Another Example of Organo-Click Reactions: TEMPO-Promoted Oxidative Azide–Olefin Cycloaddition for the Synthesis of 1,2,3-Triazoles in Water

Article abstract of DOI:10.1002/ejoc.201601121

The water-mediated, metal-free, 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) promoted oxidative [3+2] cycloaddition of organic azides with electron-deficient terminal and internal olefins was explored. A library of 1,4-disubstituted and 1,4,5-trisubstitut

Full text of DOI:10.1002/ejoc.201601121

A Journal of
Accepted Article
Title: A New Example of Organo Click Reactions: TEMPO-Promoted Oxidative
Azide-Olefin Cycloaddition for the Synthesis of 1,2,3-Triazoles in Water
Authors: J. Elangovan; D Gangaprasad; J Paul Raj; T Kiranmye; K Karthikeyan
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601121
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A New Example of Organo Click Reactions: TEMPO-Promoted
Oxidative Azide-Olefin Cycloaddition for the Synthesis of 1,2,3-
Triazoles in Water
D. Gangaprasad,[b] J. Paul Raj,[b] T. Kiranmye,[b] K. Karthikeyan,[b] and J. Elangovan*[a]
Abstract: An aqueous mediated metal-free TEMPO-promoted
oxidative [3+2] cycloaddition of organic azides with electron deficient
terminal and internal olefins is reported. A library of 1,4-disubstituted
and 1,4,5-trisubstituted-1,2,3-triazoles are synthesised from
moderate to excellent yields. This method is compatible not only with
open chain olefins but also with cyclic olefins.
alternative methods to access these privileged molecules. In this
regard, olefins were judiciously picked up as the appropriate
alternative to the alkynes to achieve the 1,2,3-triazoles. However
the product of such azide-olefin cycloaddition is triazoline which
is an unstable cyloadduct and it is likely to decompose into
various products as dictated by the reaction condition.[10]
Introduction
After the invention of copper catalyzed azide-alkyne
cycloaddition (CuAAC),[1] 1,2,3-triazoles emerged as charismatic
molecules endowed with a wide spectrum of pharmacological
applications[2] such as anticancer, anti-HIV, antituberculosis,
antifungal and antibacterial activities. Some of the representative
biologically active triazoles are outlined in Figure 1. In addition,
they have also achieved new milestones in other fields such as
drug discovery,[3] material science,[4] polymers[5] supramolecular
chemistry[6] and chemical synthesis.[7]
Figure 1. Representative examples of bioactive 1,2,3- triazoles.[2]
Scheme 1. Background of the organo catalytic oxidative azide-olefin
cycloaddition.
In spite of the conventional Huisgen cycloaddition,[8] CuAAC is
prominently desired owing to its remarkable selectivity and
functional group tolerance.[1] Being selective to 1,4-disubstituted
triazoles, CuAAC is restricted to terminal alkynes only. In
continuation, ruthenium catalyzed azide-alkyne cycloaddition
(RuAAC)[9] was developed which promotes the complementary
1,5-disubstitution on the triazole and it is compatible with internal
alkynes as well [Eq. (1), Scheme 1]. However the economic and
synthetic viabilities of alkynes pose the need of development of
In order to convert this unstable triazoline into the stable
aromatic triazole two ingenious approaches have been adopted
in the literature. First one is eliminative azide-olefin cycloaddition
(EAOC) where a olefin bearing a leaving group such as nitro,[11]
alkoxy,[12] sulphone,[13] acetate[14] etc. would be subjected to
cycloaddition with various azides and the resulting triazoline
would undergo a concomitant elimination reaction to furnish the
required 1,2,3-triazole [Eq. (2a), Scheme 1].
