Aerobic Oxidative Cycloaddition of α-Chlorotosylhydrazones with Arylamines: General Chemoselective Construction of 1,4-Disubstituted and 1,5-Disubstituted 1,2,3-Triazoles under Metal-Free and Azide-Free Conditions

Article abstract of DOI:10.1021/acs.orglett.5b01000

A novel synthetic approach toward 1,4-disubstituted 1,2,3-triazoles and 1,5-disubstituted 1,2,3-triazoles by aerobic oxidative cycloaddition of α-chlorotosylhydrazone with primary aryl amine has been developed. Significantly, the reaction proceeds smoothl

Full text of DOI:10.1021/acs.orglett.5b01000

Letter
pubs.acs.org/OrgLett
Aerobic Oxidative Cycloaddition of α‑Chlorotosylhydrazones with
Arylamines: General Chemoselective Construction of 1,4-
Disubstituted and 1,5-Disubstituted 1,2,3-Triazoles under Metal-Free
and Azide-Free Conditions
Hui-Wen Bai, Zhong-Jian Cai, Shun-Yi Wang,* and Shun-Jun Ji*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science &
Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, 215123, P. R. China
S
* Supporting Information
ABSTRACT: A novel synthetic approach toward 1,4-disub-
stituted 1,2,3-triazoles and 1,5-disubstituted 1,2,3-triazoles by
aerobic oxidative cycloaddition of α-chlorotosylhydrazone with
primary aryl amine has been developed. Significantly, the
reaction proceeds smoothly to afford 1,4-disubstituted 1,2,3-
triazoles and 1,5-disubstituted 1,2,3-triazoles under catalyst-
free, metal-free, azide-free, and peroxide-free conditions.
Scheme 1. A Proposed Route to 1,2,3-Triazoles under Metal-
Free and Azide-Free Conditions
1,2,3-Triazoles are significant five-membered ring heterocyclic
compounds, and they have been widely utilized in synthetic
intermediates, bioactive products, and pharmaceutical drugs.1 It
is well-known that the mixture of both regioisomers could be
obtained by Huisgen’s 1,3-dipolar cycloaddition of alkynes with
organic azides.2 The Cu(I)-catalyzed azide−alkyne cyclo-
addition has been exploited as a vigorous strategy for 1,4-
disubstituted triazoles with high regioselectivity indepently
developed by the groups of Sharpless and Meldal.3,4 The
CuAAC reaction has huge implications in organic synthesis
according to Sharpless’ concept of “Click Chemistry”.5
Subsequently, the 1,5-disubstituted triazole isomers were
achieved by the RuAAC reaction.6 Several other methods
including the IrAAC reaction, Pd-catalyzed alkenyl bromide−
azide cycloaddition, and Ce-catalyzed nitroolefin−azide [3 + 2]
cycloaddition have been developed for the regioselective
synthesis of triazoles.7−9 Nevertheless, all these reactions
could not avoid employing heavy metals, which restricted
their application in biological and life sciences. Metal-free
strategies containing an organocatalytic enamine-mediated
1,2,3-triazole synthesis, an enaminone-azide multicomponent
cascade reaction, and a TsOH-catalyzed nitroolefin−azide
cycloaddition have been reported for the preparation of specific
1,2,3-triazoles.10−12 However, all of these transformations are in
need of sodium azides or organic azides, which are explosive
and toxic. To the best of our knowledge, no literature reports
chemoselective construction of 1,4-disubstituted and 1,5-
disubstituted triazoles using the same strategy. Zhang and co-
workers provided a copper-mediated method to achieve the
desired 1,4-disubstituted 1,2,3-triazoles without the use of
azides.13 Westermann improved Sakai’s reaction and reported
the synthesis of 1,4-disubstituted 1,2,3-triazoles though the
condensation of α,α-dichlorotosylhydrazones and primary
amines under metal-free conditions (Scheme 1a).14,15 Recently,
Ramasastry summarized the synthetic methods for 1,2,3-
triazoles.16 There are rare methods to construct 1,2,3-triazoles,
especially the 1,5-disubstituted 1,2,3-triazoles under metal-free
and azide-free conditions. More recently, we reported a I2/
TBPB mediated oxidative reaction of N-tosylhydrazones with
arylamines, which provided a simple and general approach for
the establishment of 1,4-disubstituted triazoles (Scheme 1b).17
However, only 1,4-disubstituted isomers were obtained. On the
basis of our previous work, herein, we demonstrate a novel
synthetic approach toward 1,4-disubstituted and 1,5-disubsti-
tuted triazoles by the cycloaddition of α-chlorotosylhydrazones
with arylamines under metal-free and azide-free conditions
(Scheme 1c).
