Synthesis of Novel 2-Hetarylpyrrolidines via the Reaction of N -(4,4-diethoxybutyl)amidophosphates with C-nucleophiles
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Synthesis of novel 2-hetarylpyrrolidines via the reaction of N-(4,4-diethoxybutyl)amidophosphates with C-nucleophiles Andrey V. Smolobochkin1*, Rakhymzhan A. Turmanov2, Almir S. Gazizov1, Elizaveta A. Kuznetsova3, Alexander R. Burilov1, Mikhail A. Pudovik1 1
A. E. Arbuzov Institute of Organic and Physical Chemistry, Federal Research Center ''Kazan Scientific Center'' of the Russian Academy of Sciences, 8 Akademika Arbuzova St., Kazan 420088, Russia; e-mail: [email protected] 2 Kazan National Research Technological University, 68 Karla Marksa St., Kazan 420015, Russia 3 Alexander Butlerov Institute of Chemistry, Kazan Federal University, 29/1 Kremlyovskaya St., Kazan 420008, Russia Translated from Khimiya Geterotsiklicheskikh Soedinenii, 2020, 56(10), 1363–1365
Submitted July 8, 2020 Accepted October 5, 2020
The reactions of N-(4,4-diethoxybutyl)amidophosphates with С-nucleophiles in chloroform in the presence of trifluoroacetic acid provided new 2-hetarylpyrrolidines. The reaction proceeded under mild conditions and gave good yields in the absence of metal-based catalysts. Keywords: N-(4,4-diethoxybutyl)amidophosphate, 2-hetarylpyrrolidines, trifluoroacetic acid, heterocyclization.
Pyrrolidine derivatives are some of the most important and common heterocyclic compounds. Of particular interest are 2-hetarylpyrrolidine motifs that are present in many drug molecules. Examples of such compounds include the antiviral drugs daclatasvir,1,2 velpatasvir,3–5 elbasvir,6 samatasvir,7,8 and ledipasvir,9,10 used in the therapy of hepatitis C, and avanafil, an erectile dysfunction drug.11–13 The methods applied to the synthesis of 2-hetarylpyrrolidines can be divided into two main groups. The first group of methods involves modifications of an existing pyrrolidine ring by introducing a heterocyclic substituent. A large majority of methods in this group are based on cross-coupling reactions of heteroaromatic compounds with pyrrolidine derivatives.14–16 We should also note a few reactions of 1-pyrroline and its derivatives with aromatic nucleophiles, which provide access to substituted 0009-3122/20/56(10)-1363©2020 Springer Science+Business Media, LLC
pyrrolidines.17,18 The second group of methods represents pyrrolidine ring assembly reactions starting from hetarylsubstituted acyclic precursors.19–21 The aforementioned approaches have substantial drawbacks, as they rely on costly catalysts and/or reagents and require forcing reaction conditions. The need for an initial laborious synthesis of the starting materials, often in several steps, also creates obstacles for extending the scope of synthesized 2-hetarylpyrrolidines. We have previously established that 4,4-diethoxybutan1-amine derivatives containing an electron-withdrawing substituent at the nitrogen atom are capable of intramolecular cyclization in acidic medium, with the formation of 2-substituted pyrrolidines.22 The examples of such substituents used in our studies include sulfonyl23 and carbamoyl groups,24 as well as an 2-aminopyrimidine moiety
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