Regiospecific synthesis of 1,4,5-trisubstituted-1,2,3-triazole via one-pot reaction promoted by copper(I) salt

Article abstract of DOI:10.1055/s-2005-861860

A method for the regiospecific synthesis of 1,4,5-trisubstituted-1,2,3- triazole catalyzed by copper(I) iodide was developed. This is the first example of a regiospecific synthesis of 5-iodo-1,4-disubstituted-1,2,3-triazole, which can be further elaborated to a range of 1,4,5-trisubstituted-1,2,3-triazole derivatives. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-861860

1314
PAPER
Regiospecific Synthesis of 1,4,5-Trisubstituted-1,2,3-triazole via One-Pot
Reaction Promoted by Copper(I) Salt
1
,4,5-Trisubstitute
o
d-1,2,3-triazo
n
le via
O
ne-P
g
ot Reaction
-
Promote
M
d
by
C
opper(I) Salt ing Wu,* Juan Deng, Ya Li, Qing-Yun Chen
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Rd., Shanghai 200032, P. R. China
Fax +86(21)64166128; E-mail: ymwu@mail.sioc.ac.cn
Received 29 November 2004; revised 6 January 2005
Considering the proposed mechanism of Cu(I)-catalyzed
reaction of organo-azides with terminal alkynes, an inter-
mediate of Cu(I) salt of 1,2,3-triazole A was proposed.6a,7
It is reasonable to suggest that the intermediate A could be
trapped by electrophiles (Scheme 1).
Abstracts: A method for the regiospecific synthesis of 1,4,5-trisub-
stituted-1,2,3-triazole catalyzed by copper(I) iodide was developed.
This is the first example of a regiospecific synthesis of 5-iodo-1,4-
disubstituted-1,2,3-triazole, which can be further elaborated to a
range of 1,4,5-trisubstituted-1,2,3-triazole derivatives.
Key words: fluoroalkyl-1,4,5-trisubstituted-1,2,3-triazole, one-pot
reaction, regiospecific synthesis, fluoroalkylazide, terminal alkyne,
1,3-dipolar cycloaddition
N
N
R1
N
N
R1
N
N
?
+
E
R2
E
R2
Cu
A
[1,2,3]-Triazoles have been widely used in pharmaceuti-
cals, agrochemicals, dyes, photographic materials, and in
corrosion inhibition.1 For example, there are numerous re-
ports in the literature including anti-HIV activity,2 antimi-
crobial activity against Gram positive bacteria,3 and
selective b3 adrenergic receptor agonism of triazole com-
pounds.4 Due to their potential usefulness, several syn-
thetic methods have been developed for the construction
of triazole frameworks. Among them, the most important
and useful method is the 1,3-dipolar cycloaddition of
azide with alkyne.5 Two problems are, however, encoun-
tered in this transformation: (1) reactivity of the sub-
strates, either alkynes or azides require be activation by an
electron-withdrawing group, otherwise, the reaction must
be carried out at a higher temperature; (2) the regioselec-
tivity of the products, for unsymmetrical alkynes, a mix-
ture of regioisomers is obtained in most cases. Since
Sharpless reported a method of regioselective synthesis of
1,2,3-triazoles using Cu(I) salt as catalysis,6a this field has
become more and more active, several groups have re-
ported their results on this subject by employing different
kinds of Cu(I) salts as catalyst recently.6 We recently re-
ported a method for the regioselective synthesis of fluoro-
alkylated 1,4-disubstituted-1,2,3-triazoles catalyzed by
Cu(I) iodide.7 In this paper, we would like to report a con-
venient method for the regiosepecific synthesis of 1,4,5-
trisubstituted-1,2,3-triazoles by an one-pot reaction strat-
egy.
Scheme 1
The reaction of 2,2,3,3-tetrafluoropropylazide 1b with
phenylacetylene 2a (Scheme 2) under various conditions
was examined. The results are summarized in Table 1.
When iodine was used as an electrophilic trapping re-
agent, two products were isolated, which were separated
conveniently by flash column chromatography. The struc-
Table 1 Results of the Reaction of Organo-azide with Terminal
Alkyne in the Presence of Electrophiles
Entry Conditionsa
Yieldb (%)
3ba
42
42
50
80
14
4
4
1
2
3
4
5
6
7
CuI (1 equiv), I2, CH3CN, Et3N (5 equiv)
48
CuI (1 equiv), I2, THF, Et3N (5 equiv)
CuI (1 equiv), ICl, CH3CN, Et3N (5 equiv)
CuI (1 equiv), ICl, THF, Et3N (5 equiv)
CuI (0.2 equiv), ICl, THF, Et3N (5 equiv)
CuI (0.1 equiv), ICl, THF, Et3N (5 equiv)
CuI (1 equiv), ICl, THF, Et3N (1.2 equiv)
19
30
14
6
trace
trace
77
a All reactions were performed at r.t.
b Isolated yield.
