Metal-Free Route for the Synthesis of 4-Acyl-1,2,3-Triazoles from Readily Available Building Blocks

Article abstract of DOI:10.1002/chem.201601928

Functionalized 1,2,3-triazole heterocycles have been known for a long time and hold an extraordinary potential in diverse research areas ranging from medicinal chemistry to material science. However, the scope of therapeutically important 1-substituted 4-acyl-1H-1,2,3-triazoles is much less explored, probably due to the lack of synthetic methodologies of good scope and practicality. Here, we describe a practical and efficient one-pot multicomponent reaction for the synthesis of α-ketotriazoles from readily available building blocks such as methyl ketones, N,N-dimethylformamide dimethyl acetal, and organic azides with 100 % regioselectivity. This reaction is enabled by the in situ formation of an enaminone intermediate followed by its 1,3-dipolar cycloaddition reaction with an organic azide. We effectively utilized the developed strategy for the derivatization of various heterocycles and natural products, a protocol which is difficult or impossible to realize by other means.

Full text of DOI:10.1002/chem.201601928

DOI: 10.1002/chem.201601928
Communication
&
Heterocyclic Synthesis
Metal-Free Route for the Synthesis of 4-Acyl-1,2,3-Triazoles from
Readily Available Building Blocks
Joice Thomas,[a] Vince Goyvaerts,[a] Sandra Liekens,[b] and Wim Dehaen*[a]
thesis of fully functionalized or 1,5-disubstituted 1,2,3-triazoles
Abstract: Functionalized 1,2,3-triazole heterocycles have
from primary amines, ketones, and 4-nitrophenyl azide as a re-
been known for a long time and hold an extraordinary po-
newable source of dinitrogen through an organocascade proc-
tential in diverse research areas ranging from medicinal
ess.[5c]
chemistry to material science. However, the scope of ther-
In the context of this program to develop new synthetic
apeutically important 1-substituted 4-acyl-1H-1,2,3-tri-
protocols towards 1,2,3-triazole skeletons having medicinal
azoles is much less explored, probably due to the lack of
and supramolecular characteristics, we thought of synthesizing
synthetic methodologies of good scope and practicality.
1-substituted 4-acyl-1H-1,2,3-triazoles, for which the synthetic
Here, we describe a practical and efficient one-pot multi-
pathways are poorly represented in the literature.[6] It is well
component reaction for the synthesis of a-ketotriazoles
documented that a-ketotriazole building blocks display various
from readily available building blocks such as methyl ke-
interesting biological properties (Figure 1).[7] Recently, these
tones, N,N-dimethylformamide dimethyl acetal, and organ-
compounds have been employed as hybridization probes for
ic azides with 100% regioselectivity. This reaction is ena-
applications in nucleic acid chemistry, such as the develop-
bled by the in situ formation of an enaminone intermedi-
ment of triazole-linked DNA.[7f]
ate followed by its 1,3-dipolar cycloaddition reaction with
an organic azide. We effectively utilized the developed
strategy for the derivatization of various heterocycles and
natural products, a protocol which is difficult or impossi-
ble to realize by other means.
In the last decade, 1,2,3-triazole heterocycles have found wide
applications in almost every area of chemistry.[1] One of the
most popular reactions commonly used for the synthesis of tri-
azole heterocycles is the copper(I)-catalyzed azide-alkyne [3+2]
Figure 1. Illustration of pharmaceutically active 4-acyl-1H-1,2,3-triazoles.[7]
cycloaddition (CuAAC) reaction, often referred to as the pre-
mier example of click chemistry.[2] Recently, several metal-free
strategies have emerged as an alternative synthetic ap-
proach.[3] Among these, organocatalytic cycloaddition reactions
Generally, the synthesis of these triazoles involves a CuAAC
of azides with enolizable ketones or aldehydes via an enolate,
enamine, or iminium ion intermediate have recently received
wide attention.[4] Very recently, our group designed two gener-
al and powerful strategies to synthesize triazole heterocycles.[5]
The first method involves an organocatalytic three-component
reaction for synthesizing fully functionalized triazoles from al-
dehydes, organic azides, and nitroalkanes,[5a,b] whereas the
second approach involves a metal-free route towards the syn-
reaction of different dipolarophiles, either acetylenic carbinols,
followed by the oxidation of the 1,2,3-triazolic intermediate,[6e]
or via unstable ynones.[6,7] The synthesis of these dipolaro-
philes may require multiple steps, a large amount of reagents,
and expensive metal-catalyzed reactions, all of which may be
a limiting factor especially when diverse and large collections
of compounds are required (Figure 2). Given the increasing
demand for novel a-ketotriazole-based entities in current syn-
thesis, general reactions that allow easy access to a large li-
brary of these compounds are of significant interest.
