I2/TBPB mediated oxidative reaction of N-tosylhydrazones with anilines: Practical construction of 1,4-disubstituted 1,2,3-triazoles under metal-free and azide-free conditions

Article abstract of DOI:10.1021/ol502431b

An efficient I₂ (20 mol %)/TBPB mediated oxidative formal [4 + 1] cycloaddition of N-tosylhydrazones with anilines via C-N/N-N bond formation and S-N cleavage has been developed. This protocol represents a simple, general, and efficient approac

Full text of DOI:10.1021/ol502431b

Letter
pubs.acs.org/OrgLett
I2/TBPB Mediated Oxidative Reaction of N‑Tosylhydrazones with
Anilines: Practical Construction of 1,4-Disubstituted 1,2,3-Triazoles
under Metal-Free and Azide-Free Conditions
Zhong-Jian Cai, Xin-Mou Lu, You Zi, Chao Yang, Ling-Jie Shen, Jian Li, Shun-Yi Wang,*
and Shun-Jun Ji*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, China
S
* Supporting Information
ABSTRACT: An efficient I2 (20 mol %)/TBPB mediated
oxidative formal [4 + 1] cycloaddition of N-tosylhydrazones
with anilines via C−N/N−N bond formation and S−N
cleavage has been developed. This protocol represents a
simple, general, and efficient approach for the construction of
1,2,3-triazoles under metal-free and azide-free conditions by
utilizing a catalytic amount of I2.
Scheme 1. Metal-Free Strategies for the Construction of
1,2,3-Triazoles
1,2,3-Triazoles are important N-heterocycles with wide
applications in chemistry and material science. They serve as
versatile synthetic intermediates, biological intermediates, lead
molecules, linkers, and various drugs.1 1,2,3-Triazoles can be
obtained conventionally through a Huisgen cycloaddition of
azides and alkynes with poor regioselectivity.2 The powerful
and highly regioselective copper-catalyzed azide−alkyne-cyclo-
addition (CuAAC), developed independently by the Sharpless
and Meldal groups,4 affords 1,4-disubstituted 1,2,3-triazoles
easily. With Sharpless’s concept of “click chemistry”,5 1,2,3-
triazoles found numerous new applications6 and their synthesis
was popularized.7−12 1,2,3-Triazoles can also be prepared by
RuAAC,8 IrAAC,9 as well as Pd-catalyzed reactions of alkenyl
bromides with azides.10 However, all of these reactions utilize
heavy metals, which are not ideal for biological applications in
view of their cytotoxicity. Recently, the organocatalytic reaction
of ketones with azides has been investigated for the synthesis of
1,4,5-trisubstituted 1,2,3-triazoles and reported by Ramachary,
Wang, and Bressy et al.11 (Scheme 1, eq 1). More recently,
Dehaen12 developed a new organocatalytic strategy to
synthesize 1,4,5-trisubstituted 1,2,3-triazoles with multicompo-
nent reactions (MCRs) of readily available aldehydes, nitro-
alkanes, and organic azides (Scheme 1, eq 2). However, all of
these reactions require sodium azides or organic azides, which
are explosive. Therefore, the development of an efficient and
straightforward synthesis of 1,2,3-triazoles from simple, readily
accessible, and inexpensive materials is highly sought after.
To the best of our knowledge, the construction of 1,2,3-
triazoles under metal-free and azide-free conditions has rarely
been reported.13 In 1986, Sakai et al. described the construction
of 1,4-substituted triazole via the condensation of a primary
amine and an α,α-dichlorotosylhydrazone under ambient
reaction conditions (Scheme 1, eq 3).13a In 2012, Westermann
et al. fully exploited the mechanism, scope, and limitations of
the Sakai triazole formation reaction and illustrated the
suitability of this transformation as a strategy for metal-free
triazole construction (Scheme 1, eq 3).13b More recently,
Zhang’s group has reported the synthesis of 1,2,3-triazoles by
the reaction of N-tosylhydrazones and anilines in the presence
of 1.0 equiv of Cu(OAc)2 and additive.14 As part of our efforts
on I2/TBHP15 or I2/O2-mediated reactions,16 herein we
demonstrate an efficient I2 (20 mol %)/TBPB mediated
oxidative formal [4 + 1] cycloaddition of N-tosylhydrazones
with anlines with broad functional groups tolerance via C−N/
N−N bond formation and S−N cleavage, which provides a
simple and general approach for the construction of 1,2,3-
triazoles in moderate to good yields under metal-free and azide-
free conditions (Scheme 1, eq 4).
