Highly efficient synthesis of vinyl substituted triazoles by Au(I) catalyzed alkyne activation

Article abstract of DOI:10.1016/j.bmcl.2009.03.096

Au(I) catalyzed 1,2,3-triazole addition to non-activated alkyne was reported. A large group of substituted NH-1,2,3-triazoles were suitable for this transformation along with both internal and terminal alkynes. The N-1 and N-2 vinyl substituted 1,2,3-tria

Full text of DOI:10.1016/j.bmcl.2009.03.096

Bioorganic & Medicinal Chemistry Letters 19 (2009) 3899–3902
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Highly efficient synthesis of vinyl substituted triazoles by Au(I) catalyzed
alkyne activation
*
Haifeng Duan, Wuming Yan, Sujata Sengupta, Xiaodong Shi
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, WV 26506, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Au(I) catalyzed 1,2,3-triazole addition to non-activated alkyne was reported. A large group of substituted
NH-1,2,3-triazoles were suitable for this transformation along with both internal and terminal alkynes.
The N-1 and N-2 vinyl substituted 1,2,3-triazoles were prepared in up to 98% yield with as low as 0.2%
catalyst loading, thereby providing a new protocol for the synthesis of potentially biological-active
vinyl-triazole building blocks.
Received 2 March 2009
Revised 19 March 2009
Accepted 23 March 2009
Available online 26 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
1,2,3-Triazoles
Au catalysis
Alkyne activation
Regioselective
Stereoselective
With the discovery of the Cu-catalyzed azide-alkyne 1,3-dipolar
cycloaddition (CuAAC, often referred as ‘click-chemistry’) at the
beginning of this century, 1,2,3-triazoles have become one of the
most important heterocycles in chemical and biological re-
searches.1 Within the last five years, the importance of this hetero-
cyclic building block has been continuously demonstrated in
research fields from material science2 and chemical biology3 to
medicinal chemistry.4 Suggested by the numerous reports in liter-
ature, one great advantage of the 1,2,3-triazoles is its bio-compat-
ibility, which allowed the application of click chemistry in both
in vitro and in vivo studies.5 Compared to the dominant studies
regarding the application of the CuAAC reaction as a biocompatible
coupling strategy, recently, more efforts have been focused on the
investigation of the triazole motif itself as a biologically active
building block for new drug discovery. Therefore, a significant
growing need was generated for effective synthetic methods in
preparing diverse functionalized triazole analogues.
As one extremely efficient synthetic method, the Cu catalyzed
‘click chemistry’ possesses some potential limitation: (a) with the
application of substituted azides, the CuAAC gives N-1 substituted
triazoles as the dominant products; (b) the usage of the substituted
azide makes the products heavily rely on the availability of alkyl/
aryl azides. Recently, Sharpless and Fokin reported the effective
synthesis of N-2 alkyl triazole through substitutent dynamic equi-
librium.6 Meanwhile, our group reported the regio-selective N-2
alkylation7 and arylation8 through post NH-triazole functionaliza-
tion. Herein, we report the Au(I) catalyzed NH-triazole addition to
alkynes with excellent yields and stereoselectivity (trans-addi-
tion). To the best of our knowledge, this is the first successful
example in achieving vinyl substituted 1,2,3-triazoles through al-
kyne addition, which will surely benefit medicinal chemistry re-
searches that targets the application of 1,2,3-triazole building
blocks as potential drug candidates.
A) Thermo-cycloaddition of alkyne and alkene with azide
2
R1
R2
1
N
N
R3
3 N
N
5
N3 R3
or
+
EWG
14
R2
R
Produced only N-1 substituted triazoles
R1
R2
B) Metal catalyzed 1,3-dipolar addition
Cu (I) or Ru (II)
N
R2
R2
N
N
N
N
N3 R2
R1
+
or
R1
H
H
R1
Two challenges in triazole synthesis:
a) N-2 functionalization; b) limitation on the substituted azide.
Scheme 1. General approach in the preparation of 1,2,3-triazoles.
H2C
H2C
H+
H3C
N
N N
N
N
N
N N N
* Corresponding author. Tel.: +1 304 293 3435; fax: +1 304 293 4904.
E-mail address: Xiaodong.Shi@mail.wvu.edu (X. Shi).
Scheme 2. Vinyl azide: challenging substrate for dipolar cycloaddition due to the
existence of equilibrium.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.096

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H. Duan et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3899–3902
Table 1
A) Elimination of alkyl halide
Screening of catalyst for triazole-alkyne additiona
N
N
BrCH2CH2Br
NaOH
N
N
N
N
34% yield
N
N
N
H
N
cat.
Tol.
N
+
Only N-1 product
Ph
H
N
H
B) Benzyne click chemistry
N3
Ph
N
N
N
Ph
3a
TMS
1a
2a
CsF
20%
OTf
Catalyst
Loading (%)
Temp (°C)
Time (h)
Yieldsb (%)
Ph
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
AuCl
AuCl3
5
5
5
5
5
1
0.2
5
5
5
5
5
5
5
5
80
80
rt
6
6
12
20
5
82
88
15
60
C) NH-triazole alkyne addition: ideal path to access vinyl triazoles
R4
R2
R2
PPh3AuOTf
PPh3AuOTf
PPh3AuOTf
PPh3AuOTf
PPh3AuOTf
CuI
Cu(OAc)2
Sc(OTf)2
HOTf
N
N
N
N
R3
R4
+
NH
50
80
80
80
80
80
80
80
80
80
80
80
N
R1
>99%
96
92
N.R.
N.R.
<5%
10
68%
N.R.
20
R3
R1
6
12
12
12
12
12
12
12
12
12
Scheme 3. Synthesis of vinyl triazole.
As indicated in Scheme 1, the two most general approaches in
the preparation of 1,2,3-triazoles are the cycloaddition of alkyne/
alkene with substituted azides through either thermo condition
or metal catalyzed 1,3-dipolar additions. Although the metal cata-
lyzed dipolar addition significantly improved the reaction effi-
ciency, giving the N-1 substituted triazoles in excellent yields,
one challenge in this approach is the limitation on the substituted
azides. For example, the metal catalyzed dipolar addition between
alkynes and vinyl-substituted azides has never been reported in
literature,9 possibly due to the poor stability (high energy material)
and existence of different resonance structures (Scheme 2). As a re-
sult, the preparation of vinyl-triazole was very challenging.
Driven by the growing interest in triazole research, some meth-
ods regarding the synthesis of vinyl-triazoles have been recently
reported. The two most general methods reported in literature
were through the elimination of alkyl halide10 and the cyclization
of vinyl azides with highly reactive benzyne intermediate11
(Scheme 3).
In(OTf)3
La(OTf)3
AgOTf
Pd(OAc)2
N.R.
a
Reactions were carried out by dissolving 1a (1.0 equiv), 2a (1.5 equiv) and
catalyst in toluene (0.2 M).
b
Determined by NMR.
For the elimination approach, significant amounts of bis-triazole
byproducts were usually formed and the substrate scope was very
limited. The benzyne click chemistry provided an interesting alter-
native strategy in preparing triazoles, however, again, vinyl azides
suffered from poor yields and limited substrate scope. Therefore,
efficient synthetic routes to access vinyl-triazoles are highly desir-
able. Considering the strong nucleophilicity of NH-triazole, and
more importantly, the easy access to this building block based on
our recently reported cascade synthesis,12 we wondered whether
the NH-triazole alkyne addition could be achieved as a new strategy
Table 2
Substituted scope of alkynes in the Au(I) catalyzed triazole additiona
N
N
N
PPh3AuOTf
Tol. 80 o
N
+
R3
R4
R4
H
N
N
C
H
R3
1a
2
3
Alkyne
Product
Cat. (%)
Time (h)
Yieldb (%)
N
N
3b: R3 = p-Me-Ph
3c: R3 = p-F-Ph
3d: R3 = n-Bu
0.2
0.2
0.2
12
10
12
94
96
90
N
N
p-Me-Ph
p-F-Ph
n-Bu
H
H
H
R3
N
N
3e: R3 = R4 = Ph
1.0
1.0
1.0
30
20
12
70
83
82
Ph
n-Pr
TMS
Ph
n-Pr
CH3
3f: R3 = R4 = n-Pr
3g: R3 = CH3, R4 = H
R4
H
R3
N
N
N
N
N
N
CH3
Ph
H
Ph
CH3
1.0
1.0
20
20
84
81
Ph
H
H3C
3h: 1:1 of the two regio isomer
N
N
N
N
N
CH3
H
N
n-Pr
H
n-Pr
CH3
n-Pr
H3C
3i: 1:1 of the two regio isomer
a
Reactions were carried out by dissolving 1a (1.0 equiv), 2 (1.5 equiv) and PPh3AuOTf in toluene (0.2 M) and heating at 80 °C.
Isolated yields.
b

H. Duan et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3899–3902
3901
Table 3
Substituted scope of different NH-triazolesa
R2
R4
R2
R1
N
N
0.2-1% PPh3AuOTf
Tol. 80 oC
N
N
R3
R4
+
R1
N
N
R3
H
2
4
1
1N
N
N
N
Pr
2
N
H
N
N
Cy
N
Ph
N 3
Ph
Ph
Pr
Ph
4b
4a
4c
0.2% cat., 87% yield N1:N2:N3 = 20:80:0
0.2% cat., 91% yield N1:N2:N3 = 22:78:0b
1.0% cat., 81% yield N1:N2:N3 = 18:82:0
Pr
1
1
H
N
N
N
N
Ph
Ph
Ph
Ph
2
2
N
3
N
N
N
N 3
Ph
Pr
Ph
Ph
Ph
4d
4e
4f
0.2% cat., 90% yield N1:N2:N3 = 24:71:5
1.0% cat., 85% yield N1:N2:N3 = 22:78:0
0.2% cat., 88% yield N1:N2:N3 = 20:80:0
1
N
O
1
N
Ph
2
1
N
N
3
Ph
2
N
3
2
N
3
N
Cy
Ph
N
Ph
Ph
N
Ph
Ph
4h
0.2% cat., 93% yield N1:N2:N3 = 18:82:0
4i
0.2% cat., 84% yield N1:N2:N3 = 0:100:0
4g
0.2% cat., 87% yield N1:N2:N3 = 29:71:0
a
Reactions were carried out by dissolving 1a (1.0 equiv), 2 (1.5 equiv) and PPh3AuOTf in toluene (0.2 M) and heating at 80 °C.
Ratio of the products were determined by NMR.
b
for the synthesis of vinyl triazoles with high efficiency and a much
better substrate scope. The reaction between benzotriazole 1a and
terminal alkyne 1b were then performed in the presence of various
promoters. The results are summarized in Table 1.
As shown in Table 3, all NH-triazoles are suitable for this
reaction, giving the alkyne addition products in excellent yields.
Only trans additions were observed, giving exclusive single dou-
ble-bond isomers. The substituents on the triazoles showed a
strong influence on the N-regio-selectivity, where most C-4-phe-
nyl substituted triazoles gave N-2 isomers as the major products.
Increasing the steric hindrance on the C-4 and C-5 position did
not show a dramatic difference towards the regio-selectivity.
However, application of carbonyl-substituted NH-triazole led to
the formation of a single N-2 isomer, similar to the results that
we reported recently regarding the post N-2 alkylation7 and N-
2 arylation8 of NH-triazoles. Considering the great efficiency,
excellent stereo-selectivity of double bonds, broad substrate
scope and controllable triazole nitrogen regio selectivity, it is
our belief that the reported method would provide a good
strategy for the preparation of various vinyl-triazoles and
thereby benefiting researches involving 1,2,3-triazoles as building
blocks.
Reaction at room temperature gave either very low yields or no
reaction at all for all catalysts tested due to the slow reaction rate
or lack of reactivity. By increasing the reaction temperature, the Au
complexes were identified as the best catalysts in activating the al-
kyne. With 5% loading of PPh3AuOTf at 80 °C, the desired vinyl tri-
azole 3a was obtained in quantitative yield (entry 5). The reaction
gave excellent regio selectivity, where, only the N-1 substituted
Markovnikov’s product was observed. Although some other cata-
lysts, such as In(OTf)3, indicated modest reactivity, the superior
efficiency of the Au(I) catalysts made them an ideal catalytic sys-
tem for this transformation. Different alkynes were then applied
to the reaction to investigate the substrate scope. The results are
summarized in Table 2.
As indicated in Table 2, the transformation was suitable for a
variety of substituted alkynes. The terminal alkynes gave higher
than 90% yields of only the Markovnikov’s products even with only
0.2% catalyst loading. Impressively, the reaction also worked very
well with internal alkynes, which are usually challenging sub-
strates to be activated by metal catalysts. With 1% catalyst loading,
the desired addition products were prepared in good yields. Nota-
bly, although the regio-selectivity of the asymmetric alkynes was
poor (3h, 3i), the reaction reached excellent double-bond selectiv-
ity and only the trans addition products were formed in all cases. The
double-bond stereochemistry was confirmed by NOE experiments.
Meanwhile, both alkyl and aryl substituted alkynes were suitable
for this reaction. With this highly efficient catalytic triazole addi-
tion strategy, we then investigated the N-selectivity with different
NH-triazoles as shown in Table 3.
Acknowledgements
We thank the C. Eugene Bennett Department of Chemistry, the
Eberly College of Arts and Science, and the WV Nano Initiative at
West Virginia University for the financial support. X.S. thanks
ACS-PRF for financial support.
Supplementary data
Detailed experimental procedures and spectral data for all new
compounds are provided. Supplementary data associated with this
article can be found, in the online version, at doi:10.1016/
j.bmcl.2009.03.096.

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Rev. 2008, 28, 278; (d) Whiting, M.; Muldoon, J.; Lin, Y. C.; Silverman, S. M.;
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