Received: April 7, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01000
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Organic Letters
Letter
a
We initiated our study by α-chlorotosylhydrazone and aniline
3a in the conditions of DMSO (1 mL), 50 °C for 3 h. As the α-
chlorotosylhydrazone could be easily generated from the
addition of α-chloroacetophenone 1a and p-toluene-
sulfonhydrazide 2a in the solvent Et2O (1 mL), we adopted a
one-pot method without isolating the intermediate. To our
delight, 1,4-diphenyl-1,2,3-triazole 4a was detected in 38% LC-
yield. With the aim to improve the yield of 4a, we examined the
influences of solvents, temperature, ratio of substrates, and so
on. Among the different solvents, it was found that DMF was
the suitable solvent for this reaction (Table 1, entries 1−10).
Scheme 2. Substrate Scope of Reaction
a
Table 1. Optimization of the Reaction Conditions
b
entry
atmosphere
temp (°C)
solvent
THF
yield (LC)
1
air
air
air
air
air
air
air
air
air
air
air
air
air
air
air
air
O2
Ar
50
50
50
50
50
50
50
50
50
50
40
60
70
80
50
50
50
50
57
33
40
5
2
toluene
MeCN
CH2Cl2
DMF
3
4
5
64
38
36
21
41
17
57
41
37
28
6
DMSO
1,4-dioxane
EA
7
8
9
MeOH
CHCl3
DMF
10
11
12
13
14
15
16
17
18
DMF
DMF
a
Reaction conditions (unless otherwise noted): 1a (0.3 mmol) and 2a
(0.3 mmol) were performed in Et2O (1 mL) at room temperature for
12 h. Then removing the solvent, DMF (1 mL) and 3 (0.6 mmol)
were added at room temperature. The mixture was stirred at 50 °C for
DMF
c
DMF
37
d
DMF
51
b
c
DMF
75
8
3 h. Isolated yield. 3 (0.3 mmol) was used. The reaction was
performed for 6 h. The reaction was performed for 20 h. The
reaction was performed for 8 h.
d
e
DMF
a
Reaction conditions: 1a (0.3 mmol) and 2a (0.3 mmol) were
performed in Et2O (1 mL) at room temperature for 12 h. Then after
removal of the solvent, solvent (1 mL) and 3a (0.6 mmol) were added
b
at room temperature. The mixture was stirred at 50 °C for 3 h. Yields
electron-withdrawing substituents (−Cl, −Br, −COOEt)
proceeded smoothly with good yields (4b, 4i, 4d−4f).
Similarly, when β-CH3 substituted arylamines were participat-
ing in the reactions, the desired products 4c and 4j were
obtained in 69% and 58% yields, respectively. Nevertheless,
when 2-bromoaniline with a sterically demanding substituent
group was used, the triazole 4h could also be observed in 38%
yield. 2-Naphthylamine also exhibited good reactivity to give
the product 4g. Unfortunately, 4-nitroaniline resulted in the
corresponding product 4k in 11% yield. These results indicated
that the electronic effect of the substituents of arylamines
influenced the yields. Subsequently, different in situ prepared α-
chlorotosylhydrazones were applied to the reaction with aniline
3. A longer reaction time was required when the benzene ring
of α-chloroketones was bearing a substituent group. In the case
of aromatic rings containing electron-donating groups (−CH3,
−OCH2CH3), the yields of the reaction decreased slightly. The
reactions were compatible with the substituents of 3-F and 4-
Br, giving the compounds 4o and 4p in good yields,
respectively. The reaction of 2-chloro-1-(4-nitropheyl)ethan-
1-one could also work. However, the yield of 4q was only 14%.
Unfortunately, the reaction of alkyl amine such as benzylamine
were determined by LC analysis using biphenyl as the internal
c
d
standard. 2a:3a = 1:1.5. 2a:3a = 1:2.5
Increasing or decreasing the temperature did not have a
beneficial effect on the reaction (Table 1, entries 11−14).
