Palladium-catalyzed olefination and arylation of 2-substituted 1,2,3-triazole N -oxides

Article abstract of DOI:10.1021/ol401002w

Two highly efficient protocols for the regioselective synthesis of 2-substituted 4-alkenyl- and 4-aryl-1,2,3-triazoles by the palladium-catalyzed C-H functionalization of 1,2,3-triazole N-oxides are reported. A possible pathway of direct alkenylation with 1-octene and vinyl acetate is discussed.

Full text of DOI:10.1021/ol401002w

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Palladium-Catalyzed Olefination and
Arylation of 2‑Substituted 1,2,3-Triazole
N‑Oxides
Wei Liu,† Yahui Li,† Bo Xu,† and Chunxiang Kuang*,‡
Department of Chemistry, Tongji University, Siping Road 1239, Shanghai 200092,
P. R. China, and Key Laboratory of Yangtze River Water Environment,
Ministry of Education, Siping Road 1239, Shanghai 200092, P. R. China
kuangcx@tongji.edu.cn
Received February 22, 2013
ABSTRACT
Two highly efficient protocols for the regioselective synthesis of 2-substituted 4-alkenyl- and 4-aryl-1,2,3-triazoles by the palladium-catalyzed
CÀH functionalization of 1,2,3-triazole N-oxides are reported. A possible pathway of direct alkenylation with 1-octene and vinyl acetate is
discussed.
Transition-metal-catalyzed CÀH bond activation for
CÀC bond formation is attracting considerable attention
as a valuable tool in organic synthesis.1 The Pd-catalyzed
activation of the CÀH bonds of arenes or alkanes has
been widely explored.2 Recently, the CÀH bond activation
of pyridine N-oxides has been found to serve as a typical
platform for the 2-functionalization of the pyridine species.3
Additionally, Fagnou et al.4 found that higher reactivity
was observed for N-oxides of electron-deficient six-
membered heterocycles and for N-oxides derived from
electron-rich five-membered heteroarenes.
Given the unique chemical and structural properties
of 1,2,3-triazoles, they have been extensively investigated
and applied in material science and medicinal chemistry
(Figure 1).5 Recently described methods for the direct
catalytic functionalization of triazole and its derivatives
have also been proven attractive but are mainly limited
to the N-1 position.6 To our knowledge, a few methods
have been reported for the direct functionalization of
† Tongji University.
‡ Ministry of Education
(1) (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107.
(b) Lutz, A.; Ruben, V.; Anant, R. K. Angew. Chem., Int. Ed. 2009, 48,
9792. (c) Corbet, J. P.; Mignani, G. Chem. Rev. 2006, 106, 2651. (d)
Hassan, J.; Sevignon, M.; Gozzi, C.; Shulz, E.; Lemaire, M. Chem. Rev.
2002, 102, 1359. (e) Beccalli, E. M.; Broggini, G.; Martinelli, M.;
Sottocornola, S. Chem. Rev. 2007, 107, 5318. (f) Le Bras, J.; Muzart,
J. Chem. Rev. 2011, 111, 1170.
(2) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154. (b) Lebrasseur, N.; Larrosa, I. J. Am .Chem .Soc. 2008,
130, 2926. (c) Zhang, Y.; Feng, J.; Li, C.-J. J. Am. Chem. Soc. 2008, 130,
2900.
(3) (a) Campeau, L. C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc.
2005, 127, 18020. (b) Leclerc, J.-P.; Fagnou, K. Angew. Chem., Int. Ed.
2006, 45, 7781. (c) Leclerc, J.-P.; Fagnou, K. Angew. Chem. 2006, 118,
7945. (d) Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008,
130, 9254. (e) Tan, Y.; Fabiola, B.-L; Hartwig, J. F. J. Am. Chem. Soc.
2012, 134, 3683.
(4) (a) Huestis, M.-P.; Fagnou, K. Org. Lett. 2009, 11, 1357. (b)
Campeau, L. C.; Bertrand-Laperle, M.; Leclerc, J.-P.; Villemure, E.;
Goreslky, S.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 3276. (c) Zhao,
D.; Wang, W.; Lian, S.; Yang, F.; Lan, J.; You, J. Chem.;Eur. J. 2009,
15, 1337. (d) Wu, J.-L.; Cui, X.-L.; Chen, L.-M.; Jiang, G.-J.; Wu, Y.-J.