N
N
+
HCF2CF2CH2
N
I
N
HCF2CF2CH2
N
N
HCF2CF2CH2N3
+
Ph
Ph
H
Ph
1b
2a
3ba
4
Scheme 2 Reaction of organo-azide with terminal alkyne in the presence of electrophiles.
SYNTHESIS 2005, No. 8, pp 1314–1318
x
x
.
x
x
.2
0
0
5
Advanced online publication: 09.03.2005
DOI: 10.1055/s-2005-861860; Art ID: F17604SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
1,4,5-Trisubstituted-1,2,3-triazole via One-Pot Reaction Promoted by Copper(I) Salt
1315
Table 2 Results of the Reaction of Azides with Terminal Alkynes
tures of them were easily determined by NMR and mass
spectroscopy and were shown to be iodotriazole 3ba and
triazole 4, respectively. The yields of 3ba are not satisfac-
tory probably due to the low electrophilicity of iodine in
THF or acetonitrile (entries 1, 2). This yield was dramati-
cally increased when ICl was used as an electrophile in
THF (up to 80%, entry 4). A stoichiometric amount of CuI
was required, otherwise, low conversion yields were ob-
served (entries 5, 6); triethylamine is also required.
Entry Azides (R1)
Alkynes (R2)
Ph
Product Yielda (%)
1
2
CF3CH2
3aa
3ab
3ac
3ad
3ba
3bb
3bc
3bd
3ca
3cc
3cd
3da
3dc
3ea
48
61
82
73
77
63
74
74
48
78
81
72
72
34
CF3CH2
C4H9
3
CF3CH2
CO2-allyl
CONH-allyl
Ph
4
CF3CH2
5
HCF2CF2CH2
HCF2CF2CH2
HCF2CF2CH2
HCF2CF2CH2
CF3(CF2)5CH2
CF3(CF2)5CH2
CF3(CF2)5CH2
PhCH2
The scope of this transformation is partly revealed by the
examples in Table 2 and Scheme 3. As can be seen in
Table 2, it was found that the reaction can be adapted to
many different substrates, the azide may be substituted by
2,2-dihydropolyfluoroalkyl groups (entry 1, 2, 3 etc.),
benzyl group (entry 12, 13), and alkyl group (entry 14).
The alkynes may be substituted by aromatic, alkyl, ester,
and amide groups. The yield of this transformation is
moderate to good.
6
C4H9
7
CO2-allyl
CONH-allyl
Ph
8
9
10
11
12
13
14
CO2-allyl
CONH-allyl
Ph
CuI (1 equiv), Et3N
N
R1
N
N
ICl, THF
R2
R1N3
+
r.t., 20 h
I
R2
PhCH2
CO2-allyl
Ph
1
2
3
C8H17
R1
R2
2a Ph
1a CF3CH3
a Isolated yield.
1b H(CF)2CH2
1c n-C6F13CH2
1d PhCH2
2b n-C4H9
2c CO2-allyl
2d CONH-allyl
N
R1
N
N
1e n-C8H17
CuI, Et3N, THF, r.t.
R1N3
+
+
Ph
R3
X
Scheme 3 Synthesis of 5-iodo-1,4-disubstituted-1,2,3-triazoles.
R3
Ph
1
6
7
It was interesting to note that with two terminal triple
bonds on the substrate, the reaction with two equivalents
of azide, resulted in bis-1,2,3-triazole compound 5 in 76%
yield (Scheme 4).
R3-X
R1
6a CH2=CHCH2Br,
6b PhCOCl,
6c CH3COCl.
1b HCF2CF2CH2
1d PhCH2
Scheme 5 Synthesis of 2,4,5-trisubstituted-1,2,3-triazoles.
