A general metal-free route towards the synthesis of 1,2,3-triazoles from readily available primary amines and ketones

Article abstract of DOI:10.1039/c5cc08347h

An unprecedented approach that enables the direct and selective preparation of 1,5-disubstituted 1,2,3-triazoles from abundantly available building blocks such as primary amines, enolizable ketones and 4-nitrophenyl azide as a renewable source of dinitrogen via an organocascade process has been developed. Furthermore, this efficient methodology also enables the synthesis of fully functionalized and fused N-substituted heterocycles.

Full text of DOI:10.1039/c5cc08347h

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A General Metal-Free Route Towards the Synthesis of 1,2,3-
Triazoles From Readily Available Primary Amines and Ketones
Joice Thomas,a Sampad Jana,a Jubi John,a Sandra Liekens,b and Wim Dehaen *a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
limitations are the low substrate scope of the other component
with reactivity limited mostly to activated carbonyl compounds. A
very general and metal-free procedure to synthesize 1,5-
disubstituted 1,2,3-triazoles is still lacking. Also, none of these
methodologies have yet beenapplied to synthesize triazole
derivatives of readily available natural products which could for
instance facilitate structure activity relationship studies of
bioactive/drug-like molecules.
An unprecedented approach that enables the direct and
selective preparation of 1,5-disubstituted 1,2,3-triazoles from
abundantly available building blocks such as primary amines,
enolizable ketones and 4-nitrophenyl azide as a renewable
source of dinitrogen via an organocascade process has been
developed. Furthermore, this efficient methodology also
enables the synthesis of fully functionalized and fused N-
substituted heterocycles.
In 1965, Pocar et al. described the reaction of an isolated
imine/enamine (derived from acetone and propylamine) with 4-
nitrophenyl azide (3a) which yielded 1-propyl-5-methyl-1,2,3-
triazole in moderate yield.9a Surprisingly, this report remained
virtually unnoticed, and no further attempts were made towards
the further development of this protocol. One of the central
challenges that could be associated with this method is the
reversibility of the imine/enamine formation, hampering its
isolation. This led us to the design of a multicomponent reaction
starting from an enolizable ketone, primary amine and 3a. We
surmised that both the imine formation and the isomerization to
enamine can be accelerated by a catalytic amount of an organic
acid. The reaction would proceed via a sequence of, (a) Schiff base
formation, (b) tautomerisation to the enamine, (c) 3+2
cycloaddition reaction with 3a, and (d) aromatization with the loss
of 4-nitroaniline (5a). Such a cascade process that combines
multiple individual transformations in one operation is particularly
attractive in triazole synthesis because isolation of the intermediate
species, which may be difficult and time consuming especially when
large collections of compounds are required, is avoided. Moreover,
amines and ketones are inexpensive and abundantly present in
biologically active natural products. Even more alluring is that this
could lead to previously inaccessible 1,5-disubstitued 1,2,3-triazoles
via a metal-free pathway.7f-h
In recent years, 1,2,3-triazole-containing molecules have
received attention in diverse fields.1 Currently, the most publicized
ways to access 1,4- and 1,5-disubstituted 1,2,3-triazoles are the Cu-
and
Ru-catalyzed
azide-alkyne
cycloaddition
reactions,
respectively.2 However, the limited access to terminal alkynes and
the toxicity of the heavy metal catalysts hampers a wider
exploration.3 Several metal-free methods have been developed for
the regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles.4
Nevertheless, selective pathways towards 1,5-disubstituted
triazoles are rather scarce.5 It is well documented that the cis-
locked geometry present in 1,5-disubstituted triazoles could be an
advantage to increase biological activity and binding affinity
towards several biological targets.6 Unfortunately, the lack of an
efficient and very general synthetic route to achieve a diverse
library of these isomers limits their applications in medicinal
chemistry.6c
More recently, significant attention has been given to the
preparation of diversely functionalized 1,2,3-triazoles via
organocatalysis rather than metal catalyzed routes.7-8
Unfortunately, the scope of these reactions is mostly limited to
aromatic groups at the N1-position of the triazole heterocycles and
extension to aliphatic substituents is cumbersome. Moreover, most
transformations reported so far relied on organic azides that are
mostly non-commercial and potentially hazardous. Other major
In order to validate this synthetic design, we have chosen
acetophenone (1a), 4-methoxybenzylamine (2a) and 3a as model
substrates. After some optimization (see supporting information),
we found that the three-component reaction of 1a, 2a and 3a in a
respective molar ratio of 1:1.4:1 using 30 mol% of acetic acid as
catalyst over 4 Å molecular sieves in 1M solution of toluene at
100°C were the reaction conditions of choice. The desired product
4a was obtained after 12 h with an isolated yield of 93%. As
expected, quantitative conversion of 3a to 5a was also observed.
