Catalyst-free synthesis of fused 1,2,3-triazole and isoindoline derivatives: Via an intramolecular azide-alkene cascade reaction

Article abstract of DOI:10.1039/c6gc01553k

Benzyl bromides bearing an ortho-substituted α,β-unsaturated ketone moiety are found to be promising precursors for the synthesis of fused 1,2,3-triazole and isoindoline derivatives via an intramolecular azide-alkene cascade reaction under catalyst free conditions. Fused 1,2,3-triazole derivatives 2 were synthesized in excellent yields by treating compounds 1 with sodium azide in DMF at room temperature, whereas isoindoline derivatives 3 were produced in moderate to good yields only by slight modification of the reaction conditions. Both reactions call for simple and mild conditions, display broad substrate scopes and result in good regiospecificity.

Full text of DOI:10.1039/c6gc01553k

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DOI: 10.1039/C6GC01553K
Green Chemistry
ARTICLE
Catalyst‐Free Synthesis of Fused 1,2,3‐Triazole and
Isoindoline Derivatives via Intramolecular Azide‐Alkene
Cascade Reaction
Received 00th January 20xx,
Accepted 00th January 20xx
Yu‐Yang Xie,a,+ Ying‐Chun Wang,b,+ Yan‐He,a Da‐Chao Hu,a Heng‐Shan Wanga,* and Ying‐Ming Pana,*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Benzyl bromides bearing ortho‐substituted α, β‐unsaturated ketone moiety are found to be promising precursors for
synthesis of fused 1,2,3‐triazole and isoindoline derivatives via intramolecular azide‐alkene cascade reaction under catalyst
free conditions. Fused 1,2,3‐triazole derivatives 2 were synthesized in excellent yields by treating compounds 1 with
sodium azide in DMF at room temperature, whereas isoindoline derivatives 3 were produced in moderate to good yields
only by slight modification of the reaction conditions, and both reactions call for simple and mild conditions, display broad
substrate scopes and result in good regiospecificity.
example, 1,2,3‐triazolo[1,5‐a]quinoxaline is a potent inhibitor
Introduction
of human methionine aminopeptidase type 2 (hMetAP2).3a
Development of an efficient strategy for rapid synthesis of
skeletally distinct molecular scaffolds is crucial to the
generation of diverse chemical libraries for biological
screening.1 Among various approaches to the synthesis of N‐
heterocycles, intramolecular azide‐alkene cascade reaction has
proven to be versatile method for providing ready access to
diverse N‐heterocycles.2 However, under metal‐free conditions,
these cascade reactions normally require high temperature
Bicyclic[1,2,3]triazoles can suppress UVA‐induced damage in
human fibroblasts, which may provide potential prevention
against photoaging.3b So far, extensive works have generated
many approaches for the synthesis of 1,2,3‐triazoles
derivatives.4 Likewise, isoindoline derivatives have also
received considerable attention due to their diverse array of
pharmaceutical functionalities such as antihypertensive,5
antipsychotic,6 antiulcer,7
antiviral8 and antileukemic
o
(>100 C),2b, 2c the use of microwaves2e or photocatalysis.2a
activities.9 Consequently, convenient access to these
heterocyclic frameworks is highly appealing. In connection
with our interest in the development of new synthetic routes
for the preparation of nitrogen‐containing heterocycles,10 we
Herein, we report a simple and efficient methodology for the
synthesis of fused 1,2,3‐triazole and isoindoline derivatives
from benzyl bromides containing ortho‐substituted α, β‐
unsaturated ketone moiety and sodium azide, in which,
intramolecular azide‐alkene cascade reaction can be easily
induced under very mild and catalyst free conditions. Fused
1,2,3‐triazole derivatives were synthesized in excellent yields
hypothesized
cycloaddition of benzyl azides
corresponding benzyl bromides
that
the
intramolecular
4
1
azide‐alkene
in situ generated from the
and subsequent oxidation of
the resulting triazolines
2 10a
if the unstable triazoline intermediates
decomposition and 1,2‐H migration,10b cyclic imines
obtained, which tautomerize to the corresponding exocyclic
enamines2e, 11
as shown in Scheme 1.
5
would produce fused 1,2,3‐triazoles
underwent
could be
by treating compounds
1 with sodium azide in DMF at room
,
5
temperature, whereas isoindoline derivatives were selectively
produced in moderate to good yields only by slight
modification of the reaction conditions.