J. Am. Chem. Soc. 2009, 131, 13888.
Figure 1. Present medicines containing 1,2,3-triazole.
r
10.1021/ol401002w
XXXX American Chemical Society

2-substituted 1,2,3-triazole.7 Based on the key contribu-
tions of Fagnou,3aÀc,4a we propose the 4-functionalization
of 2-substituted 1,2,3-triazole species using the highly
regioselective CÀH bond activation approach and 2-sub-
stituted 1,2,3-triazole N-oxides. In this paper, we report
two new protocols for CÀC formation at the 5-position of
2-substituted 1,2,3-triazole N-oxides, namely, site-selective
alkenylation and direct cross-coupling with inactivated
arenes.
Table 1. Optimization of Typical Reaction Conditionsa
Based on the FujiwaraÀMoritani approach,8 we first
optimized the reaction conditions using 2-substituted
1,2,3-triazole N-oxide (1a) and methyl acrylate (Table 1).
The nature of oxidants, additives, and solvent play critical
roles in the reaction efficiency. No reaction occurred in
dioxane when no additive was used (entry 1). Pyridine
produced a higher yield than K2CO3, Et3N, and DBU
(entries 2À5). Among the oxidants screened (entries 5À7),
Ag2CO3 was selected as the most effective one. Further-
more, the addition of t-BuOH with dioxane significantly
improved the 3a yield (entries 8À12). Finally, the reaction
very efficiently proceeded when 5 mol % of Pd(OAc)2
was used in combination with Ag2CO3 (1.5 equiv.) and
pyridine (2.0 equiv) (entry 9). This method is highly site
selective at the 5-position, and no regioisomeric products
of 3a were observed. Additionally, the reaction proceeded
with complete stereoselectivity and generated (E)-3a ex-
clusively. The chemoselectivity was also remarkably high
because double alkenylation did not occur at all.
oxidant
additive
(2 equiv)
yield of 3ac
entry (1.5 equiv)
solvent (v/v)
dioxane
(%)
1
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2O
none
trace
45
5
2
K2CO3
EtN3
DBU
dioxane
dioxane
dioxane
3
4
12
68
43
37
5
pyridine dioxane
pyridine dioxane
pyridine dioxane
6
7
AgAcO
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
8
pyridine 10% t-BuOH/dioxane 76
pyridine 20% t-BuOH/dioxane 92
pyridine 30% t-BuOH/dioxane 81
9
10
11
12b
pyridine t-BuOH
pyridine t-BuOH
55
trace
a Reaction conditions: 1a (0.3 mmol), 2a (1.2 mmol), Pd(OAc)2
(5 mol %), 125 °C, and 8 h (unless otherwise noted). b Reaction at
100 °C for 8 h, after which the rest of the catalyst (0.12 mmol, 20 mol %)
and Ag2CO3 (2 equiv) were added and the reaction proceeded for
another 24 h. c Yield of isolated product.
We then tested the protocol for the Pd-catalyzed alke-
nylation of 3a on the alkenylation of other 2-substituted-
1,2,3-triazole N-oxides and alkenes (Table 2). Diverse
decorated products 3bÀj formed in high yields, and regioi-
someric products were not observed.
Interestingly, high yields of 1-octene and vinyl acetate
were also obtained under the same reaction conditions, as
shown in Table 3. However, the isomer distribution of the
products considerably differed from those of the alkenes in
Table 2. 1-Octene produced three isomers 3ka, 3kb, and
3kc; vinyl acetate produced a mixture of 3la and 3lb
(Table 3).
The Pd-catalyzed direct cross-coupling reactions be-
tween 1-octene and vinyl acetate as coupling partners
have been reported.9 However, the direct alkenylation of
triazole derivatives is rarely reported. We propose that
the Pd-catalyzed vinylation proceeds through a pathway
different from the typical mechanism of the Heck reaction.
In path A, the resulting PdÀC bond of A adds to the
carbonÀcarbon double bond of 1-octene to form the Pd
complexes B and C. The β-H elimination of B to reverse
carbon occurred, resulting in theformationof3ka and 3kb.
