Synthesis of α-substituted 2-(1H-1,2,4-triazol-3-yl)acetates and 5-amino-2,4-dihydro-3H-pyrazol-3-ones via the Pinner strategy

Article abstract of DOI:10.1016/j.tetlet.2021.152956

A series of 2-(1H-1,2,4-triazol-3-yl)acetates, as well as 4-mono- and 4,4-disubstituted 5-amino-2,4-dihydro-3H-pyrazol-3-ones (including spirocyclic derivatives) have been synthesized using the Pinner reaction strategy. α-Mono- and α,α-disubstituted ethyl cyanoacetates were converted into the corresponding carboxyimidate salts that served as the key intermediates. Their further reaction with formylhydrazide or hydrazine hydrate provided triazolylacetates or aminopyrazolones (including spirocyclic derivatives), depending on the structure of the starting Pinner salt and the nature of the nucleophile. The scope and limitations of the developed synthetic method have been established.

Full text of DOI:10.1016/j.tetlet.2021.152956

Tetrahedron Letters 69 (2021) 152956
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of
a-substituted 2-(1H-1,2,4-triazol-3-yl)acetates and
5-amino-2,4-dihydro-3H-pyrazol-3-ones via the Pinner strategy
Dmytro M. Khomenko a,b, , Roman O. Doroshchuk a,b, Hanna V. Ivanova b, Borys V. Zakharchenko b,
⇑
Ilona V. Raspertova b, Oleksandr V. Vaschenko b, Sergiu Shova c, Alexey V. Dobrydnev a,b, Yurii S. Moroz b,d
,
b
Oleksandr O. Grygorenko a,b, , Rostyslav D. Lampeka
⇑
a Enamine Ltd., Chervonotkatska Street 78, Kyiv 02094, Ukraine
b Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine
c Petru Poni” Institute of Macromolecular Chemistry, Aleea Gr. Ghica Voda 41A, 700487 Iasi, Romania
d Chemspace, Ilukstes iela 38-5, Riga LV-1082, Latvia
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 2-(1H-1,2,4-triazol-3-yl)acetates, as well as 4-mono- and 4,4-disubstituted 5-amino-2,4-dihy-
dro-3H-pyrazol-3-ones (including spirocyclic derivatives) have been synthesized using the Pinner reac-
Received 11 December 2020
Revised 17 February 2021
Accepted 24 February 2021
Available online 2 March 2021
tion strategy.
a-Mono- and a,a-disubstituted ethyl cyanoacetates were converted into the
corresponding carboxyimidate salts that served as the key intermediates. Their further reaction with
formylhydrazide or hydrazine hydrate provided triazolylacetates or aminopyrazolones (including spiro-
cyclic derivatives), depending on the structure of the starting Pinner salt and the nature of the nucle-
ophile. The scope and limitations of the developed synthetic method have been established.
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Cyclization
Nitrogen heterocycles
Imidates
Spiro compounds
Azoles
Since 1877 when A. Pinner and Fr. Klein had discovered the syn-
thesis of carboximidate hydrohalides (now referred to as the Pin-
ner salts) [1,2], this class of substances became an important part
of the synthetic toolbox for organic chemists. These carboxylic acid
derivatives have attracted much attention due to their remarkable
reactivity towards carbo- and hetero-nucleophiles that has been
widely exploited for the synthesis of numerous organic compounds
including nitrogen heterocycles [3–5]. Pyrazoles and 1,2,4-tria-
zoles are examples of such heterocycles that have attracted much
attention because of their remarkable applications in the pharma-
ceutical industry. In particular, these heterocycles have been incor-
porated into numerous marketed medicines such as diuretic
Muzolimine for treatment of hypertension [6,7], antiviral agent
Ribavirin for cure of chronic Hepatitis C virus (HCV) [8–10], or
alpha blocker Dapiprazole used to reverse mydriasis after an eye
examination [11–13].Fig 1.
As a part of our ongoing efforts towards the synthesis of triazole
derivatives for drug discovery [14–19], we have turned our atten-
tion to non-fused (1,2,4-triazol-3-yl)acetates – promising synthetic
intermediates for organic and medicinal chemistry. Several syn-
thetic approaches to these compounds have been developed to
date. Among them are EtONa-mediated cyclizations of ethyl malo-
nyl-3-thiosemicarbazide followed by desulfurization with Raney
Ni (Scheme 1, pathway A) [20,21]; a reaction of ethyl 3-ethoxy-
3-iminopropanoate with monosubstituted hydrazines and subse-
quent ring closure with HC(OEt)3 or Ac2O (pathway B) [22,23]; or
the two-step condensation of ethyl 3-alkoxy-3-iminopropanoates
with hydrazides (pathways C) [24,25]. Surprisingly,
a-mono- [26]
and -disubstituted [27,28] non-fused (1,2,4-triazol-3-yl)ac-
a,a
etates 1 appeared to be largely underrepresented in the literature
and have never been obtained via the Pinner reaction strategy.
Herein, we have turned our attention to a-mono- and a,a-disubsti-
tuted ethyl cyanoacetates (2) as the possible starting materials for
the preparation of the title compounds. A possible complication of
the selected strategy can include an alternative reaction pathway
including nucleophilic attack of the intermediate carboxyimidates
3 at the ester moiety (Scheme 2). Such reactions leading to 3-
amino-1H-pyrazol-5(4H)-ones 4 have been known in the literature
[29–35]. This work is aimed at studying the scope and limitation of
⇑
Corresponding authors at: Taras Shevchenko National University of Kyiv,
Volodymyrska Street 60, Kyiv 01601, Ukraine.
E-mail addresses: dkhomenko@ukr.net (D.M. Khomenko), gregor@univ.kiev.ua
(O.O. Grygorenko).
https://doi.org/10.1016/j.tetlet.2021.152956
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

