Copper(I)-catalyzed direct arylation of 1,4-disubstituted 1,2,3-triazoles with aryl iodides

Article abstract of DOI:10.3987/COM-08-11546

Treatment of 1,4-disubstituted 1,2,3-triazoles with aryl iodides in the presence of a catalytic amount of copper chloride and lithium tert-butoxide (stoichiometric) in DMF at 140 °C leads to arylation at the 5-position. Various combinations of substituted

Full text of DOI:10.3987/COM-08-11546

HETEROCYCLES, Vol. 78, No. 3, 2009
645
HETEROCYCLES, Vol. 78, No. 3, 2009, pp. 645 - 655. © The Japan Institute of Heterocyclic Chemistry
Received, 11th September, 2008, Accepted, 15th October, 2008, Published online, 20th October, 2008
DOI: 10.3987/COM-08-11546
COPPER(I)-CATALYZED DIRECT ARYLATION OF
1,4-DISUBSTITUTED 1,2,3-TRIAZOLES WITH ARYL IODIDES
Shin-ichi Fukuzawa,* Eiji Shimizu, and Kenichi Ogata
Department of Applied Chemistry, Institute of Science and Engineering, Chuo
University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan
Abstract – Treatment of 1,4-disubstituted 1,2,3-triazoles with aryl iodides in the
presence of a catalytic amount of copper chloride and lithium tert-butoxide
(stoichiometric) in DMF at 140 °C leads to arylation at the 5-position. Various
combinations of substituted aryl iodides and 1,4-disubstituted 1,2,3-triazoles
bearing functional groups were found to be compatible.
INTRODUCTION
Heteroaromatic compounds such as azoles have received much attention and found wide application in
medicinal chemistry and materials science. Direct arylation of the C–H bonds of heterocycles—i.e.,
functionalization of aromatic heterocycles—is of current interest because it represents a possible
alternative approach to conventional cross-coupling reactions with organometallic reagents and would not
require reactive functional groups such as halogens or metal moieties.1
As 1,2,3-triazoles are often found in biologically active compounds, they are important heterocycles in
medicinal as well as organic chemistry.2 The reaction of terminal alkynes with organic azides gives 1,4-
or 1,5-disubstituted 1,2,3-triazoles using copper and ruthenium catalysts, respectively.3
1,4,5-Trisubstituted 1,2,3-triazoles, which also show biological activity,4 may be prepared by reaction of
internal alkynes, but with a lack of regioselectivity and/or generality.4b, 5 Two traditional cross-coupling
reactions have been proposed for regioselective synthesis of 1,4,5-trisubstituted 1,2,3-triazoles; the
Negishi coupling reaction of 4-metallated (zinc)-1,2,3-triazoles with aryl halides,6 and the Suzuki
coupling reaction of 5-iodo-1,2,3-triazoles with arylboric acids.7 The possibility of taking advantage of
the ready availability of 1,4-disubstituted 1,2,3-triazoles via the copper-catalyzed reaction—i.e., click
chemistry—renders direct arylation with aryl halides preferable. Using this reaction, Gevorgyan reported
palladium-catalyzed direct arylation of 1,2,3-triazoles with aryl bromides.8 Recently, Oshima and
Ackerman independently reported palladium-catalyzed direct arylation of 1,2,3-triazoles with aryl

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HETEROCYCLES, Vol. 78, No. 3, 2009
chlorides using microwave9 and conventional heating,10 respectively, and using tricyclohexylphosphine as
a ligand. These reactions are effective for synthesis of 1,4,5-trisubstituted 1,2,3-triazoles; however, the
development of an inexpensive catalyst to use instead of expensive palladium is desirable. Quite recently,
copper-catalyzed direct arylation of 1,2,3-triazoles has been reported by Ackerman et al. 11 while we are
preparing this paper. We have independently examined similar copper-catalyzed (combination of
CuI/LiOBut/DMF catalyst system)12 direct C-5 arylation of 1,4-disubstituted 1,2,3-triazoles with aryl
iodides and would like to report our original results including preliminary mechanistic considerations.13
RESULTS AND DISCUSSION
At
the outset,
we optimized
the Cu-catalyzed
direct
phenylation
reaction
of
1-benzyl-4-phenyl-1,2,3-triazole 1 with iodobenzene using CuI as a catalyst and LiOBut as a base in
DMF at 140 °C (Scheme 1). The results are shown in Table 1. Analysis of the reaction mixture by
GC/MS revealed the presence of the 5-phenylated product 2 (entry 4). The product was isolated in 74%
yield after purification by preparative TLC. The use of other bases—K2CO3, KOBut, and NaOBut—gave
negligible amounts of the product (entries 1 – 3). Solvents other than DMF were also examined (DMSO,
Table 1. Optimization of Cu-catalyzed direct phenylation of 1-benzyl-4-phenyl-1,2,3-triazole 1 with
iodobenzenea
entry
Cu salt
base
solvent
yield (%)b of 2
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuCl
CuCl
CuBr
CuCN
CuCl2
K2CO3
KOBut
NaOBut
LiOBut
LiOBut
LiOBut
LiOBut
LiOBut
LiOBut
LiOBut
LiOBut
LiOBut
DMF
DMF
DMF
DMF
DMSO
NMP
dioxane
DMF
DMF
DMF
DMF
DMF
0
trace
trace
74
15c
29
12
74
9
75d
73
10
11
12
68
70
a1 (0.5 mmol), PhI (1.5 mmol), solvent (1.0 mL), Cu salt (0.05 mmol), base (1.0 mmol); 140 °C, 12 h.