[a] Dr. J. Thomas, V. Goyvaerts, Prof. Dr. W. Dehaen
Molecular Design and Synthesis, Department of Chemistry
KU Leuven, Celestijnenlaan 200F, 3001 Leuven (Belgium)
E-mail: wim.dehaen@chem.kuleuven.be
A solution to overcome these drawbacks has emerged from
the realization that enaminones can be considered as a synthet-
ic equivalent to ynones.[8] We envisioned that enaminone dipo-
larophiles prepared in situ by a condensation reaction of the
corresponding enolizable ketones, containing three a-hydro-
gens, with N,N-dimethylformamide dimethyl acetal (DMF di-
methyl acetal, 2),[9] may undergo a regioselective enamine-
mediated cycloaddition reaction with organic azides. Aromati-
[b] Prof. Dr. S. Liekens
Department of Microbiology and Immunology
Rega Institute for Medical Research
KU Leuven, 3000 Leuven (Belgium)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201601928.
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zation of the triazoline intermediate D through a syn-elimina-
tion of dimethylamine is the plausible driving force for the
final step. Based on this postulated reaction mechanism, the
rate of the 1,3-dipolar cycloaddition reaction is strongly depen-
dent on the electronic nature of the dipole and the dipolaro-
phile. For instance, increasing the electron-donating character
of enaminone and the electron-withdrawing character of azide
will lower the HOMOdipolarophile–LUMOdipole gap, which in turn in-
creases the reaction rate and vice versa.[10]
Figure 2. Summary of previous[6,7] and present work.
zation by spontaneous elimination of dimethylamine eventual-
ly results in the assembly of the a-ketotriazoles. Obviously, this
approach features significant advantages: 1) the use of readily
available building blocks such as methyl ketones is appealing
because they are inexpensive (the price of acetophenone and
N,N-dimethylformamide dimethyl acetal combined is 225 times
lower than the price of analogous 1-phenyl-2-propyn-1-one)
and abundantly present in biologically active natural products,
2) metal-free synthesis and 3) the rapid and convergent syn-
thesis of triazole heterocycles without isolation of the inter-
mediate species, which facilitates the structure–activity rela-
tionship studies of bioactive/drug-like molecules.
Scheme 1. Proposed reaction mechanism.
With this optimized reaction in hand, we first explored the
generality of this protocol to a variety of acetophenones
having both electron-donating and electron-withdrawing
groups (Table 1, 4a–4e). Very interestingly, the library was fur-
ther extended to triazoles containing heterocyclic moieties
such as pyridines (4 f and 4g) and thiophene 4h in excellent
yields. To our delight, the transformation of acetylferrocene to
4-ferrocenoyl-decorated 1,2,3-triazole 4i occurred in good
yield, providing access to triazole derivatives that are otherwise
difficult to synthesize. However, the reaction with aliphatic
methyl ketones, such as acetone, resulted in a diminished yield
under the optimized reaction conditions. A possible explana-
tion is undesirable aldol condensation during the microwave
irradiation with 2. Fortunately, by using an excess of acetone
(three equivalents), the expected 4-acetyl-triazoles 4j and 4k
were obtained with excellent yields. Under similar circumstan-
ces, an unsymmetrical ketone, such as 2-heptanone, only gave
45% of the product 4l. In the light of this result, we reasoned
that a competition exists between the two possible places for
enaminone formation, where only the less substituted enami-
none will give the anticipated product. We were pleased to
find that 1-adamantyl methyl ketone also delivered the corre-
sponding triazole 4m in a good yield of 68%.