D.M. Khomenko, R.O. Doroshchuk, H.V. Ivanova et al.
Tetrahedron Letters 69 (2021) 152956
the aforementioned strategy for the synthesis of substituted
triazolylacetates 1 or 3-amino-1H-pyrazol-5(4H)-ones 4, as well
as factors affecting the chemoselectivity of this transformation.
First of all, a series of appropriately substituted cyanoacetates
2a–f was converted into the corresponding carboximidate
hydrochlorides 3a–f adopting the literature procedures [36–39].
The latter, in turn, were allowed to react with formylhydrazide
under base-mediated conditions (Table 1).
(Table 1, Entries 1–3). At the same time, the utilization of interme-
diates 3d–fÁHCl bearing an annulated (hetero)cyclic substituent
afforded mixtures of appropriately substituted triazolylacetates
1d–f and spirocyclic aminopyrazolones 4d–f at different ratios
(Table 1, Entries 4–6).
These results might suggest that the nature of the a-substituent
in 3 played a crucial role for the reaction direction with formylhy-
drazide. Apparently, a possibility of prototropy (or lack thereof) as
well as conformational aspects of 3 could account for the selective
formation of triazolylacetates 1a,b and 1d–f and aminopyrazolones
4c–f.
Intriguingly, while the unsubstituted (3aÁHCl) and 2-i-Pr-substi-
tuted (3bÁHCl) derivatives were completely converted into tria-
zolylacetates 1a,b, the
exclusively turned into the corresponding aminopyrazolone 4c
a
,
a
-dimethylated counterpart 3cÁHCl was
Thus, the deprotonation of carboximidate hydrochlorides
(pKa ~ 5 [40]) with a base might lead to either imino ethers or
imino enoles depending on the substitution at the a-carbon atom.
Specifically, the salts of unsubstituted (3aÁHCl) as well as 2-i-Pr-
substituted (3bÁHCl) imidates were likely converted into the corre-
sponding ethyl 3-ethoxy-3-hydroxyacrylimidates 3a and 3b, while
hydrochloride of
a
,
a
-dimethylated imidate 3cÁHCl – into 3-ethoxy-
3-iminopropanoate 3c (Scheme 3). The close proximity as well as
coplanar position of imino group and enol functionalities in 3
allowed for the hydrogen bonding that further reinforced the
adopted conformation (Fig. 2).
Next, ethyl 3-ethoxy-3-hydroxyacrylimidates 3a and 3b reacted
with formylhydrazide as the Michael acceptors providing the
interim amidine 5, that underwent the intramolecular condensa-
tion to give the corresponding triazolylacetates 4a,b (Scheme 4).
Contrary to the above, 3c reacted with formylhydrazide at the
carbonyl moiety first. There might be two possible reasons for this.
On the one hand, a lone pair of electrons of the imine moiety pre-
cluded the formylhydrazide attack at the imidate fragment. On the
other hand, hydrogen bonding increased the electrophilicity of the
Fig. 1. 5-Aminopyrazolone and 1,2,4-triazole-containing marketed drugs.
Scheme 1. Known approaches to 2-(1,2,4-triazol-3-yl) acetates.
Scheme 2. Reaction of carboxyimidate hydrochlorides with formylhydrazide.
2