Received: August 20, 2014
© XXXX American Chemical Society
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Letter
a
Table 1. Optimization of the Reaction Conditions
entry
catalyst (mol %)
temp (°C)
oxidant (equiv)
solvent (mL)
additive (equiv)
yield (LC−MS)
1
I2 (20)
NaI (20)
KI (20)
NIS (20)
TBAI (20)
PIDA (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
80
80
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBPB (2)
TEMPO (2)
CHP (2)
CH3CN (3)
CH3CN (3)
CH3CN (3)
CH3CN (3)
CH3CN (3)
CH3CN (3)
CH3CN (3)
CH3CN (3)
CH3CN (3)
CH3CN (3)
CH3CN (3)
toluene (3)
39
2
13
3
80
10
4
80
32
5
80
16
6
80
NR
67
7
80
8
80
NR
50
9
80
10
11
12
13
14
15
16
17
18
19
20
21
22
80
K2S2O8 (2)
O2 (2)
41
80
16
80
TBPB (2)
TBPB (2)
TBPB (2)
TBPB (2)
TBPB (2)
TBPB (2)
TBPB (2)
TBPB (2)
TBPB (2)
TBPB (2)
TBPB (2)
68
80
DMF (3)
trace
26
80
DMSO (3)
80
1,4-dioxane (3)
DCE (3)
75
80
70
80
EtOH (3)
43
b
100
100
100
100
100
1,4-dioxane (3)
1,4-dioxane (3)
1,4-dioxane (3)
1,4-dioxane (3)
1,4-dioxane (3)
89 (84)
HOAc (2)
PivOH (2)
Na2CO3 (2)
Et3N (2)
86
86
NR
trace
a
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), catalyst (0.1 mmol), oxidant (1.0 mmol), addtive (1.0 mmol), solvent (3 mL), 12 h; TBHP =
tert-butyl hydroperoxide (70% in water); TBPB = tert-butyl peroxybenzoate; TEMPO = 2,2,6,6-tetramethyl-1-piperidinyloxy; CHP = cumene
b
hydroperoxide. The yields were determined by LC analysis using biphenyl as the internal standard. Isolated yield.
Our study was initiated by treating 4-methyl-N′-(1-
phenylethylidene)benzenesulfonohydrazide 1a and p-toluidine
2a with I2 (20 mol %) in the presence of TBHP (2.0 equiv) and
CH3CN (3 mL), 80 °C for 12 h. To our delight, 4-phenyl-1-(p-
tolyl)-1H-1,2,3-triazole 3a was formed in 39% yield by LC. In
order to improve the yield of 3a, we further screened different
catalysts, solvents, oxidants, and reaction temperature, as well as
additives (for more details see Supporting Information). As
presented in Table 1, the reaction proceeded less efficiently in
other iodine-containing catalysts such as NaI, KI, NIS, TBAI,
and PIDA (Table 1, entries 2−6). After further screening of
reaction was carried out in 1,4-dioxane, it was noted that the
LC yield of 3a could be increased to 75% (Table 1, entry 15).
Moreover, a higher temperatrue could further increase the LC
yield of 3a to 89% in further (Table 1, entry 16). However, the
yield did not improve significantly when HOAc or PivOH was
added to the reaction (Table 1, entries 19 and 20).
Furthermore, we failed to isolate the desired product 3a
when base (such as Na2CO3 and Et3N) was added to the
reaction. Thus, the optimized catalytic system was established:
1a (0.5 mmol), 2a (0.5 mmol), I2 (0.1 mmol), TBPB (1.0
mmol), and 1,4-dioxane (3 mL) at 100 °C for 12 h.
Scheme 2. Reactions with Various N-Tosylhydrazones and
2a
a
a
Reaction conditions: 1 (0.5 mmol), 2a (0.5 mmol), I2 (0.1 mmol),
With the optimized conditions in hand, we next investigated
the substrate scope of this protocol (Scheme 2). A range of N-
tosylhydrazones could be converted into the corresponding 1,4-
disubstituted 1,2,3-triazoles in moderate-to-good yield (3b−3i,
53−80%). It was found that electron-donating groups (-CH3,
-OCH3, -t-Bu) or halogen-substituted (-F, -Cl, -Br) substrates
could react smoothly to afford the desired products. Notably,
when ortho- or meta-CH3 substituted N-tosylhydrazones were
TBPB (1.0 mmol), 1,4-dioxane (3 mL), 100 °C, 12 h. Isolated yields.
used as the substrates, a similar yield was observed (3h, 74%, 3i,
68%). The structure of 3g was further confirmed by X-ray
crystallography.17 It is interesting to note that some triazoles
bearing halide functional group such as 3e−3g show poor
B
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Letter
solubility in most of the deute rated solvents but have good
solubility in deuterated trifluoroacetic acid.