For complex C, 3kc was obtained because β-H elimination
only occurred at one carbon.9c In path B, complexes E and
F formed similar to 1-octene. The β-H elimination of E and
β-OAc elimination of F resultedin the formation of 3la and
3 lb, respectively (Scheme 1).9d
Surprisely, we found that 2-substituted 5-aryl-1,2,3-
triazole N-oxide was produced as a side product 3m in
addition to the desired alkenylated compound (3a) when
the alkenylation reaction was carried outinbenzene. Based
on the various conditions screened using 1a and benzene,
the optimal conditions for the arylation of N-oxides were
as follows: benzene (40 equiv), Pd(OAc)2 (5 mol %),
Ag2CO3 (1.5 equiv), and 100 °C. Using the optimized
protocol, 3mÀr formed in high yields. This system was
alsoappliedtootherarenessuchasp-xylene, m-xylene, and
(5) (a) Chabre, Y. M.; Roy, R. Curr. Top. Med. Chem. 2008, 8, 1237.
(b) Hanselmann, R.; Job, G. E.; Johnson, G.; Lou, R. L.; Martynow,
J. G.; Reeve, M. M. Org. Process Res. Dev. 2010, 14, 152. (c) Rozkiewicz,
D. I.; Janczewski, D.; Verboom, W.; Ravoo, B. J.; Reinhoudt, D. N.
Angew. Chem., Int. Ed. 2006, 45, 5292. (d) Heal, W. P.;Wickramasing-he,
S. R.; Leatherbarrow, R. J.; Tate, E. W. Org. Biomol. Chem. 2008, 6,
2308. (e) Mamidyala, S. K.; Finn, M. G. Chem. Soc. Rev. 2010, 39, 1252.
(f) Zhang, P.; Ling, C. Org. Lett. 2010, 12, 3096. (h) Chem. Commun.
2007, 2034. (g) Fazio, M. A.; Lee, O. P.; Schuster, D. I. Org. Lett. 2008, 10,
4979.
(6) (a) Ackermann, L.; Potukuchi, H. K.; Landsberg, D.; Vicente, R.
Org. Lett. 2008, 10, 3081. (b) Ackermann, L.; Althammer, A.; Fenner, S.
Angew. Chem. 2009, 121, 207. (c) Ackermann, L.; Vicente, R.; Born, R.
Adv. Synth. Catal. 2008, 350, 741.
(7) (a) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. J. Am. Chem, Soc.
2002, 125, 7786. (b) Chen, Y.; Liu, Y.; Petersena, J. L.; Shi, X. Chem.
Commun. 2008, 3254. (c) Kalisiak, J.; Sharpless, K. B.; Fokin, V. V. Org.
Lett. 2008, 10, 3171. (d) Liu, Y.; Yan, W.; Chen, Y.; Petersen, J. L.; Shi,
X. Org. Lett. 2008, 10, 5389. (e) Wang, X.; Zhang, L.; Lee, H.; Haddad,
N.; Krishnamurthy, D.; Senanayake, C. H. Org. Lett. 2009, 11, 5026.
(8) (a) Fujiwara, Y.; Moritani, I.; Danno, S.; Asano, R.; Teranishi, S.
J. Am. Chem. Soc. 1969, 91, 7166. (b) Yokota, T.; Tani, M.; Sakaguchi,
S.; Ishii, Y. J. Am. Chem. Soc. 2003, 125, 1476. (c) Zhang, H.; Ferreira,
E. M.; Stoltz, B. M. Angew. Chem., Int. Ed. 2004, 43, 6144. (d) Godfrey,
C. D.; Gaunt, M. J. Angew. Chem., Int. Ed. 2005, 44, 3125.
(9) (a) Kikukawa, K.; Naritomi, M.; He, G.-X.; Wada, F.; Matsuda,
T. J. Org. Chem. 1985, 50, 299. (b) Yu, J.-Y.; Kuwano, R. Angew. Chem.,
Int. Ed. 2009, 48, 7217. (c) Zhang, Y.-X.; Li, Z.-J.; Liu, Z.-Q. Org. Lett.
