Site-selective direct arylation of 1,2,3-triazole N-oxides

Article abstract of DOI:10.1002/ejoc.201300747

An efficient route for the synthesis of 2,4-disubstituted 1,2,3-triazoles by the regioselective direct arylation of 2-aryl-1,2,3-triazole N-oxides with Ar-X [X = Br, I and B(OH)₂] is demonstrated. The reaction proceeds through Pd-catalyzed C-H bond activation, and the influence of the aryl halides on the reactivity is investigated. An efficient route for the synthesis of 2,4-disubstituted 1,2,3-triazoles by the regioselective direct arylation of 2-aryl-1,2,3-triazole N-oxides with Ar-X [X = Br, I and B(OH)₂] is demonstrated. The reaction proceeds through Pd-catalyzed C-H bond activation, and the influence of the aryl halides on the reactivity is investigated. Copyright

Full text of DOI:10.1002/ejoc.201300747

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300747
Site-Selective Direct Arylation of 1,2,3-Triazole N-Oxides
Wei Liu,[a] Yahui Li,[a] Yue Wang,[a] and Chunxiang Kuang*[a,b]
Keywords: Arylation / Nitrogen heterocycles / C–H activation / Regioselectivity / Palladium
An efficient route for the synthesis of 2,4-disubstituted 1,2,3-
triazoles by the regioselective direct arylation of 2-aryl-1,2,3-
triazole N-oxides with Ar–X [X = Br, I and B(OH)2] is demon-
strated. The reaction proceeds through Pd-catalyzed C–H
bond activation, and the influence of the aryl halides on the
reactivity is investigated.
Ar–X [X = Br, I, and B(OH)2] and 2-aryl-1,2,3-triazole N-
oxides, and many of the products were obtained in good
yields. The resulting 1,2,3-triazole N-oxides were also ef-
ficiently deoxygenated to the desired products.
Introduction
The formation of carbon–carbon bonds by direct aryl-
ation has recently emerged as an attractive alternative to
the use of stoichiometric organometallic reagents in the
preparation of biaryl compounds.[1] Various protocols that
involve the coupling of electron-rich, electron-neutral, and
electron-deficient arenes have been developed.[2]
Over the past decade, 1,2,3-triazoles have attracted in-
creasing attention as an important class of heterocycles
with numerous applications in materials and medicinal
chemistry (Figure 1).[3] To the best of our knowledge, the
direct arylation of 1,2,3-triazole rings is mainly limited to
1-substituted 1,2,3-triazole derivatives,[4] and the direct
arylation of 2-substituted 1,2,3-triazoles has rarely been re-
ported. We assumed that the introduction of the N-oxide
moiety would increase the electron density of the electron-
poor 1,2,3-triazole ring system[2e] and enhance the Brønsted
acidity[5] of the adjacent C–H bond of the 1,2,3-triazole.
Herein, we report an efficient synthesis of 2,4-disubstituted
1,2,3-triazoles on the basis of the direct arylation between
Results and Discussion
On the basis of the results of published methods for the
arylation of heteroarene N-oxides,[6] we tested the reaction
of 2-(p-tolyl)-1,2,3-triazole N-oxide (1a) with iodobenzene
(Table 1). The PCy3 (Cy = cyclohexyl) ligand was more ef-
fective than both PtBu3–HBF4 and PPh3 (Table 1, en-
Table 1. Screening for optimal reaction conditions.[a]
Figure 1. Drugs containing the 1,2,3-triazole ring.
[a] Department of Chemistry, Tongji University,
Siping Road 1239, Shanghai 200092, China
E-mail: kuangcx@tongji.edu.cn
[b] Key Laboratory of Yangtze River Water Environment, Ministry
of Education,
[a] Reaction conditions: 1a (0.3 mmol), iodobenzene (0.36 mmol),
Pd(OAc)2 (5 mol-%), toluene, 24 h (unless otherwise noted).