Importantly, this reaction also worked fine under acid free
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conditions without significantly affecting the yield of 4a (85%)
although the required reaction time was longer (24 h). To check the
synthetic utility of the method at a larger scale, the optimized
reaction was carried out on a five gram scale of 1a. Indeed, the
reaction proceeded efficiently and furnished the desired product in
an undiminished yield of 88%. An even more interesting aspect of
the bulk synthesis was the easiness of purification of 4a in an atom
economic way simply by the diazotization of the eliminated 5a to its
diazonium salt from the crude reaction mixture itself followed by its
extraction to the aqueous layer and the pure product 4a to the
organic layer. Finally, treatment of the diazonium salt with NaN3
lead to the regeneration of 3a in high yield (82%), which could then
be reused (Fig. 1).
With this newly developed metal-free three-component
protocol we first set out to survey the scope and limitations of this
methodology with a variety of aromatic and aliphatic enolizable
ketones. Acetophenones with both electron-donating and electron-
withdrawing groups smoothly underwent these transformations
(4a-4i) (Table 1a). To our delight, various interesting heterocyclic
moieties were amenable to the reaction providing access to triazole
derivatives which are otherwise difficult to synthesize (4l-4n). The
utility of this reaction was further demonstrated by the
transformation of acetyl ferrocene and 6-acetyl uracil. It is worth
mentioning that these reactions failed under an acidic environment
but fortunately under acid-free conditions the expected products
4o and 4p were obtained in good yields.
Table 1. Scope with respect to the ketones.a
Figure 1. Bulk synthesis of 1,2,3-triazole 4a and the regeneration of the 4-nitrophenyl
azide 3a. PMB= 4-methoxybenzyl.
We conducted several control experiments (see supporting
information and Fig. 2) to understand the mechanism of the
reaction. 9
a
Reaction conditions: 1 (1.0 equiv.), 2a (1.3 equiv.), 3a (1.0 equiv.), CH3COOH (30
mol%), toluene (0.4 mL), 100 °C, 12 h, Isolated yield. 40 h. 3.0 equivalents of 1g. d
b
c
e
f
CH3COOH (0 mol%), 24 h. CH3COOH (0 mol%), DMF (0.6 mL), 12 h. Reaction
Conditions: 1p (1.0 equiv.), 2a (2.8 equiv.), 3a (2.0 equiv.), toluene (1.5 mL), 100 °C, 72
h. e 24 h.
Figure 2. Proposed mechanistic experiments and catalytic cycles. a Scheme showing the
b
synthesis of the triazoline intermediate 6a and its conversion to 4a and 5a. The 1H
NMR spectra showing the clean formation of the triazole 4a and 5a upon heating the
Next, we investigated the scope of this reaction towards the
synthesis of 1,4,5-trisubstituted 1,2,3-triazoles (Table 1b). For
instance, aryl or alkyl ketone precursors such as aryl propanones or
5-nonanone lead to the expected trisubstituted triazoles in
c
triazoline intermediate 6a in presence of 8 mol% of CH3COOH in CDCl3 at 65° C.
Postulated mechanism. R3NH3+CH3COO- indicates the in situ formation of the organic
salt when CH3COOH reacts with R3NH2.
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a
Reaction conditions: 1 (1.0 equiv.), 2a (1.3 equiv.), 3a (1.0 equiv.), CH3COOH (30
mol%), toluene (0.4 mL), 100 °C, 12 h, Isolated yield. b CH3COOH (0 mol%), 24 h. c 48 h,
CH3COOH (30 mol%). d 48 h.
excellent yield (4q-4t). However, the extension of this reaction to
activated methylene ketones such as ethyl benzoylacetate leads to
the well-known Dimroth product formed by the 3+2 cycloaddition
of 3a with either the enolate or enamine intermediate.10 An initial
investigation with an unsymmetrical ketone, for example 2-
butanone, gave mostly the expected product 4u together with a
noticeable amount of 18% of the other regioisomer 4v (Table 1c). In
light of these results, we reasoned that during the course of the
reaction an equilibrium mixture of the two enamines will form and
the composition of this is in favor of the most substituted enamine.
This eventually gives 4u as the major isomer. On the other hand,
the ease of attack onto the less hindered enamine leads to a minor
amount of the kinetic product 4v. Interestingly, methyl isopropyl
ketone led to 10% of the stable triazoline intermediate 6w derived
from the more substituted enamine together with 56% of the
kinetic product 4w. We then examined the scope of this reaction
with respect to different cyclic ketones (Table 1d). The synthesis of
N1-alkyl derivatives of carbo- as well as O- and N-heterocyclic fused
triazole derivatives is scarcely reported (4x-4ab). Additionally,
different aromatic bicyclic ketones were also compatible with the
reaction (4ac-4ag). The high regioselectivity obtained with 2-
tetralone shows that cycloaddition occurs with the most stable
enamine, thus yielding 4ag as the sole product.
