Alkyl Propiolates Participated [3+2] Annulation for the Switchable Synthesis of 1,5- and 1,4-Disubstituted 1,2,3-Triazoles Containing Ester Side Chain

Article abstract of DOI:10.1002/cctc.201801366

By means of a featured enamine activation, the alkyl propiolates have been successfully employed in the [3+2] annulation for the synthesis of 1,2,3-triazoles. The synthesis of both 1,4- as well as the hardly available 1,5-disubstituted 1,2,3-triazoles can be selectively accessed by using tosyl azide and tosyl hydrazine as nitrogen source, respectively.

Full text of DOI:10.1002/cctc.201801366

Accepted Article
Title: Alkyl propiolates participated [3+2] annulation for the switchable
synthesis of 1,5- and 1,4-disubstituted 1,2,3-triazoles containing
ester side chain
Authors: Shuo Cao, Yunyun Liu, Changfeng Hu, Chengping Wen, and
Jie-Ping Wan
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10.1002/cctc.201801366
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Alkyl propiolates participated [3+2] annulation for the switchable
synthesis of 1,5- and 1,4-disubstituted 1,2,3-triazoles containing
ester side chain
Shuo Cao,[a] Yunyun Liu,[a] Changfeng Hu,[b] Chengping Wen*[b] and Jie-Ping Wan*[a]
Abstract: By means of a featured enamine activation, the alkyl
propiolates have been successfully employed in the [3+2] annulation
for the synthesis of 1,2,3-triazoles. The synthesis of both 1,4- as well
as the hardly available 1,5-disubstituted 1,2,3-triazoles can be
selectively accessed by using tosyl azide and tosyl hydrazine as
nitrogen source, respectively.
The synthesis of 1,5-disubstituted 1,2,3-triazoles, however, is
hardly accessible by this protocol. To develop applicable
approaches allowing the selective synthesis of 1,5-disubstituted
1,2,3-triazoles, huge endeavours has been devoted. In this
regard, the synthesis employing the catalysis of transition metal
species such as iridium,[6] ruthenium,[7] nickel[8] have been
disclosed. The rare earth samarium has also been found as
practical catalyst in catalyzing the synthesis of 1,5-disubstituted
1,2,3-triazoles.[9] Recently, by utilizing enoic acids as the
reaction partners of organoazides, Kumar et al[10] accomplished
the copper-catalyzed cycloaddition providing 1,5-disubstituted
Introduction
Owing to their daily increasing applications in the discovery of
organic compounds with valuable biological function,
designation of functional materials as well as multiple other
areas, the 1,2,3-triazole heterocycle keeps receiving extensive
attention and research interest from chemical community.[1] As
the fundamental step before any application exploration, the
synthesis of 1,2,3-triazoles occupies particularly crucial
position.[2] As classical route in 1,2,3-triazole ring construction,
the copper-catalyzed alkyne azide cycloaddition (CuAAC)
constitutes the main tool to access 1,2,3-triazoles for a long
period.[3] In order to develop complementary synthetic methods
free of transition metal utilization, however, tremendous efforts
have been made over the last two decades, and notable
advances have been gained.[4] Among the presently known
tactics enabling the metal-free 1,2,3-triazole synthesis, the
enamine-based annulation has turned out to be the most reliable
one. By making use of enamines as building blocks or
designated intermediates, a number of methodologies have
been successfully established for the synthesis of 1,2,3-triazoles
with metal-free operation. More notably, besides the favorable
feature of metal-free condition, enamine-based reactions also
bring novel transformation pathways and selectivity to the 1,2,3-
triazole synthesis.[5]
1,2,3-triazoles based on
a
featured decarboxylation.