bIsolated yield. cA diphenylated product was detected by GC/MS. dReaction time 9 h.
NMP, dioxane), but these were found not to be suitable for the reaction (entries 5 – 7). CuCl, CuBr, and
CuCN and even CuCl2 were found to be effective as Cu catalysts for direct arylation, giving the product
in moderate to good yields (entries 8 – 12). When the reaction time was shortened from 12 h to 9 h,

HETEROCYCLES, Vol. 78, No. 3, 2009
647
H
Ph
Ph
Ph
Cu salt (10 mol%)
N
N
PhI, solvent, base
140 oC, 12 h
N
N
Bn
Bn
N
N
1
2
Scheme 1
a good yield was still obtained (entry 9). The corresponding reactions with chloro- and bromobenzene did
not proceed, and unreacted 1 was recovered.
After optimizing the reaction conditions, we then examined the scope with respect to aryl iodides; the
results of these experiments are summarized in Table 2. It is notable that in the reaction of 1 with
iodobenzene, small amounts (2 – 3%) of diphenylated product (probably both 4- and benzylic phenylated
product) were often detected by GC/MS analysis. In order to prevent the diphenylation reaction,
1-n-octyl-4-phenyl-1,2,3-triazole 3 was used as a 1,4-disubstituted triazole for the coupling reaction. The
reactions of 3 with various aryl iodides were carried out under optimized conditions, using CuCl/LiOBut
in DMF at 140 °C for 9 h (CuCl was the choice of catalyst for economical reasons). The coupling
reactions with o-, m-, and p-iodotoluene and 1-iodo-3,5-xylene proceeded smoothly to give the
corresponding 5-arylated products 4 in excellent yields (entries 2 – 5). p-Iodoanisole also reacted with 3
to give the product in high yield (entry 6). In contrast, the reaction with halogeno-substituted
iodobenzenes gave the corresponding products in low to moderate yields (entries 8 – 10).
Coupling with p-bromoiodobenzene occurred chemoselectively at the iodo-substituted carbon with
moderate yield (entry 10), while the reaction with p-trifluoromethyl iodobenzene gave a low yield (entry
11). These results may suggest that the reactivity of electron-rich iodobenzene was high enough to give
the corresponding coupling products in satisfactory yields, while electron-deficient aryl iodides tended to
show lower reactivity toward the coupling reaction. Indeed, the reactions with methyl o-iodobenzoate and
p-iodoacetophenone gave negligible amounts of the relevant coupling products (entries 13 – 14), while
the use of p-iodo-N,N-dimethylaniline gave the product in good yield (entry 7). It is surprising that the
coupling reaction with 2-bromopyridine proceeded to give the corresponding product in moderate yield
despite the fact that the reaction with bromobenzene did not proceed (entry 12).
The scope of the reaction with respect to 1,4-disubstituted 1,2,3-triazole 5 (Scheme 2) is shown in Table 3.
Investigation of phenylation reactions of 1-n-octyl-4-alkyl- or 4-aryl-substituted 5 (R1 = n-octyl) showed
that the reactions with these substrates were successful, giving the corresponding products in high yield
(entries 1, 3 – 7). The reaction with the 4-TMS derivative was the exception, giving a low yield, probably
due to the steric hindrance (entry 2). The presence of an electron-donating or withdrawing group as a
substituent of the phenyl group did not significantly affect the yield. The reaction with 1-substituted
1,2,3-triazole gave the the 5-arylated product as a single product showing that arylation occurred at only

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HETEROCYCLES, Vol. 78, No. 3, 2009
Table 2. Scope of the phenylation reaction with aryl iodidesa
H
Ph
Ar
Ph
CuCl (10 mol%)
ArI, DMF, LiOBut
140 oC, 9 h
N
N
N
N
Oct
Oct
N
N
3
4
ArI
ArI
entry
4
yield (%)b
entry
4
yield (%)b
F
1
4a
4b
98
99
8
9
67
4h
I
I
I
Me
2
49
4i
F
I
Me
3
4
4c
4d
95
99
10
11
4j
64
30
Br
I
I
I
4k
Me
F3C
I
N
5
6
7
4e
4f
80
99
96
12
13
14
54
4l
I
I
Br
Me
4m
4n
0c
MeO
I
O
CO2Me
d
4g
–
Me2N
I
I
a3 (0.5 mmol), ArI (1.5 mmol), DMF (1.0 mL), CuCl (0.05 mmol), LiOBut (1.0 mmol).
bIsolated yield. cAcetophenone was detected (~10%). dThe coupling product was detected (~3%).