We decided to use readily available acetophenone 1a, 2,
and phenyl azide 3a as the model substrates for optimizing
the reaction conditions (see Supporting Information). The opti-
mized conditions involve the in situ synthesis of the enami-
none intermediate from 1a and 2 either by microwave (MW)
irradiation at 1508C over a period of 25 min, or by convention-
al heating (D) at 1008C over a period of 12 h in a sealed tube.
This is followed by the addition of one equivalent of phenyl
azide 3a in toluene and continued heating at 1008C over
a period of 12 h. These optimized conditions allowed for com-
pound 4a to be isolated with a yield of 86% and 100% regio-
selectivity (Reaction 1). On a preparative scale (17 mmol), it
was possible to achieve 4a using only conventional heating
conditions. We started the reaction with 2 g of 1a, and pro-
duced 3.4 g of 4a in a comparable yield of 82%.
Next, a variety of aromatic and aliphatic azides could be
converted to the corresponding triazoles in moderate to high
yields ((Table 1, 4n–4q). Generally, in contrast to the acetylenic
carbinol and the ynone pathways,[6–8] aryl azides bearing elec-
tron-withdrawing functional groups exhibit higher reaction
rates and yields when compared to aliphatic and electron-do-
nating aromatic azides. Interestingly, a protected sugar bearing
sterically demanding secondary azide could be effectively
transformed into its triazole analogue 4r using the current
conditions. Moreover, applicability of this synthetic methodolo-
gy to the conversion of azidothymidine (AZT, an antiretroviral
medication used to prevent and treat HIV/AIDS) to the corre-
sponding 4-acyl-1,2,3-triazole 4s was demonstrated with an
isolated yield of 72%.[11a] Worth noting is that a metal-free tet-
raarylporphyrin functionalized with 4-acyl-triazole 4t was syn-
thesized in 61% yield with this protocol, whereas applying the
A possible reaction mechanism is depicted in Scheme 1. In
the first step, a molecule of methoxide is expelled from 2,
giving rise to the iminium ion A. The enolate B, which is
formed after deprotonation of 1, can attack the iminium
carbon of A to generate the enaminone C after the loss of an-
other molecule of methanol.[9] This enaminone species acts as
the electron-rich olefinic partner in the reaction with the azide
dipole 3 by an inverse-electron-demand [3+2] cycloaddition
process with complete regioselectivity, to form 4. The aromati-
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bond angles and the relatively acidic C-4 proton of the 4-ben-
zoyl-substituted 1,2,3-triazole, when compared to its aryl-deriv-
ative, can give a different perspective towards the develop-
ment of novel anion-binding receptors or metal chelators by
the cooperative effect of having two or more of these triazole
heterocycles within the same molecule.[12] As a proof of the
synthetic viability, novel oligotriazole bidentate ligands 5–8
were obtained in good to acceptable yields from readily avail-
able starting materials in a single step (Reaction 2). A prelimi-
nary investigation of the pentad receptor 5 towards the affinity
Table 1. Generality of triazole synthesis.[a]
1
of anions using H NMR spectroscopic studies indicates that it
can bind chloride anion due to the cumulative binding effects
of the triazole CHs and the benzene CHs (see Supporting Infor-
mation). An upcoming study will focus on the supramolecular
anion-binding properties and solid-state features of these ma-
terials. The pyridoyl derivative 7 can be considered as an ana-
logue of the well-known ligand [2,6-bis(1,2,3-triazol-4-yl)pyri-
dine] (BTP), which has been extensively studied as a complex-
ing agent for several applications in coordination chemistry.[12b]
[a] Reaction conditions: 1 (1.0 equiv), 2 (1.2 equiv), 3 (1.0 equiv), MW,
1508C, 25 min and D, 1008C, 12 h; isolated yields provided. [b] D, 1008C,
24 h. [c] 3.0 equiv of 1. [d] D, 1008C, 2 h. [e] D, 1008C, 48 h. [f] D, 1008C,
72 h. [g] DMF, D, 1008C, 72 h. [h] 2 (2.4 equiv), D, 1008C, 12 h. [i] 2
(2.4 equiv), D, 1008C, 6 h. [j] 2 (2.4 equiv), DMF, D,1008C, 72 h.
