Ruthenium-catalyzed 1,3-dipolar cycloaddition of trifluoromethylated propargylic alcohols with azides

Article abstract of DOI:10.1016/j.tetlet.2008.04.065

The 1,3-dipolar cycloaddition of trifluoromethylated propargylic alcohols 1 with azides in the presence of catalytic [Cp*RuCl₂]_n afforded exclusively 4-trifluoromethyl-1,4,5-trisubstituted-1,2,3-triazoles 2 in high yields.

Full text of DOI:10.1016/j.tetlet.2008.04.065

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3927–3930
Ruthenium-catalyzed 1,3-dipolar cycloaddition of
trifluoromethylated propargylic alcohols with azides
Chun-Tao Zhang a, Xingang Zhang b, Feng-Ling Qing a,b,
*
a College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Road, Shanghai 201620, China
b Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
Received 1 December 2007; revised 30 March 2008; accepted 1 April 2008
Available online 13 April 2008
Abstract
*
The 1,3-dipolar cycloaddition of trifluoromethylated propargylic alcohols 1 with azides in the presence of catalytic [Cp RuCl2]n
afforded exclusively 4-trifluoromethyl-1,4,5-trisubstituted-1,2,3-triazoles 2 in high yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: 1,3-Dipolar cycloaddition; Triazole; Trifluoromethylated compound
The trifluoromethyl-substituted molecules are a class of
interesting compounds because of their relevant properties1
for the pharmaceutical and agrochemical areas.2 Hence,
the development of new synthetic methods and exploration
of the utility of such kind of compounds are of great
importance.3 On the other hand, the construction of
1,2,3-triazole derivatives is a matter of current interest.4
It has been demonstrated that the 1,2,3-triazole derivatives
exhibit antimicrobial, antiviral and antitumour activities5
and have a range of important applications in industries.
To obtain these heteroarenes, the most widely used method
is Huisgen 1,3-dipolar cycloaddition of azides with
alkynes.6 However, because of the high activation energy,
these cycloadditions are often very slow even at elevated
temperature (80–120 °C for 12–24 h) and produce a mix-
ture of regioisomers. Recently, new methodologies based
on catalysts have been reported for the construction of
1,2,3-triazoles. The ‘click’ chemistry reported by Sharpless
group described that the Cu(I)-catalyzed cycloaddition can
be conducted at room temperature and results in 1,4-disub-
stituted triazoles in high regioselectivity.7 This type of cop-
per catalysis, however, is restricted to the cycloadditions of
terminal alkynes. More recently, the discovery of the ruthe-
*
nium catalyst Cp RuCl(PPh3)2 allows the use of terminal
alkynes and internal alkynes as well. In contrast to the cop-
per-catalyzed 1,3-dipolar cycloaddition, the sole 1,5-disub-
stituted triazoles were produced in the case of the
cycloadditions terminal alkynes and azides under ruthe-
nium catalysis.8 The regioselectivity of the cycloaddition
of azides with unsymmetrical alkynes depends on the nat-
ure of the alkynes substituents albeit no rationale was pre-
sented.9 Although efforts have been made to study the
scope of the cycloaddition of internal alkynes,9a the reactiv-
ity of trifluoromethylated internal alkynes and the regiose-
lectivity of the cycloaddition of azides with them have not
been investigated so far. Accordingly, we were interested in
investigating the feasibility of the synthesis of trifluorome-
thylated 1,2,3-triazoles and the regioselectivity of 1,3-dipo-
lar cycloaddition of azides with trifluoromethylated
alkynols 1.
Trifluoromethylated propargylic alcohols 1 were easily
prepared from 2-bromo-3,3,3-trifluoropropene and
ketones (aldedydes) in the presence of 2 equiv of LDA
(Scheme 1).10
*
Corresponding author. Tel.: +86 21 54925187; fax: +86 21 64166128.
E-mail address: flq@mail.sioc.ac.cn (F.-L. Qing).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.065

3928
C.-T. Zhang et al. / Tetrahedron Letters 49 (2008) 3927–3930
1
CF
Br
R
1) 2.0 equiv. LDA
3
F C
3
2
O
R
2)
HO
1
2
R
R
1
Scheme 1.
CF3
N
Ph
OH
N
Ph
HO
OH
Ph
PhCH2N3
H2O, 80 oC
CF3
+
Ph
CF3
Ph
N N
N N
1a
2a
3
Scheme 2. Uncatalyzed cycloaddition of benzyl azide with 1a.
Fig. 1. The crystal structure of 3.
Recently, Ju et al. reported that the 1,3-dipolar cycload-
dition of azides with electron-deficient alkynes proceeded
smoothly in water without any catalysts.11 Accordingly,
the thermal (uncatalyzed) cycloaddition of benzyl azide
with 4,4,4-trifluoro-1-phenyl-2-butyn-1-ol 1a in water was
investigated. A mixture of benzyl azide and 1a in water
was stirred at 80 °C for 48 h to give a mixture of regioisom-
ers 2a and 3 in 58% isolated yield. The ratio of 2a:3 was
52:48 (Scheme 2). This is different from the previous ther-
mal cycloaddition of electron-deficient internal alkynes
with azides, which only results in type 2a isomer.11 Struc-
ture 3 was determined by the X-ray diffraction analysis
(Fig. 1).12
Table 1
Pd-catalyzed cycloaddition of trifluoromethyl propargylic alcohol 1a with
benzyl azidea
Entry
Catalyst
2a:3
Isolated yield (%)
1
2
3
a
Pd(OAc)2/PPh3
PdCl2(dppf)
Pd(PPh3)4
57:43
54:46
77:23
81
86
90
A mixture of 1a, benzyl azide and 5% palladium catalyst was stirred in
reflux benzene for 5 h.
To improve the yield and regioselectivity of this 1,3-
dipolar cycloaddition, the cycloaddition of 1a with benzyl
Table 2
Ruthenium-catalyzed cycloaddition of trifluoromethyl propargylic alcohols and azidesa
R2
R1
OH
R1
R2
[Cp*RuCl2]n; R3N3
THF, reflux
R3
CF3
N
CF3
HO
N N
1
2
Entry
1
Alkynol 1
Azide
1,2,3-Triazole 2
Isolated yield (%)
89
Ph OH
OH
Ph
CF3
N
2a
PhCH2N3
CF3
1a
Ph
N N
Ph
OH
C8H17
n
n-C 8H17N3
89
2a'
CF3
N
N N
Ph
OH
N
Ph
Ph
Ph
Ph
2
1b
PhCH2N3
64
CF3
HO
CF3
CF3
2b
Ph
N N
Ph
OH
N
n-C 8H17N3
82 (73b)
2b'
n
C8H17
N N