2012, 14, 226. (d) Matsuura, Y.; Tamura, M.; Kochi, T.; Sato, M.;
Chatani, N.; Kakiuchi, F. J. Am. Chem. Soc. 2007, 129, 9858.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Reactions of 2-Substituted 1,2,3-Triazole N-Oxides
and Alkenesa
Table 3. Reactions of 3a with 1-Octene and Vinyl Acetatea
a Reaction conditions: 1a (0.3 mmol), 2 (1.2 mmol), Pd(OAc)2
(0.015 mmol, 5 mol %), Ag2CO3 (1.5 equiv), pyridine (2 equiv), 125 °C,
and 8 h. b Isolated yield.
Scheme 1. Possible Reaction Pathways for the Reaction of 1a
with 1-Octene and Vinyl Acetate
a Reaction conditions: 1 (0.3 mmol), 2 (1.2 mmol), Pd(OAc)2
(0.015 mmol, 5 mol %), Ag2CO3 (1.5 equiv), pyridine (2 equiv), 125 °C,
and 8 h. b Isolated yield.
1,2-dichlorobenzene, and 3pÀr were obtained in moderate
yields (Table 4). However, isomers were obtained which
are difficult to separate when toluene and iodobenzene was
applied to this catalytic system.
The resultant alkenylated and arylated N-oxides (e.g., 3e
and 3m) were readily deoxygenated and produced 2-sub-
stituted 4-alkenyl and 4-aryl-1,2,3-triazoles using typical
methods in high yields (Scheme 2).10 To the best of our
knowledge, a few methods for the synthesis of 2-substi-
tuted 4-alkenyl-1,2,3-triazoles have been reported.
Although a few reports have described the synthesis of
2-substituted 4-phenyl-1,2,3-triazoles,11,7d Pd-catalyzed
direct arylation method still remains a challenge. As shown
(10) (a) Sasa, D.; Tzschucke, C. C. Org. Lett. 2011, 13, 2310. (b)
Balicki, R. Synthesis 1989, 8, 645.
(11) (a) Ueda, S.; Su, M,-J; Buchwald, S. L. Angew. Chem., Int. Ed.
2011, 50, 8944. (b) Wen, J.; Hu, Y,-Z. Synth. Commun. 2006, 36, 2461. (c)
Moderhack, D.; Daoud, A. J. Heter. Chem. 2003, 40, 625. (d) Luo, Y.;
Hu, Y,-Z. Synth. Commun. 2003, 33, 3513. (f) Mohareb, R. M.; Habashi,
A.; Hafez, E. A. A.; Sherif, S. M. Arch. Pharm. 1987, 320, 776.
in Scheme 3, no reaction occurred at the C4 or C5 sites
under the same conditions when we explored if 1a was
deoxygenated. Obviously, our approach was an efficient
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 4. Reactions of 2-Substituted-1,2,3-Triazole N-Oxides
and Arenesa
Scheme 2. Deoxygenation for 2-Substituted 1,2,3-Triazole
N-Oxides
Scheme 3. Inert 4 and 5 Sites of 2-Substituted 1,2,3-Triazole
impact on direct functionalization and on the increasing
number of metal-catalyzed heterocycle transformations
that can utilize the N-oxide activation strategy in the rapid
functionalization of these substrates.
Acknowledgment. The present work was supported
by the Natural Science Foundation of China (No.
21272174), the Key Projects of Shanghai in Biomedicine
(No.08431902700), and the Scientific Research Founda-
tion of the State Education Ministry for Returned
Overseas Chinese Scholars. We also thank the Center for
Instrumental Analysis, Tongji University, China.
a Reaction conditions: 1 (0.3 mmol), 2 (40 equiv), Pd(OAc)2
(0.015 mmol, 5 mol %), Ag2CO3 (1.5 equiv), 100 °C, and 8 h (unless
otherwise noted). b Yield of isolated product.
alternative to the 4-functionalization of 2-substituted
1,2,3-triazoles.
In summary, we report for the firsttime two novel proto-
cols of the 4-C-alkylation and arylation of 2-substituted
1,2,3-triazoles by the Pd-catalyzed oxidative CÀC bond
formation of 2-substituted 1,2,3-triazole N-oxides with
high regioselectivity. The reaction preferably occurred
at C5 because of the activity of 2-substituted 1,2,3-triazole
N-oxides at this site. This reactivity may have a wide
Supporting Information Available. Typical experimen-
tal procedures, characterization data, and 1H NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX