Facile One-Pot Parallel Synthesis of 3-Amino-1,2,4-triazoles

Article abstract of DOI:10.1021/acscombsci.8b00060

A 1,2,4-triazole motif is present in numerous commercialized and investigational bioactive molecules. Despite its importance for medicinal chemistry, there is a lack of convenient combinatorial approaches toward this molecular core. Herein, we present a synthetic strategy suitable for the quick preparation of a library of structurally diverse 1,2,4-triazoles in a one-pot setting. The key steps include the formation of thioureas followed by S-alkylation using 1,3-propane sultone and consecutive ring closure leading to the desired 1,2,4-triazoles. Parallel synthesis yields thousands of 1,2,4-triazoles in a cost- and time-efficient manner from commercially available chemicals.

Full text of DOI:10.1021/acscombsci.8b00060

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Article
A facile one-pot parallel synthesis of 3-amino-1,2,4 – triazoles
Andrey V. Bogolyubsky, Olena Savych, Anton V. Zhemera, Sergey E. Pipko,
Alexander V. Grishchenko, Anzhelika I. Konovets, Roman O. Doroshchuk, Dmytro
N. Khomenko, Volodymyr Brovarets, Yurii S. Moroz, and Mykhailo Vybornyi
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.8b00060 • Publication Date (Web): 06 Jun 2018
Downloaded from http://pubs.acs.org on June 7, 2018
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A facile oneꢀpot parallel synthesis of 3ꢀaminoꢀ1,2,4
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–
triazoles
‡
§, ‡
Andrey V. Bogolyubsky, (bogolubsk@gmail.com) Olena Savych,
‡
#
(
ELANASAVICH@gmail.com) Anton V. Zhemera (anton@mail.enamine.net) Sergey E. Pipko,
‡
(spas@bg.net.ua) Alexander V. Grishchenko
,
(a.grishchenko@mail.enamine.net) Anzhelika I.
‡
||
£,
Konovets, (a.konovets@mail.enamine.net) Roman O. Doroshchuk, (rdoroschuk@univ.kiev.ua)
|
|
§
Dmytro N. Khomenko, (dkhomenko@ukr.net) Volodymyr S. Brovarets,
#†
‡
(brovarets@bpci.kiev.ua) Yurii S. Moroz, (ysmoroz@gmail.com) and Mykhailo Vybornyi
‡
§
Enamine Ltd., 78 Chervonotkatska Street, Kyiv, 02094, Ukraine
Department of Chemistry of Bioactive Nitrogen-Containing Heterocyclic Bases, Institute of Bioorganic
Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Kyiv, 02094, Ukraine
#
ChemBioCenter, Kyiv National Taras Shevchenko University, 61 Chervonotkatska Street, Kyiv, 02094,
Ukraine
£ The Institute of High Technologies, Kyiv National Taras Shevchenko University, 4 Glushkov Street, Building
5, Kyiv, 03187, Ukraine
|| Department of Chemistry, Kyiv National Taras Shevchenko University, 64 Volodymyrska Street, Kyiv,
0
1601, Ukraine
†
Chemspace, Ilukstes iela 38-5, Riga, LV-1082, Latvia
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KEYWORDS: 1,2,4,ꢀtriazole, thiourea, 2,2,2ꢀtrifluoroethylthiocarbamate, ring closure, Sꢀ
alkylation.
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ABSTRACT. A 1,2,4ꢀtriazole motif is present in numerous commercialized and investigational
bioactive molecules. Despite its importance for medicinal chemistry, there is a lack of
convenient combinatorial approaches towards this molecular core. Herein, we present a synthetic
strategy suitable for the quick preparation of a library of structurally diverse 1,2,4ꢀtriazoles in a
oneꢀpot setting. The key steps include the formation of thioureas followed by Sꢀalkylation using
1,3ꢀpropanesultone and consecutive ring closure leading to the desired 1,2,4,ꢀtriazoles. Parallel
synthesis yields thousands of 1,2,4ꢀtriazoles in a costꢀ and timeꢀefficient manner from
commercially available chemicals.
Introduction. Accessing combinatorial libraries of potentially bioactive molecules in a costꢀ
1
efficient manner remains among the practical challenges in the modern drug discovery.
Supported by the growing potential of computational methods, optimization of existing and
elaboration of new synthetic strategies leading to new drugꢀlike molecules has become
indispensable in medicinal chemistry. In the early stages, the efficiency of drug discovery often
relies on the ability to identify the active compounds from an enormously large yet virtual or
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readily available pool of structures. Despite the existence of wellꢀestablished guidelines to
deliver these chemical structures, such as Lipinski’s “rule of five” or similar criteria for
fragmentꢀoriented hit identification projects, a thorough exploration of the chemical space
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,4
remains a daunting challenge. In this regard, a myriad of structurally and functionally diverse
molecules which are synthetically undemanding remains unexplored solely because of the
availability issue. This obstacle often occurs because of tedious and unreliable synthetic
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protocols which can influence the pace of drug discovery process. Therefore, increasing the
diversity and modularity of chemical synthesis can help to overcome these limitations and
provide medicinal chemists with an enhanced capacity to detect and evolve the compounds of
interest. Furthermore, a newly developed method should meet certain important criteria, such as
safety of chemical synthesis, the possibility of automation, and economic feasibility.
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Figure 1. Representative bioactive molecules containing an aminotriazole motif.
Recently, the derivatives of 1,2,4ꢀtriazoles drew our attention due to the high abundance of
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bioactive molecules containing this structural motif. This fiveꢀmembered ring is also a
promising bioisosteric replacement of a cisꢀamide bond, further extending the scope of potential
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applications. Not surprisingly, the 3ꢀaminoꢀ1,2,4ꢀtriazole core is present in many experimental
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and investigational compounds – some examples are shown in Figure 1.
Over the years, numerous synthetic approaches towards 1,2,4ꢀtriazoles have been reported in
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literature.
chemistry.
Considerable efforts were directed to adopt these methods to solid phase
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However, the majority of the attempts are practically illꢀsuited for the generation
of large libraries due to the inherent shortcomings. The major practical problems emerge from
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applying high temperatures, microwave irradiation, the formation of volatile and harmful
chemicals, low purity and low yields of final products. In this regard, there is an existing demand
for more convenient and efficient synthetic pathways which could match an everꢀgrowing
number of biological targets currently present in the research pipelines.
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Recognizing the importance of further exploring the utility of 1,2,4ꢀ triazoles, we aimed to
develop a method suitable for the preparation of a diverse library of drugꢀlike compounds
containing a 3ꢀaminoꢀ1,2,4ꢀ triazole core. Herein, we propose an easy, oneꢀpot synthetic route
towards millions of the substituted aminotriazoles performed in a parallel synthesis setting.
Briefly, the key steps include the formation of an asymmetrically substituted thiourea from
bis(2,2,2ꢀtrifluoroethyl) thiocarbonate , followed by alkylation of the thiourea with 1,3ꢀ
propanesultone and the ring closure in the aminotriazole motif upon addition of corresponding
hydrazides (Scheme 1). The identity and purity of the formed 3ꢀaminoꢀ1,2,4ꢀ triazole derivatives
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were confirmed by H, C NMR, and LCꢀMS.
Scheme 1. Synthetic route towards a library of triazoles 9.
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Results and discussion. A general method of synthesis of the substituted 3ꢀaminoꢀ1,2,4ꢀtriazoles
is reported in this work. To prove its efficiency for the synthetic purposes, a representative
library of drugꢀlike molecules containing the aminotriazole core (compounds 9, Scheme 1) was
successfully prepared in a oneꢀpot setting using parallel synthesis. The final library of separated
and characterized products includes 146 compounds (73% success rate) with different
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substituents (R ꢀR ) at variable positions. Importantly, the method yields a set of triazoles
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containing diverse moieties – aliphatic, aromatic and heteroaromatic – exclusively from the
commercially available reagents. This aspect is of high importance in generating screening
libraries with an increased diversity in a timeꢀ and costꢀeffective manner, avoiding the need of
synthesizing commercially irrelevant and often unstable intermediate chemicals.
Scheme 2. Synthesis of bis(2,2,2ꢀtrifluoroethyl) thiocarbonate.
Table 1. A representative set of the substituted 3ꢀaminoꢀ1,2,4ꢀ triazoles and overall yields of
separated materials.
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The structures of representative triazoles 9 and their overall yields are shown in Table 1; a full
list and further characterization of these compounds can be found in the Supporting Information
(SI). The 3ꢀaminoꢀ1,2,4ꢀ triazoles 9 were prepared on a hundred milligram scale in four steps
starting from bis(2,2,2ꢀtrifluoroethyl) thiocarbonate 1. The latter compound is a stable yet
reactive thiocarbonate ester; it is readily accessible in one step from thiophosgene and
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trifluoroethanol via fractional distillation (Scheme 2). Based on our previous findings, the
usage of the trifluoroethyl substituents as leaving groups enables to achieve suitable profiles of
22,23
kinetics and selectivity of the stepwise aminolysis reaction in the case of carbonate esters.
A
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similar approach applied to thiocarbonate esters gives an excellent starting material for the
reliable utilization in synthetic projects which require the formation of thiocarbamates or
thioureas either as target or intermediate compounds. Indeed, compared to volatile and toxic
thiophosgene or its analogs, compound 1 is an easyꢀtoꢀhandle reagent that interacts consistently
with a wide range of amines. The formation of asymmetrical thiourea derivatives 5 occurs via
consecutive couplings of bis(2,2,2ꢀtrifluoroethyl) thiocarbonate with corresponding amines,
although under different conditions (Scheme 3). Importantly, all amines tested in this project
were randomly selected from our database. The first coupling step involves the reaction of 1 (1.5
eqv.) with a primary amine 2 (Figure 2). In general, the formation of an intermediate