Other electrophiles were also examined in this trapping
reaction. It was found that under the same reaction condi-
tions, when 2.5 equivalents of allyl bromide were used as
an electrophile, three products were obtained: the desired
product 5-allyl-1,2,3-triazoles 7 (46%); as well as two ad-
ditional products 5-iodo 3 (6%) and 4 (42%), 3 was
formed by the reaction of Cu(I) salt intermediate of 1,2,3-
triazole A with I2 which was present as an impurity in
Cu(I) iodide, while 4 was the hydrolysis product of A. It
was interesting to note that in the presence of 4 Å molec-
ular sieve a 63% yield of 5-allyl-1,4-disubstituted-1,2,3-
triazole 7 was obtained. Acylation took place simulta-
neously when benzoyl chloride or acetyl chloride was
added to the reaction system, the results are listed in
Scheme 5 and Table 3. Unfortunately only moderate
yields resulted, while other electrophiles such as trimeth-
ylsilyl chloride, ethyl chloroformate, methylsulfonyl
chloride, benzyl bromide, and butyl bromide did not un-
dergo a similar transformation under the same reaction
conditions probably due to their low electrophilicity.
1
All compounds were characterized by H NMR, 19F
NMR, IR spectroscopy, mass spectroscopy, and elemental
analysis and their structure determined on the basis of our
previous paper.7
Based on our previous paper,7 the reaction mechanism for
the formation of 1,4-disubstituted 1,2,3-triazole is that
proposed in Scheme 6. Cu(I) first inserts into the terminal
alkyne, forming copper(I) acetylide I, which then reacts
with fluoroalkyl azide to form the intermediate of Cu(I)
salt of 1,2,3-triazole A; this intermediate A is trapped by
ICl and other electrophiles to form the final products 3 or
7. As the catalyst Cu(I) iodide was transformed to Cu(I)
N
N
76%
HCF2CF2CH2
N
I
N
N
N CH2CF2CF2H
I
O
HCF2CF2CH2N3
+
O
O
O
5
Scheme 4
Synthesis 2005, No. 8, 1314–1318 © Thieme Stuttgart · New York

1316
Y.-M. Wu et al.
PAPER
crude product was purified by flash chromatography on a silica gel
column (hexane–EtOAc, 5:1) as eluent.
Table 3 Results of Synthesis of 2,4,5-Trisubstituted-1,2,3-triazoles
Entry Azide (R1) R3-X
Product 7 Yield (%)
5-Iodo-4-phenyl-1-(2,2,2-trifluoroethyl)-1H-[1,2,3]triazole
(3aa)
White solid; mp 164–165 °C.
IR: 1100, 1189, 1400, 1447 cm–1.
1H NMR: d = 5.10 (q, J = 8 Hz, 2 H), 7.41–7.54 (m, 3 H), 7.93–7.98
1
2
3
4
5
6
HCF2CF2CH2
PhCH2
7ba
7da
7bb
7db
7bc
7dc
63a
62a
57a
61a
34b
27b
Br
Br
HCF2CF2CH2
PhCH2
PhCOCl
PhCOCl
CH3COCl
CH3COCl
(m, 2 H).
19F NMR: d = –69.71 (t, J = 8 Hz, 3 F).
MS: m/z (%) = 353 (M+, 7), 325 (42), 242 (41), 198 (51), 89 (100).
HCF2CF2CH2
PhCH2
Anal. Calcd for C10H7F3IN3: C, 34.02; H, 2.00; N, 11.90; F, 16.14.
Found: C, 34.03; H, 2.22; N, 11.91; F, 16.48.
a Isolated yield.
b Mixture with iodotriazole, determined by 1H NMR.
4-Butyl-5-iodo-1-(2,2,2-trifluoroethyl)-1H-[1,2,3]triazole (3ab)
White solid; mp 57–58 °C.
IR: 1120, 1169, 1397, 1525, 2322, 2967, 3018 cm–1.
CuI
R2
CuLn
R2
H
1H NMR: d = 0.96 (t, J = 7 Hz, 3 H), 1.34–1.47 (m, 2 H), 1.65–1.77
(m, 2 H), 2.70 (t, J = 8 Hz, 2 H), 5.99 (q, J = 8 Hz, 2 H).
I
N
R1
N
N
R1-N3
R2
CuLn
19F NMR: d = –69.99 (t, J = 8 Hz, 3 F).
MS: m/z (%) = 333 (M+, 1), 262 (97), 206 (50), 178 (19), 136 (100).
LnCu
R2
I
A
Anal. Calcd for C8H11F3IN3: C, 28.85; H, 3.33; N, 12.62; F, 17.11.
Found: C, 28.87; H, 3.35; N, 12.57; F, 17.20.