C-5 position (entry 8). The reactions with 1-p-methylphenyl derivatives bearing a phenyl or n-butyl group
at the 4-position were also successful, giving the corresponding products in reasonable yields (entries 9 –
10). Combining these results with those shown in Table 1, it can be seen that the reaction does not favor
any particular substituents at the 1- and 4-positions of the starting 1,4-disubstituted 1,2,3-triazoles: any
substituents may be compatible with the reaction.

HETEROCYCLES, Vol. 78, No. 3, 2009
649
H
R2
Ph
R2
CuCl (10 mol%)
PhI, DMF, LiOBut
140 oC, 9 h
N
N
N
N
R1
R1
N
N
5
6
Scheme 2
Table 3. Scope of the phenylation reaction with respect to 1,4-disubstituted-1,2,3-triazole 5a
entry
R1
R2
6
yield (%)b
1
2
3
4
5
6
7
8
9
10
Oct
Oct
Oct
Oct
Oct
Oct
Oct
Oct
n-Bu
TMS
6a
6b
6c
6d
6e
6f
6g
6h
6i
81
23
91
63
99
99
99
91
73
84
p-MeC6H4
ferrocenyl
p-CF3C6H4
o-FC6H4
p-FC6H4
H
p-MeC6H4
p-MeC6H4
Ph
n-Bu
6j
a3 (0.5 mmol), PhI (1.5 mmol), DMF (1.0 mL), CuCl (0.05 mmol), LiOBut (1.0 mmol).
bIsolated yield.
The reaction presumably proceeds via deprotonation at C-5 position by LiOBut followed by cupration via
lithium-copper transmetallation; coupling of the resulting organocopper species with aryl iodide leads to
the corresponding 5-aryl 1,2,3-triazole (Scheme 3).14 An electrophilic mechanism may be ruled out
because the reaction was not affected by the presence of C-4 electron-rich and -poor substituents. Kinetic
isotope effect was examined in the reaction of iodobenzene with C-5-deuterated 1,2,3-triazole. No isotope
effect was observed suggesting that C-H activation mechanisms is not plausible in the reaction.8
H
Ph
Ar
Ph
N
N
N
N
R
R
N
+
N
Cu(I)
LiOBut
Ar
R
I
Cu
Ph
Cu
Ph
N
N
R
N
N
N
N
ArI
Scheme 3

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HETEROCYCLES, Vol. 78, No. 3, 2009
In conclusion, the copper-catalyzed reaction of 1,4-disubstituted 1,2,3-triazoles with aryl iodides was
examined. The reaction with electron-rich aryl iodides gave the corresponding 1,4,5-trisubstituted
1,2,3-triazoles in a good yield, but the reaction with electron-poor aryl iodides gave the coupling products
in low yield. Several types of the starting 1,4-disubstituted 1,2,3-triazoles bearing various substituents
were used successfully.
EXPERIMENTAL
1
General. H- and 13C-NMR spectra were recorded using a Varian Mercury 300 NMR (300 MHz)
spectrometer as solutions in CDCl3. The chemical shifts are reported in δ units downfield from the
internal reference, Me4Si. The GC/MS analyses were carried out using a Hewlett-Packard 5975B/6890N
instrument equipped with a capillary column (helium as carrier gas). Flash column chromatography was
performed on a Yamazen YFLC-254 equipped with a UV detector using Merck Silica Gel 60. Preparative
TLC was conducted using a 20 x 20 cm glass sheet coated with a 2 mm thick layer of Merck Kieselgel 60
PF254. Starting 1,4-disubsituted 1,2,3-triazoles were prepared by the Sharpless' Cu catalyzed Click reaction
of organic azides with alkynes.3 All commercial aryl iodides are used without further purification.
General procedure for the coupling reaction of triazole with aryl iodide. In a 20 mL Schlenk tube
containing a magnetic stirring bar were charged CuCl (5.0 mg, 0.05 mmol), triazole 3 (129 mg, 0.5
mmol), LiOBut (80.0 mg, 1.0 mmol) and dry DMF (1 mL) under a slight pressure of nitrogen.
p-Iodotoluene (163 mg, 1.5 mmol) was then added using a syringe through the septum with stirring at rt.