The versatility of this methodology was further exemplified
by synthesizing previously inaccessible symmetrical and asym-
metrical diphenylditriazole ketones 9 and 10 starting from the
acyl-triazole 4k in reasonable yields (Reaction 3). It is worth
mentioning that this class of unique triazole skeletons cannot
be easily accessed by existing methods, which highlights the
synthetic utility of this approach.
CuAAC reaction would have led to undesired CuII-metalated
porphyrinate.[11d]
We further examined the scope of the reaction with respect
to ketones containing acidic hydrogens. Surprisingly, subject-
ing the substrate 3-acetylindole 1u to the standard reaction
conditions resulted in an unexpected methylation of indole
that eventually leads to the triazole derivative 4u in 43% yield
together with 48% of unreacted starting material. We specu-
late that the methylating agent could be the intermediate A
(Scheme 1) formed from 2 under the reaction circumstances,
and the presence of the unreacted starting material indicates
that the alkylation occurs only after the enaminone formation.
When the reaction was repeated with excess of 2, the yield of
4u was improved to 76%. Similarly, 4-hydroxyacetophenone
led to the expected methoxy analogue 4w. Also, repeating the
reaction with AZT but with an excess of 2 led to the methylat-
ed thymidine nucleoside (4x). It is interesting to note that the
alkylation does not occur in the case of the enaminone inter-
mediate derived from 2-hydroxyacetophenone 1b (4b,
Table 1). This can be explained by considering the difficulty in
abstracting the proton of the aromatic OH group due to the
strong intramolecular H-bonding with the neighboring oxygen
atom of the oxo functionality.[9b]
Encouraged by the broad applicability of this methodology,
we further targeted the transformation of bioactive natural
products, containing an acetyl functional group, to the corre-
sponding a-ketotriazole derivatives, which could for instance
facilitate the structure–activity relationship studies of bioac-
tive/drug-like molecules (Scheme 2). Accordingly, triazolization
of acetovanillone with an excess of 2 led to the corresponding
1,2,3-combretatriazole derivative 12a after the methylation of
the hydroxyl group.[7g] Applying this approach to the neuroac-
tive endogenous steroid hormone, pregnenolone 11 b, provid-
ed the expected product 12b furnished with an a-ketotriazole
heterocycle in 76% yield[11c] Platanic acid 11 c is a naturally oc-
curring pentacyclic triterpenoid and has gained much atten-
tion in natural product chemistry because of its potent anti-
HIV activity. However, 1,2,3-triazole derivatives of these triterpe-
By using a bifunctional building block containing multiple-
acetyl/azide functional groups, more than one triazole moiety
can be incorporated in a single molecule. A possible applica-
tion for these multicomponent reactions (MCRs) lies within the
field of supramolecular chemistry.[12] For instance, different
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Scheme 2. Scope with respect to the natural products.
noids have not been investigated to date. Application of this
synthetic methodology to platanic acid delivered the methyl
ester of the expected product 12c in good yield.[11b]
Scheme 3. Miscellaneous multicomponent reactions.
Given the success of this reaction for the synthesis of a-ke-
totriazoles, the generality of this protocol was further tested.