7
3
Fused 1,2,3‐triazoles represent
a class of important
heterocycles which display significant biological activities.3 For
a.State Key Laboratory for Chemistry and Molecular Engineering of Medicinal
Resources, School of Chemistry and Pharmaceutical Sciences of Guangxi
Normal University Guilin 541004, People’s Republic of China
b.College of Chemistry and Chemical Engineering, Jishou University, Jishou
416000, People’s Republic of China
Phone: (+86)‐773‐5846279; fax: (+86)‐773‐5803930; e‐mail:
panym2013@hotmail.com; whengshan@163.com
†These authors contributed equally to this work
Electronic Supplementary Information (ESI) available: [General experimental
procedures, and spectral data, NMR spectra, high resolution mass spectra for
all compounds]. See DOI: 10.1039/x0xx00000x
Scheme 1 Proposed intramolecular azide‐alkene cascade
reaction.
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Results and discussion
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DOI: 10.1039/C6GC01553K
To test our hypothesis, fused 1,2,3‐triazole formation via the
intramolecular azide‐alkene cycloaddition was first evaluated
and representative results are summarized in Table 1. As
expected, under catalyst free conditions, the reaction
proceeded smoothly by treating ready available (E)‐3‐(2‐
Table 1 Optimization of reaction conditions for fused 1,2,3‐
triazole 2aa
(bromomethyl)phenyl)‐1‐phenylprop‐2‐en‐1‐one
1a with
sodium azide in DMF at room temperature for 6 h to give
fused 1,2,3‐triazole 2a in an excellent yield of 89% (Table 1,
entry 1), and the structure of the product 2a was
unambiguously confirmed by X‐ray crystallography (Fig. 1). The
addition 5 mol% of metal triflates to the reaction mixture did
not speed up the cycloaddition progress and improve the yield
(Table 1, entries 2‐5 vs. entry 1). Other metal catalyzed
reactions were also attempted, however, the results were not
encouraging as either poor yield or no reaction was observed
in these cases (Table 1, entries 7‐10). DMF was found as a
suitable solvent for this transformation, other solvents, such as
toluene, PhCl, dioxane and CH2Cl2 did not give any reaction
(Table 1, entries 11‐14). Use of DMSO and CH3CN resulted in
no formation of 2a (Table 1, entries 15‐16). Furthermore,
when the reaction was conducted under nitrogen, only a trace
amount of desired product was detected, confirming that air
(O2) acts as the oxidant for the success formation of fused
1,2,3‐triazole (Table 1, entry 17).
Entry
Catalyst
Solvent
Yieldb (%)
1
2
3
none
DMF
DMF
DMF
89
88
87
Sm(OTf)3 (5 mol%)
Sc(OTf)3 (5 mol%)
4
5
La(OTf)3 (5 mol%)
Cu(OTf)2 (5 mol%)
Cu(OAc)2 (5 mol%)
CuI (5 mol%)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
86
83
0
6
7
0
8
Pd(OAc)2 (5 mol%)
Pd(Ph3P)4 (5 mol%)
AgOAc (5 mol%)
21
55
52
9
10
11
12
13
14
15
16
17c
none
none
none
none
none
none
none
toluene
PhCl
N.R.
N.R.
N.R.
N.R.
0
1,4‐dioxane
CH2Cl2
CH3CN
DMSO
0
DMF
trace
a Reactions conditions: 0.5 mmol of 1a and 0.6 mmol of sodium
azide in the presence of catalyst in solvent at 25 oC for 6 h (except
b
for entry 1 and entries 11‐16). Isolated yield of pure product
Fig.1 X‐ray crystal structure of fused 1,2,3‐triazole 2a (CCDC
1414992).
c
based on 1a
.
The reaction was carried out under nitrogen
atmosphere (1 atm).
A series of benzyl bromides
1 were prepared (see the
The 1,3‐dipolar cycloaddition reaction of organic azides with
olefins has been intensively studied for the synthesis of
triazolines.11, 12 Triazolines usually decompose after the loss of
nitrogen to form aziridines or imines through thermal13 or
photochemical decomposition,14 which led us to envisage that
under uncatalyzed thermal conditions, the regioselective
synthesis of isoindoline derivatives may be realized. Thus, the
optimization of the isoindoline derivatives synthesis, including
the ratio of 1a to NaN3 and reaction temperature, was then
investigated (Table S1 in the Supporting Information). After a
series of experiments, the optimized reaction conditions were
eventually identified as 1a (0.5 mmol) and 1.0 equiv of sodium
azide in 2 mL of DMF at 10 oC for 3 h and then at 60 oC for 1 h
under the atmosphere of nitrogen (see Table S1, entry 4 in the
Supporting Information).
Supporting Information for details) to investigate the scope for
the synthesis of fused 1,2,3‐triazole derivatives under catalyst
free conditions as described for 2a (Table 1, entry 1), and the
results are outlined in Table 2. It was observed that a wide
range of R3 groups (aryl, heteroaryl and alkyl) were well
tolerated, providing the corresponding desired products in
excellent yields (85%‐92%) (2b‐j). Furthermore, no obvious
electronic and steric effects of substituents on the phenyl ring
of the R3 moiety were observed. The electronic nature of the
R1 group was also studied. The results show that electron‐
donating (‐OCH3) and ‐withdrawing (‐F) substituents had no
substantial impact on the efficacy of the reaction because the
fused 1,2,3‐triazoles 2k‐l were obtained in similar high yields.
