 (s, major isomer, 2H),
4.70 (s, major isomer) and 4.55 (s, minor isomer, 2H), 3.52 (br s, minor
isomer) and 3.08 (br s, major isomer, 1H), 2.63 (q, J = 7.6 Hz, 2H), 1.23
(t, J = 7.6 Hz, minor isomer) and 1.03 (t, J = 7.6 Hz, major isomer, 3H);
13C NMR (151 MHz, CDCl3) δ 147.9, 144.6, 136.5, 135.4, 135.2, 131.6,
129.2, 129.1, 128.6, 128.5, 127.7, 127.3, 56.1, 52.5, 52.3, 52.1, 18.5, 16.3,
14.5, 13.5; HRMS (ESI-TOF) calcd for C12H16N3Oþ (M þ H)
218.1293, found 218.1297.
3-(1-Methyl-1H-1,2,3-triazol-5-yl)pyridine (8:). Following
general procedure A, but not flushing with nitrogen after catalyst
addition, with use of iodomethane (12.5 μL, 0.20 mmol), sodium azide
(13.0 mg, 0.20 mmol), and 3-ethynylpyridine (10.3 mg, 0.10 mmol)
provided 3-(1-benzyl-1H-1,2,3-triazol-5-yl)pyridine (8) as a brownish
oil. Yield 2.9 mg (18%); 1H NMR (400 MHz, CDCl3) δ 9.04 (br s, 1H),
8.65 (br s, 1H), 8.22 (d, J = 7.5 Hz, 1H), 7.84 (s, 1H), 7.41 (br s, 1H),
4.19 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 149.5, 147.3, 133.2, 132.3,
124.0, 121.1, 37.1 (two aromatic signals overlap); HRMS (ESI-TOF)
calcd for C8H9N4þ (M þ H) 161.0827, found 161.0835.
1-Isopentyl-5-((phenylthio)methyl)-1H-1,2,3-triazole (9):
Following general procedure B with use of 1-bromo-3-methylbutane
(49.9 μL, 0.40 mmol), sodium azide (26.0 mg, 0.40 mmol), and
phenyl(prop-2-yn-1-yl)sulfane (28.4 μL, 0.20 mmol) provided 1-iso-
pentyl-5-((phenylthio)methyl)-1H-1,2,3-triazole (9) as a yellowish-
brown oil. Yield 38.1 mg (73%); 1H NMR (400 MHz, CDCl3) δ 7.33
(s, 1H), 7.32-7.27 (m, 5H), 4.32-4.24 (m, 2H), 4.06 (s, 2H), 1.83-
1.75 (m, 2H), 1.68-1.59 (m, 1H), 0.97 (d, J = 6.6 Hz, 6H); 13C NMR
(101 MHz, CDCl3) δ 133.9, 133.5, 132.7, 132.2, 129.4, 128.2, 46.6, 38.8,
27.5, 25.9, 22.4; HRMS (ESI-TOF) calcd for C14H20N3Sþ (M þ H)
262.1378, found 262.1384. The 1,5-substitution pattern was confirmed
by a 2D NOESY experiment.
1-(3-Methoxybenzyl)-5-(1-methyl-1H-imidazol-5-yl)-1H-
1,2,3-triazole (4): Following general procedure A with use of 1-
(bromomethyl)-3-methoxybenzene (28.0 μL, 0.20 mmol), sodium
azide (13.0 mg, 0.20 mmol), and 5-ethynyl-1-methyl-1H-imidazole
(10.2 μL, 0.10 mmol) provided 1-(3-methoxybenzyl)-5-(1-methyl-
1H-imidazol-5-yl)-1H-1,2,3-triazole (4) as a yellowish oil. Yield 25.0
1
mg (93%); H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 7.55 (br s,
1H), 7.19 (t, J = 7.8 Hz, 1H), 7.11 (br s, 1H), 6.82 (dd, J = 8.4, 2.3 Hz,
1H), 6.61-6.53 (m, 2H), 5.46 (s, 2H), 3.71 (s, 3H), 3.16 (s, 3H); 13
C
NMR (151 MHz, CDCl3) δ 160.1, 140.4, 136.4, 135.2, 131.8, 130.1,
126.6, 119.8, 118.4, 114.4, 112.9, 55.4, 52.4, 31.9; HRMS (ESI-TOF)
calcd for C14H16N5Oþ (M þ H) 270.1355, found 270.1357.