Alternatively, the in situ preparation of alkynyl metal reagents
such as alkynyl magnesium, alkynyl zinc, and alkynyl lithium[11]
as well as aqueous NMe4OH promoted alkyne-azide
annulation[12] can also lead to the synthesis of 1,5-disubstsituted
1,2,3-triazoles. Due to the employment of transition metal
catalyst, sensitive organometal reagents, restricted product
diversity, and/or the harsh reaction conditions in these methods,
their synthetic application does not yet meet the requirement of
the 1,5-disubstituted 1,2,3-triaozoles synthesis. In this
background, the enamine-based annulation reaction has been
found as a powerful tool by offering metal-free and operationally
practical routes towards the 1,5-disubstituted 1,2,3-triazoles. Cui
and co-workers reported in 2013 a novel method on the
regioselective synthesis of 1,5-disubstituted 1,2,3-triazoles via
base promoted cyclization reactions of enamines with tosyl
azide wherein the C(alkynyl)-C(carbonyl) bond cleavage was
involved.[13] Our group has developed a different synthetic
approach by employing tertiary enaminones, tosyl hydrazine and
primary amines via the catalysis of molecular iodine.[14]
Interestingly, During the preparation of this present work, Jiang
and Du et al[15] reported their results in the synthesis of 1,5- and
1,4,5-substituted 1,2,3-triazoles via the reactions of
enaminoesters and tosyl hydrazine in the presence of KI/TBAI
and TBHP (Scheme 1A).
Inherently, the regioselectivity of classical CuAAC determines
the style of 1,4-disubstitution in the 1,2,3-triazole products by
employing terminal alkynes and organoazides as substrates.
On the other hand, as commercially available and stable alkyne
derivatives, alkyl propiolates have been previously employed as
alkyne substrate in CuAAC, which provides classical 1,4-
disubstituted 1,2,3-triazoles (Scheme 1B).[16] However, in our
previous work, we have disclosed that the electron deficient
alkynes such as alkyl propiolates can be easily transformed into
the enamines in the presence of a secondary amine, and
thereafter enable the designation of various domino reactions
via the reactive enamine intermediate.[17] Therefore, we envision
that such enamine activation strategy can also be used to
design the synthesis of divergent 1,2,3-triazoles under metal-
free conditions.[18] Herein, we report for the first time the metal-
free annulation reactions of alkyl propiolates with tosyl hydrazine
[a]
[b]
S. Cao, Prof. Dr. Y. Liu, Prof. Dr. J.-P. Wan
College of Chemistry and Chemical Engineering
Jiangxi Normal University
Nanchang 330022, P. R. China
E-mail: wanjieping@jxnu.edu.cn
C. Hu, Prof. Dr. C. Wen
College of Basic Medical Sciences
Zhejiang Chinese Medical University
Hangzhou 310053, P. R. China
E-mail: cpwen.zcmu@yahoo.com
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/cctc.201801366
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for the regioselective synthesis of 1,5-disubstituted 1,2,3-
triazoles. Notably, the switchable synthesis of 1,4-disubstituted
1,2,3-triazoles is also achieved by employing tosyl azide as the
nitrogen source (Scheme 1C).
entry
1
sec. amine
piperazine
morpholine
DEA
temp. (oC)
110
solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
yield (%)[b]
43
2
110
31
3
110
trace
trace
31
4
Et2NH
110
5
piperazine
piperazine
piperazine
-
100
6
120
62
7
130
56
8
120
nr
9[c]
10[d]
11[e]
12[f]
13[g]
14
15
16
17
18
piperazine
piperazine
piperazine
piperazine
piperazine
piperazine
piperazine
piperazine
piperazine
piperazine
120
trace
59
120
120
nr
120
54
120
60
120
28
Scheme 1 Different synthetic strategies for 1,5-disubstituted and other 1,2,3-
triazoles
reflux
120
EtOH
trace
nr
ethyl lactate
H2O
reflux
reflux
nr
Results and Discussion
toluene
trace
At the beginning, the reaction of ethyl propiolate 1a, aniline 2a
and tosyl hydrazine 3 was tentatively run in the presence of
piperazine and molecular iodine in DMSO, which was found to
provide the 1,5-disubstituted 1,2,3-triazole 4a with moderate
yield (entry 1, Table 1). Comparing with the parallel experiments
employing different secondary amines such as morphorline,
diethanolamine (DEA) and diehtylamine, piperazine was proved
to be the best secondary amine in promoting the target reaction
(entries 2-4, Table 1). The examination on the impact of reaction
[a] General conditions: 1a (0.3 mmol), 2a (0.3 mmol), 3 (0.45 mmol), amine
additive (0.15 mmol) and I2 (0.24 mmol) in 2 mL of solvent stirred for 12 h. [b]
Yield of isolated products based on 1a. [c] 0.09 mmol piperazine was used. [d]
0.24 mmol piperazine was used. [e] No I2 was employed. [f] 0.15 mmol I2 was
used. [g] 0.3 mmol I2 was used.
confirmed DMSO as the best medium (entries 14-18, Table 1).