C.-T. Zhang et al. / Tetrahedron Letters 49 (2008) 3927–3930
3929
Table 2 (continued)
Entry
Alkynol 1
Azide
1,2,3-Triazole 2
Isolated yield (%)
85
1c
3
PhCH2N3
CF3
HO
OH
2c
CF3
N
Ph
N N
92 (66b)
OH
C8H17
n-C 8H17N3
n
CF3
2c'
N
N N
Ph
OH
1d
4
PhCH2N3
95 (92b)
CF3
OH
N
CF3
CF3
2d
Ph
Ph
N N
Ph
OH
n-C 8H17N3
86
n
C8H17
2d'
N
N
N
a
The reaction was conducted in THF at 66 °C.
The reaction was conducted in benzene at 80 °C.
b
azide under the palladium catalysis was carried out. As
shown in Table 1, the cycloaddition was completed in 5 h
and the isolated yields of products (2a and 3) were
improved to 81–90%. However, the regioselectivities of
the cycloaddition in all the palladium catalysts were still
poor (entries 1–3).
Acknowledgement
We greatly thank the National Natural Science Founda-
tion of China and the Shanghai Municipal Scientific Com-
mittee for the financial support.
To our delight, when the cycloaddition of 1a and benzyl
azide was conducted in the presence of [Cp RuCl2]n
References and notes
*
(10 mol % base on Ru) in reflux THF for 5 h, the 19F
NMR of the reaction mixture showed that only one isomer
was formed and product 2a was isolated in 89% yield
(Table 2, entry 1). We then investigated the reaction of var-
ious trifluoromethylated propargylic alcohols with benzyl
or alkyl azides under these reaction conditions.13 These
results are presented in Table 2. It was noteworthy that
all the reactions afforded exclusively 4-trifluoromethyl-
1,4,5-trisubstituted-1,2,3-triazoles in high yields. The steric
tertiary alcohols 1b–c can also lead to the products in good
yields. The yields of cycloaddition reaction in reflux THF
were higher than those of in reflux benzene. The regioselec-
tivity of the cycloaddition of trifluoromethylated propargy-
lic alcohols was similar to that of the ruthenium-catalyzed
cycloaddition of ussymmetrical disubstituted alkynes bear-
ing a carbonyl group.9a These regiochemical results implied
that the cycloaddition was presumably controlled by the
polarity effect.
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In conclusion, we have developed a convenient method
for the regioselectivity synthesis of 4-trifluoromethyl-
14
1,4,5-trisubstituted-1,2,3-triazoles
by the ruthenium
catalyzed cycloaddition of trifluoromethyl alkynols with
azides.

3930
C.-T. Zhang et al. / Tetrahedron Letters 49 (2008) 3927–3930
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12. Crystal data have been deposited at the Cambridge Crystallographic
Data Center with reference number CCDC 667050.
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*
(150 mg, 0.75 mmol), [Cp RuCl2]n (15 mg, 0.05 mmol based on Ru)
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and THF (2.5 ml) was stirred at 66 °C for 5 h under nitrogen
atmosphere. The mixture was then cooled and the solvent was
removed by rotary evaporation. The residue was purified by flash
chromatography to give 2a (153 mg, 89% yield) as a white solid. 1H
NMR (CDCl3, 400 MHz): d 7.33–7.29 (m, 3H), 7.23–7.19 (m, 5H),
7.04–7.00 (m, 2H), 6.35 (d, J = 4.3 Hz, 1H), 5.41 (q, J = 3.0 Hz, 2H),
2.87 (d, J = 4.6 Hz, 1H); 19F NMR (CDCl3, 376 MHz): d À58.739 (s);
13C NMR (CDCl3,100 MHz) d 55.0, 66.4, 123.99 (q, J = 262 Hz),
128.3, 130.55, 130.6, 130.7, 131.2, 131.3, 136.62 (q, J = 38 Hz), 137.6,
142.5; MS (EI) m/z 334 (M++1, 100). Anal. Calcd for C17H14F3N3O:
C, 61.26; H, 4.23; N, 12.61. Found: C, 61.09; H, 4.40; N, 12.55.
14. Some examples of triazole groups connected to fluoroalkyl moieties:
(a) Bonnamour, J.; Legros, J.; Crousse, B.; Bonnet-Delpon, D.
Tetrahedron Lett. 2007, 48, 8360; (b) Wu, Y. M.; Deng, J.; Fang, X.;
Chen, Q. Y. J. Fluorine Chem. 2004, 125, 1415; (c) Peng, W. M.; Zhu,
S. Z. Tetrahedron Lett. 2003, 59, 4395.
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