Scheme 4. Synthetic Expansion of the Reaction of 1 and 2
Next, we explored the scope of aniline (Scheme 3). The
reactions of aniline or 4-substituted anilines with N-
a
Scheme 3. Reactions of Various 1a and Anilines 2
Based on the results and the literature reports,13,18,19
plausible mechanism for the I2/TBPB mediated oxidative
formal [4 + 1] cycloaddition toward 1,2,3-triazoles is illustrated
in Scheme 5. The N-tosylhydrazone 1a is converted to a iodo-
a
Scheme 5. A Plausible Mechanism
a
substituted intermediate A, in the presence of I2. The azoalkene
B18 is formed by the leaving of HI along with a catalytic cycle of
I− being oxidized to I2 by TBPB. Then, the addition of 2a to
the in situ generated azoalkene B to give C, which is further
oxidized to give the corresponding radical cation D19 under
basic conditions. An intramolecular addition takes place to
furnish the intermediate E. After a further oxidation of E,
followed by a subsequent oxidation of E to give the desired
product 3a.
In conclusion, we have developed an efficient I2/TBPB
mediated oxidative formal [4 + 1] cycloaddition of N-
tosylhydrazones with anilines. This transformation provides a
practical synthetic method for the construction of 1,2,3-
triazoles in the absence of azides and heavy metals. This
protocol involves the functionalization of the C(sp3)−H bond,
the formation of C−N/N−N bonds, and the cleavage of S−N
in one manipulation. Further studies to understand the
mechanism of the I2/TBPB mediated reaction and extend
this protocol to synthetic applications are ongoing in our
laboratory.
Reaction conditions: 1a (0.5 mmol), 2 (0.5 mmol), I2 (0.1 mmol),
TBPB (1.0 mmol), 1,4-dioxane (3 mL), 100 °C, 12 h. Isolated yields.
tosylhydrazone took place smoothly to furnish the desired
1,4-disubstituted 1,2,3-triazoles 3j−3n in 56−87% isolated
yields. The fluoro, chloro, and bromo group could be tolerated
in the reaction conditions to generate the desired functionalized
1,4-disubstituted 1,2,3-triazoles in moderate yields (3o−3q,
54−67%). The reaction of ethyl 4-aminobenzoate could also
lead to the desired product 3r in 38% yield, which is probably
due to the electron-withdrawing effect of the ester group.
Moreover, the reaction is not affected by the position of the
substituents on the aromatic ring of anilines (3s−3t, 76−80%).
When more sterically demanding substrates (2-isopropylaniline
and [1,1′-biphenyl]-2-amine) were applied, the reaction
proceeded smoothly to afford the desired products 3u and 3v
in 80% and 83% yields, respectively. The structure of 3v was
also further confirmed by X-ray crystallography (for details see
Supporting Information).17
The synthetic expansion of this metal-free and azide-free
oxidative formal [4 + 1] cycloaddition reaction are demon-
strated in Scheme 4. When N-tosylhydrazone 1a was treated
with the alkenyl- or alkynyl-aniline (3x, 3y), the desired
products could be obtained in 64% and 49% yields, respectively.
It should be noted that the optimized conditions could tolerate
the alkene and alkyne functional groups.
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures and characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
C
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Y.; Wang, J. Chem.Eur. J. 2011, 17, 3584. (c) Belkheira, M.; Abed,
D. E.; Pons, J.-M.; Bressy, C. Chem.Eur. J. 2011, 17, 12917.
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(13) (a) Sakai, K.; Hida, N.; Kondo, K. Bull. Chem. Soc. Jpn. 1986, 59,
179. (b) van Berkel, S. S.; Brauch, S.; Gabriel, L.; Henze, M.; Stark, S.;
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: shunyi@suda.edu.cn.
*E-mail: shunjun@suda.edu.cn.
Notes
The authors declare no competing financial interest.
(14) Chen, Z.; Yan, Q.; Liu, Z.; Xu, Y.; Zhang, Y. Angew. Chem., Int.
Ed. 2013, 52, 13324.
(15) Cai, Z.-J.; Wang, S.-Y.; Ji, S.-J. Org. Lett. 2013, 15, 5226.
(16) Hao, W.-J.; Wang, J.-Q.; Xu, X.-P.; Zhang, S.-L.; Wang, S.-Y.; Ji,
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(17) Compounds 3g and 3v were determined by X-ray
crystallography. See the Supporting Information for full details.
CCDC 1001829 (3g) and 1001828 (3v) contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Natural Science Foundation of
China (No. 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 and Soochow Uni-
versity for financial support.
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