N
R1
LnCu
N
N
N
ICl
R1
N
I
N
+
CuCl
R2
Allyl 5-Iodo-1-(2,2,2-trifluoroethyl)-1H-[1,2,3]triazole-4-car-
boxylate (3ac)
R2
A
White solid; mp 103–104 °C.
IR: 1114, 1178, 1266, 1519, 1720, 2976, 3020 cm–1.
Scheme 6 The mechanism of the synthesis of 1,4,5-trisubstituted-
1,2,3-triazoles.
1H NMR: d = 4.92 (d, J = 5 Hz, 2 H), 5.11 (q, J = 8 Hz, 2 H), 5.34
(d, J = 11 Hz, 1 H), 5.48 (d, J = 17 Hz, 1 H), 6.00–6.14 (m, 1 H).
19F NMR: d = –69.61 (t, J = 8 Hz, 3 F).
chloride, a stoichiometric amount of CuI was required in
this reaction.
MS: m/z (%) = 360 (M+ – 1, 4), 276 (7), 233 (15), 153 (49), 41 (100).
In conclusion, we have developed a convenient one-pot
method for the regiospecific synthesis of 1,4,5-trisubsti-
tuted-1,2,3-triazoles catalyzed by Cu(I) iodide; this meth-
od can be used to synthesize different multiple substituted
1,2,3-triazole derivatives, which might be used in many
different areas. This result also confirmed the existence of
Cu(I) salt of 1,2,3-triazole A. Furthermore the iodo group
of 5-iodo-1,2,3-triazole compounds have the potential to
be transformed into a range of functional groups, and this
research is ongoing.
Anal. Calcd for C8H7F3IN3O2: C, 26.61; H, 1.95; N, 11.64; F, 15.79.
Found: C, 26.51; H, 2.18; N, 11.52; F, 15.29.
Allyl 5-Iodo-1-(2,2,2-trifluoroethyl)-1H-[1,2,3]triazole-4-car-
boxamide (3ad)
White solid; mp 120–121 °C.
IR: 1117, 1178, 1265, 1557, 1652, 2961, 3399 cm–1.
1H NMR: d = 4.09 (t, J = 8 Hz, 2 H), 5.54 (q, J = 8 Hz, 2 H), 5.21
(d, J = 11 Hz, 1 H), 5.30 (d, J = 17 Hz, 1 H), 5.85–5.99 (m, 1 H),
7.25–7.39 (br, 1 H).
19F NMR: d = –69.71 (t, J = 8 Hz, 3 F).
MS: m/z (%) = 360 (M+, 8), 276 (11), 233 (40), 205 (34), 150 (67),
Melting points and boiling points are uncorrected. IR spectra were
obtained with a Perkin-Elmer 983G spectrometer as KBr disks.
NMR spectra were recorded either on a Varian-360L or Bruker
AM-300 spectrometer with CDCl3 as solvent. Chemical shifts were
reported in parts per million relative to TMS as an external standard
56 (100).
Anal. Calcd for C8H8F3IN4O: C, 26.69; H, 2.24; N, 15.56; F, 15.83.
Found: C, 26.67; H, 2.39; N, 15.50; F, 15.67.
1
(d = 0) for H NMR spectra and CFCl3 as an internal standard
(d = 0) for 19F NMR (upfield shift being designated as negative)
spectra. Coupling constants are given in Hertz (Hz). Low- and high-
resolution mass spectra were recorded on a Hewlett-Packard HP-
5989A and a Finnigan MAT spectrometer, respectively. Elemental
analyses were performed at this institute.
5-Iodo-4-phenyl-1-(2,2,3,3-tetrafluoropropyl)-1H-[1,2,3]triaz-
ole (3ba)
White solid; mp 152–153 °C.
IR: 1093, 1236, 1538 cm–1.
1H NMR: d = 5.07 (t, J = 13 Hz, 2 H), 6.04 (tt, J1 = 3 Hz, J2 = 53
Compounds 3; Typical Procedure
Hz, 1 H), 7.42–7.55 (m, 3 H), 7.92–7.99 (m, 2 H).
Under a N2 atmosphere, to a Schlenk tube, fluoroalkylazide (0.5
mmol), terminal alkyne (0.5 mmol), Et3N (0.6 mmol), THF (5 mL),
ICl (0.5 mmol), and CuI (0.5 mmol) were added successively. The
mixture was stirred at r.t. for 20 h. After removal of the solvent, the
19F NMR: d = –136.87 (d, J = 52 Hz, 2 F), –118.68 (t, J = 12 Hz, 2
F).