Second approach is oxidative azide-olefin cycloaddition
(OAOC) where the triazoline formed by azide-olefin
cycloaddition would subsequently be oxidized into the
corresponding triazole [Eq. (2b), Scheme 1]. In this area, various
metal catalysts such as CuI,[15] Ce(OTf)3,[16] CuO,[17] Cu(OTf)2,[18]
Cu(OAC)2,[19] and Fe2O3-nanoparticles[20] were employed to
achieve the OAOC of organic azides with electron deficient
olefins. Besides that, our research group has also reported the
construction of 1,2,3-triazoles by CuO-nanoparticles catalyzed
[3+2] cycloaddition of organic azides and electron deficient
olefins.[21] However the major drawback of metal catalysts
particularly copper is its cytotoxicity and hence it can’t be
desirable for the labeling of biomolecules in live cells.[22]
[a]
[b]
Dr. J. Elangovan
Department of Chemistry
H.H. The Rajah's College
Pudukkottai, Tamilnadu - 622001, India.
E-mail: elangoorganic@gmail.com
Department of Chemistry,
B. S. Abdur Rahman University,
Seethakathi Estate, Vandalur, Chennai - 600048, India.
Fax: 91-44-2750520; Tel: 91-44-2751450 Ext. 138.
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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Moreover, problems such as Alzheimer’s disease, hepatitis and
neurological disorders can also be caused on excessive intake.
Hence it is imperative to develop metal-free protocols to
accomplish the 1,2,3-triazoles. In response to that overwhelming
demand, recently K2CO3 promoted OAOC of chalcones and
azides have been reported in aqueous solution.[23] In addition to
that, ‘organo click’ reactions [24] were developed where organo
catalysts would be employed instead of metal catalysts to
accomplish the triazoles. The ‘organo click’ reactions
encapsulate the EAOC of enamines (electron rich olefins)
prepared insitu from various carbonyl compounds with organic
azides (mostly aryl azides) catalyzed by amines [Eq. (3),
Scheme 1]. In addition to enamine mediated organo click
reactions, enolate mediated organo click reaction has also been
reported.[25] However to the best of our knowledge, organo
catalysts for the electron deficient olefins such as α,β-
unsaturated enones and quinones have not been reported so far
[Eq. (4),Scheme 1]. Here we report the unprecedented oxidative
cycloaddition of organic azides with electron deficient olefins
promoted by TEMPO.
prolonged only with oxygen (in the absence of TEMPO), only
35% yield of triazole was obtained which ascertains the
combined role of oxygen and TEMPO in this system (Table 1,
entry 24).
Table 1. Optimization of metal-free OAOC.[a]
Entry
Oxidant
(Equiv)
Additive
Solvent
Yield of
3a(%)b
Yield of
4a(%)b
1[c]
2
TEMPO (1.0)
TEMPO (1.0)
TEMPO (1.0)
TEMPO (1.0)
TEMPO (1.0)
TEMPO (1.0)
TEMPO (1.0)
TEMPO (1.0)
TEMPO (1.0)
TEMPO (1.0)
-
-
H2O
MeOH
CH3CN
Dioxane
THF
DMSO
CHCl3
Toluene
DMF
-
81
33
-
-
-
-
-
-
-
3
-
14
4
-
33
5
-
Trace
Trace
Trace
58
6
-
Results and Discussion
7
-
At the outset, we began our optimization with chalcone (1a) with
benzyl azide (2a) as representative substrates using water as
the solvent and TEMPO as the oxidant. Despite the formation of
meager amount of triazole (3a) in the room temperature, the
yield gradually increased up to 81% when the temperature was
8
-
trace
trace
9
-
66
10[d]
11
12
13
14
15
16
17
18
19
20
21
22
23
24
[a]
-
79
o
elevated up to 90 C (Table 1, entry 1). While solvent variation
-
-
20
was attempted, poor yield of 3a was obtained in the solvents
such as methanol, acetonitrile and 1,4-dioxane (Table 1, entry 2-
4). Apparantly, solvents like THF, DMSO and CHCl3 have played
a hostile role since the yield slumped into trace amount while
employing these solvents (Table 1, entry 5-7). On the other
hand, substantial increment of triazole formations was observed
with toluene and DMF in spite of the trace amount of enaminone
4a (Table 1, entry 8-9). To our surprise, significant enhancement
of yield was observed when the reaction was performed in neat
condition (Table 1, entry 10). On the other hand, when the
TEMPO was eliminated from the neat reaction, the yield
dramatically dropped to 20% witnessing the pivotal role played
by TEMPO (Table 1, entry 11). Fixing the water as the best
solvent, various oxidants such as K2S2O8, oxone, t-BuOOH and
CAN (Ceric ammonium nitrate) also were investigated in the
place of TEMPO and it was unambiguously ascertained that
none of them is on par with TEMPO (Table 1, entry 12-15).