To investigate the scope of the 1,5-disubstituted 1,2,3-triazole
synthesis, the reactions employing different alkyl propiolates 1
and aryl amines 2 were then conducted. The results from this
section were outlined in Table 2. According to the results, this
method showed fine tolerance to both substrates. Anilines
containing substitutions of different properties, such as alkyl,
alkoxy, halogen and nitro in the para- site all participated the
synthesis to give the expected products with moderate to good
yields (4b, 4d, 4g and 4i, Table 2). In addition, aniline substrates
containing substituents in ortho- and meta-position were also
well tolerated (4c, 4e, 4f, 4h and 4j, Table 2). On the other hand,
varying the alkyl group in 1 was also allowed, and related
products were given with satisfactory yields (4k-4m, Table 2).
No notable effect of the substituent in either component 1 or 2
could be defined with the present data.
o
temperature indicated that 120 C was preferred (entries 5-7,
Table 1), and a control experiment without using secondary
amine at this temperature did not provide product 4a (entry 8,
Table 1). Later on, the loading of piperazine and I2 were varied,
respectively, but no improved result was obtained (entries 9-13,
Table 1). The requirement of relative high loading of piperazine
could be ascribed to the partial deactivation of piperazine
resulting from the in situ generated proton acid (see Scheme 2
for the proposed mechanism). In next step, this reaction was
performed in various media with different polarity, which
Table 1 Optimization on the conditions providing 1,5-disubstituted 1,2,3-
triazoles[a]
Table 2 Scope on the synthesis 1,5-disubstituted 1,2,3-triazoles[a]
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10.1002/cctc.201801366
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was found by varying the loading of t-BuONa (entries 16-18,
Table 3).
Table 3 Optimization on the synthesis 1,4-disubstituted 1,2,3-triazole[a]
R1
Et
R2
product
4a
yield(%)[b]
62
H
entry
1
sec. amine
piperazine
piperazine
piperazine
piperazine
piperazine
piperazine
morpholine
DEA
base additive
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
Et3N
solvent
acetone
AcOEt
CH3CN
EtOH
yield(%)[b]
57
Et
4-CH3
2-CH3
4-CH3O
2-CH3O
3-CH3O
4-Br
4b
4c
64
Et
61
2
57
Et
4d
4e
58
3
70
Et
54
4
trace
54
Et
4f
61
5
DCE
Et
4g
4h
4i
67
6
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
trace
54
Et
3-Cl
62
7
Et
4-Cl
67
8
52
Et
3-NO2
4-CH3
4-Br
4j
71
9
Et2NH
trace
trace
trace
30
Me
Me
Me
4k
63
10
11
12
13
14
15
16[c]
17[d]
18[e]
-
4l
70
piperazine
piperazine
piperazine
piperazine
piperazine
piperazine
piperazine
piperazine
4-Cl
4m
64
MeONa
KOH
[a] General conditions: propiolate 1 (0.3 mmol), primary amine 2 (0.3 mmol),
tosyl hydrazine 3 (0.45 mmol), piperazine (0.15 mmol) and I2 (0.24 mmol) in
DMSO (2 mL) stirred at 120 oC for 12 h. [b] Yield of isolated products based on
1.