2-(2-(5-Phenyl-1H-1,2,3-triazol-1-yl)ethyl)isoindoline-1,3-
dione (10): Following general procedure B with use of 2-(2-bro-
moethyl)isoindoline-1,3-dione (112.9 mg, 0.40 mmol), sodium azide
(26.0 mg, 0.40 mmol), and ethynylbenzene (22.4 μL, 0.20 mmol)
provided 2-(2-(5-phenyl-1H-1,2,3-triazol-1-yl)ethyl)isoindoline-1,3-
dione (10) as a yellow oil. Yield 58.5 mg (92%); 1H NMR (400 MHz,
CDCl3) δ 7.75-7.68 (m, 4H), 7.65 (s, 1H), 7.36 (s, 5H), 4.76-4.72 (m,
2H), 4.01-3.96 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 167.6, 138.2,
134.2, 133.5, 131.8, 129.6, 129.2, 128.8, 126.7, 123.5, 46.2, 37.8; HRMS
Di-tert-butyl ((1,10-(naphthalene-2,6-diylbis(methylene))-
bis(1H-1,2,3-triazole-5,1-diyl))bis(methylene))dicarbamate
(5): Following general procedure A with use of 2,6-bis(bromo-
methyl)naphthalene (62.8 mg, 0.20 mmol) and tert-butyl prop-2-yn-1-
ylcarbamate (31.0 mg, 0.20 mmol) provided di-tert-butyl ((1,10-(naph-
thalene-2,6-diylbis(methylene))bis(1H-1,2,3-triazole-5,1-diyl))bis-
(methylene)) dicarbamate (5) as an off-white solid. Yield 57.0 mg (52%,
purity 96%); 1H NMR (800 MHz, DMSO-d6) δ 7.85 (d, J = 8.5 Hz, 2H),
7.68 (s, 2H), 7.55 (s, 2H), 7.48-7.44 (m, 2H), 7.33 (d, J = 8.4 Hz, 2H),
5.75 (s, 4H), 4.18 (d, J = 5.2 Hz, 4H), 1.29 (s, 18H); 13C NMR (151
MHz, DMSO-d6) δ 155.5, 136.0, 133.7, 132.8, 132.2, 128.5, 125.9,
þ
(ESI-TOF) calcd for C18H15N4O2 (M þ H) 319.1195, found
319.1209.
5-(4-Fluorophenyl)-1-(2-nitrobenzyl)-1H-1,2,3-triazole
(11): Following general procedure A with use of 1-(bromomethyl)-2-
nitrobenzene (86.4 mg, 0.40 mmol, purified by flash chromatography),
sodium azide (26.0 mg, 0.40 mmol), and 1-ethynyl-4-fluorobenzene
(23.2 μL, 0.20 mmol) provided 5-(4-fluorophenyl)-1-(2-nitrobenzyl)-
þ
125.8, 78.4, 50.6, 32.9, 28.0; HRMS (ESI-TOF) calcd for C28H37N8O4
(M þ H) 549.2938, found 549.2943. The 1,5-substitution pattern was
1
1H-1,2,3-triazole (11) as an off-white solid. Yield 54.6 mg (92%); H
confirmed by a 2D NOESY experiment.
5-(1-Methyl-1H-imidazol-5-yl)-1-(4-phenoxybutyl)-1H-
1,2,3-triazole (6): Following general procedure B with use of (4-
bromobutoxy)benzene (106.0 mg, 0.46 mmol), sodium azide (13.0 mg,
0.20 mmol), and 5-ethynyl-1-methyl-1H-imidazole (20.4 μL, 0.2 mmol)
provided 5-(1-methyl-1H-imidazol-5-yl)-1-(4-phenoxybutyl)-1H-1,2,3-
triazole (6) as a brownish oil. Yield 41.7 mg (70%); 1H NMR (400 MHz,
CDCl3) δ 7.74 (s, 1H), 7.64 (s, 1H), 7.31-7.19 (m, 3H), 6.95-6.91
NMR (400 MHz, CDCl3) δ 8.16 (dd, J = 8.1, 1.4 Hz, 1H), 7.82 (s, 1H),
7.60 (td, J = 4.6, 2.3 Hz, 1H), 7.52 (td, J = 8.1, 1.4 Hz, 1H), 7.26-7.20
(m, 2H), 7.14-7.08 (m, 2H), 6.80 (dd, J = 7.7, 0.9 Hz, 1H), 5.97 (s,
2H); 13C NMR (101 MHz, CDCl3) δ 163.6 (d, 1JCF = 251.2 Hz), 147.0,
138.1, 134.6, 133.6, 131.8, 130.6 (d, 3JCF = 8.5 Hz), 129.4, 128.8, 125.6,
122.5 (d, 4JCF = 3.5 Hz), 116.7 (d, 2JCF = 22.0 Hz), 49.2; HRMS (ESI-
TOF) calcd for C15H12FN4O2þ (M þ H) 299.0944, found 299.0943.