When TEMPO oxidation was tried with some co-oxidants,
oxygen was found to be the best co-oxidant to propel the
reaction (Table 1, entry 16-19). At the same time, when this
oxidation was attempted under nitrogen atmosphere, the
efficacy was retarded to a great extent though stoichiometric
amount of TEMPO was utilized (Table 1, entry 20). Fixing the
oxygen as the best co-oxidant, when the amount of TEMPO was
increased from 0.2 equivalent to 0.5 equivalent, we resolved to
fix 0.5 equivalent of TEMPO as the suitable amount to propel
this reaction (Table 1, entry 21 - 23). When the reaction was
K2S2O8 (1.0)
Oxone (1.0)
t-BuOOH (1.0)
CAN (1.0)
-
H2O
Trace
20
-
-
-
H2O
-
H2O
30
trace
-
H2O
5
-
TEMPO (0.2)
TEMPO (0.2)
TEMPO (0.2)
TEMPO (0.2)
TEMPO (1.0)
TEMPO (0.4)
TEMPO (0.5)
TEMPO (0.6)
-
K2S2O8
NaOCl
Oxone
Oxygen
N2
H2O
10
-
H2O
44
23
H2O
32
trace
H2O
50
-
-
-
-
-
-
H2O
46
O2
H2O
80
O2
H2O
83
O2
H2O
84
O2
H2O
35
Reaction conditions: Chalcone (1.0 equiv), Azide (1.5 equiv), oxidant and
[b]
[c]
solvent (4 mL) were heated for 12h.
Isolated yields.
The yield of 3a
obtained when the reaction was carried out at room temperature, 50 oC and
70 oC are 10%, 30% and 62% without the formation of 4a. Reaction was
[d]
carried out in neat condition with 3.0 equiv of azide.
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Having established the optimized condition (Table 1, entry 22)
for metal-free OAOC of electron deficient olefin and azide, we
extended that condition to various azides with the chalcone (1a).
While comparing with benzyl azide (2a), substitutions such as
chloro, methyl and methoxy on the aromatic ring have reduced
the yield of the triazoles almost equally (Table 2, entry 1-4).
Electron deficient nitro group has considerably suppressed the
efficacy of the reaction since yield has dropped into 58 % (Table
2, entry 5). Similarly, unlike benzyl azides, electron deficient
phenyl azide also has significantly retarded the yield (Table 2,
entry 6). On the contrary, aliphatic azides such as phenethyl and
n-octyl azides have enormously enhanced the yield (Table 2,
entry 7-8). Ethyl-2-azidoacetate (2i) which is an electron poor
aliphatic azide has comparatively furnished a moderate yield of
triazole (Table 2, entry 9).
entry 11-13). It is worth mentioning that, as the aliphatic
substitution increases in the enone, the yield of the product
proportionally decreases (Table 3, entry 14-16). Apart from
enones, methyl cinnamate and cinnamaldehyde also react
comfortably rendering moderate and good yields of triazoles
(Table 3, entry 17-18). As a sign of selectivity, terminal alkene
such as methyl vinyl ketone responds feebly to this reaction
condition furnishing exceedingly poor yield of triazole than the
internal alkenes discussed earlier (Table 3, entry 19).