Appreciatively, substrate with steric hindrance (R2 = alkyl)
fairly tolerated the reaction conditions and led to good yield
(78%) (2m).
2 | J. Name., 2012, 00, 1-3
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Journal Name ARTICLE
Table 2 Substrate scope for the synthesis of fused 1,2,3‐
triazole derivatives 2a,b
and methyl (3i) groups were also transformed inVtioewtAhreticlteaOrnglienet
DOI: 10.1039/C6GC01553K
compounds in similar satisfactory yields. Unfortunately, no
desired product 3j was obtained when treatment of the
substituted benzyl bromide substrate (R2 = CH3) with sodium
azide under these reaction conditions. In addition, the double
bond in the products
3 were determined as E‐configuration on
the basis of their spectral and analytical data. For example, the
1H NMR spectra of 3f in CDCl3 shows a broad absorption peak
nearby 10.47 ppm, suggesting that there is a strong intramolecular
hydrogen bonding between amine hydrogen and carbonyl oxygen
atom15 (see Figure S1 in the Supporting Information). The key
NOESY correlation between CH‐6 and CH‐9 also confirmed this
relative configuration of compound 3f (see Figure S2 in the
Supporting Information).
ESI/MS experiments were performed to gain evidence for
the possible intermediates in the proposed mechanism. Under
the atmosphere of nitrogen, a mixture of 1f (0.5 mmol) and
sodium azide (0.5 mmol) in DMF (2.0 mL) was reacted at 10 oC
for 3 h [Eq. (1)] and 50 μL of the mixture was used for the ESI
analysis in CH3OH. The ESI/MS analyses showed a peak at m/z
294.1240, which was identified as a triazoline species 5f (see
the Supporting Information).
a Reactions conditions: 0.5 mmol of
2 mL of DMF at 25 oC for 6 h.
1 and 0.6 mmol of sodium azide in
b Isolated yield of pure product based on
1.
Table 3 Substrate scope for the synthesis of isoindoline
derivatives 3a,b
Conclusions
In summary, a convenient, efficient and regioselective method
has been developed for the synthesis of fused 1,2,3‐triazole
and isoindoline derivatives using benzyl bromides bearing an
ortho‐substituted α, β‐unsaturated ketone moiety under
catalyst free conditions. The simple and mild conditions, broad
substrate scopes, good to excellent yields and operational
simplicity make this process very significant for academic
research and practical applications. Further studies on the
scope and synthetic applications of these reactions are
currently in progress.
Acknowledgements
a Reactions conditions:
1 (0.5 mmol), NaN3 (1.0 equiv.), DMF (2 mL), N2,
We would like to thank the National Natural Science
Foundation of China (21362002 and 81260472), the Guangxi
Natural Science Foundation of China (2014GXNSFDA118007
and 2016GXNSFEA380001), State Key Laboratory for Chemistry
and Molecular Engineering of Medicinal Resources
(CMEMR2014‐A02 and CMEMR2012‐A20), Hunan Province
Natural Science Foundation of China (2016JJ4075), and Science
Research Project of Hunan Provincial Department of Education
(16B211).
10 oC for 3 h then rise to 60 oC for 1 h.
b Isolated yield of pure product based on
1
.
Under the optimal conditions as for 3a, a range of reactions
of selected benzyl bromides and sodium azide were carried
out, and the results are summarized in Table 3. Consistent with
the results of fused 1,2,3‐triazole synthesis, the substituent
effect on the phenyl ring was not apparent, either with an
electron‐withdrawing (3b and 3c) or an electron‐donating
1
group (3d
corresponding isoindoline derivatives in good yields.
, 3e and 3f), benzyl bromides 1 gave the
Notes and references
1
For some reviews, see: (a) W. R. J. D. Galloway, A. Isidro‐
Llobet and D. R. Spring, Nature Commun., 2010, , 80; (b) C. J.
Additionally, substrates bearing 2‐thienyl (3g), 1‐naphthyl (3h
)
1
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DOI: 10.1039/C6GC01553K
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DOI: 10.1039/C6GC01553K
R3
O
R3
N
O
NaN3
NaN3
H
DMF, N2
R3
DMF, air
O
R1
1) 10 oC, 3 h
2) 60 oC, 1 h
25 OC, 6 h
Br
R1
N N
NH
R2
R2
R2
3
1
2
R1 = EWG or EDG
R2 = H or alkyl
R3 = aryl, heteroaryl, alkyl
13 examples
10 examples
catayst free
simple and mild conditions
broad substrate scopes and good regiospecificity
A simple and efficient methodology has been developed for regioselective synthesis
of fused 1,2,3-triazole and isoindoline derivatives under catalyst free conditions.