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NOTE
5-(1-Methyl-1H-imidazol-5-yl)-1-(3-phenylpropyl)-1H-
1,2,3-triazole (12): Following general procedure B with use of (3-
chloropropyl)benzene (57.9 μL, 0.40 mmol), sodium azide (26.0 mg,
0.40 mmol), and 5-ethynyl-1-methyl-1H-imidazole (20.4 μL, 0.2 mmol)
provided 5-(1-methyl-1H-imidazol-5-yl)-1-(3-phenylpropyl)-1H-1,2,3-
(2) For some recent reviews on applications of the copper-catalyzed
click reaction we refer to a themed issue of Chem. Soc. Rev., see: (a) Finn,
M. G.; Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1231 and the articles
following this editorial article. We also refer to the following: (b) Wu, P.;
Fokin, V. V. Aldrichim. Acta 2007, 40, 7.
(3) (a) Zhang, L.; Chen, X. G.; Xue, P.; Sun, H. H. Y.; Williams, I. D.;
Sharpless, K. B.; Fokin, V. V.; Jia, G. C. J. Am. Chem. Soc. 2005,
127, 15998. (b) Boren, B. C.; Narayan, S.; Rasmussen, L. K.; Zhang,
L.; Zhao, H. T.; Lin, Z. Y.; Jia, G. C.; Fokin, V. V. J. Am. Chem. Soc. 2008,
130, 8923. For a study focused on the regioselectivity of internal alkynes
in this reaction see also:(c) Majireck, M. M.; Weinreb, S. M. J. Org. Chem.
2006, 71, 8680. (d) Grecian, S.; Fokin, V. V. Angew. Chem., Int. Ed. 2008,
47, 8285.
1
triazole (12) as a brownish oil. Yield 25.2 mg (47%); H NMR (400
MHz, CDCl3) δ 7.75 (s, 1H), 7.64 (s, 1H), 7.31-7.25 (m, 2H), 7.23-
7.18 (m, 1H), 7.16-7.11 (m, 3H), 4.31 (t, J = 7.3 Hz, 2H), 3.54 (s, 3H),
2.65 (t, J = 7.6 Hz, 2H), 2.23-2.14 (m, 2H); 13C NMR (101 MHz,
CDCl3) δ 140.4, 140.1, 134.2, 131.4, 128.7, 128.4, 126.5, 126.4, 118.5,
47.8, 32.6, 32.3, 31.6; HRMS (ESI-TOF) calcd for C15H18N5þ (M þ H)
268.1562, found 268.1562.
1-Benzyl-5-(4-fluorophenyl)-1H-1,2,3-triazole (13): Follow-
ing general procedure B with use of benzyl chloride (46.5 μL, 0.40
mmol), sodium azide (26.0 mg, 0.40 mmol), and 1-ethynyl-4-fluoro-
benzene (23.2 μL, 0.20 mmol) provided 1-benzyl-5-(4-fluorophenyl)-
1H-1,2,3-triazole (13) as a yellowish oil. Yield 49.1 mg (97%); 1H NMR
(400 MHz, CDCl3) δ 7.71 (s, 1H), 7.31-7.26 (m, 3H), 7.24-7.18 (m,
2H), 7.13-7.08 (m, 2H), 7.08-7.04 (m, 2H), 5.52 (s, 2H); 13C NMR
(101 MHz, CDCl3) δ 163.5 (d, 1JCF = 250.4 Hz), 137.3, 135.5, 133.6,
131.1 (d, 3JCF = 8.5 Hz), 129.0, 128.4, 127.2, 123.1 (d, 4JCF = 3.5 Hz),
(4) Rasmussen, L. K.; Boren, B. C.; Fokin, V. V. Org. Lett. 2007,
9, 5337.
(5) For applications in organic/medicinal chemistry, see(a) Oppil-
liart, S.; Mousseau, G.; Zhang, L.; Jia, G. C.; Thuery, P.; Rousseau, B.;
Cintrat, J. C. Tetrahedron 2007, 63, 8094. (b) Imperio, D.; Pirali, T.;
Galli, U.; Pagliai, F.; Cafici, L.; Canonico, P. L.; Sorba, G.; Genazzani,
A. A.; Tron, G. C. Bioorg. Med. Chem. 2007, 15, 6748. (c) Pradere, U.;
Roy, V.; McBrayer, T. R.; Schinazi, R. F.; Agrofoglio, L. A. Tetrahedron
2008, 64, 9044. (d) Kelly, A. R.; Wei, J. Q.; Kesavan, S.; Marie, J. C.;
Windmon, N.; Young, D. W.; Marcaurelle, L. A. Org. Lett. 2009,
11, 2257. (e) Horne, W. S.; Olsen, C. A.; Beierle, J. M.; Montero, A.;
Ghadiri, M. R. Angew. Chem., Int. Ed. 2009, 48, 4718. (f) Crich, D.; Yang,
F. Angew. Chem., Int. Ed. 2009, 48, 8896. (g) Takasu, K.; Azuma, T.;
Takemoto, Y. Tetrahedron Lett. 2010, 51, 2737. For selected applica-
tions in material science, see:(h) Qin, A. J.; Lam, J. W. Y.; Jim, C. K. W.;
Zhang, L.; Yan, J. J.; Haussler, M.; Liu, J. Z.; Dong, Y. Q.; Liang, D. H.;
Chen, E. Q.; Jia, G. C.; Tang, B. Z. Macromolecules 2008, 41, 3808. (i)
Nulwala, H.; Takizawa, K.; Odukale, A.; Khan, A.; Thibault, R. J.; Taft,
B. R.; Lipshutz, B. H.; Hawker, C. J. Macromolecules 2009, 42, 6068. (j)
Brady, S. E.; Shultz, G. V.; Tyler, D. R. J. Inorg. Organomet. Polym. Mater.