Table 3. Substrate Scope of Olefins and Azides.[a]
Entry
R1
R2
R3
1
3
Yield
(%)[b]
Table 2. TEMPO promoted OAOC of 1a with various azides.[a]
1
2
4-(Cl)Ph
4-(Br)Ph
4-(Br)Ph
4-(Br)Ph
4-(OMe)Ph
4-(Me)Ph
4-(NO2)Ph
2-(OH)Ph
Ph
Ph
Ph
Bn
Bn
1b
1c
1c
1c
1d
1e
1f
3j
3k
3l
88
91
99
95
91
84
79
42
98
90
89
86
86
77
60
48
44
80
28
3
Ph
4-(Me)Bn
4-(MeO)Bn
Bn
Entry
R1
Yield (3) (%)b
83 (3a)
77 (3b)
76 (3c)
74 (3d)
58(3e)
4
Ph
3m
3n
3o
3p
3q
3r
1
2
3
4
5
6
7
8
9
PhCH2 (2a)
5
Ph
4-(Cl)PhCH2 (2b)
4-(CH3)PhCH2 (2c)
4-(CH3O)PhCH2 (2d)
4-(NO2)PhCH2 (2e)
Ph (2f)
6
Ph
Bn
7
Ph
Bn
8
Ph
Bn
1g
1h
1i
9
4-(Br)Ph
3-(Me)Ph
Ph
Bn
62 (3f)
10
11
12
13
14
15
16
17
18
19[c]
Ph
Bn
3s
3t
PhCH2CH2 (2g)
C6H13 (2h)
83 (3g)
89 (3h)
72 (3i)
Furanyl
Thiophenyl
Furanyl
Ph
Bn
1j
Ph
Bn
1k
1l
3u
3v
3w
3x
3y
3z
C2H5OCOCH2 (2i)
Me
Bn
[a]Reaction conditions: Chalcone (1.0 equiv), Azide (1.5 equiv), TEMPO (0.5
[b]
equiv) and water (4 mL) were heated at 90 oC for 12h under oxygen ballon.
Me
Bn
1m
1n
1o
1p
1q
1r
Isolated yields.
Et
Ph
Bn
Et
CH3
OMe
H
Bn
On other part of the reaction, various olefins were screened with
benzyl azides to infer the efficacy of this method on olefins
(Table 3). Variation of substitutions on both the carbonyl side
and the olefin side of the enone was meticulously studied.
Chlorophenyl, bromophenyl and methoxyphenyl substitutions on
the olefin side invariably furnished excellent yields of triazoles
(Table 3, entry 1-5). Electron withdrawing nitro group has
substantially retarded the efficacy than the methyl group (Table
3, entry 6-7). On the contrary, very noticeable decline of yield
(42%) has been observed with 2-hydroxy phenyl substitution on
the olefin side (Table 3, entry 8). Bromophenyl substitution on
the carbonyl side also has excessively boosted the reaction to
an excellent yield (Table 3, entry 9). Heterocyclic aromatic
substitutions such as furanyl and thiophenyl substitutions also
have smoothly promoted the reaction with good yields (Table 3,
Ph
Bn
Ph
Bn
3za
3zb
H
Me
Bn
[a]
Reaction conditions: Olefin (1.0 equiv), Azide (1.5 equiv), TEMPO (0.5
equiv) and water (4 mL) were heated at 90 °C for 12h under oxygen balloon.
[b] Isolated yields. [c] Reaction conditions: Olefin (3.0 equiv), Azide (1.0 equiv),
TEMPO (0.5 equiv) under oxygen balloon.
As the most flamboyant part of this work, cyclic enones and
dienones such as cyclohexenone and naphthaquinone also
were subjected to TEMPO promoted oxidative cycloaddition with
benzyl azide. Despite being rarely attempted in the literature,26
these olefins also could witness the versatile scope of this
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European Journal of Organic Chemistry
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COMMUNICATION
protocol by furnishing good yields of triazoles (Scheme 2).
Conclusions
In conclusion we have developed
a metal-free, TEMPO
promoted and water mediated oxidative cycloaddition of organic
azides with various electron deficient olefins to construct a
diverse array of disubstituted and trisubstituted 1,2,3-triazoles.