The tube was stirred at rt for 5 min and placed in a preheated oil bath (140 °C) for 9 h. The reaction
mixture was allowed to cool to rt and diluted with EtOAc (50 mL). The solution was washed with brine
(25 mL x 2), dried over MgSO4, filtered, and the solvent was removed using a rotary evaporator that left a
yellow residue. The GC/MS analysis revealed the presence of 1,4,5-trisubstituted triazole 4d. The mixture
containing the product was subjected to flash chromatography on silica gel (hexane/EtOAc = 10/1 as
eluent) to afford the pure product. Yield, 172 mg, 99%.
2:White solid; mp 103-104 °C. 1H NMR (CDCl3, 300 MHz) δ 5.39 (s, 2H), 7.00-7.57 (m, 15H); 13C NMR
(CDCl3) δ 52.0, 126.7, 127.4, 127.6, 127.8, 128.1, 128.4, 128.6, 129.1, 129.6, 130,0, 130.9, 133.8, 135.3,
144.5. Anal. Calcd for C21H17N3: C, 81.00; H, 5.50; N, 13.49. Found: C, 80.66; H, 5.54; N, 13.37 EI MS
m/z 311.2.
1
4a: Colorless oil. H NMR (CDCl3, 300 MHz) δ 0.86 (t, 3H, J = 7.0 Hz), 1.20 (m, 10 H), 1.75-1.77 (m,
2H), 4.19 (t, 2H, J = 7.4 Hz), 7.2-7.4 (m, 5H), 7.5-7.6 (m, 5H); 13C NMR (CDCl3) δ 14.0, 22.4, 26.2, 28.7,
28.8, 29.9, 31.5, 48.1, 126.6, 127.4, 128.1, 128.3, 129.2, 129.5, 129.8, 131.0, 133.5, 144.0. ESI HRMS
calcd for C22H27N3 [M+ H] 334.2266, found 334.2307. EI MS m/z 333.2.

HETEROCYCLES, Vol. 78, No. 3, 2009
651
4b: Colorless oil. 1H NMR (CDCl3, 300 MHz) δ 0.86 (t, 3H, J = 7.0 Hz), 1.20 (m, 10 H), 1.70-1.77 (m,
13
2H), 2.00 (s, 3H), 4.03 (dt, 1H, J = 7.4, 13.5 Hz), 4.15 (dt, 1H, J = 7.4, 13.5 Hz), 7.2-7.6 (m, 9H); C
NMR (CDCl3) δ 13.9, 19.4, 22.4, 26.2, 28.7, 28.8, 29.7, 31.5, 47.9, 125.6, 126.6, 127.4, 127.5, 128.4,
129.9, 130.2, 130.8, 131.2, 132.6, 137.7, 143.9. Anal. Calcd for C23H29N3: C, 79.50; H, 8.41; N, 12.09.
Found: C, 79.66; H, 8.54; N, 12.17. EI MS m/z 347.3.
4c: Colorless oil. 1H NMR (CDCl3, 300 MHz) δ 0.85 (t, 3H, J = 7.0 Hz), 1.20 (m, 10 H), 1.73-1.80 (m,
13
2H), 2.40 (s, 3H), 4.17 (t, 2H, J = 7.3 Hz), 7.1-7.6 (m, 7H), 7.5-7.6 (d, 2H); C NMR (CDCl3) δ 14.0,
21.3, 22.5, 26.3, 28.7, 28.9, 30.0, 31.6, 48.1, 126.6, 127.0, 127.4, 128.1, 128.3(C), 128.3(CH), 129.1,
130.3. 131.1, 133.7, 139.1, 143.9. Anal. Calcd for C23H29N3: C, 79.50; H, 8.41; N, 12.09. Found: C, 79.19;
H, 8.73; N, 12.22. EI MS m/z 347.3.
1
4d: Colorless oil. H NMR (CDCl3, 300 MHz) δ 0.86 (t, 3H, J = 7.0 Hz), 1.20 (m, 10 H), 1.75-1.78 (m,
2H), 2.46 (s, 3H), 4.19 (t, 2H, J = 7.3 Hz), 7.18-7.32 (m, 7H), 7.5-7.6 (m, 2H); 13C NMR (CDCl3) δ 13.9,
21.3, 22.4, 26.2, 28.7, 28.8, 29.9, 31.5, 48.0, 124.9, 126.5, 127.3, 128.2, 129.6, 129.9, 131.1, 133.5, 139.5,
143.8. ESI HRMS calcd for C23H29N3 [M+ H] 348.2422, found 348.220. EI MS m/z 347.3.
4e: White solid; mp 54-55 °C. 1H NMR (CDCl3, 300 MHz) δ 0.85 (t, 3H, J = 7.0 Hz), 1.20 (m, 10 H),
1.76-1.81 (m, 2H), 2.36 (s, 6H), 4.17 (t, 2H, J = 7.3 Hz), 6.92 (s, 2H), 7.18 (s, 1H), 7.2-7.3 (m, 3H),
13
7.56-7.59 (m, 2H); C NMR (CDCl3) δ 14.1, 21.2, 22.5, 26.3, 28.7, 28.9, 30.0, 31.6, 48.0, 126.5, 127.4,
127.5, 128.0, 128.3(C), 128.3(CH), 131.2, 133.9. 138.9, 143.8. Anal. Calcd for C24H31N3: C, 79.73; H,
8.64; N, 11.62. Found: C, 79.76; H, 8.74; N, 11.26. EI MS m/z 361.3.
4f: Colorless oil. 1H NMR (CDCl3, 300 MHz) δ 0.86 (t, 3H, J = 7.0 Hz), 1.21 (m, 10 H), 1.77-1.78 (m,
2H), 3.88 (s, 3H), 4.18 (t, 2H, J = 7.3 Hz), 7.02 (d, 2H, J = 8.6 Hz), 7.2-7.3 (m, 5H), 7.57 (d, 2H, J = 6.5
13
Hz); C NMR (CDCl3) δ 14.0, 22.5, 26.3, 28.8, 28.9, 30.0, 31.6, 48.0, 55.3, 114.7, 119.9, 126.6, 127.4,
128.3, 131.2, 133.4, 144.0, 155.7, 160.4. Anal. Calcd for C23H29N3O: C, 76.00; H, 8.04; N, 11.56, O, 4.40.
Found: C, 75.96; H, 8.02; N, 11.64; O, 4.39 EI MS m/z 363.3.
1
4g: Colorless oil. H NMR (CDCl3, 300 MHz) δ 0.86 (t, 3H, J = 7.0 Hz), 1.21 (m, 10 H), 1.77-1.80 (m,
2H), 3.03 (s, 6H), 4.18 (t, 2H, J = 7.3 Hz), 6.78 (d, 2H, J = 8.8 Hz), 7.14 (d, 2H, J = 8.8Hz), 7.2-7.3 (m,
13
3H), 7.61 (d, 2H, J = 6.7 Hz); C NMR (CDCl3) δ 14.0, 22.5, 26.3, 28.8, 28.9, 30.0, 31.6, 40.1, 48.0,
112.3, 114.4, 126.6, 127.1, 128.2, 130.6, 131.6, 134.2, 143.7, 150.7. Anal. Calcd for C24H32N4: C, 76.55;
H, 8.57; N, 14.88. Found: C, 76.66; H, 8.54; N, 14.87. EI MS m/z 376.3.
1
4h: Colorless oil. H NMR (CDCl3, 300 MHz) δ 0.86 (t, 3H, J = 7.0 Hz), 1.21 (m, 10 H), 1.77-1.82 (m,
2H), 4.19 (t, 2H, J = 7.3 Hz), 7.22-7.32 (m, 6H), 7.52-7.58 (m, 3H); 13C NMR (CDCl3) δ 14.0, 22.5, 26.2,

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HETEROCYCLES, Vol. 78, No. 3, 2009
28.7, 28.8, 29.6, 31.5, 48.5, 116.0 (d, JC-F = 15.3 Hz), 116.5 (d, JC-F = 21.1), 124.9 (d, JC-F = 3.9 Hz), 126.5,
127.6, 127.7, 128.4, 130.8, 132.0, 132.1 (d, JC-F = 8.1 Hz), 145.1, 160.0 (d, JC-F = 249.7 Hz). ESI HRMS
calcd for C22H26FN3 [M+ H] 352.2188, found 352.2285. EI MS m/z 351.2.
1
4i: Colorless oil. H NMR (CDCl3, 300 MHz) δ 0.86 (t, 3H, J = 7.0 Hz), 1.20 (m, 10 H), 1.76-1.78 (m,
13
2H), 4.18 (t, 2H, J = 7.3 Hz), 7.18-7.34 (m, 7H), 7.5-7.6 (m, 2H); C NMR (CDCl3) δ 13.9, 22.5, 26.3,
28.7, 28.8, 29.9, 31.5, 48.1, 116.6 (d, JC-F = 21.9 Hz), 124.1 (d, JC-F = 18.7 Hz), 126.6, 127.6, 128.4, 130.8,
131.8 (d, JC-F = 8.3 Hz), 132.5, 144.2, 163.2 (d, JC-F = 250.6 Hz). ESI HRMS calcd for C22H26FN3 [M+ H]
352.2188, found 352.2185. EI MS m/z 351.2.
1
4j: Colorless oil. H NMR (CDCl3, 300 MHz) δ 0.86 (t, 3H, J = 7.0 Hz), 1.20 (m, 10 H), 1.76-1.80 (m,
13
2H), 4.19 (t, 2H, J = 7.3 Hz), 7.21 (d, 2H, J = 8.4 Hz), 7.2-7.3 (m, 5H), 7.66 (d, 2H, J = 8.4 Hz); C
NMR (CDCl3) δ 14.0, 22.5, 26.3, 28.7, 28.9, 30.0, 31.6, 48.2, 124.0, 126.7, 127.0, 127.7, 128.4, 130.6,
131.4, 132.6, 138.5, 144.2. Anal. Calcd for C22H26BrN3: C, 64.08; H, 6.36; N, 10.19. Found: C, 63.86; H,
6.64; N, 10.17. EI MS m/z 411.2, 413.2.
1
4k: Colorless oil. H NMR (CDCl3, 300 MHz) δ 0.86 (t, 3H, J = 7.0 Hz), 1.25 (m, 10 H), 1.74-1.81 (m,
13
2H), 4.25 (t, 2H, J = 7.4 Hz), 7.27-7.32 (m, 3H), 7.47-7.50 (m, 4H), 7.78 (d, 2H, J = 8.1 Hz); C NMR
(CDCl3) δ 14.0, 22.5, 26.3, 28.8, 28.9, 30.1, 31.6, 48.4, 123.6 (q, JC-F = 272.6 Hz), 126.3 (q, JC-F = 3.6 Hz),
126.9, 127.9, 128.5, 130.5, 131.7 (q, JC-F = 33.5 Hz), 132.1, 144.7, 146.9, 155.6. ESI HRMS calcd for
C23H26F3N3 [M+ H] 402.2188, found 402.2260. EI MS m/z 401.2.
4l: Colorless oil. 1H NMR (CDCl3, 300 MHz) δ 0.85 (t, 3H, J = 7.0 Hz), 1.21 (m, 10 H), 1.73-1.80 (m,
13
2H), 4.54 (t, 2H, J = 7.3 Hz), 7.27-7.37 (m, 5H), 7.52 (m, 2H), 7.69 (m, 1H), 8.79 (m, 1H); C NMR
(CDCl3) δ 14.0, 22.5, 26.3, 28.8, 28.9, 30.0, 31.6, 49.1, 123.5, 125.5, 127.7, 127.9, 128.5, 130.9, 132.1,
136.8, 145.3, 148.1, 150.2. Anal. Calcd for C21H26N4: C, 75.41; H, 7.84; N, 16.75. Found: C, 75.16; H,
7.54; N, 16.67. EI MS m/z 334.2.
1
6a: Colorless oil. H NMR (CDCl3, 300 MHz) δ 0.81-0.86 (m, 6H), 1.17-1.34 (m, 12 H), 1.56-1.73 (m,
13
4H), 2.62 (t, 2H, J = 7.8 Hz), 4.19 (t, 2H, J = 7.3 Hz), 7.28 (m, 2H), 7.50 (m, 3H); C NMR (CDCl3) δ
13.6, 13.9, 22.2, 22.4, 24.6. 26.2, 28.7, 28.8, 29.9, 31.5, 31.7, 48.1, 127.9, 128.8, 129.0, 129.4, 147.2,
155.6. Anal. Calcd for C20H31N3: C, 76.63; H, 9.97; N, 13.40. Found: C, 76.56; H, 10.04; N, 13.28. EI MS
m/z 313.3.
1
6b: Colorless oil. H NMR (CDCl3, 300 MHz) δ 0.13 (s, 9H), 0.86 (t, 3H, J = 7.0 Hz), 1.18 (m, 10 H),
13
1.72-1.75 (m, 2H), 4.14 (t, 2H, J = 7.4 Hz), 7.24-7.27 (m, 2H), 7.47-7.53 (m, 3H); C NMR (CDCl3) δ
–0.95, 14.0, 22.5, 26.4, 28.8, 28.9, 30.2, 31.6, 47.6, 126.7, 128.6, 129.0, 129.3, 129.8, 143.2. Anal. Calcd
for C19H31N3Si: C, 69.25; H, 9.48; N, 12.75. Found: C, 68.96; H, 9.74; N, 12.35. EI MS m/z 329.2.

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1
6c: White solid; mp 50-51 °C. H NMR (CDCl3, 300 MHz) δ 0.85 (t, 3H, J = 7.0 Hz), 1.19 (m, 10 H),
1.75-1.78 (m, 2H), 2.29 (s, 3H), 4.18 (t, 2H, J = 7.3 Hz), 7.05 (d, 2H, J = 8.0 Hz), 7.31 (m, 2H), 7.45 (d,
13
2H, J = 8.0 Hz), 7.50 (m, 3H); C NMR (CDCl3) δ 13.9, 21.0, 22.4, 26.2, 28.7, 28.8, 29.9, 31.5, 48.0,
126.5, 128.1, 128.9, 129.1, 129.4, 129.8, 133.1, 137.1, 144.0, 147.2. ESI HRMS Calcd for C23H29N3 [M+
H] 348.2422, found 348.4220. EI MS m/z 347.3.
