Iodine-Mediated Condensation–Cyclization of α-Azido Ketones with p-Toluenesulfonyl Hydrazide for Synthesis of 4-Aryl-NH-1,2,3-Triazoles

Article abstract of DOI:10.1002/ejoc.202000146

A molecular iodine mediated condensation–cyclization reaction for the synthesis of 4-aryl-NH-1,2,3-triazoles has been developed from readily available α-azido acetophenones and p-toluenesulfonyl hydrazide. This reaction provides a metal-free strategy for the sequential formation of C–N and N–N bonds in mild condition.

Full text of DOI:10.1002/ejoc.202000146

A Journal of
Accepted Article
Title: Iodine-Mediated Condensation/Cyclization of α-Azido Ketones
with p-Toluenesulfonyl Hydrazide for Synthesis of 4-Aryl-
NH-1,2,3-Triazoles
Authors: Ming-Tian Ren, Min Li, An-Jing Wang, Jie Gao, Xiang-Xiang
Zhang, and Wen-Ming Shu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000146
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10.1002/ejoc.202000146
European Journal of Organic Chemistry
COMMUNICATION
Iodine-Mediated Condensation/Cyclization of α-Azido Ketones
with p-Toluenesulfonyl Hydrazide for Synthesis of 4-Aryl-NH-
1,2,3-Triazoles
Ming-Tian Ren,[a],‡ Min Li,[a],‡ An-Jing Wang,[a] Jie Gao,*[b] Xiang-Xiang Zhang,[a] and Wen-Ming Shu*[a]
‡These authors contributed equally to this work.
[a]
[b]
College of Chemistry and Environmental Engineering, Yangtze University,
Jingzhou 434023, P. R. China
E-mail: shuwm@yangtzeu.edu.cn
Hubei Key Laboratory of Radiation Chemistry and Functional Materials, Hubei University of Science and Technology,
Xianning 437100, P. R. China
E-mail: gaojie2019@hbust.edu.cn
Supporting information for this article is given via a link at the end of the document.
Abstract: A molecular iodine mediated condensation/cyclization
reaction for the synthesis of 4-aryl-NH-1,2,3-triazoles has been
developed from readily available α-azido acetophenones and p-
nitroolefins and sodium azide for the synthesis of 4-aryl-NH-1,2,3-
triazoles (path III).[4c, 9] Kuang reported a Cu-catalyzed cyclization
reaction leading to 1H-1,2,3-triazoles from 1,1-dibromoalkenes
and sodium azide (path IV).[10] Barluenga reported a Pd-catalyzed
cyclization for the construction of NH-triazoles from alkenyl
halides and sodium azide (path V).[11] Kuang developed a
palladium-catalyzed reaction for the preparation of 4-aryl-1H-
1,2,3-triazoles from anti-3-aryl-2,3-dibromopropanoic acids and
sodium azide (path VI).[12] Furthermore, there are other efficient
synthetic strategies that give access to NH-1,2,3-triazoles in one-
pot procedures.[13] Despite these advances, these methods share
a limitation in that inorganic azides are not good substrates.
However, organic azides have been utilized to synthesize NH-
1,2,3-triazoles for needing two-step reaction. Therefore, the
development of versatile and practical methods that utilize
organic azides for the direct synthesis of NH-1,2,3-triazoles is
highly desirable. Based on our research interest in 1,2,3-
triazole,[14] herein, we report an efficient strategy access to
toluenesulfonyl hydrazide. This reaction provides
a metal-free
strategy for the sequential formation of C-N and N-N bonds in mild
condition.
NH-1,2,3-triazoles are an important class of nitrogen-containing
heterocyclic compounds, and their derivatives exhibit widespread
potent biological and pharmaceutical activities, such as inhibition
of IDO, hMetAP2, HER2, and VIM-2, and anticancer activity
(Figure 1).[1]
Figure 1. Selected biologically active NH-1,2,3-triazoles.
Because of their importance, several excellent works on the
synthesis of NH-1,2,3-triazoles have been reported.[2] The main
synthetic routes to NH-1,2,3-triazoles include the copper-
catalyzed azide-alkyne cycloaddition (CuAAC),[3] substituted
alkene reactions with sodium azide,[4] deprotection of N-protected
1,2,3-triazoles[5] and others[6]. For example, Yang et al. explored
an efficient preparation of N-unsubstituted 1,2,3-triazoles by
copper-mediated cycloaddition of nonactivated terminal alkynes
and sodium azide (path I, Scheme 1a).[7] Lee and coworkers
demonstrated a noble Ag-decorated graphene oxide catalyst for
use in a decarboxylative click reaction (path II).[8] Later, the Guan
Group developed a p-TsOH-mediated 1,3-dipolar cycloaddition of
Scheme 1. Strategies for the construction of 4-Aryl-NH-1,2,3-Triazoles.
1
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10.1002/ejoc.202000146
European Journal of Organic Chemistry
COMMUNICATION
NH-1,2,3-triazoles
condensation/cyclization of
toluenesulfonyl hydrazide (Scheme 1b).
via
a
molecular
α-azido ketones
iodine
promoted
with p-
With the optimized conditions in hand, we subsequently
investigated the substrate scope of this reaction, as shown in
Scheme 2. The results indicate that the electronic nature of the
substrate had little effect on the reaction. Various α-azido ketones
bearing electron-donating (4-Me, 3,4-2Me, 3-OMe, 4-OMe, Ph)
substituents attached to the benzene ring afforded the
corresponding products in good yields (3a–3e, and 3p; 69-87%).
In addition, the α-azido ketones with electron-withdrawing groups
(3-NO2, 4-NO2, 3-CN, and 4-CN) could also be converted into
corresponding products 3l-3o in moderate-to-good yields (56-
75%). Furthermore, the halo-substituted (4-F, 3-Cl, 4-Cl, 3,4-2Cl,
3-Br, 4-Br) substrates worked well to produce the expected
products 3f-3k in good-to-excellent yields (70-89%). Much to our