To demonstrate the utility of this reaction in material science, novel
oligotriazole derivatives 7&8 derived from bi/tri-acetyl compounds
could be generated in good yields after multiple MCRs without
being affected by any steric hindrance (Fig. 3). Polymeric or
dendritic triazole materials are of current interest.1 The need for
building blocks having multiple azide groups may be a limiting
factor since they are potentially shock-sensitive compounds.11 We
surmised that the present approach is
a safer alternative.
Accordingly, readily available tris(2-aminoethyl)amine was
subjected to reaction conditions to afford the C3-symmetric
derivative 9 in good yield. To further demonstrate the utility of this
approach to dendrimer chemistry, the modification of the 2nd
generation dendron 10 with cyclohexanone was considered. Clean
conversion to a monodisperse fused polytriazole amine 11 in
reasonable yield was observed.
In a next series of experiments the substitution pattern in the
amine part was varied (4ah-4aq). More importantly, substrates
bearing unprotected secondary amines such as 4ak and 4al could
be effectively transformed using the current conditions.
Remarkable functional group tolerance was observed in the case of
allyl amine and 2,2-dimethoxyethylamine where the alkene and
acetal functionalities remained intact under acid-free conditions
(4am&4an). This elegant strategy was also applied to synthesize
chiral-unit-containing triazoles by using different chiral amines
(4ao&4ap). As expected, the extension of our protocol to aromatic
amines gave a dissatisfactory yield of only 25% (4aq) caused by the
lower reactivity of the intermediate enamines. However, the N-aryl
triazoles are easily obtained by other methods. 5,7-8
Figure 3. Substrate scope of the various multifunctional building blocks.
To fully exploit the versatility of this MCR, bioactive natural
products containing functional groups such as primary amines and
enolizable ketones were investigated to access novel and unique
triazole-containing natural products which are expected to enable
SAR studies facilitating subsequent drug developments for human
diseases (Table 3). The application of the triazolation condition to
the histamine 12a and tryptamine 12b led to the expected 1,5-
disubstituted 1,2,3-triazoles in reasonable yields (13a and 13b).
Leelamine 12c (an optically active diterpene amine which binds
weakly to human cannabinoid receptors) was also structurally
modified to new triazole entities 13c.12 Addtionally sphingoid base,
phytosphingosine 12d was easily modified to non-hydrolysable
ceramide analogue 13d (amide bond of ceramide was replaced by
bioisosteric 1,2,3-triazole functionality) in a single step without
doing a laborious protection/deprotection strategy.13 Several D-ring
tethered heterocyclic compounds of estrone 12e were identified as
useful templates for the design of inhibitors of steroidogenic
enzymes such as 17β-hydroxysteroid dehydrogenases.14 This
Table 2. Scope with respect to the amines.a
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a
Reaction Conditions: 1or 12 (1.0 equiv.), 12 or 2a (1.3 equiv.), 3a (1.0 equiv.),
b
CH3COOH (30 mol%), toluene (0.4 mL), 100 °C, 12 h, Isolated yield. CH3COOH (0
c
d
e
mol%), 24 h. 48 h. CH3COOH (0 mol%), 48h. 12 (1 equiv.), 2 (2.8 equiv.), 3a (2.0
equiv.), CH3COOH (30 mol%), toluene (1 mL), 100 °C, 72 h.
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In conclusion, we have developed a universal approach to
access 1,2,3-triazole derivatives in a single step from simple and
readily available enolizable carbonyl compounds and amines which
could be considered not as the end point, but as the initial point for
the rapid generation of complex triazole derivatives that are
inaccessible by other means. In contrast to other well-established
1,5- or fused triazole syntheses where different organic azides that
are non-commercial and potentially dangerous are used to bring
diversity, this strategy makes use of a readily available organic azide
(3a) and readily available aliphatic amines as the sources of
nitrogen of the triazole heterocycles. We successfully illustrated the
utility of this reaction in natural products by systematically
transforming them into diverse triazole derivatives. The fifty-five
examples of this unprecedented triazole synthesis show the scope
and limitations of this strategy.
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We thank KU Leuven for financial support. Erasmus Mundus Lot 13,
Euro-India is acknowledged for the doctoral fellowship to S.J. Mass
spectrometry was made possible by the support of the Hercules
Foundation of the Flemish Government (grant 20100225–7).
Notes and references
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