[b] Bromobenzene was used as the aryl halide. [c] Chlorobenzene
was used as the aryl halide. [d] Yield of isolated product.
Siping Road 1239, Shanghai 200092, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300747.
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Eur. J. Org. Chem. 2013, 5272–5275

Site-Selective Direct Arylation of 1,2,3-Triazole N-Oxides
tries 1–3). Although the desired conditions for 2-substituted phenyl (Table 2, entry 15), and 3-chloro-4-fluorophenyl
1,2,3-triazole N-oxide arylation provided direct product 3a (Table 2, entry 12) moieties also underwent the reaction.
in 87% isolated yield (Table 1, entry 2), we investigated
Interestingly, 3a could also be obtained in 68% yield if
whether the reaction might be performed under signifi- phenylboronic acid was used as the coupling partner, and
cantly milder conditions (Table 1, entries 4–6). At room 3q was obtained with complete (E) stereoselectivity in 63%
temperature, the product was obtained in only 12% yield yield when (E)-2-bromovinylbenzene was applied to this
(Table 1, entry 4). The yield of the desired product signifi- catalytic system instead of an aryl halide (Scheme 1). No
cantly increased at 50 °C (Table 1, entry 5). As expected, the product was afforded if benzyl bromide, 2-phenylethynyl
yield increased to 89% if the reaction was performed at bromide, or cinnamyl bromide was used as the coupling
80 °C (Table 1, entry 6). However, a lower yield was ob- partner.
tained if the base was changed from 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU) to Et3N or pyridine (Table 1, entries 7–
9). Bromobenzene produced a slightly lower yield (Table 1,
entry 10), and chlorobenzene resulted in a significantly
lower yield (Table 1, entry 11), even if the reaction was per-
formed at 110 °C (Table 1, entry 12).
With the optimized conditions in hand, we investigated
the scope of the reaction of 2-aryl-1,2,3-triazole N-oxides 1
with aryl halides 2 (Table 2). Diverse decorated products
3b–p were formed in good to excellent yields. Both electron-
rich (Table 2, entries 2, 3, 5, 6, and 16) and electron-poor
(Table 2, entries 4 and 7) aryl halides were compatible. 2-
Scheme 1. Reactions of 1a with 2-bromovinylbenzene and phen-
ylboronic acid.
Bromopyridine (2h) and 2-bromothiophene (2i) were also
suitable in this system (Table 2, entries 8 and 9). Notably,
aryl groups at the N-2 position of the triazole ring bearing
m-tolyl (Table 2, entries 1–9, 16), phenyl (Table 2, entries 10
We propose that the Pd-catalyzed direct arylation pro-
ceeds through a pathway similar to the typical mechanism
of the direct arylation reaction of pyridine N-oxide.[7] The
reaction was proposed to involve a concerted metalation–
deprotonation (CMD) mechanism for the C–H activation
and 11), 1-naphthyl (Table 2, entries 13 and 14), 4-chloro-
step (Scheme 2).
Table 2. Arylation of 2-aryl-1,2,3-triazoles N-oxides at the C-5
position.[a]
Scheme 2. Possible reaction pathway.
The influence of the aryl halide on the reaction was in-
vestigated by a competition experiment (Scheme 3). Under
the reaction conditions, 1a was treated with both aryl hal-
ides 2g and 2e. We found that the main product, as detected
by analysis of the crude reaction mixture by 1H NMR spec-
troscopy, was 3g, which arises from reaction of aryl halide
2g with an electron-withdrawing group. The result from the
competition experiment indicates that, relative to aryl hal-
ides bearing electron-donating groups, aryl halides bearing
electron-withdrawing groups should have higher reactivity
and show a higher reaction rate in the formation of inter-
[a] Conditions: 1 (0.50 mmol), 2a (0.60 mmol), Pd(OAc)2 (5.0 mol-
%), PCy3 (5.0 mol-%), K2CO3 (1.0 mmol), toluene (2.0 mL), 80 °C,
24 h. [b] Yield of isolated product.