Changing the amount of aniline 3a led to lower yields (Table 1,
entries 15−16). A higher yield was obtained in an atmosphere
of O2, while, in the Ar atmosphere, a trace of product 4a was
detected (Table 1, entries 17−18). Consequently, the
optimized conditions were obtained: 1a (0.3 mmol), 2a (0.3
mmol), Et2O (1 mL), 12 h, 3a (0.6 mmol), DMF (1 mL), 50
°C, 3 h.
Under our optimized experimental conditions, different
arylamines and α-chloroketones were tested. As listed in
Scheme 2, various arylamines were tested in the reaction of α-
chlorotosylhydrazones which could be in situ observed by the
condensation of α-chloroketones with p-TsNHNH2 and
directly used for the next step reaction without further
purification. lt was found that a range of arylamines could be
transformed into the corresponding 1,4-disubstituted-1,2,3-
triazoles in moderate to good yields. Arylamines bearing
electron-donating substituents (−CH3, −OCH2CH3) or
B
DOI: 10.1021/acs.orglett.5b01000
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
failed to give the desired products under the identical
conditions.
Scheme 4. Control Experiments
Since 1,4-disubstituted 1,2,3-triazoles could be obtained by
the cyclization of α-chloroketones derived tosylhydrazones with
arylamines under mild conditions, we reasoned that 1,5-
disubstituted triazoles could also be obtained utilizing the same
strategy by the reaction of α-chloroaldehyde derived tosylhy-
drazones and arylamines. Considering that α-chloroaldehydes
were easily oxidized, the required α-chlorotosylhydrazones 5
were synthesized separately in Et2O in good yields. Fortunately,
this idea worked well. The reaction of 2-chloro-3-phenypropa-
nal derived tosylhydrazone 5a and aniline 4a proceeded
smoothly to give the desired 5-benzyl-1-phenyl-1,2,3-triazole
6a in 60% isolated yield (Scheme 3). With this promising result
a
Scheme 3. Substrate Scope of Reaction
Meanwhile, the intermediate B also could not lead to 4a in the
presence of anline (Scheme 4, eq 2). To our surprise, the
reaction of intermediate B with aniline hydrochloride (1 equiv
or 20 mol %) gave 4a in 92% and 90% yields, respectively
(Scheme 4, eqs 3 and 4). These results indicated that a proton
has a significant role in the reactions.
Based on the results at hand and the literature reports, a
plausible reaction pathway is proposed in Scheme 5. α-
Scheme 5. Mechanism Studies
a
Reaction conditions (unless otherwise noted): 3 (0.6 mmol) was
added to a stirred ice-cooled (0 °C) solution of 5 (0.3 mmol) in DMF
(1 mL). The mixture was stirred for at 0 °C for 1 h and then warmed
b
c
to 50 °C for 4 h. Isolated yield. 3 (0.3 mmol) was used. The reaction
was performed for 8 h.
in hand, we next explored a range of arylamines with 5a. The 4-
substituted anilines with electron-donating groups (−CH3,
−OCH2CH3) provided the product 6b and 6i in good yields,
respectively. The substrates of 4-bromoaniline and ethyl 4-
aminobenzoate could also be converted to the desired products
in lower yields for their poor nucleophilicity. Moreover, the
transformation was not influenced by the position of the
substituent groups, even the steric hindrance at the β-position
on benzene rings (6e, 6f, 6g, 6h). 2-Chlorooctanal derived
tosylhydrazone 5b could also take part in the reactions to give
the 1,5-disubstituted 1,2,3-trazoles 6j and 6k smoothly in good
yields, respectively.
Chlorotosylhydrazone easily converts to the azoalkene A and
leaves aniline hydrochloride by the reaction with anline. The
1,4-addition of A with amine gives B.18 B (Ts functional group
of B) is protonated by benzenaminium to give the activated
intermediate C. After intramolecular cyclization of C with the
leaving of 4-methylbenzenesulfinic acid, D is formed. D loses
H+ to give the neutral intermediate E. Following subsequent
further oxidation by O2, E converts to the desired 1,2,3-triazole.
In summary, we have developed a new methodology for the
synthesis of 1,4-disubstituted and 1,5-disubstituted 1,2,3-
triazoles from arylamines with α-chloroketone derived tosylhy-
drazones and α-chloroaldehyde derived tosylhydrazones.
Significantly, this transformation provides selective synthesis
of both regioisomers of 1,2,3-triazoles under metal-free and
azide-free conditions. Further investigations to establish other
heterocylic compounds by α-chlorotosylhydrazones under mild
To further understand the reaction mechanism, the control
experiments of B have been carried out as shown in Scheme 4.
It was found that the intermediate B failed to result in the
triazole 4a under the standard conditions (Scheme 4, eq 1).
C
DOI: 10.1021/acs.orglett.5b01000
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(9) Wang, Y. C.; Xie, Y. Y.; Qu, H. E.; Wang, H. S.; Pan, Y. M.;
Huang, F. P. J. Org. Chem. 2014, 79, 4463−4469.
conditions are ongoing in our laboratory and will be reported in
due course.
(10) (a) Brunner, M.; Maas, G.; Klarner, F.-G. Helv. Chim. Acta 2005,
88, 1813−1825. (b) Belkheira, M.; El Abed, D.; Pons, J.-M.; Bressy, C.
Chem.Eur. J. 2011, 17, 12917−12921. (c) Danence, L. J. T.; Gao, Y.;
Li, M.; Huang, Y.; Wang, J. Chem.Eur. J. 2011, 17, 3584−3587.
(d) Seus, N.; Goncalves, L. C.; Deobald, A. M.; Savegnago, L.; Alves,
D.; Paixao, M. W. Tetrahedron. 2012, 68, 10456−10463. (e) Wang, L.;
Peng, S.; Danence, L. J. T.; Gao, Y.; Wang, J. Chem.Eur. J. 2012, 18,
6088−6093. (f) Li, W.; Jia, Q.; Du, Z.; Wang, J. Chem. Commun. 2013,
49, 10187−10189.
ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures and characterization data.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01000.
■
S
(11) Cheng, G.; Zeng, X.; Shen, J.; Wang, X.; Cui, X. Angew. Chem.,
Int. Ed. 2013, 52, 13265−13268.
AUTHOR INFORMATION
Corresponding Authors
■
(12) (a) Thomas, J.; John, J.; Parekh, N.; Dehaen, W. Angew. Chem.,
Int. Ed. 2013, 53, 10155−10159. (b) Quan, X.-J.; Ren, Z.-H.; Wang,
Y.-Y.; Guan, Z.-H. Org. Lett. 2014, 16, 5728−5731.
(13) (a) Chen, Z. K.; Yan, Q. Q.; Liu, Z. X.; Xu, Y. M.; Zhang, Y. H.
Angew. Chem., Int. Ed. 2013, 52, 13324−13328. (b) Chen, Z.; Yan, Q.;
Yi, H.; Liu, Z.; Lei, A.; Zhang, Y. Chem.Eur. J. 2014, 20, 13692−
13697.
*E-mail: shunyi@suda.edu.cn.
*E-mail: shunjun@suda.edu.cn.
Notes
The authors declare no competing financial interest.
(14) van Berkel, S. S.; Brauch, S.; Gabriel, L.; Henze, M.; Stark, S.;
Vasilev, D.; Wessjohann, L. A.; Abbas, M.; Westermann, B. Angew.
Chem., Int. Ed. 2012, 51, 5343−5346.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Natural Science Foundation of
China (21172162, 21372174), the Young National Natural
Science Foundation of China (No. 21202111), the Ph.D.
Programs Foundation of Ministry of Education of China
(2013201130004), the Young Natural Science Foundation of
Jiangsu Province (BK2012174), PAPD, Key Laboratory of
Organic Synthesis of Jiangsu Province (KJS1211), and
Soochow University for financial support.
(15) Sakai, K.; Hida, N.; Kondo, K. Bull. Chem. Soc. Jpn. 1986, 59,
179−183.
(16) Ramasastry, S. S. V. Angew. Chem., Int. Ed. 2014, 53, 14310−
14312.
(17) Cai, Z.-J.; Lu, X.-M.; Zi, Y.; Yang, C.; Shen, L.-J.; Li, J.; Wang, S.-
Y.; Ji, S.-J. Org. Lett. 2014, 16, 5108−5111.
(18) (a) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone, P.;
Mantellini, F.; Perrulli, F. R.; Santeusanio, S. Eur. J. Org. Chem. 2009,
3109−3112. (b) Rossi, E.; Arcadi, A.; Abbiati, G.; Attanasi, O. A.;
Crescentini, L. D. Angew. Chem., Int. Ed. 2002, 41, 1400−1402.