51
t-BuOK
55
Na2CO3
t-BuONa
t-BuONa
t-BuONa
NR
Being inspired by this enamine activation-based synthesis of
triazoles 4, we envisaged that such activation pathway could
also be utilized for the designation of a metal-free annulation
providing 1,4-disubstituted 1,2,3-triazoles, which would thus
complement the previous CuAAC in the synthesis of identical
products (Scheme 1B). First, substrates 1a, 2a were subjected
with piperazine and FeCl3 since a Lewis acid was required for
the transamination between the in situ generated tertiary
enamine and the primary amine,[19] and 0.5 equiv piperazine was
also employed in the reaction because of the co-presence of
weakly acidic FeCl3. The subsequent employment of tosyl azide
5 together with t-BuONa in one-pot operation enabled the
formation of 1,4-disubstutituted 1,2,3-triazole 6a with fair yield
(entry 1, Table 3). In the screening of reaction medium, including
AcOEt, MeCN, EtOH, 1,2-dichloroethane (DCE) and DMSO,
MeCN turned out to be the most proper medium (entries 2-6,
Table 3). Subsequently, different secondary amines and blank
experiments were also conducted, and piperazine was found as
the best candidate (entries 7-10, Table 3). On the other hand,
among the tested base additives such as Et3N, MeONa, KOH, t-
BuOK and Na2CO3, t-BuONa was found as the most favorable
promoter (entries 11-15, Table 3). No further improved result
trace
35
61
[a] General conditions: 1a (0.3 mmol), 2a (0.3 mmol), secondary amine (0.15
mmol) and FeCl3 (0.15 mmol) in 2 mL of solvent, stirred for 2 h at rt, then tosyl
azide 5 (0.4 mmol) and base addtive (0.45 mmol), further stirred at rt for 2 h.
[b] Yield of isolated products based on 1a. [c] 0.15 mol t-BuONa was used. [d]
0.3 mol t-BuONa was used. [e] 0.6 mmol t-BuONa was used.
In the successive work investigating the synthetic scope, a class
of different anilines were utilized to react with alkyl propiolates
and tosyl azide. Correspondingly, the 1,4-disubstituted 1,2,3-
triazles 6 containing various functional groups derived from
anilines 2 were acquired with good to excellent yield (6a-6l,
Table 4). The alkyl, alkoxyl, halogen and nitro in the aniline
component were well suited the synthesis of target products and
displayed no evident effect to the yield regardless their individual
property. In addition, both ethyl and methyl propiolates could
take part in the synthesis without observable distinction (6m-6o,
Table 4), demonstrating the fine tolerance of the synthetic
method to different alkyl propiolates.
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Table 4 Scope on the synthesis of 1,4-disubstituted 1,2,3-triazoles[a]
Correspondingly, the general reaction processes based on this
enamine activation are proposed (Scheme 3). In the reactions
producing 1,5-disubstituted 1,2,3-triazoles, the tertiary enamine
intermediate 7 undergoes a transamination with aniline to give
NH-enamine intermediate 8. 8 reacts with tosyl hydrazine to
provide intermediate 9. By means of the isomeric form 9’, an
iodination reaction takes place on the acidic C(sp3)-H bond to
give intermediate 10 in the presence of iodine. Subsequently,
the nucleophilic substitution of aniline to 10 could afford
intermediate 11. This intermediate undergoes similar
transformations as proposed by Jiang et al[15] to provide product
4a. On the other hand, in the reaction with tosyl azide, the
R1
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
Me
R2
product
6a
yield(%)[b]
70
H
4-CH3
2-CH3
3-CH3
4-CH3O
3-CH3O
4-Br
6b
6c
71
formation of the NH-enaminoester
8 enables analogous
67
transformations in previously reported [3+2] cycloaddition of NH-
enaminone to provide the 1,4-disubstituted 1,2,3-triazoles 6a.[5a]
It is notable that the part of the in situ formed HI can be
regenerated to molecular iodine under air atmosphere with
heating, and thus promotes the completion of the reaction.[20]
6d
6e
64
68
6f
72
6g
6h
6i
79
2-Cl
73
3-Cl
76
4-Cl
6j
77
2,4-Me2
3-NO2
4-Br
6k
68
6l
81
6m
6n
6o
77
3-Cl
75
3-CH3
69
Scheme 3 The proposed reaction mechanism
[a] General conditions: alkyl propiolate 1 (0.3 mmol), aniline 2 (0.3 mmol),
piperazine (0.15 mmol) and FeCl3 (0.15 mmol) in 2 mL of CH3CN stirred for 2
h at rt. Then added Tosyl azide (0.4 mmol) and NaOtBu (0.45 mmol) stirred for
2 h; [b] Yield of isolated products based on 1.
Conclusions
In conclusion, by making use of a key enamine activation
resulting from the aza-Michael addition of secondary amine to
alkyl propiolates, we successfully realized the first metal-free
synthetic method toward 1,5-disubstituted 1,2,3-triazoles via the
reaction of alkyl propiolates, primary amines and tosyl hydrazine.
