Tetrahedron Letters
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
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Corresponding authors at: Taras Shevchenko National University of Kyiv,
Volodymyrska Street 60, Kyiv 01601, Ukraine.
(O.O. Grygorenko).
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.