thiocarbamate 3 occurs at 75°C in acetonitrile in 2 h and the conversion can be easily monitored
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by H NMR or LCꢀMS. All volatile components present in the mixture, including remaining 1
and 2,2,2ꢀtrifluoroethylethanol, are conveniently removed at this stage by evaporation under
reduced pressure, yielding crude compound 3. The purity of the intermediate 3 was sufficient for
utilization in the next step. Our results demonstrate that compounds 2 applicable for the scheme
mostly represent nucleophilic amines, whereas introducing anilines or hetarylamines in a oneꢀpot
protocol led to unsuccessful experiments. Some of the used derivatives 2 are presented in Figure
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, capturing the major chemotypes tested in this project. The following stage – formation of a
thiourea 5 – is accomplished via coupling of 3 and a secondary amine 4 in the presence of DBU.
This transformation proceeds successfully after heating the mixture in acetonitrile at 100°C for
16 h in a sealed vial. At this stage, the secondary aliphatic amines 4 were selected to ensure a
regioselective ring closure reaction into 9 at later stages. Using primary amines will lead to a
mixture of final products 9 which is not compliant with the requirements for parallel synthesis.
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Noteworthy, the stepwise coupling of amines and bis(2,2,2ꢀtrifluoroethyl) thiocarbonate
represents a valid strategy of achieving large libraries of asymmetrical thiourea derivatives which
not only serve as the precursors for triazole synthesis but also form an independent class of
bioactive molecules on their own. With regard to thioureas, one of the competitive advantages of
the current protocol over other methods reported in literature resides in total reliance on
commercial compounds. This statement is further supported by a wide selection of structurally
and functionally diverse amines which abound in many catalogs, including ours (Figure 2, 3).
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Figure 2. Amines 2.
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Figure 3. Amines 4.
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Scheme 3. Synthesis of the unsymmetrical thioureas 5.
Scheme 4. Synthesis of 1,2,4ꢀaminotriazoles 10 from thioureas 5.
Scheme 5. Removal of 6 via reaction with triethylamine.
The next step includes conversion of the crude thioureas 5 into isothioureas 7 (Scheme 4).
Adding a twoꢀfold excess of a mild alkylating agent, 1,3ꢀpropanesultone 6, leads to the formation
of an isothiourea moiety which later serves as a suitable leaving group during the final ring
closure reaction to yield 9. At this stage, the usage of 6 was substantiated by advantageous safety
and purification parameter profiles, such as nonꢀvolatile nature and polarity of all sulfonate
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derivatives which are formed upon ring opening of 6. The Sꢀalkylation reaction leading to 7
requires heating the mixture of 5 and 6 to 100°C for 16 h. An excess of 6 and acidic sulfonate 7
was routinely quenched by adding triethylamine and equilibrating the reaction at 100°C for 30
min (Scheme 5). Finally, the derivatives 7 were easily converted into target 3ꢀaminoꢀ1,2,4ꢀ
triazoles 9 by treating them with an equimolar amount of hydrazides 8 at 100°C for 16 h. A
diverse set of hydrazides was tested and successfully used in this reaction. The process proceeds
smoothly with various aliphatic, aromatic and heteroaromatic hydrazide derivatives (Figure 4).
The final reaction mixture was then evaporated, reꢀdissolved in chloroform and washed with
water to remove the excess of remaining sulfonates. Importantly, the usage of polar sulfonates
was crucial to increase the efficiency of the final purification compared to other alkylating agents
which were tested for the Sꢀalkylation reaction. The target products 9 were successfully purified
by reverseꢀphase HPLC on C columns.
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Figure 4. Hydrazides 8.
Expanding chemical space with synthetically feasible compounds. Virtual highꢀthroughput
screening (vHTS) has eclipsed the classical HTS on the primary stages of drug discovery
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projects. Indeed, vHTS is not limited to offꢀtheꢀshelf compounds: all theoretically possible
structures are screened. But an important challenge in vHTS is the availability of the hits from
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virtual screens. More than 10 years ago, we have introduced REAL database
(REAL –
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readily accessible) to answer this question. High synthetic feasibility of compounds in the
database is achieved through the following criteria applied during the enumeration:
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ꢀ
only qualified reagents available in at least 10 g amount are included;
only wellꢀvalidated parallel chemistry protocols are utilized.
The REAL compounds are additionally filtered based on the physicochemical criteria
2
7
28
(
Lipinski and Veber rules) to represent the medicinal chemistryꢀrelevant molecules.
We found that a substituted 1,2,4ꢀtriazole motif, including 3ꢀaminoꢀ1,2,4ꢀ triazoles, is