In addition, by altering tosyl hydrazine to tosyl azide, and
modifying reaction conditions, the switchable synthesis of 1,4-
disubstituted 1,2,3-triazoles has also been accomplished via
metal-free triazole annulation. The results included herein
disclose the distinctive new applications of the commercially
available alkyl propiolates in the synthesis of divergent 1,2,3-
triazoles.
In previous study, we discovered that the alkyl propiolates can
react fast with piperazine to provide enaminoester of type 7,[17c]
we then accordingly performed the control experiments by
directly employing 7 for the potential synthesis of both 4 and 6.
Under the standard conditions without secondary amine,
enaminoester 7 reacted with aniline 2a and tosyl hydrazine 3 to
provide product 4a with 46% yield (Eq 1, Scheme 2). On the
other hand, the reaction of 7, 2a and tosyl azide gave 1,2,3-
triazole 6a with 83% yield (Eq 2, Scheme 2). These results
confirmed that the formation of enamine intermediate was the
key step enabling the synthesis of these 1,2,3-triazoles.
Experimental Section
General procedure for the synthesis of 1,2,3-triazoles 4
In a 25 mL round bottom flask was successively charged with alkyl
propiolate 1 (0.3 mmol), piperazine (0.15 mmol), primary amine 2 (0.3
mmol), tosyl hydrazine 3 (0.45mmol), I2 (0.24 mmol) and DMSO (2mL).
Scheme 2 Control experiments
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The vessel was then stirred at 120 oC for 12 h. Upon completion (TLC), 5
mL water was added, and the resulting suspension was extracted with
EA (3 × 8 mL). The organic layers were combined and dried overnight
with anhydrous MgSO4. After filtration, the solution was employed to
reduced pressure to remove the solvent. The residue was subjected to
flash silicon column chromatography to provide pure products by using
mixed EA and petroleum ether (PE) as eluent (VPE : VEA = 10:1~6:1).
G. Nie, Z. Zhou, L. Jia, Y. Chen, J. Org. Chem. 2017, 82, 9198. (e) Q.
Wang, X. Shi, X. Zhang, X. Fan, Org. Biomol. Chem. 2017, 15, 8529. (f)
Y. Chen, G. Nie, Q. Zhang, S. Ma, H. Li, Q. Hu, Org. Lett. 2015, 17,
1118. (f) W. Wu, J. Wang, Y. Wang, Y. Huang, Y. Tan, Z. Weng,
Angew. Chem. Int. Ed. 2017, 56, 10476.
[4]
[5]
(a) G.-L. Wu, Q.-P. Wu, Adv. Synth. Catal. 2018, 360, 1949. (b) H.-W.
Bai, Z.-J. Cai, S.-Y. Wang, S.-J. Ji, Org. Lett. 2015, 17, 2898. (c) B.
Alcaide, P. Almendros, C. Lázaro-Milla, Chem. Commun. 2015, 51,
6992.
General procedure for the synthesis of 1,2,3-triazoles 6
(a) J.-P. Wan, S. Cao, Y. Liu, Org. Lett. 2016, 18, 6034. (b) S. S. V.
Ramasastry, Angew. Chem. Int. Ed. 2014, 53, 14310. (c) L. J. T.
Danence, Y. Gao, M. Li, Y. Huang, J. Wang, Chem. Eur. J. 2011, 17,
3584. (d) W. Li, Z. Du, J. Huang, Q. Jia, K. Zhang, J. Wang, Green
Chem. 2014, 16, 3003. (e) J. Thomas, J. John, N. Parekh, W. Dehaen,
Angew. Chem. Int. Ed. 2014, 53, 10155. (f) Z. Chen, Q. Yan, Z. Liu, Y.
Zhang, Chem. Eur. J. 2014, 20, 17635. (g) A. Ali, A. G. Corrêa, D.
Alves, J. Zukerman-Schpector, B. Westermann, M. A. B. Ferreira, M. W.
Paixão, Chem. Commun. 2014, 50, 11926.