Eur. J. Org. Chem. 2013, 5272–5275
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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W. Liu, Y. Li, Y. Wang, C. Kuang
SHORT COMMUNICATION
Scheme 3. Competition experiment.
mediate 1 in Scheme 2 for the direct arylation in this sys- This method may be a valuable alternative to traditional
tem.
cross-coupling techniques for synthesizing 2,4-disubstituted
The deoxygenation of the resultant arylated N-oxides to 1,2,3-triazoles.
the desired 1,2,3-triazoles in high yields was conveniently
achieved by Pd-catalyzed reduction with ammonium for-
mate (Table 3).[6a,8] To the best of our knowledge, although
several reports have described the synthesis of 2,4-disubsti-
tuted 1,2,3-triazoles, Pd-catalyzed direct arylation still poses
significant challenges.[9,2e] In contrast to these reported ap-
proaches, our catalytic system offers complete regioselectiv-
ity and high functional group tolerance. Additionally, it was
found that no products were afforded under our catalytic
system if 1a was deoxygenated. Thus, this protocol provides
a useful alternative to the synthesis of 2,4-disubstituted
1,2,3-triazoles.
Experimental Section
General Procedure for the Direct Arylation of 2-Aryl-1,2,3-triazole
N-Oxides: A mixture of 2-substitued-1,2,3-triazole N-oxide 1
(0.5 mmol), aryl halide 2 (0.6 mmol), Cy3 (0.025 mmol), Pd(OAc)2
(0.025 mmol), and K2CO3 (1.0 mmol) in toluene (2 mL) was stirred
at 80 °C for 24 h under an atmosphere of N2. The mixture was
diluted with CH2Cl2 and filtered through a plug of silica gel. The
organic phase was evaporated in vacuo. The resulting residue was
purified by using preparative silica gel TLC (hexane/EtOAc, 4:1–
2:1) to yield product 3.
Supporting Information (see footnote on the first page of this arti-
Table 3. Deoxygenation for 1,2,3-triazole N-oxides.[a]
cle): Experimental procedures, characterization data, and copies of
1
the H NMR and 13C NMR spectra.
Acknowledgments
The present work was supported by the National Natural Science
Foundation of China (NSFC) (grant number 21272174), the Key
Projects of Shanghai in Biomedicine (grant number 08431902700),
and the Scientific Research Foundation of the State Education
Ministry for Returned Overseas Chinese Scholars. The authors
would also like to thank the Center for Instrumental Analysis,
Tongji University, China.
[1] a) I. V. Seregin, V. Gevorgyan, Chem. Soc. Rev. 2007, 36, 1173–
1193; b) C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111, 1215–
1292; c) T. W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110,
1147–1169; d) Y.-N. Wang, X.-Q. Guo, X.-H. Zhu, R. Zhong,
L.-H. Cai, X.-F. Hou, Chem. Commun. 2012, 48, 10437–10439;
e) M. Lafrance, K. Fagnou, J. Am. Chem. Soc. 2006, 128,
16496–16497; f) T. Yan, L. Chen, C. Bruneau, P. H. Dixneuf,
H. Doucet, J. Org. Chem. 2012, 77, 7659–7664; g) L. Ackerm-
ann, Pure Appl. Chem. 2010, 82, 1403–1413; h) D. A. Colby,
R. G. Bergman, J. A. Ellman, Chem. Rev. 2010, 110, 624–655;
i) K. Hirano, M. Miura, Synlett 2011, 3, 294–307; j) M. Catel-
lani, E. Motti, N. Dellaca, R. Ferraccioli, Eur. J. Org. Chem.
2007, 4153–4165; k) L. Ackermann, R. Vicente, A. R. Kapdi,
Angew. Chem. 2009, 121, 9976–10011; Angew. Chem. Int. Ed.
2009, 48, 9792–9826; l) N. Dastbaravardeh, M. Schnürch,
M. D. Mihovilovic, Eur. J. Org. Chem. 2013, 2878–2890; m)
S. H. Cho, J. Y. Kim, J. Kwak, S. Chang, Chem. Soc. Rev. 2011,
40, 5068–5083; n) J. Yamaguchi, A. D. Yamaguchi, K. Itami,
Angew. Chem. 2012, 124, 9092–9142; Angew. Chem. Int. Ed.
2012, 51, 8960–8990.
[a] Conditions: 1,2,3-triazole N-oxide (0.50 mmol), Pd/C
(0.10 mmol), HCOONH4 (5 mmol), MeOH (3 mL), 50 °C, 8 h.
[b] Yield of isolated product.
Conclusions
In conclusion, we demonstrated the efficient direct cou-
pling between 2-aryl-1,2,3-triazole N-oxides and aryl hal-
ides as the key step in synthesizing 2,4-disubstituted 1,2,3-
triazoles. We also found that our protocol can be applied
to a broad range of coupling partners and triazole N-oxides.
[2] a) B. S. Lane, M. A. Brown, D. Sames, J. Am. Chem. Soc. 2005,
127, 8050–8057; b) M. Lafrance, C. N. Rowley, T. K. Woo, K.
5274
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5272–5275

Site-Selective Direct Arylation of 1,2,3-Triazole N-Oxides
Fagnou, J. Am. Chem. Soc. 2006, 128, 8754–8756; c) D. Alber-
ico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174–238;
d) J. C. Lewis, R. C. Bergman, J. A. Ellman, Acc. Chem. Res.
2008, 41, 1013–1025; e) W. Liu, Y. H. Li, B. Xu, C. X. Kuang,
Org. Lett. 2013, 15, 2342–2345.
gew. Chem. 2006, 118, 7945; Angew. Chem. Int. Ed. 2006, 45,
7781–7786; c) S. H. Cho, S. J. Hwang, S. Chang, J. Am. Chem.
Soc. 2008, 130, 9254–9256; d) D. Schipper, J. M. El-Salfiti, C. J.
Whipp, K. Fagnou, Tetrahedron 2009, 65, 4977–4983; e) L.-C.
Campeau, D. R. Stuart, J.-P. Leclerc, M. Bertrand-Laperle, E.
Villemure, H.-Y. Sun, S. Lasserre, N. Guimond, M. Lecavallier,
K. Fagnou, J. Am. Chem. Soc. 2009, 131, 3291–3306; f) M. P.
Huestis, K. Fagnou, Org. Lett. 2009, 11, 1357–1360; g) D. La-
pointe, T. Markiewicz, C. J. Whipp, A. Toderian, K. Fagnou,
J. Org. Chem. 2011, 76, 749–759; h) H. Zhao, R. F. Wang, P.
Chen, T. G. Brian, M. H. Ming, W. Zhang, Org. Lett. 2012, 14,
1872–1875; i) J. T. Myers, J. M. Hanna Jr., Tetrahedron Lett.
2012, 53, 612–615; j) A. Larivee, J. J. Mousseau, A. B. Charette,
J. Am. Chem. Soc. 2008, 130, 52–54; k) L.-C. Campeau, B.-L.
Megan, J.-P. Leclerc, E. Villemure, S. Gorelsky, K. Fagnou, J.
Am. Chem. Soc. 2008, 130, 3276–3277; l) L.-C. Campeau, D. J.
Schipper, K. Fagnou, J. Am. Chem. Soc. 2008, 130, 3266–3267;
m) H. Andersson, M. Gustafsson, R. Olsson, F. Almqvist, Tet-
rahedron Lett. 2008, 49, 6901–6903; n) D. J. Schipper, L.-C.
Campeau, K. Fagnou, Tetrahedron 2009, 65, 3155–3164.
[3] a) M. Whiting, J. Muldoon, Y.-C. Lin, S. M. Silverman, W.
Lindstrom, A. J. Olson, H. C. Kolb, M. G. Finn, K. B.