1
6d: Brown oil. H NMR (CDCl3, 300 MHz) δ 0.85 (t, 3H, J = 7.0 Hz), 1.19 (m, 10 H), 1.7-1.8 (m, 2H),
3.99 (s, 5H), 4.13-4.16 (m, 4H), 4.44 (t, 2H, J = 1.9 Hz), 7.35-7.39 (m, 2H), 7.55-7.58 (m, 3H); 13C NMR
(CDCl3) δ 14.0, 22.5, 26.3, 28.8, 28.9, 29.9, 31.6, 48.1, 66.5, 68.2, 69.2, 75.9, 128.3, 129.0, 129.6, 130.1,
132.2, 143.4. Anal. Calcd for C26H31FeN3: C, 70.75; H, 7.08; N, 9.52. Found: C, 70.66; H, 6.84; N, 9.17
1
6e: White solid; mp 53-54 °C. H NMR (CDCl3, 300 MHz) δ 0.85 (t, 3H, J = 7.0 Hz), 1.25 (m, 10 H),
1.77-1.81 (m, 2H), 4.20(t, 2H, J = 7.4 Hz), 7.33-7.35 (m, 2H), 7.48-7.55 (m, 4H), 7.67 (d, 2H, J = 8.1
Hz); 13C NMR (CDCl3) δ 13.9, 22.4, 26.2, 28.7, 28.8, 29.9, 31.5, 48.2, 124.1 (q, JC-F = 272.7 Hz), 125.2 (q,
JC-F = 3.6 Hz), 126.6, 127.6, 129.4, 129.7, 129.9, 134.5 (d, JC-F = 13.1 Hz), 142.6, 147.2, 155.6. ESI
HRMS calcd for C23H26F3N3 [M+ H] 402.2188, found 402.2260. EI MS m/z 401.2.
1
6f: Colorless oil. H NMR (CDCl3, 300 MHz) δ 0.86 (t, 3H, J = 7.0 Hz), 1.21 (m, 10 H), 1.82 (m, 2H),
4.29 (t, 2H, J = 7.5 Hz), 6.97 (d, 1H, J = 8.9 Hz), 7.15 (d, 1H, J = 7.5 Hz), 7.26-7.28 (m, 3H), 7.45 (m,
3H), 7.61 (d, 1H, J = 7.5 Hz); 13C NMR (CDCl3) δ 13.9, 22.4, 26.2, 28.7, 28.8, 29.8, 31.5, 48.4, 115.6 (d,
JC-F = 21.7 Hz), 118.9 (d, JC-F = 14.5 Hz), 123.9 (d, JC-F = 3.8 Hz), 127.7, 128.7, 129.1, 129.2, 129.7 (d,
JC-F = 8.7 Hz), 131.1 (d, JC-F = 2.4 Hz), 135.4, 146.0, 159.2 (JC-F = 245.8 Hz). ESI HRMS calcd for
C22H26FN3 [M+ H] 352.2188, found 352.2285. EI MS m/z 351.2.
1
6g: White solid; mp 68-69 °C. H NMR (CDCl3, 300 MHz) δ 0.86 (t, 3H, J = 7.0 Hz), 1.20 (m, 10 H),
13
1.76-1.78 (m, 2H), 4.20 (t, 2H, J = 7.3 Hz), 6.92 (t, 2H, 8.8 Hz), 7.26-7.32 (m, 2H), 7.5-7.6 (m, 5H); C
NMR (CDCl3) δ 14.0, 22.5, 26.3, 28.7, 28.9, 30.0, 31.6, 48.2, 115.3 (d, JC-F = 21.6 Hz), 127.2 (d, JC-F
=
2.9 Hz), 127.9, 128.3 (d, JC-F = 8.1 Hz), 129.3, 129.7, 129.8, 133.3, 143.3, 162.2 (d, JC-F = 247.0 Hz). ESI
HRMS calcd for C22H26FN3 [M+ H] 352.2188, found 352.2271. EI MS m/z 351.2.
1
6h: Colorless oil. H-NMR(CDCl3, 300 MHz) δ 0.83 (t, 3H, J = 7.0 Hz), 1.20 (m, 10 H), 1.80-1.85 (m,
2H), 4.32 (t, 2H, J = 7.3 Hz), 7.37 (m, 5H), 7.68 (s, 1H); 13C-NMR (CDCl3) δ 13.9, 22.4, 26.2, 28.6, 28.8,
29.6, 31.4, 48.1, 127.1, 128.5, 128.8, 129.2, 132.8, 137.5. Anal. Calcd for C16H23N3: C, 74.67; H, 9.01; N,
16.33. Found: C, 74.58; H, 8.91; N, 15.97. EI MS m/z 257.2.
6i: White solid; mp 203-205 °C.1H NMR (CDCl3, 300 MHz) δ 2.35 (s, 3H), 7.1-7 .6 (m, 14H); 13C NMR
(CDCl3) δ 21.1, 120.3, 124.9, 127.3, 127.8, 128.4, 129.0. 129.4, 129.7, 130.1, 134.0, 139.0, 144.6. Anal.