MS: m/z (%) = 385 (M+, 3), 366 (1), 357 (32), 230 (51), 89 (100).
Synthesis 2005, No. 8, 1314–1318 © Thieme Stuttgart · New York

PAPER
1,4,5-Trisubstituted-1,2,3-triazole via One-Pot Reaction Promoted by Copper(I) Salt
1317
Anal. Calcd for C11H8F4IN3: C, 34.31; H, 2.09; N, 10.91; F, 19.73.
Found: C, 34.16; H, 2.17; N, 10.97; F, 19.88.
19F NMR: d = –126.10 (2 F), –122.83 (4 F), –121.79 (2 F), –114.77
(2 F), –81.00 (3 F).
MS: m/z = 611 (M+).
4-Butyl-5-iodo-1-(2,2,3,3-tetrafluoropropyl)-1H-[1,2,3]triazole
(3bb)
White solid;mp 67–68 °C.
Anal. Calcd for C13H7F13IN3O2: C, 25.55; H, 1.15; N, 6.88; F, 40.42.
Found: C, 25.57; H, 1.09; N, 6.92; F, 40.60.
IR: 1107, 1235, 1437, 2966 cm–1.
Allyl 5-Iodo-1-(2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-
1H-[1,2,3]triazole-4-carboxamide (3cd)
White solid; mp 114–115 °C.
IR: 1151, 1200, 1556, 1655, 3421 cm–1.
1H NMR: d = 4.10 (t, J = 6 Hz, 2 H), 5.15 (t, J = 14 Hz, 2 H), 5.21
(d, J = 9 Hz, 1 H), 5.30 (d, J = 17 Hz, 1 H), 5.86–6.10 (m, 1 H),
7.25–7.39 (br, 1 H).
1H NMR: d = 0.96 (t, J = 7 Hz, 3 H), 1.32–1.46 (m, 2 H), 1.62–1.76
(m, 2 H), 2.70 (t, J = 8 Hz, 2 H), 4.94 (t, J = 13 Hz, 2 H), 5.98 (tt,
J1 = 3 Hz, J2 = 53 Hz, 1 H).
19F NMR: d = –137.14 (d, J = 53 Hz, 2 F), –119.10 (t, J = 13 Hz, 2
F).
MS: m/z (%) = 346 (M+ – 19, 2), 294 (100), 238 (42), 210 (39), 168
(98).
19F NMR: d = –123.12 (2 F), –122.83 (4 F), –121.91 (2 F), –115.13
Anal. Calcd for C9H12F4IN3: C, 29.61; H, 3.31; N, 11.51; F, 20.82.
Found: C, 29.23; H, 3.28; N, 11.32; F, 20.87.
(2 F), –80.96 (3 F).
MS: m/z (%) = 610 (M+, 13), 591 (3), 526 (10), 483 (25), 455 (35),
400 (81), 80 (56), 56 (100).
Allyl 5-Iodo-1-(2,2,3,3-tetrafluoropropyl)-1H-[1,2,3]triazole-4-
carboxylate (3bc)
White solid; mp 75–76 °C.
Anal. Calcd for C13H8F13IN4O: C, 25.59; H, 1.32; N, 9.18; F, 40.48.
Found: C, 25.64; H, 1.36; N, 9.10; F, 40.60.
IR: 1108, 1226, 1518, 1718, 3012 cm–1.
1H NMR: d = 4.89–4.92 (m, 2 H), 5.07 (t, J = 14 Hz, 2 H), 5.31–5.51
1-Benzyl-5-iodo-4-phenyl-1H-[1,2,3]triazole (3da)
White solid; mp 128–129 °C.
(m, 2 H), 5.81–6.18 (m, 2 H).
19F NMR: d = –136.19 (d, J = 52 Hz, 2 F), –117.96 (t, J = 14 Hz, 2
F).
IR: 1155, 1230, 1446, 3031 cm–1.
1H NMR: d = 5.72 (s, 2 H), 7.32–7.53 (m, 8 H), 7.94–8.00 (m, 2 H).
MS: m/z (%) = 361 (M+, 2), 234 (6), 206 (39), 91 (100).
MS: m/z = 393 (M+).
Anal. Calcd for C15H12IN3: C, 49.88; H, 3.35; N, 11.63. Found: C,
49.79; H, 3.42; N, 11.65.
Anal. Calcd for C9H8F4IN3O2: C, 27.50; H, 2.05; N, 10.69; F, 19.33.
Found: C, 27.44; H, 2.28; N, 10.62; F, 19.40.
Allyl 1-Benzyl-5-iodo-1H-[1,2,3]triazole-4-carboxylate (3dc)
White solid; mp 85–86 °C.
1H NMR: d = 4.87–4.89 (m, 2 H), 5.29–5.33 (m, 1 H), 5.41–5.48 (m,
1 H), 5.68 (s, 2 H), 5.99–6.10 (m, 1 H), 7.25–7.31 (m, 2 H), 7.32–
7.37 (m, 3 H).
Allyl 5-Iodo-1-(2,2,3,3-tetrafluoropropyl)-1H-[1,2,3]triazole-4-
carboxamide (3bd)
White solid;mp 114–115 °C.
IR: 1117, 1258, 1557, 1646, 2959, 3382 cm–1.
1H NMR: d = 4.07–4.13 (m, 2 H), 5.05 (t, J = 14 Hz, 2 H), 5.19–5.33
(m, 2 H), 5.80–6.18 (m, 2 H).
19F NMR: d = –136.12 (d, J = 53 Hz, 2 F), –117.95 (t, J = 14 Hz, 2
F).
MS: m/z (%) = 369 (M+, 1), 242 (13), 91 (100).
Anal. Calcd for C13H12IN3O2: C, 42.30; H, 3.28; N, 11.38. Found:
C, 42.23; H, 3.27; N, 11.30.
MS: m/z (%) = 392 (M+, 11), 265 (47), 237 (31), 182 (100), 51 (38).
5-Iodo-1-octyl-4-phenyl-1H-[1,2,3]triazole (3ea)
White solid; mp 76–77 °C.
IR: 1153, 1227, 1447, 2919 cm–1.
Anal. Calcd for C9H9F4IN4O: C, 27.57; H, 2.31; N, 14.29; F, 19.38.
Found: C, 27.71; H, 2.37; N, 14.14; F, 19.14.
1H NMR: d = 0.90 (m, 3 H), 1.23–1.45 (m, 10 H), 1.95–2.00 (m, 2
H), 4.45 (t, J = 7 Hz, 2 H), 7.41–7.51 (m, 3 H), 7.93–7.97 (m, 2 H).
MS: m/z (%) = 383 (M+, 6), 243 (100), 228 (41), 116 (88), 91 (54).
5-Iodo-4-phenyl-1-(2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluorohep-
tyl)-1H-[1,2,3]triazole (3ca)
White solid; mp 164–165 °C.
IR: 1139, 1209, 3024 cm–1.
1H NMR: d = 5.20 (t, J = 14 Hz, 2 H), 7.40–7.60 (m, 3 H), 7.92–8.03
Anal. Calcd for C16H22IN3: C, 50.14; H, 5.49; N, 10.96. Found: C,
50.25; H, 5.69; N, 10.85.
(m, 2 H).
5-Iodo-1-(2,2,3,3-tetrafluoropropyl)-1H-[1,2,3]triazol-4-yl-
methyl 5-iodo-1-(2,2,3,3-tetrafluoropropyl)-1H-[1,2,3]triazole-
4-carboxylate (5)
19F NMR: d = –126.36 (2 F), –123.27, –122.92 (4 F), –121.91 (2 F),
–115.14 (2 F), –80.96 (3 F).
White solid; mp 185–186 °C.
IR: 1100, 1202, 1423, 1513, 1741, 3015 cm–1.
1H NMR: d = 5.20–5.41 (m, 4 H), 5.50 (s, 2 H), 6.37–6.78 (m, 2 H).
MS: m/z (%) = 603 (M+, 1), 575 (20), 448 (29), 242 (35), 89 (100).
Anal. Calcd for C15H7F13IN3: C, 29.87; H, 1.17; N, 6.97; F, 40.95.
Found: C, 29.91; H, 1.46; N, 7.14; F, 41.03.
19F NMR: d = –139.09 (d, J = 52 Hz, 4 F), –121.11, –120.77 (m, 4
F).
MS: m/z (%) = 675 (M+ + 1, 1), 519 (15), 336 (27), 308 (98), 294
(83), 167 (80), 80 (64), 51 (100).
Allyl 5-Iodo-1-(2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-
1H-[1,2,3]triazole-4-carboxylate (3cc)
White solid; mp 133–134 °C.
IR: 1140, 1229, 1522, 1730 cm–1.
1H NMR: d = 4.94–4.97 (m, 2 H), 5.21 (t, J = 14 Hz, 2 H), 5.36–5.50
Anal. Calcd for C12H8F8I2N6O2: C, 21.38; H, 1.20; N, 12.47; F,
22.55. Found: C, 21.41; H, 1.32; N, 12.45; F, 22.75.
(m, 2 H), 5.05–6.17 (m, 1 H).
Synthesis 2005, No. 8, 1314–1318 © Thieme Stuttgart · New York

1318
Y.-M. Wu et al.
PAPER
Compounds 7; Typical Procedure
4-Acetyl-5-phenyl-3-(2,2,3,3-tetrafluoropropyl)-3H-[1,2,3]tria-
zole (7bc)
1H NMR: d = 2.82 (s, 3 H), 5.40 (t, J = 14 Hz, 2 H), 5.96 (tt, J1 = 52
Hz, J2 = 3 Hz, 1 H), 7.40–7.60 (m, 5 H).
19F NMR: d = –136.53 (d, J = 52 Hz, 2 F), –119.59 (t, J = 14 Hz,
2F).
Under an N2 atmosphere, to a Schlenk tube, fluoroalkylazide (0.5
mmol), terminal alkyne (0.5 mmol), Et3N (0.6 mmol), THF (5mL),
electrophile (1.25 mmol) and CuI (0.5 mmol) were added succes-
sively. The mixture was stirred at r.t. for 20 h. After removal of sol-
vent, the crude product was purified by flash chromatography on a
silica gel column (hexane–EtOAc, 5:1).
4-Acetyl-3-benzyl-5-phenyl-3H-[1,2,3]triazole (7dc)
1H NMR: d = 2.12 (s, 3 H), 5.87 (s, 2 H), 7.28–7.54 (m, 10 H).
5-Allyl-4-phenyl-1-(2,2,3,3-tetrafluoropropyl)-1H-[1,2,3]tri-
azole (7ba)
White solid; mp 70–71 °C.
1H NMR: d = 3.66–3.70 (m, 2 H), 4.88 (t, J = 14 Hz, 2 H), 4.99 (d,
J = 17 Hz, 1 H), 5.28 (d, J = 10 Hz, 1 H), 5.88–6.03 (m, 1 H), 6.04
(tt, J1 = 53 Hz, J2 = 3 Hz, 1 H), 7.36–7.51 (m, 3 H), 7.62–7.70 (m,
2 H).
Acknowledgment
The authors thank the Science and Technology Commission of
Shanghai Municipality (No. 035211018) and the National Natural
Science Foundation of China (NNSFC) (No. 20472104) for finan-
cial support.
19F NMR: d = –137.36 (d, J = 51 Hz, 2 F), –119.68 (t, J = 14 Hz, 2
F).
MS: m/z (%) = 299 (M+, 23), 270 (86), 170 (78), 156 (42), 129
(100), 115 (52), 89 (45), 77 (31).
References
(1) For reviews see: (a) Fan, W.-Q.; Katrisky, A. R. In
Comprehensive Heterocyclic Chemistry II, Vol. 4; Katrisky,
A. R.; Rees, C. W.; Scriven, C. W. V., Eds.; Elsevier
Science: Oxford, 1996, 1–126. (b) Dehne, H. In Methoden
der organischen Chemie (Houben–Weyl), Vol. E8d;
Schumann, E., Ed.; Thieme: Stuttgart, 1994, 305–405.
(c) Abu-Orabi, S. T.; Alfah, M. A. I.; Jibril Mari’I, F. M.;
Ali, A. A.-S. J. Heterocycl. Chem. 1989, 26, 1461.
(2) Alvarez, R.; Velazquez, S.; San-Felix, A.; Aquaro, S.;
Clercq, E. D.; Perno, C. F.; Karlesson, A.; Balzarini, J.;
Camarasa, M. J. J. Med. Chem. 1994, 37, 4185.
Anal. Calcd for C14H13F4N3: C, 56.19; H, 4.38; N, 14.04; F, 25.39.
Found: C, 56.01; H, 4.36; N, 13.91; F, 25.40.
5-Allyl-1-benzyl-4-phenyl-1H-[1,2,3]triazole (7da)
Colorless liquid.
1H NMR: d = 3.43–3.48 (m, 2 H), 4.93 (d, J = 17 Hz, 1 H), 5.17 (d,
J = 10 Hz, 1 H), 5.55 (s, 2 H), 5.76–5.91 (m, 1 H), 7.17–7.22 (m, 2
H), 7.30–7.49 (m, 6 H), 7.66–7.72 (m, 2 H).
13C NMR: d = 27.05, 52.12, 117.71, 127.22, 127.87, 128.33, 128.67,
128.99, 130.34, 131.39, 132.27, 135.06, 145.86.
(3) Genin, M. J.; Allwine, D. A.; Anderson, D. J.; Barbachyn,
M. R.; Emmert, D. E.; Garmon, S. A.; Graber, D. R.; Grega,
K. C.; Hester, J. B.; Hutchinson, D. K.; Morris, J.; Reischer,
R. J.; Ford, C. W.; Zurenco, G. E.; Hamel, J. C.; Schaadt, R.
D.; Stapert, D.; Yagi, B. H. J. Med. Chem. 2000, 43, 953.
(4) Brockunier, L. L.; Parmee, E. R.; Ok, H. O.; Candelore, M.
R.; Cascieri, M. A.; Colwell, L. F.; Deng, L.; Feeney, W. P.;
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Wyvratt, M. J.; Fisher, M. H.; Weber, A. E. Bioorg. Med.
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MS: m/z (%) = 275 (M+, 8), 246 (2), 156 (100), 91 (82), 77 (18), 57
(96).
HRMS: m/z calcd for C18H17N3, 275.1422; found 275.1417.
4-Benzoyl-5-phenyl-3-(2,2,3,3-tetrafluoropropyl)-3H-[1,2,3]tri-
azole (7bb)
White solid; mp 118–119 °C.
1H NMR: d = 5.33 (t, J = 14 Hz, 2 H), 5.91 (tt, J1 = 53 Hz, J2 = 3 Hz,
1 H), 7.17–7.30 (m, 5 H), 7.36–7.42 (m, 2 H), 7.44–7.51 (m, 1 H),
7.66–7.70 (m, 2 H).
(5) (a) Katritzky, A. R.; Zhang, Y.; Singh, S. K. Heterocycles
2003, 60, 1225. (b) Gothelf, K. V.; Jørgensen, K. A. Chem.
Rev. 1998, 98, 863.
19F NMR: d = –135.86 (d, J = 53 Hz, 2 F), –118.83 (t, J = 15 Hz, 2
F).
(6) (a) Rostovtsev Green, V. V. L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem. Int. Ed. 2002, 41, 2596. (b) Tornfe, C.
W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057. (c) Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.;
Sharpless, K. B.; Finn, M. G. J. Am. Chem. Soc. 2003, 125,
3192. (d) Lober, S.; Rodriguez-Loaiza, P.; Gmeiner, P. Org.
Lett. 2003, 5, 1753. (e) Pérez-Balderas, F.; Ortega-Munoz,
M.; Morales-Sanfrutos, J.; Hernández-Mateo, F.; Calvo-
Flores, F. G.; Calvo-Asín, J. A.; Isac-García, J.; Santoyo-
González, F. Org. Lett. 2003, 5, 1951. (f) Krasinski, A.;
Fokin, V. V.; Sharpless, K. B. Org. Lett. 2004, 6, 1237.
(g) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. J. Am. Chem.
Soc. 2003, 125, 7786. (h) Kamijo, S.; Jin, T.; Huo, Z.;
Yamamoto, Y. J. Org. Chem. 2004, 69, 2386.
MS: m/z (%) = 363 (M+, 2), 335 (8), 218 (10), 105 (100), 89 (17),
77 (50).
Anal. Calcd for C18H13F4N3O: C, 59.51; H, 3.61; N, 11.57; F, 20.92.
Found: C, 59.30; H, 3.62; N, 11.57; F, 21.00.
(4-Benzoyl-3-benzyl-5-phenyl-3H-[1,2,3]triazole (7db)
White solid; mp 64–65 °C.
1H NMR: d = 5.76 (s, 2 H), 7.15–7.26 (m, 10 H), 7.37–7.45 (m, 3
H), 7.47–7.54 (m, 2 H).
MS: m/z (%) = 339 (M+, 2), 310 (1), 105 (19), 91 (100), 77 (23).
Anal. Calcd for C22H17N3O: C, 77.86; H, 5.05; N, 12.38. Found: C,
77.65; H, 5.04; N, 12.30.
(i) Appukkuttan, P.; Dehaen Fokin Wim, V. V.; Van der
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Synthesis 2005, No. 8, 1314–1318 © Thieme Stuttgart · New York