Sharpless, J. H. Elder, V. V. Fokin, Angew. Chem. 2006, 118,
1463–1467; Angew. Chem. Int. Ed. 2006, 45, 1435–1439; b) R.
Hanselmann, G. E. Job, G. Johnson, R. L. Lou, J. G. Mar-
tynow, M. M. Reeve, Org. Process Res. Dev. 2011, 15, 367–375;
c) P. L. Golas, K. Matyjaszewski, Chem. Soc. Rev. 2010, 39,
1338–1354; d) Y. R. Hua, A. H. Flood, Chem. Soc. Rev. 2010,
39, 1262–1271; e) Y.-B. Jiang, C.-X. Kuang, Mini-Rev. Med.
Chem. 2013, 13, 713–719.
[4] a) S. Chuprakov, N. Chernyak, A. S. Dudnik, V. Gevorgyan,
Org. Lett. 2007, 9, 2333–2336; b) L. Ackermann, R. Vicente,
R. Born, Adv. Synth. Catal. 2008, 350, 741–748; c) L. Ackerm-
ann, A. Althammer, S. Fenner, Angew. Chem. 2009, 121, 207–
210; Angew. Chem. Int. Ed. 2009, 48, 201–204; d) L. Ackerm-
ann, H. K. Potukuchi, D. Landsberg, R. Vicente, Org. Lett.
2008, 10, 3081–3084; e) L. Ackermann, R. Vicente, A. Al-
thammer, Org. Lett. 2008, 10, 2299–2302; f) M. Iwasaki, H.
Yorimitsu, K. Oshima, Chem. Asian J. 2007, 2, 1430–1435; g)
L. Ackermann, R. Vicente, Org. Lett. 2009, 11, 4922–4925; h)
B. Liégault, D. Lapointe, L. Caron, A. Vlassova, K. Fagnou,
J. Org. Chem. 2009, 74, 1826; i) O. René, K. Fagnou, Adv.
Synth. Catal. 2010, 352, 2116; j) H. Tao, W. Min, L. Pinha, W.
Lei, Chin. J. Chem. 2012, 30, 979; k) S. I. Kozhushkov, H. K.
Potukuchi, L. Ackermann, Catal. Sci. Technol. 2013, 3, 562.
[5] a) S. A. Kreuger, W. W. Paudler, J. Org. Chem. 1972, 37, 4188–
4190; b) W. W. Paudler, S. A. Humphrey, J. Org. Chem. 1970,
35, 3467–3470.
[7]
[8]
a) H.-Y. Sun, S. I. Gorelsky, D. R. Stuart, L.-C. Campeau, K.
Fagnou, J. Org. Chem. 2010, 75, 8180–8189; b) Y. Tan, B.-L.
Fabiola, J. F. Hartwig, J. Am. Chem. Soc. 2012, 134, 3683–
3686.
a) D. Sasa, C. C. Tzschucke, Org. Lett. 2011, 13, 2310–2313; b)
K. S. Kanyiva, Y. Nakao, T. Hiyama, Angew. Chem. 2007, 119,
9028–9030; Angew. Chem. Int. Ed. 2007, 46, 8872–8874.
[9] a) S. Ueda, M.-J. Su, S. L. Buchwald, Angew. Chem. 2011, 123,
9106–9109; Angew. Chem. Int. Ed. 2011, 50, 8944–8947; b) Y.-
X. Liu, W.-M. Yan, Y.-F. Chen, J. L. Petersen, X.-D. Shi, Org.
Lett. 2008, 10, 5389–5392; c) Y. Luo, Y.-Z. Hu, Synth. Com-
mun. 2003, 33, 3513–3517.
Received: May 21, 2013
Published Online: July 12, 2013
[6] a) L. C. Campeau, S. Rousseaux, K. Fagnou, J. Am. Chem.
Soc. 2005, 127, 18020–18021; b) J.-P. Leclerc, K. Fagnou, An-
Eur. J. Org. Chem. 2013, 5272–5275
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