This method can be a potential alternative to the existing copper
and ruthenium catalysed azide-alkyne cycloaddition because of
its metal-free condition and aqueous mediation. Olefins used
here are comparatively cheaper than alkynes and they can be
easily accessed by synthetic or commercial means. Most
importantly this protocol has demonstrated a broad substrate
scope of olefins bearing ketones, esters and aldehydes. Rare
substrates like cyclohexenone and naphthoquinone also have
successfully undergone oxidative cycloaddition. This method is
distinct from the previously reported organo click reactions
because this method uses electron deficient olefins instead of
the electron rich enamines. Organo click reactions are limited to
Scheme 2. TEMPO promoted OAOC of cyclic enones.
In order to elicit insight on the mechanistic details, the following
observations were made. When this reaction was attempted
under nitrogen atmosphere, the yield of the triazole was greatly
suppressed even though one equivalent of TEMPO was
employed (Table 1, entry 20). This indicates the role of oxygen
in the reaction. Reaction in the oxygen atmosphere (without
TEMPO) also has failed to boost up the reaction to a convincing
yield of the product (Table 1, entry 24). This testifies the
combined role of TEMPO and oxygen in this transformation.
Since 0.5 equivalent of TEMPO was adequate to complete the
reaction under oxygen atmosphere, it is evident that TEMPO,
after being used up in the reaction process, gets regenerated at
27
aryl azides while this method is versatile to aryl, aliphatic and
benzyl azides. We hope that these salient attributes will merit
this method as a highly desirable one among the other existing
methods.
1
some stage by oxygen. H NMR of the crude reaction mixture of
Experimental Section
methyl vinyl ketone (1r) and benzyl azide (2a) furnished a
characteristic peak at chemical shifts at 8.77 ppm (CH from the
imine carbon) strongly suggests the involvement of imine-type
intermediate. From these observations, we suggest a possible
mechanism of the TEMPO promoted OAOC of electron deficient
olefins and organic azides as follows. The triazoline A generated
from azide-alkene cycloaddition is proposed to give the radical
cation B. Subsequently, the radical cation B, by losing hydrogen
radical, leads to the formation of iminium ion species C which
equilibrates with its amino carbenium species D. The iminium
type intermediate C is successfully aromatized into the required
triazole E by losing a proton. In the meantime TEMPO is
converted to its hydroxylamine form which is readily reoxidized
by oxygen.
A mixture of olefin (1.0 mmol), azide (1.5 mmol), and TEMPO (0.5 mmol)
and water (4 mL) were heated at 90 °C for 12h under oxygen balloon.
After completion of the reaction as monitored by TLC, the reaction
mixture was extracted with ethyl acetate (2 x 30 mL) and the combined
organic solutions were dried with Na2SO4. The solvent was evaporated,
and the resulting crude product was purified by column chromatography.
Acknowledgements
The authors thank the CSIR (02(0148)/13/EMR-II), New Delhi
for the financial support.
Keywords: Metal-Free [3+2] Cycloaddition ● 1,2,3-Triazoles ●
Azide-Olefin Cycloaddition ●TEMPO
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This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601121
COMMUNICATION
COMMUNICATION
A New Example of Organo Click Reactions:
TEMPO-Promoted Oxidative Azide-Olefin
Cycloaddition for the Synthesis of 1,2,3-
Triazoles in Water
Eur. J. Org. Chem. Year, Volume, Page – Page
D. Gangaprasad,[b] J. Paul Raj, [b] T. Kiranmye, [b]
K. Karthikeyan, [b] and J. Elangovan*[a]
A TEMPO-promoted oxidative [3+2] cycloaddition of organic azides with electron deficient internal, terminal
and cyclic olefins is reported under aqueous medium. A diverse array of substituted 1,2,3-triazoles are
synthesized from moderate to excellent yields.
This article is protected by copyright. All rights reserved