In a 25 mL round bottom flask was charged with alkyl propiolate 1 (0.3
mmol) and piperazine (0.15 mmol), primary amine 2 (0.3 mmol), FeCl3
(0.15 mmol) and MeCN (2mL). The resulting mixture was stirred at rt for
2 h. Tosyl azide 5 (0.4 mmol) and t-BuONa (0.45 mmol) were then added,
and the vessel was further stirred for 2 h at rt. Upon completion (TLC), 5
mL water was added, and the resulting suspension was extracted with 3
× 8 mL ethyl acetate (EA). The organic layers were combined and dried
overnight with anhydrous MgSO4. After filtration, the solution was
employed to reduced pressure to remove the solvent. The residue was
subjected to flash silicon column chromatography to provide pure
[6]
[7]
L. Zhang, X. G. Chen, P. Xue, H. H. Y. Sun, I. D. Williams, K. B.
Sharpless, V. V. Fokin, G. C. Jia, J. Am. Chem. Soc. 2005, 127, 15998.
(a) L. K. Rasmussen, B. C. Boren, V. V. Fokin, Org. Lett. 2003, 9, 5337.
(b) B. C. Boren, S. Narayan, L. K. Rasmussen, L. Zhang, H. Zhao, Z.
Lin, G. Jia, V. V. Fokin, J. Am. Chem. Soc. 2008, 130, 8923. (c) J. R.
Johansson, P. Lincoln, B. Nordén, N. Kann, J. Org. Chem. 2011, 76,
2355.
products by using the mixed EA and petroleum ether (PE) as eluent (VPE
VEA = 3:1~6:1).
:
[8]
W. G. Kim, M. E. Kang, J. B. Lee, M. H. Jeon, S. Lee, J. Lee, C. Bonseo,
P. M. S. D. Cal, S. Kang, J.-M. Kee, G. J. L. Bernardes, J.-U. Rohde, W.
Choe, S. Y. Hong, J. Am. Chem. Soc. 2017, 139, 12121.
L. Hong,W. Lin, F. Zhang, R. Liu, X. Zhou, Chem. Commun. 2013, 49,
5589.
Acknowledgements
This work is financially supported by the National Natural
Science Foundation of China (21562025), the Science Fund for
[9]
Distinguished
Young
Scholars
in
Jiangxi
Province
[10]
[11]
N. Kumar, M. Y. Ansari, R. Kant, A. Kumar, Chem. Commun. 2018, 54,
2627.
(20162BCB23023) and an Open Project of the Key Laboratory
of Rheumatic Diseases of Traditional Chinese Medicine in
Zhejiang Province.
(a) A. Krasiński, V. V. Fokin, K. B. Sharpless, Org. Lett. 2004, 6, 1237.
(b) C. D. Smith, M. F. Greaney, Org. Lett. 2013, 15, 4826. (c) M. E.
Meza-Aviña, M. K. Patel, C. B. Lee, T. J. Dietz, M. P. Croatt, Org. Lett.
2011, 13, 2984.
Keywords: alkyl propiolate • annulation • enamine activation •
[12]
S. W. Kwok, J. R. Fotsing, R. J. Fraser, V. O. Rodionov, V. V. Fokin,
Org. Lett. 2010, 12, 4217.
switchable • 1,2,3-triazoles
[13] G. Cheng, X. Zeng, J. Shen, X. Wang, X. Cui, Angew. Chem. Int. Ed.
2013, 52, 13265.
[1]
(a) S. G. Agalave, S. R. Maujan, V. S. Pore, Chem. Asian J. 2011, 6,
2696. (b) X.-L. Wang, K. Wan, C.-H Zhou, Eur. J. Med. Chem. 2010, 45,
4631. (c) S. B. Ferreira, A. C. R. Sodero, M. F. C. Cardoso, E. S. Lima,
C. R. Kaiser, F. P. Silva Jr., C. F. Ferreira, J. Med. Chem. 2010, 53,
2364. (d) R. J. Thibault, K. Takizawa, P. Lowenheilm, B. Helms, J. L.
Mynar, J. M. J. Fréchet, C. J. Hawker, J. Am. Chem. Soc. 2006, 128,
12084. (e) Q.-H. Lin, Y.-C. Li, Y.-Y. Li, Z. Wang, W. Liu, C. Qi, S.-P.
Pang, J. Mater. Chem. 2012, 22, 666.