2010, 20, 511. For a review on click polymers, see:(k) Qin, A. J.; Lam,
J. W. Y.; Tang, B. Z. Chem. Soc. Rev. 2010, 39, 2522.
2
116.3 (d, JCF = 21.9 Hz), 52.0; HRMS (ESI-TOF) calcd for
C15H13FN3þ (M þ H) 254.1093, found 254.1083.
2-(1-(3-(Trifluoromethyl)benzyl)-1H-1,2,3-triazol-5-yl)-
pyridine (14): Following general procedure B with use of 1-
(chloromethyl)-3-(trifluoromethyl)benzene (60.8 μL, 0.40 mmol),
sodium azide (26.0 mg, 0.40 mmol), and 2-ethynylpyridine (20.6 μL,
0.20 mmol) provided 2-(1-(3-(trifluoromethyl)benzyl)-1H-1,2,3-tria-
zol-5-yl)pyridine (14) as a yellowish oil. Yield 37.4 mg (61%, purity
99%); 1H NMR (400 MHz, CDCl3) δ 8.69-8.66 (m, 1H), 8.04 (s, 1H),
7.78-7.72 (m, 1H), 7.60-7.56 (m, 2H), 7.50-7.43 (m, 2H), 7.37 (t, J =
7.7 Hz, 1H), 7.31-7.27 (m, 1H), 6.21 (s, 2H); 13C NMR (101 MHz,
CDCl3) δ 149.6, 146.8, 137.4, 137.2, 135.7, 133.8, 131.5 (q, 4JCF = 1.3 Hz),
130.9 (app d, 2JCF = 32.4 Hz), 129.2, 125.2 (q, 3JCF = 3.9 Hz), 124.9 (q, 3JCF
= 3.8 Hz), 124.0 (app d, 1JCF = 272.3 Hz), 123.7, 122.9, 52.9; HRMS (ESI-
TOF) calcd for C15H12F3N4þ (M þ H) 305.1014, found 305.1009.
(6) Kwok, S. W.; Fotsing, J. R.; Fraser, R. J.; Rodionov, V. O.; Fokin,
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(8) (a) Maksikova, A. V.; Serebraykova, E. S.; Tikhonova, L. G.;
Vereschchagin, L. I. Chem. Heterocycl. Compd. 1980, 1284. (b) Feldman,
A. K.; Colasson, B.; Fokin, V. V. Org. Lett. 2004, 6, 3897. (c)
Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; Van der Eycken, E. Org.
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’ ASSOCIATED CONTENT
Supporting Information. Copies of H NMR and 13C
1
S
b
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
(9) Daniels, M.; Kirss, R. U. J. Organomet. Chem. 2007, 692, 1716.
(10) Khan, M. M. T.; Bhadbhade, M. M.; Siddiqui, M. R. H.;
Venkatasubramanian, K.; Tikhonova, J. A. Acta Crystallogr., Sect. C:
Cryst. Struct. Commun. 1994, 50, 502.
Corresponding Author
*E-mail: johan.johansson@chalmers.se.
(11) Livingston, R. L.; Rao, C. N. R. J. Phys. Chem. 1960, 64, 756.
’ ACKNOWLEDGMENT
We thank Annika Langborg Weinmann at AstraZeneca R&D
M€olndal for kindly providing us with HRMS data of the products.
We also thank Dr. Thomas Antonsson and Dr. Mikael Sellꢀen for
inspiring discussions. The Swedish NMR Centre is acknowl-
edged for the use of high field NMR instruments. We thank Dr.
Mate Erdelyi for advice concerning NOESY experiments. This
work was funded by King Abdullah University of Science and
Technology (KAUST).
’ REFERENCES
(1) Tornoe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
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