satisfaction, when the substituents were heterocycles (2-furyl, 2-
thienyl) or 2-naphthyl the products were provided in 67%-80%
yield (3q-3s). However, cyclopropyl α-azido ketone was not
tolerated in this annulation reaction, and we could not gain the
corresponding product 3t.
Initially, we employed 2-azido-1-phenylethan-1-one (1a) and p-
toluenesulfonyl hydrazide 2 as a model reaction to screen the
reaction conditions, and the results are summarized in Table 1.
To our delight, triazole 3a was furnished with 51% yield in the
presence of 0.3 equivalent iodine at 90 °C for 3 h (Table1, entry
1). Subsequently, the equivalent of iodine was evaluated, and 0.5
equivalent was found to be the most efficient for the reaction
(entries 2–4). In addition, the product 3a was not afforded when
the reaction was performed in the absence of I2 and additives
(entry 5). Variation of the reaction temperature confirmed that
100 °C was the optimal condition for this protocol, with yields up
to 69% (entries 6-9). In order to further improve the yield, additives
(K2S2O8, TBHP, DTBP, H2O2, and Oxone) were added, and TBHP
increased the yield to 87% (entries 10–14). Furthermore, the
product 3a was also afforded when the reaction proceeded in the
presence of TBHP only, but the yield was 67% (entry 15). Other
solvents (DMF, DMA, dioxane, toluene, CH3NO2, and AcOH) lead
to lower yields (entries 16–21). Further investigation into the
iodine source (NaI and KI) revealed that molecular iodine was an
efficient reagent for this transformation (entries 22–23).
Table 1. Optimization of the Reaction Conditions. [a]
Entry
Solvent
Additive
I2 (equiv)
Temp. (°C)
Yield (%)[b]
1
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
-
0.3
0.5
0.8
1.0
-
90
51
59
57
55
0
2
-
90
3
-
90
4
-
90
5
-
90
6
-
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
-
120
110
100
80
66
65
69
52
56
87
63
71
80
67
13
15
0
7
-
8
-
9
-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
K2S2O8
TBHP
DTBP
H2O2
Oxone
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
100
100
100
100
100
100
100
100
100
100
100
100
100
100
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
DMA
dioxane
toluene
CH3NO2
AcOH
Scheme 2. Scope of α-azido ketones. All the reactions were performed with 1
(1.0 mmol, 1.0 equiv), 2 (1.0 mmol, 1.0 equiv), I2 (0.5 mmol, 0.5 equiv) and
TBHP (1.0 mmol, 1.0 equiv) in DMSO at 100 °C for 3 h. Yields are for the
isolated products.
0
0
40
20[c]
8[d]
DMSO
DMSO
Encouraged by the results described above, the scope of α-
azido ketones was further examined (Scheme 3). To our delight,
when α-substituent was an electron-donating methyl or phenyl
group, the corresponding products 3u-3w were obtained in
[a] Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2 (0.2 mmol, 1.0 equiv), and
addictive (0.2 mmol, 1.0 equiv) in solvent for 3 h. [b] Isolated yield. [c] NaI
instead of I2. [d] KI replaced of I2.
2
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10.1002/ejoc.202000146
European Journal of Organic Chemistry
COMMUNICATION
moderate-to-good yields (58-82%). Unfortunately, the substrate
with an electron-withdrawing ester at α position was not tolerated
in this cyclization reaction, and we could not obtain the
corresponding product 3x.
via the formation of a new N-N bond.[16] Finally, intermediate A
produced intermediate B by the elimination of nitrogen in the
presence of TBHP, which is then converted to the final product 3a
via a [1,5]-H shift.
Scheme 5. A Possible Mechanism.
Scheme 3. Scope of α-azido ketones.
In conclusion, we have developed an iodine mediated
condensation/cyclization reaction from α-azido ketones and p-
toluenesulfonyl hydrazide. This method provides a metal-free
strategy for the convenient and efficient construction of NH-1,2,3-
triazoles from simple substrates. Research on further applications
of this method is in progress in our laboratory.
In order to gain insight into the reaction mechanism, we
performed a series of control experiments, as shown in Scheme
4. Initially, α-azido phenylethanone (1a) reacted with p-
toluenesulfonyl hydrazide (2) in CH3CN at room temperature for
48h leading to α-azido N-tosylhydrazone 1a′ with 68% yield. If this
reaction was carried out in the presence of iodine, the yield
increased to 85%, and the reaction time was shortened to 6 hours.
Later, compound 1a′ could be transformed into the target product
3a in 89% yield in the presence of TBHP in DMSO at 100 °C for
3h. These results indicated that iodine promoted the first
condensation process, and 1a′ is a possible intermediate for this
reaction.
Notes
The authors declare no competing financial interest.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (Grant 21801022) for financial support. This work was also
supported by the Yangtze Youth Talents Fund (No. 2016cqn25).
Keywords: iodine-mediated • condensation/cyclization • α-azido
ketones • p-toluenesulfonyl hydrazide • NH-1,2,3-triazoles
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4
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Entry for the Table of Contents
1,2,3-Triazole Synthesis
An iodine-mediated cyclization reaction leads to a wide variety of 4-aryl-NH-1,2,3-triazoles from α-azido acetophenones and p-
toluenesulfonyl hydrazide is described.The reaction likely follows a condensation with intramolecular N-N bond formation.
5
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