(c) Attanasi, O. A.; Favi, G.; Filippone, P.; Giorgi, G.; Mantellini, F.;
Moscatelli, G.; Spinelli, D. Org. Lett. 2008, 10, 1983−1986.
(d) Attanasi, O. A.; Favi, G.; Filippone, P.; Mantellini, F.;
Moscatelli, D.; Perrulli, F. R. Org. Lett. 2010, 12, 468−471.
(e) Attanasi, O. A.; Favi, G.; Mantellini, F.; Moscatelli, G.;
Santeusanio, S. Adv. Synth. Catal. 2011, 353, 1519−1524. (f) Chen,
REFERENCES
■
(1) (a) Wamhoff, H. In Comprehensive Heterocyclic Chemistry, Vol. 5;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; p 669.
(b) Abu-Orabi, S. T.; Atfah, M. A.; Jibril, I.; Mari’I, F. M.; Ali, A. A. J.
Heterocycl. Chem. 1989, 26, 1461−1468. (c) Fan, W.-Q.; Katritzky, A.
R. In Comprehensive Heterocyclic Chemistry II, Vol. 4; Katritzky, A. R.,
Rees, C. W., Scriven, E. F. V., Eds.; Elsevier Science: Oxford, 1996; p
1−126. (d) Alvarez, R.; Velazquez, S.; San, F.; Aquaro, S.; De, C.;
Perno, C. F.; Karlsson, A.; Balzarini, J.; Camarasa, M. J. J. Med. Chem.
1994, 37, 4185−4181. (e) Baures, P. W. Org. Lett. 1999, 1, 249−252.
(f) Palmer, L. M.; Janson, C. A.; Smith, W. W. PCT Int. Appl. 2005; p
347. CODEN: PIXXD2 WO 2005016237 A2 20050224, CAN:
142:256748 (patent written in English).
J.-R.; Dong, W.-R.; Candy, M.; Pan, F.-F.; Jorres, M.; Bolm, C. J. Am.
̈
Chem. Soc. 2012, 134, 6924−6927. (g) Hatcher, J. M.; Coltart, D. M. J.
Am. Chem. Soc. 2010, 132, 4546−4547. (h) Tong, M.-C.; Chen, X.; Li,
J.; Huang, R.; Tao, H.; Wang, C.-J. Angew. Chem., Int. Ed. 2014, 53,
4680−4684.
(2) (a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565−598.
(b) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 633−645.
(c) Huisgen, R.; Knorr, R.; Mobius, L.; Szeimies, G. Chem. Ber. 1965,
̈
98, 4014−4021.
(3) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem. 2002, 114, 2708−2711; Angew. Chem., Int. Ed. 2002, 41,
2596−2599.
(4) Tornøe, C. W.; C. Christensen, C.; Meldal, M. J. Org. Chem.
2002, 67, 3057−3064.
(5) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2001, 40, 2004−2021.
(6) (a) Zhang, L.; Chen, X. G.; Xue, P.; Sun, H. H. Y.; Williams, I. D.;
Sharpless, K. B.; Fokin, V. V.; Jia, G. J. Am. Chem. Soc. 2005, 127,
15998−15999. (b) Rasmussen, L. K.; Boren, B. C.; Fokin, V. V. Org.
Lett. 2007, 9, 5337−5339. (c) Boren, B. C.; Narayan, S.; Rasmussen, L.
K.; Zhang, L.; Zhao, H.; Lin, Z.; Jia, G.; Fokin, V. V. J. Am. Chem. Soc.
2008, 130, 8923−8930. (d) Johansson, J. R.; Lincoln, P.; Norden, B.;
Kann, N. J. Org. Chem. 2011, 76, 2355−2359. (e) For Sm(III)-
catalyzed azide−alkyne cycloaddition, see: Hong, L.; Lin, W.; Zhang,
F.; Liu, R.; Zhou, X. Chem. Commun. 2013, 49, 5589−5591.
(7) Ding, S.; Jia, G.; Sun, J. Angew. Chem., Int. Ed. 2014, 53, 1877−
1880.
(8) Barluenga, J.; Valdes
Angew. Chem., Int. Ed. 2006, 45, 6893−6896.
́ ́
, C.; Beltran, G.; Escribano, M.; Aznar, F.
D
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