D.M. Khomenko, R.O. Doroshchuk, H.V. Ivanova et al.
Tetrahedron Letters 69 (2021) 152956
Table 1
The reaction of 3ÁHCl with formylhydrazide.
Entry Starting compound
Intermediate 3 (isolated yield,
Product 1 (yield by 1H NMR / isolated, %) Product 4 (yield by 1H NMR / isolated, %) R1/R2
2
%)
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
3aÁHCl (81)
3bÁHCl (75)
3cÁHCl (67)
3dÁHCl (40)
3eÁHCl (82)
3fÁHCl (77)
1a (100/78)
1b (100/73)
1c (0/0)
1d (85/32)
1e (40/31)
1f (50/19)a
4a (0/0)
4b (0/0)
4c (100/72)
4d (15/5)
4e (60/46)
4f (50/30)a
H/H
i-Pr/H
Me/Me
(CH2)2
(CH2)3
(CH2)2O
(CH2)2
a
Compound 4f partially precipitated from the reaction mixture. The ratio is given for liquid reaction phase and overall yields are presented.
carbonyl group. The concerted impact of these factors resulted in
drived the imidate and carboxylate groups to possess comparable
electrophilicity that led to the formation of both possible products
(Scheme 6).
the formation of intermediate
6 followed by intramolecular
cyclization leading to aminopyrazolone 4c (Scheme 5).
At the same time, the annular atoms of the attached (hetero)-
cyclic substituent in 3e and 3f pushed both the imidate and car-
bonyl groups out of the plane due to the repulsive 1,3-
interactions, thus disrupting the hydrogen bonding (Fig. 2). This
Based on this, the interaction between cyclopropyl derivative
3d and formylhydrazide looks odd at the first glance since it should
demonstrate the reactivity similar to that of 3c. A possible reason
behind this might be the larger plane angle value between the car-
boximidate and the carboxylate moieties caused by the cyclo-
propane moiety, which hampered the formation of the
intramolecular hydrogen bond in the structure of 3d and defined
the somewhat preferred initial attack of the nucleophile at the car-
boximidate group. This assumption was confirmed by DFT calcula-
tions. In particular, the predicted Gibbs free energy value for the
Scheme 3. Reaction of carboxyimidate hydrochlorides with formylhydrazine.
Fig. 2. Proposed tautomeric forms and conformations of 3a–f.
Scheme 5. The proposed mechanism for formation of 4c.
Scheme 4. A proposed mechanism for the formation of 1a,b.
Scheme 6. The synthesis of 1e,f and 4e,f.
3