[14]
[15]
J.-P. Wan, S. Cao, Y. Liu, J. Org. Chem. 2015, 80, 9028.
W. Huang, C. Zhu, M. Li, Y. Yu, W. Wu, Z. Tu, H. Jiang, Adv. Synth.
Catal. 2018, 360, 3117.
[16]
(a) C. Vidal, J. García-Álvarez, Green Chem. 2014, 16, 3515. (b) K.
Wang, X. Bi, S. Xing, P. Liao, Z. Fang, X. Meng, Q. Zhang, Q. Liu, Y, Ji,
Green Chem. 2011, 13, 562. (c) Y. Liu, X. Wang, J. Xu, Q. Zhang, Y.
Zhao, Y. Hu, Tetrahedron 2011, 67, 6294.
[17] (a) L. Yang, L. Wei, J.-P. Wan, Chem. Commun. 2018, 54, 7475. (b) J.-
P. Wan, Y. Lin, Q. Huang, Y. Liu, J. Org. Chem. 2014, 79, 7232. (c) J.
Wan, Y. Zhou, Y. Liu, Z. Fang, C. Wen, Chin. J. Chem. 2014, 32, 219.
[2]
For reviews, see: (a) Z. Chen, Z. Liu, G. Cao, H. Li, H. Ren, Adv. Synth.
Catal. 2017, 359, 202. (b) J.-P. Wan, D. Hu, Y. Liu, S. Sheng,
ChemCatChem 2015, 7, 901. (c) Z. Chen, G. Cao, J. Song, H. Ren,
Chin. J. Chem. 2017, 35, 1797. (d) V. A. Bakulev, T. Beryozkina, J.
Thomas, W. Dehaen, Eur. J. Org. Chem. 2018, 262. (e) C. G. S. Lima,
A. Ali, S. S. van Berkel, B. Westermann, M. W. Paixão, Chem.
Commun. 2015, 51, 10784. (f) J. John, J. Thomas, W. Dehaen, Chem.
Commun. 2015, 51, 10797. (g) F. Wei, W. Wang, Y. Ma, C.-H. Tung, Z.
Xu, Chem. Commun. 2016, 52, 14188.
[18]
For selected reviews on enamine activation, see: S. Mukherjee, J. W.
Yang, S. Hoffmann, B. List, Chem. Rev. 2007, 107, 5471. (b) B. List,
Acc. Chem. Res. 2004, 37, 548. (c) D. W. C. MacMillan, Science 2008,
455, 304. (d) C. Grondal, M. Jeanty, D. Enders, Nat. Chem. 2010, 2,
167. (e) W Notz, F. Tanaka, C. F. Barbas, Acc. Chem. Res. 2004, 37,
580.
[19] Y. Liu, R. Zhou, J.-P. Wan, Synth. Commun. 2013, 43, 2475.
[3]
For selected reviews, examples, see: (a) J. E. Hein, V. V. Fokin, Chem.
Soc. Rev. 2010, 39, 1302. (b) C. O. Kappe, E. V. der Eyken, Chem.
Soc. Rev. 2010, 39, 1280. (c) V. K. Tiwari, B. B. Mishra, K. B. Mishra, N.
Mishra, A. S. Singh, X. Chen, Chem. Rev. 2016, 116, 3086. (d) Y. Liu,
[20] J.-P. Wan, S. Zhong, Y. Guo, L. Wei, Eur. J. Org. Chem. 2017, 4401.
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10.1002/cctc.201801366
ChemCatChem
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Shuo Cao, Yunyun Liu, Changfeng Hu,
Chengping Wen* and Jie-Ping Wan*
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Alkyl propiolates participated [3+2]
annulation for the switchable
synthesis of 1,5- and 1,4-
disubstituted 1,2,3-triazoles
containing ester side chain
Text for Table of Contents
The enamine activation on alkyl propiolates enables the switchable synthesis of 1,5- and 1,4-disubstituted 1,2,3-triazoles bearing
ester side chain. The selective synthesis of 1,2,3-triazoles with different substitution styles are realized by employing different
hydrogen atom sources of tosyl hydrazine and tosyl azide. The annulation of both 1,2,3-triazole rings takes place under transition
metal-free condition, providing sustainable new routes in the synthesis of structurally divergent 1,2,3-triazole scaffolds.
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