underrepresented in public and commercial domains: a search by substructure revealed 172,714
2
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30
and 400,567 matches in the public and the commercial databases, respectively (Figure 5). Our
synthetic approach allows to significantly increase the current offer: application of the REAL
criteria afforded 5,070,919 (REAL triazoles) substituted 3ꢀaminoꢀ1,2,4ꢀtriazoles.
5
4
3
,000,000
,000,000
,000,000
2,000,000
1
,000,000
0
REAL triazoles Commercial
Public
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Figure 5. Substituted 1,2,4ꢀtriazoles in commercial, public, and REAL databases.
The REAL triazoles comprise mostly leadꢀlike molecules (4,484,635 compounds, 88%) with
3
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33
no toxic motifs, 99% compounds passed PAINS , NIH and ZINC filters (Figure S1 in SI).
0
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On the scaffold level, the REAL triazoles comprise 42,027 BemisꢀMurcko frameworks most of
which have more than one representative molecule (only 17% singletons) that is much higher
than those in the public and the commercial databases (Figure S2 in SI). This feature makes
REAL triazoles a tool for follow up libraries and lead optimization projects.
Conclusions. Herein, we report a convenient synthetic approach affording a library of molecules
containing a potentially bioactive 1,2,4ꢀaminotriazole structural motif costꢀ and timeꢀefficiently.
The proposed synthetic route leads to the target molecules with high overall yields and minimal
purification efforts, compliant with the current requirements of combinatorial chemistry. The
oneꢀpot protocol is straightforward and includes the use of only commercially available
chemicals. The modularity of this method enables the generation of triazole derivatives with a
desired set of physicochemical properties and substitution scaffolds. The method distinguishes
itself from the existing protocols since it excludes the formation of volatile and toxic chemicals,
making it appropriate for the parallel synthesis setting. The REAL triazoles enumerated based on
our approach significantly expand the current availability offer.
Experimental procedures.
General protocol of 1,2,4-aminotriazole synthesis. Compounds 1 (1.5 mmol) and 2 (1 mmol)
were mixed in a sealable vial containing 0.7 mL of acetonitrile. After sealing, the vial was heated
to 75°C for 2 h. The reaction mixture was evaporated under high vacuum, and compound 4 (1
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mmol) was added to the remaining material. After sealing, the mixture was heated to 100°C for
1
6 h yielding 5 of sufficient for the next step purity. The mixture containing product 5 was
cooled to an ambient temperature, followed by the addition of 2 mmol of sultone 6. The content
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of the vial was sealed again and equilibrated at 100°C for 16 h. Upon cooling, a portion of NEt3
(3 mmol) was added to the reaction mixture. The sealed vial was heated to 100°C for 30 min.
Finally, compound 9 (1 mmol) was added to the preꢀcooled mixture, and the reaction yielding
crude 10 was completed upon heating the system to 100°C for 16 h. The obtained reaction
mixture was evaporated and consecutively dissolved in 3 mL of chloroform. The organic layer
was washed with water (2x4 mL). The remaining organic phase was evaporated and subjected to
the HPLC purification on a C ꢀcolumn using methanolꢀwater mixture as an eluent. The
1
8
purification step yielded 10 with a purity at least 95%.
ASSOCIATED CONTENT
Supporting Information. Supporting information contains data on the abundance of 3,4,5ꢀ
trisubstituted triazoles in different databases, a list of synthesized molecules with corresponding
1
13
NMR ( H and C) and LCꢀMS information.
AUTHOR INFORMATION
Corresponding Author
Yurii S. Moroz (ysmoroz@gmail.com); Mykhailo Vybornyi (vybornyi.mykhailo@gmail.com)
Author Contributions
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The manuscript was written through contributions of all authors. All authors have given approval
&
to the final version of the manuscript. These authors (A.V.B., O.S., A.V.Z.) contributed
equally.
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Notes
The authors declare no competing financial interest.
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Figure 5
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ACS Paragon Plus Environment

ACS Combinatorial Science
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Scheme 1
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ACS Paragon Plus Environment

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ACS Combinatorial Science
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Scheme 2
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ACS Combinatorial Science
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Scheme 3
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ACS Combinatorial Science
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Scheme 4
254x190mm (96 x 96 DPI)
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ACS Combinatorial Science
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Scheme 5
254x190mm (96 x 96 DPI)
ACS Paragon Plus Environment

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ACS Combinatorial Science
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