D.M. Khomenko, R.O. Doroshchuk, H.V. Ivanova et al.
Tetrahedron Letters 69 (2021) 152956
following hypothetic isodesmic reaction involving the conformers
of 3c and 3d having intramolecular hydrogen bonds (Figure 3)
3c + cyclo-C3H6 = 3d + C3H8
was
D
G = À3.6 kcal/mol, which reflected noticeable strain energy in
the conformer of 3d (comparable to the stabilization gain typically
provided by hydrogen bonding).
Since the above method appeared to be unsuitable for obtaining
4a, 4b and 4d, as well as 1c, we have considered other synthetic
approaches to obtain these compounds. In this way, a series of
pyrazolones 4a–f was synthesized by reaction of 3a–fÁHCl with
hydrazine hydrate (Table 2).
Scheme 8. The synthesis of 9a–f.
The inability of direct synthesis of 1c from 3cÁHCl was also cir-
cumvented by an alternative synthetic pathway. Thus, ethyl tria-
zolylacetate 1a was treated with BnCl and K2CO3 in DMF in order
to install the protecting group at the heterocyclic core and prevent
the methylation of the NH group at the later step. The obtained
mixture of N-protected regioisomers 7 was exhaustively methy-
lated at the active methylene group by using an excess of MeI
2-methyl 2-(1H-1,2,4-triazol-3-yl)acetate (1 g) in 70% overall yield
(Scheme 7).
Since the last step was carried out in methanolic media, trans-
esterification took place. The use of ethanolic media was not fruit-
ful and resulted in recovery of the starting material (possibly due
to the suppressive effect of water in 96% EtOH on the catalyst
efficiency).
and NaH as a base to give a mixture of regioisomeric a,a-dimethy-
lated products 8. Eventually, Pd-catalyzed hydrogen-mediated
cleavage of the benzyl protecting group afforded the target methyl
Saponification of esters 1a,b,d–g proceeded smoothly; however,
further isolation of the corresponding carboxylic acids was compli-
cated because of partial decarboxylation. Therefore, the products
were isolated as stable sodium (9a,b) or lithium (9c–f) salts
(Scheme 8).
The structure of all products obtained was proven by standard
spectroscopic methods. The solid state structure of 4a was addi-
tionally investigated by single crystal X-ray diffraction method
(see the supporting information), which proved the tautomeric
form given above. The analysis of the packing motif has shown that
all the possibilities for hydrogen bonding were completely realized
in the crystal. As the result, the crystal structure is described as a
parallel packing of discrete 2D supramolecular networks.
In conclusion, an efficient approach to gram-scale synthesis of
Fig. 3. Conformers of 3c and 3d having an intramolecular hydrogen bond according
to DFT calculations.
a-mono- and a,a-disubstituted 2-(1H-1,2,4-triazol-3-yl)acetates
as well as 4-mono- and 4,4-disubstituted 5-amino-2,4-dihydro-
3H-pyrazol-3-ones via the Pinner reaction strategy has been devel-
oped. It was found that 2-monosubstituted as well as cyclo-
Table 2
The reaction of 3ÁHCl with hydrazide hydrate.
propane-annulated
3-imino-3-alkoxy-2-methylpropanoates
reacted with formylhydrazide affording the corresponding (1,2,4-
triazol-3-yl)acetates. At the same time, 3-imino-3-alkoxy-2-
methylpropanoates bearing an annulated carbo/heterocyclic ring
(larger than cyclopropane) turned into approximately equimolar
mixtures of the appropriately substituted triazolylacetates and
spirocyclic aminopyrazolones. An analogous reaction with hydra-
zine hydrate gave the corresponding 5-amino-2,4-dihydro-3H-
Entry
Intermediate 3
Product 4 (isolated yield, %)
R1/R2
1
2
3
4
5
6
3aÁHCl
3bÁHCl
3cÁHCl
3dÁHCl
3eÁHCl
3fÁHCl
4a (82)
4b (66)
4c (81)
4d (70)
4e (73)
4f (74)
H/H
i-Pr/H
Me/Me
(CH2)2
(CH2)3
pyrazol-3-ones in all cases. An alternative approach to a,a-disub-
stituted 2-(1H-1,2,4-triazol-3-yl)acetates was also proposed based
on the double alkylation of the methylene unit in the parent N-pro-
tected 2-(1H-1,2,4-triazol-3-yl)acetate. The saponification of
(1,2,4-triazol-3-yl)acetates allowed for the preparation of the
(CH2)2O(CH2)2
Scheme 7. The synthesis of 1g.
4

D.M. Khomenko, R.O. Doroshchuk, H.V. Ivanova et al.
Tetrahedron Letters 69 (2021) 152956
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Declaration of Competing Interest
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Acknowledgements
The work was funded by Enamine Ldt. and NIH (Grant No.
GM133836, to Y.S.M. and John Irwin). Additional funding from
Ministry of Education and Science of Ukraine, Grant No.
19BF037-03 (A.V.D. and O.O.G.) is also acknowledged. The authors
thank Dr. Andrii Kyrylchuk for DFT calculations, and Prof. Andrey A.
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