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Calcd for C21H17N3: C, 81.00; H, 5.50; N, 13.49. Found: C, 80.79; H, 5.44; N, 13.17. EI MS m/z 311.1.
6j: Colorless oil. White solid; mp 89-90 °C. 1H NMR (CDCl3, 300 MHz) δ 0.88 (t, 3H, J = 7.6 Hz), 1.36
(sext, 2 H, J = 7.6 Hz), 1.71 (quint, 2H, J = 7.6 Hz), 2.34 (s, 3H), 2.73 (t, 2H, J = 7.6 Hz), 7.17 (m, 6H),
13
7.36 (m, 3H); C NMR (CDCl3) δ 13.7, 21.1, 22.4, 24.8. 31.7, 124.6, 127.8, 128.6, 128.7, 129.5, 129.6,
133.7, 134.3, 138.6, 146.1. Anal. Calcd for C19H21N3: C, 78.32; H, 7.26; N, 14.42. Found: C, 78.16; H,
7.44; N, 14.17. EI MS m/z 291.2.
REFERENCES AND NOTES
1. (a) D. Alberico, M. E. Scott, and M. Lautens, Chem. Rev., 2007, 107, 174. (b) T. Satoh and M.
Miura, Chem. Lett., 2007, 36, 200. (c) I. V. Seregin and V. Gevorgyan, Chem. Soc. Rev., 2007, 36,
1173.
2. W.-Q. Fan, ‘Comprehensive Heterocyclic Chemistry II: 1,2,3-Triazoles,’ Vol. 4, ed. by R. C. Storr,
Pergamon: Oxford, 1996; pp. 1-126.
3. (a) H. C. Kolb, M. G. Finn, and K. B. Sharpless, Angew. Chem. Int. Ed., 2001, 40, 2004. (b) L. K.
Rasmussen, B. C. Boren, and V. V. Fokin, Org. Lett., 2007, 9, 5337. (c) L. Zhang, X. Chen, P. Xue,
H. H. Y. Sun, I. D. Williams, K. B. Sharpless, V. V. Fokin, and G. Jia, J. Am. Chem. Soc., 2005, 127,
15998. (d) V. D. Bock, H. Hiemstra, and J. H. van Maarseveen, Eur. J. Org. Chem., 2006, 51.
4. For example for biologically active 1,4,5-trisubstituted 1,2,3-triazoles, inhibitors of tumor necrosi
factor-α (TNT-α) and antagonists for GABA receptors have been reported. (a) J. S. Tullis, J. C.
VanRens, M. G. Natchus, M. P. Clark, B. De, L. C. Hsieh, and M. J. Janusz, Bioorg. Med. Chem,
Lett., 2003, 13, 1665. (b) M. S. Alam, J. Huang, F. Ozoe, F. Matsumura, and Y. Ozoe, Bioorg. Med.
Chem., 2007, 15, 5090.
5. (a) G. L'abbe, Chem. Rev., 1969, 69, 345. (b) Z.-X. Wang and H.-L. Qin, Chem. Commun., 2003,
2450. (c) S. Kamijo, T. Jin, Z. Huo, and Y. Yamamoto, Tetrahedron Lett., 2002, 43, 9707.
6. A. Akao, T. Tsuritani, S. Kii, K. Sato, N. Nonoyama, T. Mase, and N. Yasuda, Synlett, 2007, 31.
7. J. Deng, Y.-M. Wu, and Q.-Y. Chen, Synthesis, 2005, 2730.
8. S. Chuprakov, N. Chernyak, A. S. Dudnik, and V. Gevorgyan, Org. Lett., 2007, 9, 2333.
9. M. Iwasaki, H. Yorimitsu, and K. Oshima, Chem. Asian J., 2007, 2, 1430.
10. L. Ackermann, R. Vicente, and R. Born, Adv. Synth. Catal., 2008, 350, 741.
11. L. Ackermann, H. K. Potukuchi, D. Landsberg, and R. Viente, Org. Lett., 2008, 10, 3081.
12. Daugulis et al. have reported the direct arylation of azoles using CuI/ LiOBut /DMF system. H.-Q.
Do and O. Daugulis, J. Am. Chem. Soc., 2007, 129, 12404.
13. E. Shimizu, H. Murayama, and S. Fukuzawa, Abstracts of Papers, 88th Spring Meeting of the
Chemical Society of Japan, Tokyo, Japan, March, 2008; Abstract 3_H5_51; E. Shimizu and S.

HETEROCYCLES, Vol. 78, No. 3, 2009
655
Fukuzawa, Book of Abstracts, 23rd International Conference on Organometallic Chemistry, Rennes,
France, July, 2008; Abstract P224.
14. T. Yoshizumi, H. Tsurugi, T. Satoh, and M. Miura, Tetrahedron Lett., 2008, 49, 1598.