The application of this strategy to the a,b-unsaturated ketone
13 led to the synthesis of a chalcone derivative 14 with excel-
lent yield (Scheme 3). These classes of compounds were
shown to have reversible tissue transglutaminase inhibitor ac-
tivity and are usually synthesized using a multistep strategy.[7f]
Interestingly, the reaction also worked well with 3-acetylcou-
marin 15, which afforded the useful material 16. 1-Phenyl-pro-
pane-1,2-dione 17 was also successfully employed in this reac-
tion for the synthesis of a,b-diketotriazole 18, albeit in slightly
lower yield. Previously, this class of compounds was obtained
in a multi-step procedure by the catalytic oxidation of a-keto-
triazole, which was synthesized by an ynone-mediated cycload-
dition reaction.[6d] It is worth mentioning that in the case of
the activated ketones depicted in Scheme 3, conventional
heating gave better results for the generation of the respective
enaminone intermediate than the microwave conditions. Next,
we investigated the scope of this reaction towards the synthe-
To summarize, we have developed a straightforward and
practical way to access 1,4-disubstitued 4-acyl-1,2,3-triazoles
from readily available building blocks such as ketones, DMF
acetal, and organic azides using a one-pot MCR. In contrast to
other methods, this elegant strategy offers an operationally
simple single-step procedure, metal-free conditions, and dem-
onstrates a broad substrate scope. We also established the im-
portance of this reaction in various natural products. Further-
more, different bi- and tridentate ligands having supramolec-
ular interest were also synthesized. Beyond the broad useful-
ness of this new strategy, the method also offers a new
avenue for regiospecific installation of various delicate scaf-
folds and functional groups on triazole heterocycles with high
efficiency. Altogether, we anticipate that the present work will
provide a valuable route in the construction of medicinally im-
portant compounds as well as in the development of supra-
molecular functional systems.
sis of 4-nitro-substituted 1,2,3-triazoles 19 and 20 from nitro- Acknowledgements
methane, which involved in situ generation of 1-(dimethylami-
no)-2-nitroethylene and its subsequent cycloaddition reaction
with an organic azide, followed by the elimination of dimethyl
amine instead of HNO2. We then examined the possibility to
employ cyanoacetic acid as one of the starting materials to de-
velop a general method to synthesize 1,4-disubstitued 4-
cyano-1,2,3-triazole 22 by in situ generation of the correspond-
ing enaminone intermediate proceeding through a decarboxy-
lative pathway.[9a] We envisioned that the latter two examples
have a broad substrate scope and can be used as synthetic
precursors for the construction of various amino-1,2,3-triazoles.
The versatility of these MCRs was further demonstrated by syn-
thesizing 4-benzoyl-1,2,3-(NH)-triazole 24 by using tosyl azide
23 as nitrogen source.[8b] The final step of this reaction was the
elimination of N,N-dimethyl-p-toluenesulfonamide. These ex-
amples once again demonstrate the tolerance of this method
towards various reactive substrates for the generation of tria-
zole heterocycles decorated with sensitive functional groups
that are otherwise difficult to synthesize or not even accessible
by other methods.
We thank KU Leuven for financial support. Mass spectrometry
was made possible by the support of the Hercules Foundation
of the Flemish Government (grant 20100225-7).
Keywords: cycloaddition · host–guest systems · metal-free ·
multicomponent reactions · triazoles
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Received: April 25, 2016
Published online on && &&, 0000
Chem. Eur. J. 2016, 22, 1 – 6
www.chemeurj.org
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Heterocyclic Synthesis
J. Thomas, V. Goyvaerts, S. Liekens,
W. Dehaen*
&& – &&
Metal-Free Route for the Synthesis of
4-Acyl-1,2,3-Triazoles from Readily
Available Building Blocks
A metal-free route towards therapeuti-
cally important 1-substituted 4-acyl-1H-
1,2,3-triazoles was accomplished using
cheap and readily available ketones,
N,N-dimethylformamide dimethyl acetal,
and organic azides. This reaction is very
general and was extended to the syn-
thesis of various supramolecular recep-
tors as well as to the functionalization
of different natural products with a-ke-
totriazoles, all of which is otherwise not
possible by known methods.
&
&
Chem. Eur. J. 2016, 22, 1 – 6
www.chemeurj.org
6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!